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Nicotine and Vasoconstriction

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#61 NR2(x)

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Posted 09 September 2010 - 09:18 AM

Ciggarettes have other pharmacologically active compounds including harmine and Carbon Monoxide.
Harmine is a serotonin antagonist and modulates PPAR-gamma which increase insulin sentistivity.
Carbon Monoxide has strong effects on the glutamate archecture, through increased LTD
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#62 KimberCT

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Posted 09 September 2010 - 11:49 AM

Ciggarettes have other pharmacologically active compounds including harmine and Carbon Monoxide.
Harmine is a serotonin antagonist and modulates PPAR-gamma which increase insulin sentistivity.
Carbon Monoxide has strong effects on the glutamate archecture, through increased LTD

I'll also mention that the harmala alkaloids (β-Carbolines) are also MAOIs and benzodiazepine inverse agonists.  They are also carcinogenic and neurotoxic.

Folks with essential tremor, for yet unknown reasons, tend to have elevated levels of these alkaloids in the brain and CSF.

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#63 aLurker

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Posted 09 September 2010 - 12:01 PM

This thread is about nicotine. Not tobacco. Not smoking. How dangerous it is to smoke is irrelevant and has been discussed elsewhere. On a related note: addiction to cigarettes is largely due to the tobacco induced MAOI A effects in combination with nicotine. Pure nicotine by itself is far less addictive and hazardous.

I don't want this thread to derail into some preachy and irrelevant anti-smoking propaganda so can we please stay on topic and focus on nicotine, potential negative effects and how to alleviate them. Supplements which aid cardiovascular health in general might be helpful.

Edited by aLurker, 09 September 2010 - 12:08 PM.

#64 KimberCT

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Posted 09 September 2010 - 12:44 PM

This thread is about nicotine. Not tobacco. Not smoking. How dangerous it is to smoke is irrelevant and has been discussed elsewhere. On a related note: addiction to cigarettes is largely due to the tobacco induced MAOI A effects in combination with nicotine. Pure nicotine by itself is far less addictive and hazardous.

I don't want this thread to derail into some preachy and irrelevant anti-smoking propaganda so can we please stay on topic and focus on nicotine, potential negative effects and how to alleviate them. Supplements which aid cardiovascular health in general might be helpful.

I really don't think anyone was doing the above.  The research on nicotine, unfortunately, is tightly linked to smoking.  Separating the two is notoriously difficult.

Understanding the other compounds in tobacco smoke should be helpful in that regard.  Are compounds like the harmala alkaloids responsible for maintaining nicotine's vasoconstrictive properties in chronic smokers, and thus does chronic nicotine dosing by itself result in tolerance to it?

#65 aLurker

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Posted 09 September 2010 - 01:46 PM

It is precisely because tobacco has other harmful compounds that could aid vasoconstriction so much tobacco research is irrelevant here and we should focus on nicotine alone. The study you cited is a perfect example of that. You are right that there isn't as much research on nicotine alone. The prospect of tolerance to the negative effects due to chronic use is interesting. My knee jerk response to the study you cited is that it's probably not because of increased tolerance but rather due to the lack of vasosconstriction in the tail artery in the first place since the acute effects here are consistent with the chronic effects in the study you linked to.

I'm not sure about the exact dangers of a low chronic dose yet though, the animal tests that show alarming dangers seem to use very high doses of nicotine and vasoconstriction from nicotine alone seems unclear too even if the sexual response study I cited previously worries me some.

From Chronic tolerance to nicotine in humans and its relationship to tobacco dependence:

While somewhat modest in size, the literature on chronic tolerance to nicotine in humans is reasonably consistent in showing clear evidence of tolerance to subjective mood effects but little or no tolerance to cardiovascular, performance or other nicotine effects, within the limitations inherent in most human research on tolerance.

I skimmed through the paper (I might read it later) and it covers a lot of different studies, many compare the responses nicotine has on smokers to non-smokers. As I said, so far the cardiovascular effects are still somewhat uncertain to me personally so exactly how much we should worry about the lack of tolerance there is up in the air but on the other hand I find it encouraging that tolerance isn't that much of an issue on the performance effects.

Edited by aLurker, 09 September 2010 - 01:49 PM.

#66 John Barleycorn

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Posted 10 September 2010 - 03:17 AM

Understanding the other compounds in tobacco smoke should be helpful in that regard.  Are compounds like the harmala alkaloids responsible for maintaining nicotine's vasoconstrictive properties in chronic smokers, and thus does chronic nicotine dosing by itself result in tolerance to it?

A further uncertainty is whether combustion of tobacco is required for the MAO(A)1 effect. My foggy memory is saying yes for some reason. OTOH, Syrian Rue tea is certainly active (and is something to be avoided by all accounts).

#67 chrono

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Posted 10 September 2010 - 03:51 AM

I worked on this for about 3 hours last night, and lost it this morning when I restarted FF, because it was too big for the text buffer. I should have installed the Lazarus plugin a long time ago -_-

Anyway, here's a review of all the pubmed papers on nicotine and vasoconstriction (or rather, the most relevant of the ~200 to our purposes).

I was picturing that I would have to ignore a large number concerned only with smoking, but there were just a few, and some were highly relevant. It seems it was suspected fairly early on (early 80s?) that nicotine was by far the primary vasoactive, and this was confirmed in several studies. The differences in pk (inhaled nicotine works faster than IV) make for enough differences that it can't be used as a good predictor for sustained ROAs, but there were still some interesting tidbits.


Many studies examined effects through mechanism (and vice-versa), so these two categories overlap significantly.

[quote name='Eur J Pharmacol. 1977 Apr 21;42(4):315-29']
The mechanism of action of nicotine on vascular adrenergic neuroeffector transmission.
Nedergaard OA, Schrold J.

Nicotine and cocaine potentiated the constrictor response elicited by electrical-field stimulation of postganglionic adrenergic neurones. The potentiation was reversible and in the case of nicotine, no tachyphylaxis developed. The nicotine-induced potentiation was characterized by a rapid onset and an initial, transitory peak...
These results suggest (1) that nicotine potentiates the neurogenic vasoconstriction response in part by increasing the stimulation-induced release of transmitter from adrenergic neurone terminals; (2) that the site of the nicotinic receptors mediating this action is located on the outer surface of the neurones; and (3) that the potentiation is not due to blockade of noradrenaline re-uptake.[/quote]

Here is the first full text I have with a good retrospective/summary of the research, so I've included some of the full text:

[quote name='Circ Res. 1988 May;62(5):891-5']
Parasympathetic coronary vasoconstriction induced by nicotine in conscious calves.
Young MA, Knight DR, Vatner SF.

We studied the effects of intracoronary injection of nicotine and acetylcholine on coronary blood flow in nine conscious calves chronically instrumented to measure coronary blood flow, left ventricular (LV) and mean arterial pressure, LV dP/dt, and heart rate. Nicotine (5 micrograms/kg i.c.) elicited a biphasic response in coronary blood flow consisting of an initial vasoconstriction (phase 1; blood flow fell by 52 +/- 5.4% from a baseline of 66 +/- 7.5 ml/min) followed by vasodilation (phase 2, blood flow rose 119 +/- 12.7% above baseline). The change in coronary blood flow with nicotine was not associated with changes in LV systolic pressure, mean arterial pressure, or heart rate. The change in coronary blood flow was unaffected by combined alpha- and beta-adrenoceptor blockade with prazosin, rauwolscine, and propranolol but was abolished by either muscarinic blockade with atropine or ganglionic blockade with hexamethonium. Acetylcholine (0.5 microgram/kg i.c.), without affecting mean arterial pressure, elicited changes in coronary blood flow similar to those observed with nicotine, producing an initial phase of coronary vasoconstriction (blood flow fell by 71 +/- 4.9%) followed by vasodilation (blood flow rose by 228 +/- 20.7%). Both phases of the response to acetylcholine were abolished by muscarinic blockade but were unaffected by ganglionic blockade. When nicotine was injected into the left circumflex coronary artery, no change in blood flow was observed in the left anterior descending coronary artery, indicating the lack of involvement of global reflex pathways. These results suggest that nicotine locally stimulates parasympathetic nerves, which constrict the coronary circulation via a muscarinic mechanism.

The major new finding of the present study is the demonstration of striking muscarinic vasoconstriction induced by nicotine, potentially mediated via the parasympathetic nerve terminals. This is in contrast to what has previously been reported in the coronary circulation with intravenous or intracarotid administration of nicotine or with inhaled cigarette smoke...It is of interest from this standpoint that the dose of nicotine used in the present study is similar to the dose calculated by Folts and Bonebrake to equal that obtained from smoking a single cigarette.

In the present study, the effects of nicotine were abolished by the nicotinic receptor blocker hexamethonium as well as by the muscarinic antagonist atropine. This, taken together with the lack of effect of hexamethonium on acetylcholine-induced coronary constriction, suggests that nicotine acts on the cardiac parasympathetic nerves to release acetylcholine, which in turn constricts the coronary circulation. The data further suggest that the vasoconstriction is not reflexly mediated because injection of nicotine was not accompanied by concurrent coronary flow changes in the unexposed (contralateral) coronary bed. Instead, nicotine most likely stimulates cholinergic nerve terminals through a local activation of nicotinic receptors.

In the present study, nicotine slightly elevated heart rate and LV dP/dt. This is most likely a local effect on cardiac adrenergic nerve terminals because intravenous administration of nicotine (5 u,g/kg), which would be expected to reach extracardiac sympathetic ganglia, is without effect on coronary blood flow, heart rate, or LV dP/dt. The blockade of nicotine's actions by hexamethonium most likely occurs at nicotinic receptors on both parasympathetic and sympathetic nerves because both the muscarinic-mediated changes in coronary blood flow and the adrenergicalry mediated
increases in LV dP/dt and heart rate seen with nicotine are abolished by hexamethonium. The small changes in coronary blood flow that persist in the presence of muscarinic blockade reflect the adrenergically mediated component of nicotine administration. These adrenergic effects are minimal, however, because the response to nicotine was not significantly
affected by combined a- and p-adrenoceptor blockade.


[quote name='Stroke. 1998 Aug;29(8):1656-65']
Mechanisms underlying cerebrovascular effects of cigarette smoking in rats in vivo.
Iida M, Iida H, Dohi S, Takenaka M, Fujiwara H.

RESULTS: Inhalation of smoke from a 0.1 or 1 mg nicotine-containing cigarette for 1 minute caused pial arterioles to constrict at 30 seconds (7.2% and 7.3%, respectively) and then to dilate (peak at 5 to 10 minutes; 4.6% and 17.9%, respectively). Nicotine infusion caused pial vasodilation (35.7%) without an initial vasoconstriction. Repeated smoking suppressed the pial vasodilation but not the initial vasoconstriction. The vasodilation induced by a single cigarette was greatly inhibited by pretreatment with mecamylamine or glibenclamide and attenuated by propranolol or Nomega-nitro-L-arginine methyl ester; the initial vasoconstriction was inhibited by seratrodast, a thromboxane A2 receptor antagonist (n=6 in each case).
CONCLUSIONS: Single-cigarette smoking had a significant biphasic effect on cerebral arteriolar tone. The vasodilation was attenuated by repeated smoking. The vasodilation is most likely an effect of nicotine, at least in part mediated via sympathetic activation, NO production, and K+ channel activation. The vasoconstriction is partially due to thromboxane A2 induced by cigarette smoke.[/quote]

[quote name='Cardiovasc Res. 1999 Apr;42(1):201-5']
Sympathectomy inhibits the vasoactive effects of nicotine in conscious rats.
Marano G, Ramirez A, Mori I, Ferrari AU.

CONCLUSIONS: We conclude that in the conscious rat; (1) the pressor response to nicotine mainly depends on peripheral alpha-adrenergically-mediated vasoconstriction; (2) the vasomotor effect is caused by neural rather than adrenomedullary catecholamine release; (3) the nicotine-induced increase in heart rate (and presumably cardiac output) is per se unable to raise blood pressure, and (4) the nicotine-induced release of vasopressin plays no significant role in the pressor response.[/quote]

10741756: "The blockade of alpha1-adrenoceptors, but not alpha2-adrenoceptors or P2X purinoceptors, inhibited the nicotine-induced contraction by 38 +/- 7% (p < 0.05)."

237110: "These findings support the conclusion that the vasoconstriction produced by the nicotinic agonists is mediated by norepinephrine released from adrenergic nerve terminals as a result of the action of the agents on neuronal nicotinic receptors located at or near the terminals."

7399993: "adrenal catecholamines may contribute to the pulmonary hypertension induced by nicotine infusion."

6869561: intracoronary nicotine stimulates the release of acetylcholine from intrinsic cardiac nerves.

2567966: "These results suggest that carotid body chemoreceptor stimulation by nicotine can produce reflex alpha-adrenoceptor-mediated constriction of both large and small coronary arteries, and that the constriction of the small vessels is balanced by vagally-mediated dilatation."

8522735: Digital sympathetic block had a significant beneficial effect in reversing the decreased digital blood flow that occurred after smoking (and also with use of the nicotine patch), despite the elevated circulating levels of vasopressin and norepinephrine seen with smoking. The vasoactive effects of smoking are probably due to the nicotinic effects on sympathetic fibers at the ganglionic levels.

11557615: "It was observed that nicotine amplified the norepinephrine (NE)-induced concentration-dependent increase in skin vasoconstriction compared with the control."

15647745: "Nicotine significantly enhanced UTP-induced contraction and PKC activity in the artery, and attenuated endothelium-dependent vasodilatation and NO synthesis in [vascular endothelial cells]...These results indicate that nicotine potentiates contractile response through direct and indirect protein kinase C (PKC) activation in the canine basilar artery."

10385481: "In addition, nicotine, at levels observed in smokers, may potentiate norepinephrine-induced vasoconstriction. We suggest that preservation/potentiation of vasoconstrictor responses may contribute to the pathogenesis of vascular abnormalities associated with cigarette smoking."


This suggests that cigarettes and gum have the same gross cardiovascular effects, and that individuals react differently to the same plasma concentrations. Furthermore, and very importantly, a certain plasma level seems to be required for some cardio events to occur.

[quote name='Cardiovasc Res. 1988 Feb;22(2):154-8']
Nicotine induced haemodynamic changes during cigarette smoking and nicotine gum chewing: a placebo controlled study in young healthy volunteers.
Bounameaux H, Griessen M, Benedet P, Krahenbuhl B, Deom A.

...[High/low-nicotine cigs, and gum] induced similar increases in heart rate (about 20%) and systolic blood pressure (about 7%) and a decrease in digital blood flow. Although the mean haemodynamic changes parallelled the mean plasma nicotine concentration increases, no correlation was found between them when the individual values were considered. It is concluded that the nicotine induced haemodynamic changes probably occur as a result of the (local) release of vasoactive mediators such as adrenaline or noradrenaline after a threshold plasma nicotine concentration has been reached. Such a threshold may explain the large interindividual variability in susceptibility to smoking induced cardiovascular diseases.[/quote]

[quote name='Am J Physiol. 1997 May;272(5 Pt 2):H2337-42']
Effect of nicotine on endothelium-dependent arteriolar dilatation in vivo.
Mayhan WG, Patel KP.

Endothelium-dependent, but not -independent, dilatation of arterioles was modestly impaired by an infusion of a low concentration of nicotine (1.0 microgram.kg-1.min-1). Infusion of a higher concentration of nicotine (2 micrograms.kg-1.min-1), which increased the plasma level of nicotine to 14 +/- 1.6 ng/ml, produced a profound selective impairment in endothelium-dependent vasodilatation. We suggest that elevations in plasma nicotine may contribute to the pathogenesis of the peripheral vascular disease observed in smokers.[/quote]

[quote name='Nephrol Dial Transplant. 1998 Apr;13(4):940-4']
Contrasting renal effects of nicotine in smokers and non-smokers.
Halimi JM, Philippon C, Mimran A.

METHODS: In the current study the acute effects of a 4-mg nicotine gum on arterial pressure, heart rate as well as renal haemodynamics and function were assessed in non-smokers and chronic smokers.
RESULTS: In non-smokers, mean arterial pressure (+8 +/- 1 mmHg, P<0.001) and heart rate (+13 +/- 3 beats/min, P<0.001) increased whereas effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) decreased by 15 +/- 4% and 14 +/- 4% respectively...
CONCLUSIONS: These findings indicate that nicotine administration is associated with renal vasoconstriction in healthy non-smokers, possibly through alteration of a cyclic-GMP-dependent vasoactive mechanism. Tolerance to the renal effect of nicotine was observed in chronic smokers, despite the maintenance of the systemic response to nicotine.[/quote]

10783836: "...between-group comparisons of relative blood flow revealed a significant increase in the relative blood flow to the forehead skin of light smokers, when compared to heavy smokers or to non-smokers, 2 min following the smoking experience...suggesting a potential induction of tolerance in regular users of tobacco.

[indent=1]8284078: "Dose-independent vasodilation was observed at the site of [cheek snuff] application, whereas dose-dependent vasoconstriction was observed contralaterally."

6541274: Nicotine stereoisomers exert differing type, location and magnitude of microvascular effects

3184782: "A single administration of 4-mg nicotine chewing gum was followed by heart rate increase, acrodermal vasoconstriction, increase in theta and alpha frequency, decrease in delta power, and increase in the CNV magnitude."

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#68 chrono

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Posted 10 September 2010 - 03:52 AM

Blood Flow

[quote name='J Orthop Res. 2003 May;21(3):497-502']
Two week nicotine treatment selectively increases bone vascular constriction in response to norepinephrine.
Feitelson JB, Rowell PP, Roberts CS, Fleming JT.

...These results indicate that nicotine selectively accentuates the constrictor response of the bone vasculature to exogenous NE. This enhanced constriction to NE is not due to impaired endothelial cell release of nitric oxide or diminished smooth muscle response to nitric oxide. Since NE and AVP activate similar cell signaling mechanisms to induce constriction, the selective enhancement of NE-induced constriction suggests that nicotine alters a mechanism unique to NE signaling; possibly the number or binding affinity of alpha adrenergic receptors. Since endogenous NE regulates basal blood flow to bone, the effect of nicotine to augment NE-induced constriction could lead to a chronic reduction in blood flow to bone.[/quote]

[quote name='J Cardiovasc Pharmacol. 1981 Mar-Apr;3(2):317-27']
Myocardial oxygen consumption and blood flow during nicotine infusion: effect of combined alpha- and beta-adrenergic blockade.

...After adrenergic blockade, nicotine caused somewhat lesser, though still marked, elevations in myocardial oxygen consumption (+60%) and blood flow (+43%). Again, myocardial blood flow increases were uniform transmurally. Also, nicotine-induced increases in systemic arterial and left atrial pressure and in peripheral vascular resistance persisted after adrenergic blockade, whereas heart rate remained constant and aortic flow and myocardial contractility declined. The results indicate that nonadrenergic mechanisms contribute significantly to the increase in myocardial oxygen demand during nicotine infusion.[/quote]

[quote name='Circulation. 1982 Mar;65(3):465-70']
The effects of cigarette smoke and nicotine on platelet thrombus formation in stenosed dog coronary arteries: inhibition with phentolamine.

In all 21 dogs, spontaneous reductions in coronary blood flow were greatly exacerbated [by cigarette smoke] in the stenosed circumflex artery as evidenced by the number of flow reductions, the increased size of the reductions and the rate of flow reduction. Nicotine administered intravenously in doses comparable to those achieved through absorption of cigarette smoke by the lungs provoked similar responses of alpha-adrenergic stimulation and potentiation of the platelet thrombus formation...[/quote]

[quote name='Life Sci. 1985 Nov 25;37(21):1997-2003']
Mechanisms mediating canine renal vasoconstriction induced by nicotine infusion.
Hock CE, Passmore JC.

...Nicotine infusion (0.024 mg/kg/min) increased mean arterial blood pressure (MABP) (114 +/- 3.0 to 219 +/- 8.0 mmHg) and decreased total renal blood flow (TRBF) (3.12 +/- 0.34 to 1.60 +/- 0.37 ml/min/g). Nicotine infusion produced a significantly lesser blood flow in outer cortex (OC), inner cortex (IC), and outer medulla (OM) compared to control dogs...
Our data suggest that while angiotensin II mediates a portion of the action of nicotine on the OC renal vasculature, the alpha adrenergic system predominates as the mediator of nicotine-induced renal vasoconstriction in the first 7 minutes of nicotine infusion.[/quote]


[quote name='Drug Alcohol Depend. 1991 Dec;29(1):77-85']
Acute tolerance to the cardiovascular effects of nicotine.
Perkins KA, Stiller RL, Jennings JR.

For each nicotine dose [0.5, 1.0, 2.0 mg], there was substantial acute tolerance to blood pressure, but less tolerance to heart rate (except for 0.5 mg), and little tolerance to pulse amplitude responses. These findings indicate that cardiovascular adaptation to nicotine during cigarette smoking may be rapid but variable in magnitude depending on the response being measured.[/quote]

[quote name='Psychopharmacology (Berl). 1995 Mar;118(2):164-70']
Acute tolerance to nicotine in smokers: lack of dissipation within 2 hours.
Perkins KA, Grobe JE, Mitchell SL, Goettler J, Caggiula A, Stiller RL, Scierka A.

...Results demonstrated significant acute tolerance (i.e. smaller responses to nicotine challenge following nicotine versus placebo pretreatment) for most subjective measures and for heart rate. Acute tolerance dissipated with lengthening inter-dose interval for two subjective measures, dose strength and arousal, but there was no tolerance dissipation for other measures. In contrast, nicotine pretreatment resulted in acute sensitization of finger temperature (vasoconstriction) response, which dissipated with lengthening interval. No acute tolerance was observed for thermal pain detection or performance measures. These findings demonstrate that acute tolerance develops quickly to some subjective and cardiovascular effects of nicotine. However, acute tolerance to most effects did not dissipate over 2 h, suggesting that, following acute tolerance development during initial exposure, most smokers generally obtain similar magnitude of effects from each subsequent nicotine exposure (i.e. cigarettes smoked later in the day).[/quote]

[quote name='Am J Med. 1996 Oct;101(4):357-63']
Intranasal nicotine spray does not augment the adverse effects of cigarette smoking on myocardial oxygen demand or coronary arterial dimensions.
Keeley EC, Pirwitz MJ, Landau C, Lange RA, Hillis LD, Foerster EH, Conrad K, Willard JE.

RESULTS: Smoking a first cigarette increased rate pressure product (P < 0.001) and decreased coronary arterial dimensions (P < 0.0001). Subsequently, neither variable was altered by intranasal nicotine spray or a second cigarette. Despite a substantial increase in serum nicotine concentration with nicotine spray and smoking, acute cardiovascular tolerance appears to develop.[/quote]


Many studies used various antagonists to test the mechanism of nicotine's effect, but here are a few which are more viable as supplements:

[quote name='Fundam Clin Pharmacol. 2005 Apr;19(2):155-64']
Taurine treatment protects against chronic nicotine-induced oxidative changes.
Sener G, Ozer Sehirli A, Ipçi Y, Cetinel S, Cikler E, Gedik N, Alican I.

Chronic nicotine treatment impaired both the contraction and relaxation responses of the aortic rings to phenylephrine and acetylcholine, respectively. It increased lipid peroxidation, myeloperoxidase (MPO) levels and tissue collagen content of both aorta and heart samples. Taurine supplementation to nicotine-treated animals reversed the contractile dysfunction and restored the endogenous GSH levels and decreased high lipid peroxidation and MPO activities in both tissues. These data suggest that taurine supplementation effectively attenuates the oxidative damage because of chronic nicotine administration possibly by its antioxidant effects.[/quote]

This should be taken with a grain of salt, as the journal Medical Hypotheses is aptly named, and McCarty is beyond prolific in it:

[quote name='Med Hypotheses. 1996 Apr;46(4):337-47']
Fish oil may be an antidote for the cardiovascular risk of smoking.
McCarty MF.

The fact that the cardiovascular risk of ex-smokers approximates that of non-smokers after two years of abstinence, implies that accelerated atherogenesis is not the chief mechanism of smoking-related heart disease. Indeed, smoking or nicotine have adverse effects on blood rheology, thrombotic risk, coronary blood flow, and risk for arrhythmias. Omega-3-rich fish oils can be expected to correct or compensate for a remarkable number of the adverse impacts of smoking/nicotine: increased plasma fibrinogen, decreased erythrocyte distensibility, increased plasma and blood viscosity, increased platelet aggregability, increased plasminogen activator inhibitor levels, vasoconstriction of the coronary bed, reduced fibrillation threshold, increased triglycerides, reduced high-density lipoprotein cholesterol, and increased production of superoxide by phagocytes. Smokers who cannot overcome their addiction should be encouraged to substitute nicotine aerosols/gum for tobacco and advised to use supplementary fish oil and other cardioprotective nutrients.[/quote]

So, here's my summary/interpretation/observations:
  • Nicotine is definitely vasoconstrictive. It can raise heart rate, blood pressure, and myocardial oxygen consumption, and decrease blood flow.
  • There are many mechanisms implicated, the most significant being muscarinic (release of acetylcholine) and potentiation of norepinephrine at alpha1- and beta-adrenergic receptors. Protein kinase C activation (direct and indirect), NO production, and K+ channel activation also play a part.
  • The dosages used in many of these studies is equivalent to plasma levels achieved from one cigarette, or a 4mg gum.
  • Individual cardio reactions to a given level of nicotine vary.
  • A certain threshold plasma concentration is necessary for some mechanisms to begin to exert an effect
  • Nicotine was sometimes vasodilating in certain models. Inconsistencies make it hard to say how likely this is to show up in extended-release dosing.
  • Especially in acute injection/inhalation, there was sometimes a biphasic response of dilation following constriction. It is difficult to predict how this would play out over a longer dosage timeframe.
  • Acute tolerance is developed to some cardiovascular effects, which can last at least several hours. Pretreatment increased the hypothermic effect in fingers. Some effects will likely attenuate late in the period of a transdermal dose, while others (finger temp) may increase. Longer-term (between-day+) tolerance (i.e. reduction) to some cardio effects is seen in regular smokers.
  • Fish oil may ameliorate many of the negative cardio effects. Taurine may also help, largely through antioxidation. Beta blockers also had some attenuating effect.

The discussion of relative dosage in post #53 seems particularly significant in light of this. If a certain threshold is required for some mechanisms to kick in, maintaining a low dosage is critical for minimizing effects. My dosage, which is roughly equivalent to a 4mg slice of patch, is going to produce a plasma level lower than the 1 cigarette and 4mg gum studies here (one study mentioned some effect with the patch, but we can assume pretty safely that an uncut patch is used in this context).

Even so, I still think it's very important to use nicotine with restraint. I'm guessing that these effects become much more of a concern when they are experienced chronically. Based on anecdotal accounts here, constant usage will also necessitate raising the dosage pretty significantly. While chronic use will increase tolerance to some of these effects, I would guess that this would be more than offset by getting closer to/reaching the threshold concentration, and the chronic reduction in cardiovascular function. For a given dose, it seems that transdermal delivery has almost no benefits over smoking, with regard to cardiovascular damage.

(My knowledge of this physiological system is pretty weak, so I'd appreciate it if anyone can expand on my conclusions.)

Edited by chrono, 10 September 2010 - 07:28 AM.

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#69 NR2(x)

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Posted 12 September 2010 - 12:32 AM

Wow great write up, thinking that some of the material throughout this post should be stickied.Including studies of nootropic potential

Edited by NR2(x), 12 September 2010 - 12:32 AM.

#70 aLurker

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Posted 20 September 2010 - 10:12 AM

I'm considering starting to drink one or two glasses of non-alcoholic red wine a day to attenuate the effects of nicotine and for general health. The downside is that it's a quite expensive habit.

This seems relevant and I'm sure there is more information elsewhere:

Red wine against smoking

"Our findings showed that two glasses (250 ml) of red wine suspend the harmful effect of one cigarette and leads us to further investigate constituents of red wine that could reverse arterial dysfunction caused by smoking," said John Lekakis, department of clinical therapeutics, Alexandra University Hospital, Athens.

If it helps against cigarettes I suppose it should do the trick against just the nicotine too. I got cold hands the first few days I was using nicotine but now it doesn't seem to be a problem any longer, my hands are fine now. It probably has somewhat of a negative effect in the long run even if it isn't subjectively noticeable so I think it might be wise for me to take even more precautions besides my piracetam, exercise and Omega3.

Non-alcoholic (dealcoholized) seems to be comparable to alcoholic red wine in terms of effectiveness and a good step above grape skin extract due to some complex processes that occur during fermentation. Buying real red wine extract seems to be as expensive as real non-alcoholic red wine so there isn't much point to that unless someone can find me a really cheap and reliable source.

Ideally, a cheap oak barrel of the stuff would be cool to have in my room, although I suspect it might not age as well without the alcohol. Any good sources for cheap and healthy non-alcoholic red wine or equivalent extracts?

Edited by aLurker, 20 September 2010 - 10:27 AM.

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#71 chrono

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Posted 24 September 2010 - 11:46 PM

Good find! Here are the papers showing red wine's effect on nicotine's vasoactivity (your link is the second paper):

Red wine polyphenols, in the absence of alcohol, reduce lipid peroxidative stress in smoking subjects.
Abu-Amsha Caccetta R, Burke V, Mori TA, Beilin LJ, Puddey IB, Croft KD.

Phenolic compounds in red wine can exert antioxidant effects on in vitro lipoprotein oxidation. This has led to speculation that red wine consumption mediates unique anti-atherosclerotic effects compared to other alcoholic beverages. However, studies assessing the effects of red wine consumption on lipoprotein oxidation ex vivo have not been conclusive. The recent identification of the F2-isoprostanes as oxidative products of arachidonic acid has provided a reliable measure of in vivo lipid peroxidation. This randomized trial investigated changes in plasma and urinary F2-isoprostane concentrations following red wine, white wine, or dealcoholized red wine consumption in humans. Eighteen male smokers consumed, in random order, red wine, white wine, or dealcoholized red wine, for two weeks with one week washout between beverages. Plasma and urinary F2-isoprostane concentrations were measured before and after each beverage. Serum gamma-glutamyl transpeptidase (gamma-GT) and urinary 4-O -methylgallic acid were measured as markers of alcohol consumption and phenolic acid absorption, respectively. Plasma F2-isoprostanes (p < .05) decreased significantly with dealcoholized red wine but not with the alcohol-containing beverages. Urinary excretion of F2-isoprostanes showed a similar trend. gamma-GT decreased significantly with dealcoholized red wine and increased with both alcohol-containing beverages (p < .01). Urinary excretion of 4-O-methylgallic acid increased significantly (p < .001) in the 24 h urine samples following red wine or dealcoholized red wine ingestion, but not with white wine. Serum urate increased and beta-carotene decreased with both alcoholic beverages relative to dealcoholized red wine. There was no change in the antioxidants alpha- and gamma-tocopherol or vitamin C with any of the beverages. The results suggest that polyphenols in dealcoholized red wine can reduce in vivo lipid peroxidation as measured by F2-isoprostanes in smoking subjects. However, no reduction in lipid peroxidation was observed following red or white wine consumption, suggesting that any protective effects of wine drinking on cardiovascular disease are unlikely to be related to inhibition of lipid oxidation.

PMID: 11295361 [PubMed - indexed for MEDLINE]

Red wine's antioxidants counteract acute endothelial dysfunction caused by cigarette smoking in healthy nonsmokers.
Papamichael C, Karatzis E, Karatzi K, Aznaouridis K, Papaioannou T, Protogerou A, Stamatelopoulos K, Zampelas A, Lekakis J, Mavrikakis M.

BACKGROUND: Long-term smoking is believed to cause endothelial dysfunction via increased oxidative stress, whereas short-term smoking impairs vasodilatation through an as yet undefined mechanism. However, red wine and its constituents have a powerful antioxidant effect both in long-term and acute consumption. The aim of the current study was to investigate whether red wine, with or without alcohol, influences endothelial dysfunction induced by acute cigarette smoking.

METHODS: Sixteen healthy volunteers (8 males and 8 females) were recruited for a double-blind, crossover study, comprising 3 study days. Each subject smoked 1 cigarette, or smoked and drank 250 mL of red wine, or smoked and drank 250 mL of dealcoholized red wine. Flow-mediated dilatation (FMD) was measured after fasting and 15, 30, 60, and 90 minutes after each trial (smoke or smoke and drink either beverage).

RESULTS: Acute smoking of 1 cigarette caused a reduction in FMD (P <.001), which was statistically significant 15, 30, and 60 minutes after the inhalation of smoke compared to baseline levels (P <.001, P <.001, P =.043, respectively). However, simultaneous ingestion of either red wine or dealcoholized red wine with smoking did not lead to a change in [flow-mediated dilation].

CONCLUSIONS: Acute smoking caused a significant impairment in endothelial function. Simultaneous consumption of red wine or dealcoholized red wine with smoking decreased smoke's harmful effect on endothelium.

PMID: 14760339 [PubMed - indexed for MEDLINE]

Combined acute effects of red wine consumption and cigarette smoking on haemodynamics of young smokers.
Papamichael C, Karatzi K, Karatzis E, Papaioannou TG, Katsichti P, Zampelas A, Lekakis J.

OBJECTIVE: Red wine seems to improve haemodynamic variables, while smoking provokes adverse effects. The haemodynamic effects of their combined use is unknown. The purpose of the present study was to examine the acute effects of red wine and its constituents, in combination with the smoking of one cigarette, on haemodynamic parameters, such as blood pressure and wave reflections, in a group of smokers.

METHODS: Twenty smokers (12 males, eight females) participated in a double-blind, crossover study comprised of 3 study days. All subjects either smoked one cigarette, or smoked and drank 250 ml of red wine, or 250 ml of de-alcoholized red wine (containing the same type and similar concentration of antioxidants). Applanation tonometry and generalized transfer functions were used to estimate aortic pressure waveforms at baseline and 30, 60 and 90 min after each trial. The augmentation index (AIx) was used to express wave reflections.

RESULTS: Smoking increased peripheral systolic blood pressure (P < 0.005) 30 min later, but simultaneous consumption of either type of red wine caused no such effect. Additionally, smoking caused no overall effect on AIx, while smoking and drinking either regular or de-alcoholized red wine reduced AIx (P < 0.001). The reduction of AIx after red wine consumption was significantly greater than the respective reduction after de-alcoholized red wine (P = 0.004).

CONCLUSION: Antioxidant substances in red wine counteracted the smoking-induced increase in peripheral systolic blood pressure. Both alcohol and antioxidants in red wine decrease wave reflections in uncomplicated habitual smokers postprandially, indicating an additional favourable effect of red wine.

PMID: 16794477 [PubMed - indexed for MEDLINE]

This effect is probably due in part to red wine's antioxidation [1] [2] [3] [4], though the conclusion of the first study calls the magnitude of this contribution into question. The bulk of the attenuation is most likely due to red wine's reduction of endothelin-1 synthesis [5] [6] [7] [8] and increase of endothelial-type nitric oxide synthase [9] [10]. I think dealcoholized red wine or red wine extract are a good bet for an adjunct for transdermal nicotine, though it's slightly unclear how much the endothelial mechanism actually comes into play.

(wiki entry on endothelin)

Nicotine alone increases levels of endothelin-1 (ET-1) [11], and causes ET-1-mediated vasoconstriction [12] [13] and reduction in hepatic blood flow [14] (though not in all models [15]). The effect was found to be exerted at receptor ET(A) [12] or at both ET(A) and ET(B) [14]. ET-1 was found to cause vasoactivity and damage via reduction of eNOS and SOD, and an increase in Hsp70 and iNOS [13].

Most studies were carried out on cigarette smoke, or an extract thereof. Smoke increased gene expression of ET-1 via a PKC-mediated gene expression [16], and increased ET(A) expression via upregulated mRNA [17], and upregulated ET(B) through NF-kappaB signal pathways [17] and MEK/JNK MAPK-mediated transcription [18]. Smoke particles also increased local contraction of bronchial airways [19].

Note that, while some of these studies implied a complete amelioration of some vasoactive effects by antagonists of the ET receptors, it would still leave muscarinic- and adrenergic- mediated effects (mentioned in my last post) unaccounted for.

The question relevant to us is how much ET-1 is increased by transdermal delivery. Smokers were found to have increase plasma ET-1 levels for a short time after smoking [20]. Smoke particles can exert ET(x)-mediated effects independent of nicotine [21]. Low tar cigarettes (which may produce the same level of vasoconstriction as regular cigarettes [22]) did not produce significant increases in plasma ET-1, which regular cigarettes did [23], and carbon monoxide can cause an increase in ET-1 by itself [24]. While 2mg nicotine gum increased plasma ET-1 for 30 minutes [25], transdermal nicotine in nonsmokers did not [20]. There was speculation that increased ET-1 was mainly a short-lived effect of acute administration. However, as nicotine was shown to have this effect, endothelin is a potent agent, and the anti-lipid peroxidation may do some good, supplementation with red wine/extract still seems like a good bet to me (assuming no adverse risk is generated in taking it).

Edited by chrono, 25 September 2010 - 01:54 PM.

#72 chrono

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Posted 25 September 2010 - 01:06 PM

Melatonin looks like it could be useful, as well:

Melatonin reverses urinary system and aorta damage in the rat due to chronic nicotine administration.
Sener G, Kapucu C, Paskaloglu K, Ayanoglu-Dülger G, Arbak S, Ersoy Y, Alican I.

We have evaluated the changes in contractile activity and oxidant damage of corpus cavernosum, urinary bladder, kidney and aorta after chronic nicotine administration in rats. The effects of melatonin on these parameters were investigated also. Male Wistar albino rats were injected intraperitoneally with nicotine hydrogen bitartrate (0.6 mg kg(-1) daily for 21 days) or saline. Melatonin (10 mg kg(-1), i.p.) was administered either alone or with nicotine injections. Corpus cavernosum, bladder and aorta were used for contractility studies, or stored with kidneys for the measurement of malondialdehyde and glutathione levels. Corpus cavernosum, bladder, and aorta samples were examined histologically and the extent of microscopic tissue damage was scored. In the nicotine-treated group, the contraction of corpus cavernosum, bladder and aorta samples and the relaxation of corporeal and aorta tissues decreased significantly compared with controls. However, melatonin treatment restored these responses. In the nicotine-treated group, there was a significant increase in the malondialdehyde levels of the corporeal tissue, bladder, kidney and aorta, with marked reductions in glutathione levels compared with controls. Melatonin treatment reversed these effects also. Melatonin administration to nicotine-treated animals caused a marked reduction in the microscopic damage of the tissues compared with those of the untreated group. In this study, nicotine-induced dysfunction of the corpus cavernosum, bladder and aorta of rats was reversed by melatonin treatment. Moreover, melatonin, as an antioxidant, abolished elevation in lipid peroxidation products, and reduction in the endogenous antioxidant glutathione, and protected the tissues from severe damage due to nicotine exposure.

PMID: 15025861 [PubMed - indexed for MEDLINE]

Beneficial effects of melatonin on nicotine-induced vasculopathy.
Rodella LF, Filippini F, Bonomini F, Bresciani R, Reiter RJ, Rezzani R.

Tobacco smoking is responsible for death of many people each year and increases the risk of developing numerous disorders, particularly cardiovascular disease and cancer. Among the components of cigarette smoke, nicotine is known to excert proatherosclerotic, prothrombotic and proangiogenic effects on vascular endothelial cells. The current study was designed to investigate the mechanisms by which nicotine induces endothelial dysfunction and further to examine whether melatonin protects against nicotine-induced vasculopathy. Four groups of male rats (controls, melatonin-treated, nicotine treated [100 microg/mL in drinking water], and nicotine plus melatonin [5 mg/kg/day] treated) were used in this study. After 28 days all the animals were killed by decapitation and the aorta was removed. We evaluated the hydroxyproline content, and the different expression of proteins involved in several types of stress (ERK1/2), in fibrosis (TGF-beta1, NF-kappaB) and in recruitment of circulating leukocytes onto the vessel wall, including intercellular adhesion molecule-1 (ICAM-1) and vascular cellular adhesion molecule-1 (VCAM-1). These metabolic pathways are important in the development of nicotine-induced atherosclerosis and hypertension. Our results show that nicotine induces marked structural and functional alterations in the aorta. Nicotine receptor binding results in activation and phosphorylation of ERK 1/2. This enzyme, in turn, activates both TGF-beta1 and NF-kappaB; they stimulate respectively the synthesis of type I collagen, responsible of fibrosis, and moreover ICAM-1, VCAM-1 and reactive oxygen species. Based on these findings, melatonin is able to minimize the negative effects of nicotine by blocking the activation of ERK and the other signalling pathways in which this enzyme is involved.

PMID: 20050989 [PubMed - indexed for MEDLINE]

As far as I can tell from these abstracts, melatonin was coadministered with nicotine. Taking melatonin during the day might cause sleepiness, and has been shown to cause cognitive problems. But depending on the duration of these nicotine signaling effects, it might still be beneficial to take at night (not to mention its other benefits).

Edited by chrono, 25 September 2010 - 01:09 PM.

#73 Keizo

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Posted 15 April 2015 - 05:14 PM

It seems like my stiff neck, dizziness, and so on is caused by the tobacco I've been using. (At least the excess of it, I have this problem anyway though it has been under control for  a long time)


 Basically I notice lately that I feel normal in the morning, then if I smoke a cigar (which I lately tend to inhale every other puff) I start feeling bad.

I did an experiment yesterday. I took about 400mg l-tyrosine while I smoked my cigar... and while still smoking I started feeling better and less tense.

Edited by Keizo, 15 April 2015 - 05:18 PM.

#74 YOLF

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Posted 15 April 2015 - 05:43 PM

You should just quit... I know it's hard, but what if it's one of those head and neck cancers? 


Better yet, why continue to smoke? 


Things to stay away from when you quit:

Tomatoes - a source of nicotine, reminds you to want more


Things that may help you quit:

Tyrosine - you already have it, may keep you from going back to the cigarettes under stress

ginger - anti depressant qualities (tobacco has antidepressants in it)

D3 - anti depressant qualities

AAKG - anti depressant qualities, very good for beating addictions

Curcumin - anti depressant qualities

p-synephrine - boosts adrenaline (cigarettes can do this, but in a much less healthy way and only b/c they damage your heart)


Basically, start taking a bunch of mood boosters when you quit cold turkey and if you slip up and smoke a cigarette, don't take the mood boosters

#75 Keizo

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Posted 15 April 2015 - 06:26 PM

I don't have a deep addiction thankfully. I've only done this inhalation of cigars for a few weeks. I used to smoke cigars 0-7 times per week and not inhale (30-60 minute smokes), without much problem.

I am getting rid of the cigars I have and I think I should be fine. The feeling is at this point is as much "Oh well I might as well" as any urge. It certainly ruins the taste when you inhale more than once or twice /cigar.


There is also an oral fixation, which seems more pervasive (I used to use "snus" many months ago).  Along with these recent few weeks of inhaling cigars I have chewed on the part of the cigars you cut off. Mostly I don't feel the urge to put it into the mouth, but keep it around the lips and bite on it until it falls apart....


Anyway. I just took some more Tyrosine (maybe 500mg) a while after smoking a cigar this evening. It seems to help a lot in general with this. I also think the Cerebrolysin which I am using reduces the addiction potential. 


Thanks for the tips anyway. I will try and drink hot water + ginger if nothing else, instead.



Edited by Keizo, 15 April 2015 - 06:54 PM.

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#76 Heinsbeans

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Posted 27 August 2017 - 08:50 AM

Theobromine from cacao nibs/powder which is a mild stimulant(weak adenosine antagonist) and a vasodilator (lowers blood pressure unlike caffeine) might work as well. But it will also reduce the stimulatory effects of caffeine since they compete for each other in the same receptors.

Edited by Heinsbeans, 27 August 2017 - 08:55 AM.

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