nitrates

[shadar]

Asking about the overall effects of it at that water quantity.

The amount of water you use should have no impact (within reason of course). I'd imagine you'd notice lesser effects if you intake it over a longer period though. 1 scoop spread over 2 hours as compared to 1 scoop chugged.

[neuron]

Do you honestly feel oral ingestion at 600mg is going to offset tolerance? There has been no conclusive evidence showing NAC successfuly prevents tolerance from my reading. Please correct me if I'm wrong.

It seems the best way to avoid tolerance is to cycle nitrates.

As long as you separate nitrate ingestion with 12 hours, nitrate tolerance is of no concern.

Pharmaceutical nitrate-based patches for angina are generally worn 12 on/12 off.

[neuron]

Neuron has stated that caffeine is in fact not a vasoconstrictor during exercise.

It's vascular-bed dependent.

i.e. in skeletal muscle --> vasodilatory; in the GI --> vasoconstrictive, exc.

This is all dependent upon the concentration of particular receptor-type densities in the tissue.

For example, the endocrine-pancreas has primarily alpha2 receptors. In an exercise-induced energetic environment, the 'blood' is saturated with epinephrine and norepinephrine which activate the alpha2 receptor and inhibit insulin secretion. The endocrine-pancreas also possesses the beta2 receptor which has the reverse effect. In a resting environment, with low levels of circulating catecholamines, the two receptor subtypes 'compete' and negate each other, allowing normal insulin/beta-cell function. The ligand is the same but the end effect is the complete opposite. This can be extrapolated for any organ system.

[manofmany]

As long as you separate nitrate ingestion with 12 hours, nitrate tolerance is of no concern.

Pharmaceutical nitrate-based patches for angina are generally worn 12 on/12 off.

Good info. Thanks

[NO HYPE]

Do you honestly feel oral ingestion at 600mg is going to offset tolerance?

Along with vitamin C.... yes.

There has been no conclusive evidence showing NAC successfuly prevents tolerance from my reading. Please correct me if I'm wrong.

I'll see what literature I can dig up when I get the chance [if neuron doesn't beat me to it].

[NO HYPE]

As long as you separate nitrate ingestion with 12 hours, nitrate tolerance is of no concern.

Reguardless of the duration of time between nitrate ingestion, the addition of NAC & vitamin C will attenuate nitrite-mediated oxidative damage as well as nitrite-mediated GSH depletion, so their addition is still merited.

[manofmany]

Along with vitamin C.... yes.

I'll see what literature I can dig up when I get the chance [if neuron doesn't beat me to it].

Looking forward to it.

As far as the Vit C / NAC goes, are you implying that the dosage timing is critical?

[NO HYPE]

As far as the Vit C / NAC goes, are you implying that the dosage timing is critical?

Not to my knowledge.

[manofmany]

Not to my knowledge.

In that case, shouldn't most people be getting adequate amounts from diet?

[NO HYPE]

In that case, shouldn't most people be getting adequate amounts from diet?

Not for nitrite-mediated oxidative damage and/or nitrite-mediated GSH depletion. While I implied that the dosage timing for vitamin C & NAC was not overly critical, nitrates aquire a circulating half life of 5-8 hours (Tannenbaum 1994; Kelm and Yoshida 1996). Oral NAC reaches maximal plasma levels in about 2-3 hours, with a half-life of about 6-hours. The half-life of vitamin C is roughly 3-4 hours. Either way, I would dose NAC & vitamin C around the same time as nitrate ingestion, as they will still diminish the aforementioned oxidative effects of nitrates/nitrites despite the fact that nitrates will still remain in circulation.

[Illadelphia]

Just a heads up for the OP.

XF is the ONLY company that lists the amount of Nitrates in their product

[quank]

I have tried PowerShock and did not experience any headaches.

x2.

[em-dubya]

Quote:
Originally Posted by manofmany
Do you honestly feel oral ingestion at 600mg is going to offset tolerance?

Along with vitamin C.... yes.



Quote:
Originally Posted by manofmany
There has been no conclusive evidence showing NAC successfuly prevents tolerance from my reading. Please correct me if I'm wrong.

I'll see what literature I can dig up when I get the chance [if neuron doesn't beat me to it].
__________________



I'd like to see this lit. also Im really not convinced 100% on the NAC...but I am being open minded.

[manofmany]

Just a heads up for the OP.

XF is the ONLY company that lists the amount of Nitrates in their product

SAN lists the amount in CM2

[Illadelphia]

SAN lists the amount in CM2

I guess that makes 2 companies

[NO HYPE]

There has been no conclusive evidence showing NAC successfuly prevents tolerance from my reading. Please correct me if I'm wrong.

Please note that I mentioned vitamin C as well. NAC also assists in preventing nitrate tolerance, but additionaly prevents nitrite-mediated GSH depletion.



Dietary Supplement with Vitamin C Prevents Nitrate Tolerance
Eberhard Bassenge, Nelli Fink, Mikhail Skatchkov, and Bruno Fink
Institute of Applied Physiology, University of Freiburg, Hermann-Herder-Str 7, D-79104 Freiburg, Germany

coadministration of Vit-C and GTN fully maintained the GTN-induced changes in the orthostatic blood pressure, and the rise of a/b ratio was augmented by 310% for the duration of the test period. Changes in vascular tolerance in GTN-treated subjects were paralleled by upregulation of the activity of isolated platelets, which was also reversed by Vit-C administration. These findings demonstrate that dietary supplementation with Vit-C eliminates vascular tolerance and concomitant upregulation of ex vivo–washed platelet activity during long-term nonintermittent administration of GTN in humans.

In previous studies we attempted to suppress the superoxide- mediated inactivation of NO that is associated with GTN tolerance by examining the efficacy of various compounds that might intercept the free radical (8–11). Of the various antioxidants tested, including ascorbate (Vit-C), a-tocopherol (Vit-E), N-acetyl-cysteine, and dimethyl sulfoxide, Vit-C proved to be most efficient in our preliminary studies (8–12).

Taken together, these studies suggest that administration of vitamin C may prove useful for overcoming the tolerant state induced during prolonged administration of nitrovasodilators in acute ischemic syndromes or congestive heart failure. In addition, as progressive upregulation in the activity of washed ex vivo platelets coincides with vascular tolerance, these simple assays may serve as useful clinical markers to assess further the underlying mechanisms associated with the induction or reversal of nitrate tolerance.
http://www.ncbi.nlm.nih.gov/pmc/arti...df/1020067.pdf



Journal of Cardiovascular Pharmacology. February 1989 - Volume 13 - Issue 2
N-Acetylcysteine Modifies the Acute Effects of Isosorbide-5-Mononitrate in Angina Pectoris Patients Evaluated by Exercise Testing

Summary: Nitrates are well established in the treatment of angina pectoris and the presence of sulfhydryl groups seems to be fundamental to nitrate-induced vasodilatation. The present study was performed to elucidate if large oral doses of N-acetylcysteine (NAC, 2,400 mg X 2), a donor of sulfhydryl groups, given together with a single oral dose of the long-acting nitrate, isosorbide-5-mononitrate (5-ISMN, 60 mg), would modify the nitrate effect evaluated by exercise testing before and after additional sublingual doses of nitroglycerin (NTG). Ten patients with angina pectoris and angiographically proven significant coronary artery disease were included. All patients received a baseline therapy with 13 blockers. None of the patients had developed nitrate tolerance at inclusion. NAC/5-ISMN treatment significantly prolonged the total exercise time as compared with placebo/5-ISMN (7.7 +/- 2.1 min vs. 6.8 +/- 1.7 min, p < 0.05). This increase was of such magnitude that no further effect was obtained after additional NTG doses. This study demonstrated that increased availability of sulfhydryl groups can in-crease the exercise capacity in angina pectoris patients treated with 5-ISMN without nitrate tolerance.

N Engl J Med. 1987 Sep 24;317(13):799-804.
Packer M, Lee WH, Kessler PD, Gottlieb SS, Medina N, Yushak M.
Prevention and reversal of nitrate tolerance in patients with congestive heart failure.

To evaluate possible mechanisms underlying the development of nitrate tolerance, we treated 35 patients who had severe chronic heart failure with a prolonged (48-hour) intravenous infusion of nitroglycerin (6.4 micrograms per kilogram of body weight per minute) given either continuously or intermittently (12-hour infusions separated by intervals of 12 hours). Intravenous nitroglycerin produced immediate hemodynamic benefits in all patients, but the magnitude of this improvement was greatly diminished after 48 hours of continuous therapy with the drug. This attenuation was accompanied by cross-tolerance to oral isosorbide dinitrate and by an increase in heart rate, plasma renin activity, and body weight. In contrast, intermittent therapy with intravenous nitroglycerin was not associated with a loss of hemodynamic efficacy or cross-tolerance to oral nitrates and was not accompanied by changes in neurohormonal activity or body weight. In eight patients in whom nitrate tolerance developed during continuous intravenous therapy, the administration of the sulfhydryl-containing compound N-acetylcysteine (200 mg per kilogram orally) restored the hemodynamic state toward that observed at the start of the infusion of nitroglycerin (partial reversal of tolerance). In contrast, N-acetylcysteine had little hemodynamic effect in patients who were not receiving nitroglycerin. These data support the hypothesis that neurohormonal activation and depletion of sulfhydryl groups may interact to cause the loss of hemodynamic efficacy that occurs during prolonged treatment with intravenous nitroglycerin in patients with heart failure. Evaluation of the suggested role of sulfhydryl depletion in the development of tolerance will, however, require direct studies of vascular tissue.



Am J Cardiol. 1997 Jan 1;79(1):28-33.
Pizzulli L, Hagendorff A, Zirbes M, Jung W, Lüderitz B.
N-acetylcysteine attenuates nitroglycerin tolerance in patients with angina pectoris and normal left ventricular function.

The aim of this study was to assess whether N-acetylcysteine (NAC) is able to prevent tolerance to a 48-hour infusion of nitroglycerin (NTG) in the setting of normal left ventricular function. In 16 patients, the hemodynamic response to 0.8 mg sublingual (s.l.) NTG was assessed by measuring mean arterial, pulmonary artery, pulmonary capillary wedge and right atrial pressures, cardiac output, and calculation of the systemic and pulmonary vascular resistances. The parameters were obtained at baseline and 1 to 10 minutes after the s.l. NTG application (day 1). NTG was started at 1.5 microg/kg/min; concomitantly, a bolus of 2,000 mg of NAC was administered, followed by an infusion of 5 mg/kg/hour. Both infusions were continued for 48 hours, and the hemodynamic study was repeated (day 3). The same measurements were obtained in a matched control group of 15 patients with NTG infusion alone. Plasma renin activity, aldosterone, and norepinephrine were measured before and after the infusion period. The first s.l. NTG infusion (day 1) caused a significant decrease in mean arterial (p <0.01), pulmonary artery (p <0.001), and right atrial pressures (p <0.001), and in systemic (p <0.01) and pulmonary vascular resistances (p <0.001) in both groups. After the 48-hour infusion (day 3), there was a total loss of nitrate-mediated vasodilation (pressure values and vascular resistances day 3 > day 1) in 5 of 16 patients (NAC nonresponders), whereas in the other 11 of 16 patients (NAC responders), there was significant vasodilation throughout the infusion period. Tolerance had developed in 14 of 15 patients with NTG infusion alone. The same difference (responder vs nonresponder vs NTG alone) held true regarding the response to the second s.l. NTG infusion after 48 hours. The neurohormonal counter-regulation and intravascular volume expansion (increase in plasma renin activity, p <0.001, and norepinephrine, p <0.05; decrease in aldosterone, p <0.01) did not differ between responders and nonresponders. We conclude that NAC attenuates tolerance development to a continuous NTG infusion in a specific patient subgroup and that this occurs despite the same amount of neurohormonal counter-regulation and intravascular volume expansion compared with patients with tolerance development.



Dan Med Bull. 1995 Nov;42(5):473-84.
Boesgaard S.
Thiol compounds and organic nitrates.

Organic nitrates are widely used in the treatment of ischemic heart disease. The magnitude and duration of their circulatory and ischemic effects are, however, rapidly reduced during continuous treatment. The specific mechanisms underlying this tolerance development are not clear. According to the most widely accepted theory, tolerance is due to an intracellular depletion of thiol compounds (GSH and/or cysteine) involved in the conversion of nitrates to vasoactive intermediates. This presentation deals with aspects of in vivo thiol/nitrate interactions in different experimental and clinical conditions. The major results and conclusions are: The acute hypotensive effect of NTG is decreased by lowering of intracellular GSH levels. This finding emphasizes that normal intracellular thiol levels are required for optimal conversion of nitrates. Thus, intracellular GSH plays a critical role in the metabolism of NTG. Despite development of tolerance to the hypotensive effect of NTG, arterial and venous thiol levels are similar in nitrate tolerant and non-tolerant animals, suggesting that depletion of vascular thiol compounds may not be the cause of nitrate tolerance in vivo. The effect of exogenous thiol administration on intravascular thiol levels are different in nitrate tolerant and non-tolerant conscious rats. Exogenous thiol compounds (e.g. NAC) augments the hypotensive effect of NTG by a tolerance nonspecific mechanism. This effect is most likely mediated by an extracellular and/or membrane-related nitrate/thiol interaction and formation of NO. N-acetylcysteine inhibits angiotensin converting enzyme and counteracts nitrate-induced stimulation of the renin angiotensin system in vivo. Therefore, in addition to an effect on nitrate metabolism, thiol compounds may modify tolerance development by attenuating nitrate-induced counter-regulatory mechanisms. In the clinical setting, co-administration of NAC and ISDN delays and partially prevents tolerance to the antianginal and antiischemic effects normally seen in patients with stable angina pectoris during treatment with ISDN. N-acetylcysteine treatment in humans, potentiates and preserves nitrate induced venodilation and augments the effect of nitrates on small resistance vessels without affecting the response to nitrates in larger sized arteries. Thus, administration of NAC may change the normal vasodilator profile of nitrates. In conclusion, changes in cellular thiol levels may modify the hemodynamic effect of organic nitrates and the cellular handling of thiols and/or thiol related enzymes is altered after development of nitrate tolerance. In addition, a tolerance unrelated thiol/nitrate interaction, potentiating the effect of nitrates, may occur after administration of exogenous thiol compounds. In the clinical setting administration of thiols results in a characteristic change in the vasodilator profile of nitrates and an attenuation of the nitrate-induced stimulation of the renin-angiotensin system. The combination of these effects probably contributes to the improvement in antianginal and antiischemic parameters which may be seen during continuous and prolonged treatment with nitrates and thiol compounds.

[manofmany]

Journal of Cardiovascular Pharmacology. February 1989 - Volume 13 - Issue 2
N-Acetylcysteine Modifies the Acute Effects of Isosorbide-5-Mononitrate in Angina Pectoris Patients Evaluated by Exercise Testing

Summary: Nitrates are well established in the treatment of angina pectoris and the presence of sulfhydryl groups seems to be fundamental to nitrate-induced vasodilatation. The present study was performed to elucidate if large oral doses of N-acetylcysteine (NAC, 2,400 mg X 2), a donor of sulfhydryl groups, given together with a single oral dose of the long-acting nitrate, isosorbide-5-mononitrate (5-ISMN, 60 mg), would modify the nitrate effect evaluated by exercise testing before and after additional sublingual doses of nitroglycerin (NTG). Ten patients with angina pectoris and angiographically proven significant coronary artery disease were included. All patients received a baseline therapy with 13 blockers. None of the patients had developed nitrate tolerance at inclusion. NAC/5-ISMN treatment significantly prolonged the total exercise time as compared with placebo/5-ISMN (7.7 +/- 2.1 min vs. 6.8 +/- 1.7 min, p < 0.05). This increase was of such magnitude that no further effect was obtained after additional NTG doses. This study demonstrated that increased availability of sulfhydryl groups can in-crease the exercise capacity in angina pectoris patients treated with 5-ISMN without nitrate tolerance.

N Engl J Med. 1987 Sep 24;317(13):799-804.
Packer M, Lee WH, Kessler PD, Gottlieb SS, Medina N, Yushak M.
Prevention and reversal of nitrate tolerance in patients with congestive heart failure.

To evaluate possible mechanisms underlying the development of nitrate tolerance, we treated 35 patients who had severe chronic heart failure with a prolonged (48-hour) intravenous infusion of nitroglycerin (6.4 micrograms per kilogram of body weight per minute) given either continuously or intermittently (12-hour infusions separated by intervals of 12 hours). Intravenous nitroglycerin produced immediate hemodynamic benefits in all patients, but the magnitude of this improvement was greatly diminished after 48 hours of continuous therapy with the drug. This attenuation was accompanied by cross-tolerance to oral isosorbide dinitrate and by an increase in heart rate, plasma renin activity, and body weight. In contrast, intermittent therapy with intravenous nitroglycerin was not associated with a loss of hemodynamic efficacy or cross-tolerance to oral nitrates and was not accompanied by changes in neurohormonal activity or body weight. In eight patients in whom nitrate tolerance developed during continuous intravenous therapy, the administration of the sulfhydryl-containing compound N-acetylcysteine (200 mg per kilogram orally) restored the hemodynamic state toward that observed at the start of the infusion of nitroglycerin (partial reversal of tolerance). In contrast, N-acetylcysteine had little hemodynamic effect in patients who were not receiving nitroglycerin. These data support the hypothesis that neurohormonal activation and depletion of sulfhydryl groups may interact to cause the loss of hemodynamic efficacy that occurs during prolonged treatment with intravenous nitroglycerin in patients with heart failure. Evaluation of the suggested role of sulfhydryl depletion in the development of tolerance will, however, require direct studies of vascular tissue.



Am J Cardiol. 1997 Jan 1;79(1):28-33.
Pizzulli L, Hagendorff A, Zirbes M, Jung W, Lüderitz B.
N-acetylcysteine attenuates nitroglycerin tolerance in patients with angina pectoris and normal left ventricular function.

The aim of this study was to assess whether N-acetylcysteine (NAC) is able to prevent tolerance to a 48-hour infusion of nitroglycerin (NTG) in the setting of normal left ventricular function. In 16 patients, the hemodynamic response to 0.8 mg sublingual (s.l.) NTG was assessed by measuring mean arterial, pulmonary artery, pulmonary capillary wedge and right atrial pressures, cardiac output, and calculation of the systemic and pulmonary vascular resistances. The parameters were obtained at baseline and 1 to 10 minutes after the s.l. NTG application (day 1). NTG was started at 1.5 microg/kg/min; concomitantly, a bolus of 2,000 mg of NAC was administered, followed by an infusion of 5 mg/kg/hour. Both infusions were continued for 48 hours, and the hemodynamic study was repeated (day 3). The same measurements were obtained in a matched control group of 15 patients with NTG infusion alone. Plasma renin activity, aldosterone, and norepinephrine were measured before and after the infusion period. The first s.l. NTG infusion (day 1) caused a significant decrease in mean arterial (p <0.01), pulmonary artery (p <0.001), and right atrial pressures (p <0.001), and in systemic (p <0.01) and pulmonary vascular resistances (p <0.001) in both groups. After the 48-hour infusion (day 3), there was a total loss of nitrate-mediated vasodilation (pressure values and vascular resistances day 3 > day 1) in 5 of 16 patients (NAC nonresponders), whereas in the other 11 of 16 patients (NAC responders), there was significant vasodilation throughout the infusion period. Tolerance had developed in 14 of 15 patients with NTG infusion alone. The same difference (responder vs nonresponder vs NTG alone) held true regarding the response to the second s.l. NTG infusion after 48 hours. The neurohormonal counter-regulation and intravascular volume expansion (increase in plasma renin activity, p <0.001, and norepinephrine, p <0.05; decrease in aldosterone, p <0.01) did not differ between responders and nonresponders. We conclude that NAC attenuates tolerance development to a continuous NTG infusion in a specific patient subgroup and that this occurs despite the same amount of neurohormonal counter-regulation and intravascular volume expansion compared with patients with tolerance development.

This would seem to indicate very large oral doses are necessary, no?

Br J Clin Pharmacol. 1989 Oct;28(4):421-6.
N-acetylcysteine fails to attenuate haemodynamic tolerance to glyceryl trinitrate in healthy volunteers.

Hogan JC, Lewis MJ, Henderson AH.

Department of Pharmacology and Therapeutics, University of Wales College of Medicine, Cardiff.
Abstract

1. The effects of chronic dosing with N-acetylcysteine (NAC), on nitrate-induced haemodynamic changes during the acute and chronic treatment of healthy volunteers with glyceryl trinitrate (GTN) patches (Transiderm nitro) has been investigated. 2. Seven volunteers were treated in a double-blind randomised crossover manner for two periods of 4 days with 20 mg of transdermal GTN/24 h together with NAC (200 mg three times daily) or matching placebo. There was a washout period of greater than 3 days between treatment periods. 3. Haemodynamic measurements (blood pressure (BP); heart rate (HR] at rest and following maximal treadmill exercise were performed before treatment and 4 h after starting treatment on days 1 and 4. 4. Significant haemodynamic changes as evidenced by a fall in BP and rise in HR, were seen on day 1 in both the NAC and placebo phases. By day 4 the haemodynamic changes had returned towards the pre-treatment values during both the NAC and placebo phases suggesting the development of tolerance in both treatment groups. 5. These findings suggest that concurrent administration of NAC fails to prevent the development of tolerance to GTN.

Comments?

[NO HYPE]

This would seem to indicate very large oral doses are necessary, no?

No. The aforementioned citations pertained to nitroglycerin infusion. Creatine nitrate is merely a salt, therefore the dosages needed are significantly reduced.

[manofmany]

No. The aforementioned citations pertained to nitroglycerin infusion. Creatine nitrate is merely a salt, therefore the dosages needed are significantly reduced.

Gotcha, thanks for bearing with me.

[NO HYPE]

Gotcha, thanks

No problem.

[Yates Row T]

hate nitrates. both times i have tried i felt like ****. overhyped fad imo

[NO HYPE]

hate nitrates. both times i have tried i felt like ****.

Interindividual variables suck.

[shadar]

hate nitrates. both times i have tried i felt like ****. overhyped fad imo

My first few experiences with them sucked in powershock when trying it out as a pre-workout NO booster. Led to headaches, light-headedness, etc.

I didn't use it again for a month or two and then tried again as an intra-workout. This time my results were more favorable.

[neuron]

You're sure this also counts for these kind of supplements?

Nitroglycerin has a ~3 minutes half life while dietary nitrates have a half life of 5-8 hours.

It's a patch - which means it constantly releases the drug into the plasma reaching a steady-state. The half-life is only relevent when you remove the patch. The point is that nitrogen tolerance disappears very rapidly.

[neuron]

Comments?

NAC may be marginally beneficial in the context of constant nitrate exposure (i.e. IV nitrates for congestive heart failure), but not in the context of once-per-day, pre-WO dosing.

[NO HYPE]

but not in the context of once-per-day, pre-WO dosing.

What about twice per-day - pre and post?

[NO HYPE]

NAC may be marginally beneficial in the context of constant nitrate exposure (i.e. IV nitrates for congestive heart failure), but not in the context of once-per-day, pre-WO dosing.

What about nitrite-mediated oxidative damage and/or glutathione depletion?

[DGreekStallion]

NO HYPE, is there enough Vitamin C in C-BOL to reduce tolerance to the nitrates in it and PS?

[NO HYPE]

NO HYPE, is there enough Vitamin C in C-BOL to reduce tolerance to the nitrates in it and PS?

The amount of vitamin C & NAC was specifically formulated for C-BOL however, I can't really comment in reguards to the combination of C-BOL AND PS. Send a PM to Bane and get back to us.

[DGreekStallion]

Will do.