Organic nitrates: update on mechanisms underlying vasodilation, tolerance and endothelial dysfunction (original) (raw)
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Nitrates and nitrites in the treatment of ischemic cardiac disease
Cardiology in review
The organic nitrite, amyl of nitrite, was initially used as a therapeutic agent in the treatment of angina pectoris, but was replaced over a decade later by the organic nitrate, nitroglycerin (NTG), due to the ease of administration and longer duration of action. The administration of organic nitrate esters, such as NTG, continues to be used in the treatment of angina pectoris and heart failure since the birth of modern pharmacology. Their clinical effectiveness is due to vasodilator activity in large veins and arteries through an as yet unidentified method of delivering nitric oxide (NO), or a NO-like compound. The major drawback is the development of tolerance with NTG, and the duration and route of administration with amyl of nitrite. Although the nitrites are no longer used in the treatment of hypertension or ischemic heart disease, the nitrite anion has recently been discovered to possess novel pharmacologic actions, such as modulating hypoxic vasodilation, and providing cytopr...
Heart International, 2007
Nitrates are a cornerstone in the treatment of coronary heart disease and heart failure. Although they are widely used in clinical practice, their therapeutic value is partially compromised by the rapid development of tolerance. The effect of different nitrates, nitroglycerin (NTG), isosorbide dinitrate (ISDN), 5-mononitrate (5MN) and 2-mononitrate (2MN) and the mechanism responsible for nitrate tolerance were investigated on isolated rabbit hearts and aortic strips. Preparation was stimulated by different spasmogenic agents: KCl, angiotensin II (A) and noradrenaline (NA); nitrates were administered on the plateau contraction, at the concentration of maximum inhibitory effect. Nitrates produced the following maximum inhibitions on NA-induced contraction: NTG 90% (10-6 M), ISDN 60% (10-4 M), 5MN 55% (10-4 M) and 2MN 80% (10-4 M). In another series of experiments, preparations were pre-incubated with the maximum inhibitory concentration of each nitrate to evaluate the induction of tolerance. After incubation a loss of vasodilator effect of nearly 50-60% was observed for all the nitrates considered except 2MN, in which the loss of effect was significantly lower (36%). The cyclic GMP (cGMP) levels measured in the preparations were lower in the presence of 2MN than in the other compounds. These data suggest that 2MN is able to induce a lesser cGMP increase and a lesser tolerance induction; since these observations seem to be correlated the vasodilator effect of 2MN probably involves mechanisms other than guanylyl cyclase stimulation.
Nitrate Tolerance in Hypertension: New Insight Into a Century-Old Problem
Circulation Research, 2003
N itrate tolerance to a vascular physiologist is the intriguing insensitivity or loss of responsiveness to drugs whose actions mimic the powerful endogenous vasodilator and platelet inhibitor nitric oxide (NO). To the clinician, it is a serious limitation in the use of an otherwise highly promising and widely used therapeutic class of drugs collectively referred to as nitrates. Nitroglycerin (NTG) and organic nitrates are used in the therapy of ischemic heart disease and heart failure. Clinical trials such as the ISIS-4 trial showed a 20% reduction in 24-hour postinfarct mortality with the use of an oral nitrate such as isosorbide mononitrate (ISMN). Sublingual NTG is the drug of choice for chest pain and acute angina attacks, and intravenous NTG is the drug of choice in acute coronary syndromes. Oral long-acting nitrates are effective in the treatment of chronic stable angina.
Inorganic Nitrate in Angina Study: A Randomized Double‐Blind Placebo‐Controlled Trial
Journal of the American Heart Association
Background-In this double-blind randomized placebo-controlled crossover trial, we investigated whether oral sodium nitrate, when added to existing background medication, reduces exertional ischemia in patients with angina. Methods and Results-Seventy patients with stable angina, positive electrocardiogram treadmill test, and either angiographic or functional test evidence of significant ischemic heart disease were randomized to receive oral treatment with either placebo or sodium nitrate (600 mg; 7 mmol) for 7 to 10 days, followed by a 2-week washout period before crossing over to the other treatment (n=34 placebo-nitrate, n=36 nitrate-placebo). At baseline and at the end of each treatment, patients underwent modified Bruce electrocardiogram treadmill test, modified Seattle Questionnaire, and subgroups were investigated with dobutamine stress, echocardiogram, and blood tests. The primary outcome was time to 1 mm ST depression on electrocardiogram treadmill test. Compared with placebo, inorganic nitrate treatment tended to increase the primary outcome exercise time to 1 mm ST segment depression (645.6 [603.1, 688.0] seconds versus 661.2 [6183, 704.0] seconds, P=0.10) and significantly increased total exercise time (744.4 [702.4, 786.4] seconds versus 760.9 [719.5, 802.2] seconds, P=0.04; mean [95% confidence interval]). Nitrate treatment robustly increased plasma nitrate (18.3 [15.2, 21.5] versus 297.6 [218.4, 376.8] lmol/L, P<0.0001) and almost doubled circulating nitrite concentrations (346 [285, 405] versus 552 [398, 706] nmol/L, P=0.003; placebo versus nitrate treatment). Other secondary outcomes were not significantly altered by the intervention. Patients on antacid medication appeared to benefit less from nitrate supplementation. Conclusions-Sodium nitrate treatment may confer a modest exercise capacity benefit in patients with chronic angina who are taking other background medication.
Nitrate Tolerance in Hypertension
Circulation Research, 2003
Harm J. Knot N itrate tolerance to a vascular physiologist is the intriguing insensitivity or loss of responsiveness to drugs whose actions mimic the powerful endogenous vasodilator and platelet inhibitor nitric oxide (NO). To the clinician, it is a serious limitation in the use of an otherwise highly promising and widely used therapeutic class of drugs collectively referred to as nitrates. Nitroglycerin (NTG) and organic nitrates are used in the therapy of ischemic heart disease and heart failure. Clinical trials such as the ISIS-4 trial showed a 20% reduction in 24-hour postinfarct mortality with the use of an oral nitrate such as isosorbide mononitrate (ISMN). Sublingual NTG is the drug of choice for chest pain and acute angina attacks, and intravenous NTG is the drug of choice in acute coronary syndromes. Oral long-acting nitrates are effective in the treatment of chronic stable angina.
Circulation, 2001
Background-Recent studies suggest that the late phase of ischemic preconditioning (PC) can be mimicked by pretreatment with NO donors. The ability of clinically relevant NO donors to induce PC against infarction, however, has not been evaluated. Furthermore, it is unknown whether tolerance to the hemodynamic actions of nitrates also extends to their PC effects. Methods and Results-Conscious rabbits underwent a 30-minute coronary occlusion and 3 days of reperfusion. A 60-minute intravenous (IV) infusion of nitroglycerin (NTG) ending 1 hour before occlusion reduced infarct size, indicating an early PC effect. When the time interval between NTG infusion and occlusion was extended to 24 or 72 hours, the infarct-sparing action of NTG became even more pronounced, indicating a robust late PC effect. Transdermal NTG patches elicited a late PC effect that was (1) equivalent to that induced by IV NTG, demonstrating the efficacy of transdermal NTG as an alternative form of NTG delivery for inducing late PC, and (2) similar in nitrate-tolerant and -nontolerant rabbits, demonstrating that tolerance does not extend to the PC effects of NTG. Conclusions-In conscious rabbits, administration of NTG via either the IV or the transdermal route elicits a robust protective effect against infarction that lasts for 72 hours. The magnitude of NTG-induced cardioprotection is equivalent to that observed during the late phase of ischemic PC and is not affected by the development of tolerance. These findings reveal a new action of nitrates and support novel applications of these drugs for protecting the ischemic myocardium in patients. (Circulation. 2001;104:694-699.)
Nitrate tolerance in heart failure: Differential venous, pulmonary and systemic arterial effects
The American Journal of Cardiology, 1990
The hemodynamk profile of tolerance to intravenous nitroglycerin was studied in 9 patients with New York Heart Association Class III to IV congestive heart failure. After rapid dosage kulld-up to the maximal totsrated dose (decrease in pulmonary wedge pressure to 10 mm Hg or systolic blood pressure to 99 mm Hg), nitroglycerin (SW f 548 rcg/mln) was administered at a constant centinuous intravenous infusion for a total of 24 hours. The extent of nitrate tolerance at 24 hours was calculated as the percentage kbss of the beneSt achieved at time of peak effect of nitroglycerin.