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PubMed1989

Nitroglycerin delivery through a polyethylene-lined intravenous administration set.

Adsorption and delivery of nitroglycerin through a new polyethylene-lined (PEL) i.v. administration set was compared with adsorption and delivery through an identical set composed of polyvinyl chloride (PVC) rather than PEL tubing. The new delivery system consisted of PEL tubing, a transparent PVC chamber, and a silastic segment for insertion in a peristaltic pump. Nitroglycerin was prepared in concentrations of 50, 125, and 200 micrograms/mL in 0.9% sodium chloride injection and run through both administration sets at flow rates of 12 and 60 mL/hr. Samples were obtained at 0, 0.5, 1, 2,4, and 8 hours from each of three sites: bottle, junction before silastic segment, and distal end of tubing. Nitroglycerin content was assayed using a modified high-performance liquid chromatography technique. A slight but significant average loss of nitroglycerin (2.3 +/- 9.3%) was observed at the distal end with the PEL set, whereas the PVC set showed a significant average nitroglycerin loss of 39.7 +/- 12.7% at the distal end. These differences were independent of infusion rate, nitroglycerin concentration, or time of sampling. Flow rate, concentration, and time had no significant effect on nitroglycerin adsorption with the PEL set, but all three had a significant effect on nitroglycerin adsorption with the PVC set. An unexpected finding was the approximately 14% loss of nitroglycerin from the admixture bottle over time. This phenomenon, which has been observed by other investigators, needs further investigation to determine its cause. It appears that a partially PVC-based administration set should provide consistent delivery of i.v. nitroglycerin to the patient.

Chemistry, Pharmaceutical↗
PubMed1985

Nitroglycerin injection manufactured by a hospital pharmacy.

A method used by a hospital pharmacy department for manufacturing and testing a ready-to-administer i.v. nitroglycerin injection is described, and costs for this extemporaneously prepared injection are compared with costs for commercially available nitroglycerin products for i.v. use. A powder adsorbate containing one part nitroglycerin and nine parts lactose was used to prepare nitroglycerin injection in two strengths: 0.04 mg/mL (250-mL quantities) in 0.9% sodium chloride injection and 0.4 mg/mL (400-mL quantities) in 5% dextrose injection. Each batch was tested for sterility, for presence of pyrogens (endotoxin testing), and for nitroglycerin concentration (spectrophotometric assay). In one year, a total of 1217 bottles of nitroglycerin injection were prepared. This required 75 hours; preparation from commercial i.v. nitroglycerin products would have required approximately 200 hours (including admixture preparation). First-year costs for extemporaneous preparation (excluding costs of i.v. solutions and containers) were approximately $2200, far less than drug costs alone for the commercial i.v. nitroglycerin products. Nitroglycerin injection of high quality and confirmed potency was prepared extemporaneously in a hospital pharmacy department. Costs for this method were substantially less than those for use of commercial i.v. nitroglycerin products.

Costs and Cost Analysis↗
PubMed1982

Vascular tolerance to nitroglycerin and cyclic GMP generation in rat aortic smooth muscle.

Recent reports have suggested that cyclic guanosine 3', 5'-monophosphate (cGMP) may mediate drug-induced vascular smooth muscle relaxation. This hypothesis was examined by correlating increases in cGMP formation with vascular smooth muscle relaxation after sensitivities to nitroglycerin and nitroprusside were altered. Both nitroglycerin and nitroprusside produced a concentration-dependent increase in rat aortic cGMP levels, which preceded relaxation. A specific inhibition of nitroglycerin relaxation was accomplished by pretreating helical rat aortic strips with 5.5 X 10(-4) M nitroglycerin for 1 hr (in vitro nitroglycerin tolerance). Both nitroglycerin and nitroprusside were inhibited by pretreating tissues with 10(-5) M methylene blue for 1 hr. Whenever nitroglycerin or nitroprusside relaxation was inhibited, there was a corresponding inability to generate cGMP. Vascular tissues derived from nitroglycerin-tolerant animals (in vivo tolerance) exhibited a profile of cGMP reduction that closely resembled that of the in vitro model. Vascular smooth muscle relaxation induced by 8-bromoguanosine-3', 5'-monophosphoric acid was not inhibited by either in vitro nitroglycerin tolerance or methylene blue, suggesting that the subsequent action of cGMP, once formed, is not impaired. The results of this study support the contention that cGMP generation may be an important step in the promotion of vascular smooth muscle relaxation by nitroglycerin and nitroprusside.

Animals↗
PubMed1983

Nitroglycerin tolerance and cyclic GMP generation in the longitudinal smooth muscle of the guinea-pig ileum.

The effects of in vitro nitroglycerin tolerance and methylene blue pretreatment on the ability of nitroglycerin and nitroprusside to promote relaxation and tissue accumulation of cyclic GMP were examined in the carbachol-contracted longitudinal smooth muscle of the guinea-pig ileum. Nitroglycerin and nitroprusside produced concentration-dependent increases in cyclic GMP levels. However, only nitroglycerin increased cyclic GMP levels before the onset of relaxation. Nitroglycerin tolerance produced approximately 200- and 5-fold shifts to the right of nitroglycerin and nitroprusside relaxation curves, respectively. Methylene blue pretreatment produced approximately 5-fold shifts to the right of both nitroglycerin and nitroprusside relaxation curves. Whenever there was an inhibition of nitroglycerin- or nitroprusside-induced relaxation, there was a corresponding reduction of cyclic GMP generation. Methylene blue inhibited the ability of 8-bromoguanosine 3',5'-monophosphoric acid to promote smooth muscle relaxation, suggesting that it also may impair the subsequent actions of cyclic GMP. This study provides the first demonstration of nitroglycerin tolerance in a nonvascular smooth muscle and provides evidence that cyclic GMP mediates the relaxant effects of nitroglycerin in the longitudinal smooth muscle of the guinea-pig ileum. However, because nitroprusside promoted tissue accumulation of cyclic GMP subsequent to relaxation, an exclusive role for cyclic GMP-mediated relaxation for this drug in the longitudinal smooth muscle appears unlikely.

Animals↗
PubMed2002

Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial.

CONTEXT: Decompensated congestive heart failure (CHF) is the leading hospital discharge diagnosis in patients older than 65 years. OBJECTIVE: To compare the efficacy and safety of intravenous nesiritide, intravenous nitroglycerin, and placebo. DESIGN, SETTING, AND PATIENTS: Randomized, double-blind trial of 489 inpatients with dyspnea at rest from decompensated CHF, including 246 who received pulmonary artery catheterization, that was conducted at 55 community and academic hospitals between October 1999 and July 2000. INTERVENTIONS: Intravenous nesiritide (n = 204), intravenous nitroglycerin (n = 143), or placebo (n = 142) added to standard medications for 3 hours, followed by nesiritide (n = 278) or nitroglycerin (n = 216) added to standard medication for 24 hours. MAIN OUTCOME MEASURES: Change in pulmonary capillary wedge pressure (PCWP) among catheterized patients and patient self-evaluation of dyspnea at 3 hours after initiation of study drug among all patients. Secondary outcomes included comparisons of hemodynamic and clinical effects between nesiritide and nitroglycerin at 24 hours. RESULTS: At 3 hours, the mean (SD) decrease in PCWP from baseline was -5.8 (6.5) mm Hg for nesiritide (vs placebo, P<.001; vs nitroglycerin, P =.03), -3.8 (5.3) mm Hg for nitroglycerin (vs placebo, P =.09), and -2 (4.2) mm Hg for placebo. At 3 hours, nesiritide resulted in improvement in dyspnea compared with placebo (P =.03), but there was no significant difference in dyspnea or global clinical status with nesiritide compared with nitroglycerin. At 24 hours, the reduction in PCWP was greater in the nesiritide group (-8.2 mm Hg) than the nitroglycerin group (-6.3 mm Hg), but patients reported no significant differences in dyspnea and only modest improvement in global clinical status. CONCLUSION: When added to standard care in patients hospitalized with acutely decompensated CHF, nesiritide improves hemodynamic function and some self-reported symptoms more effectively than intravenous nitroglycerin or placebo.

Analysis of Variance↗
PubMed1983

Pharmacokinetics and bioavailability of intravenous and topical nitroglycerin in the rhesus monkey: estimate of percutaneous first-pass metabolism.

[14C]Nitroglycerin was administered intravenously and topically to three rhesus monkeys and the pharmacokinetics were determined. The rhesus monkey is an animal model for which percutaneous absorption is similar to that in the human. After intravenous administration the decline in plasma nitroglycerin concentration was biexponential with an initial half-life of 0.8 min (2-5 min postadministration) and a terminal half-life of 18 min (5-60 min postadministration). After topical application in an ointment, plasma concentrations of unchanged nitroglycerin were first detectable at 0.25 hr postapplication. Peak plasma nitroglycerin concentrations occurred between 4-6 hr, and nitroglycerin was still detectable at 24 hr postapplication. Plasma levels fit a biexponential curve with an alpha-phase half-life of 3.0 hr, a beta-phase half-life of 4.3 hr, and a lag time of 0.5 hr. The absolute bioavailability of topical nitroglycerin was 56.6 +/- 5.8%. The differences in bioavailability estimates between unchanged nitroglycerin and total carbon-14 is considered to be the amount of nitroglycerin which is metabolized as it is absorbed through the skin (percutaneous first-pass effect). This value for topical nitroglycerin was quite small, only 16-21% depending on the method of comparison.

Animals↗
PubMed1991

Buccal versus intravenous nitroglycerin in unstable angina pectoris.

The clinical syndrome of unstable angina includes patients with the first onset of angina, change in a previous stable pattern or the development of chest pain at rest. Administration of intravenous nitroglycerin is established therapy in unstable angina. Buccal nitroglycerin has been introduced as an alternative means of administering nitroglycerin, which provides relief of anginal pain within 2 to 3 min and a sustained effect for 3 to 5 h. Twenty-nine patients admitted to the coronary care unit due to unstable angina were randomized to receive treatment with nitroglycerin i.v. for 24 h or buccal nitroglycerin every 4 h. Therapy was titrated according to haemodynamic effects. The mean dose of buccal nitroglycerin was 4.42 mg versus 0.45 micrograms.kg-1.min-1 in the intravenous group. The efficacy of treatment was similar in the two groups. Buccal nitroglycerin appeared to cause fewer adverse effects, especially less haemodynamic intolerance and headache, although the differences were not significant. Repeated administration of buccal nitroglycerin appears to be a safe and well tolerated alternative to high-dose i.v. nitroglycerin treatment in unstable angina pectoris.

Administration, Buccal↗
PubMed1984

Variable effects of intracoronary nitroglycerin on myocardial blood flow and segmental shortening according to dose and degree of coronary occlusion.

The effects of intracoronary nitroglycerin were determined in 21 open-chest dogs. Six dogs with severe stenosis (25 mm Hg diastolic perfusion pressure) and nine dogs with moderate stenosis (40 mm Hg) received a 12 micrograms bolus followed by 44 micrograms/min intracoronary nitroglycerin. In addition, six dogs with moderate stenosis (40 mm Hg) received 5 micrograms followed by 5 micrograms/min nitroglycerin. Myocardial blood flow was measured with radioactive microspheres and segment shortening with ultrasonic crystals. At 40 mm Hg, high-dose but not low-dose nitroglycerin raised epicardial blood flow, while at 25 mm Hg nitroglycerin had no effect. Subendocardial blood flow was not affected in any group. Partial occlusion resulted in a decrease in segment shortening in the 25 mm Hg group but not at 40 mm Hg. High-dose nitroglycerin had no effect on shortening at either level of occlusion. Thus, in the presence of coronary vascular reserve, high-dose nitroglycerin may overcome coronary autoregulation. A dose equivalent to one that simulates the amount of nitroglycerin delivered to the coronary circulation by a systemic infusion did not affect myocardial blood flow. In addition, even a large dose of nitroglycerin did not affect segment shortening.

Animals↗
PubMed1985

Incomplete and delayed bioavailability of sublingual nitroglycerin.

Eight healthy male volunteers received 16 doses of sublingual nitroglycerin tablets (0.4 mg). After 8 minutes, each subject rinsed out his mouth to halt the drug absorption process. The mouth rinses were assayed by high-performance liquid chromatography for residual nitroglycerin content. Each subject also received intravenous infusions of nitroglycerin so that the absolute bioavailability could be evaluated. Plasma nitroglycerin concentrations were determined using a specific and sensitive capillary gas chromatographic method capable of quantifying 25 pg/ml of nitroglycerin. The mean bioavailability (+/- standard deviation) of sublingual nitroglycerin, estimated from plasma concentrations, was 36.2 +/- 24.9% (range 2.6 to 113%). The amount of drug not absorbed after 8 minutes, as determined from the analysis of the mouth rinses, varied from 2.7 to 65.8% (mean 31.4 +/- 18.9%) of the administered sublingual dose. Mean nitroglycerin peak concentrations of 1.89 +/- 1.64 ng/ml were obtained at a mean peak time of 5.3 +/- 2.3 minutes. Thus, sublingual absorption is not instantaneous and can be relatively slow, with peak times of as long as 10 minutes. These data indicate that nitroglycerin pharmacokinetic values should not be estimated only from sublingual doses. Additionally, attempts to correlate pharmacodynamic measurements to sublingual doses must take into account the low and variable bioavailability and the potentially long peak times after sublingual nitroglycerin administration to patients.

Administration, Oral↗
PubMed1988

Reduced thiols and the effect of intravenous nitroglycerin on platelet aggregation.

Nitroglycerin inhibits platelet aggregation in vitro and this effect may be important in its overall mechanism of action. In addition, its use has been associated with prolonged bleeding times and hemorrhagic complications. Despite these experimental and clinical observations, no significant antiplatelet effect of nitroglycerin has been observed ex vivo during intravenous nitroglycerin administration to patients. Because the in vitro antiplatelet effects of nitroglycerin have been shown by one of the investigators participating in this study to depend on the presence of sufficient stores of reduced intracellular thiol--which are readily depleted ex vivo by nitroglycerin in the formation of S-nitrosothiols--an attempt was made to unmask nitroglycerin-mediated inhibition of platelet aggregation by exposing platelets taken from patients treated with nitroglycerin to the reduced thiol N-acetylcysteine ex vivo. The obtained data demonstrate that platelets taken from patients treated with intravenous nitroglycerin manifest attenuated aggregation responses ex vivo when thiol stores are repleted. It is therefore proposed that the mechanism of action of nitroglycerin is mediated in part by its antiplatelet effect and that this effect depends on the adequacy of reduced intracellular thiol stores.

Acetylcysteine↗
PubMed1986

Desensitization to nitroglycerin in vascular smooth muscle from rat and human.

Guanylate cyclase in high speed supernatant fractions obtained from rat thoracic aorta or human coronary arteries pretreated with nitroglycerin exhibited a marked desensitization to activation by nitroglycerin, nitroprusside, and nitric oxide. However, activation of soluble guanylate cyclase by arachidonic acid was unaffected by pretreatment of vessels with nitroglycerin. Furthermore, activation of soluble guanylate cyclase by protoporphyrin IX was increased 4-fold when vessels were pretreated with nitroglycerin. Soluble guanylate cyclase partially purified from nitroglycerin-pretreated rat thoracic aorta by immunoprecipitation with a specific monoclonal antibody exhibited persistent desensitization to nitrate-induced activation. These data suggest that nitroglycerin-induced desensitization of guanylate cyclase to activation by nitrovasodilators represents a stable alteration of the enzyme. In contrast, activation by protoporphyrin IX of guanylate cyclase immunoprecipitated from nitroglycerin-pretreated or control vessels was not significantly different. This suggests that the mechanism of protoporphyrin activation of guanylate cyclase is different than the mechanism with nitrovasodilators. Activation of particulate guanylate cyclase by Lubrol-PX, hemin, or atrial natriuretic factor was not significantly different with enzyme prepared from nitroglycerin-pretreated or control vessels from rat and human. Thus, nitroglycerin-induced desensitization of rat thoracic aorta or human coronary artery results in a relatively stable molecular alteration of soluble guanylate cyclase such that the enzyme is specifically less sensitive to activation by nitrovasodilators whereas the effects of other activators of the enzyme are either unchanged or increased.

Animals↗
PubMed1996

Zaprinast, but not dipyridamole, reverses hemodynamic tolerance to nitroglycerin in vivo.

Hemodynamic tolerance to nitroglycerin was developed in spontaneously hypertensive rats following 2-3 days of pretreatment with 100 mg/kg of nitroglycerin administered s.c. 3 times/day. Tolerance was evaluated both in vivo, by administering ascending bolus doses of nitroglycerin of 1-300 micrograms/kg i.v., and ex vivo in isolated, denuded aortic vascular rings by exposure to ascending concentrations of nitroglycerin of 0.0003-100 microM. Tolerance was observed as a significant blunting of the hypotensive and vasorelaxant effect of nitroglycerin. Co-incubation of tolerant aortic rings and pretreatment of tolerant SHR with 10 microM and 0.1-10 mg/kg zaprinast, respectively, resulted in full restoration of the vasorelaxant and hypotensive effect of nitroglycerin. Zaprinast partially reversed hemodynamic tolerance at 0.01 mg/kg. Conversely, dipyridamole (10 microM) reversed tolerance ex vivo, but was ineffective in reversing tolerance in vivo at pretreatment doses of 30 and 60 mg/kg. Following a 100-micrograms/kg i.v. challenge dose of nitroglycerin, aortic cyclic guanosine monophosphate (cGMP) levels were lower in nitroglycerin tolerant SHR when compared to non-tolerant SHR. Pretreatment of tolerant SHR with 10 mg/kg zaprinast restored the increase in cGMP levels to nitroglycerin to that seen in non-tolerant SHR. Conversely, dipyridamole (30 mg/kg) pretreatment was not effective in restoring cGMP levels. These data therefore suggest that reversal of hemodynamic tolerance in vivo is related to restoration of changes in vascular cGMP levels. Zaprinast, a selective cGMP phosphodiesterase inhibitor, effectively reverses tolerance and dipyridamole, a rather non-selective inhibitor, does not.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1995

Beneficial cumulative role of both nitroglycerin and dobutamine on right ventricular systolic function in congestive heart failure patients awaiting heart transplantation.

End-stage idiopathic dilated cardiomyopathy or ischemic heart disease usually present with very low cardiac output and severe ventricular dysfunction which may require pharmacological support before heart transplantation. Right ventricular ejection fraction might be an important factor of functional capacity and survival in congestive heart failure. In order to test the immediate response of right ventricular hemodynamic parameters to nitroglycerin and dobutamine usually used to treat severe left ventricular dysfunction, we studied 17 congestive heart failure patients (15 men, two women; mean age 55 +/- 13 years) with end-stage idiopathic dilated cardiomyopathy (n = 10) or end-stage ischemic heart disease (n = 7), left ventricular ejection fraction < 35% (mean 22 +/- 8%), and sinus rhythm. A well validated thermodilution technique using a dedicated catheter with a fast catheter-computer response, permitting instantaneous measurements of right ventricular ejection fraction, was used. Right ventricular hemodynamic parameters were recorded at baseline, after an intravenous bolus injection of 3 mg nitroglycerin and after an intravenous infusion of dobutamine administered after nitroglycerin until normalization of cardiac index or a maximal dose of 15 micrograms/kg/min. Pulmonary artery mean pressure significantly decreased after nitroglycerin (43 +/- 9 mmHg at baseline vs. 31 +/- 10 mmHg after nitroglycerin, P < 0.0001) and did not subsequently change after dobutamine (32 +/- 10 mmHg after dobutamine, ns). Cardiac index was not affected by nitroglycerin (1.7 +/- 0. l/min/m2 at baseline vs. 2.0 +/- 0.3 l/min/m2 after nitroglycerin, ns), but dramatically increased after dobutamine (3.0 +/- 1.0 l/min/m2 after dobutamine, P < 0.0001). Concomitantly to the changes of these two parameters, right ventricular ejection fraction progressively increased (14 +/- 8% at baseline vs. 20 +/- 10% after nitroglycerin (P < 0.0006) vs. 28 +/- 13% after dobutamine (P < 0.0001)). Progressive increase of right ventricular ejection fraction after administration of nitroglycerin followed by administration of dobutamine suggests the beneficial cumulative role of both medications on right ventricular systolic function in severe congestive heart failure.

Cardiomyopathy, Dilated↗
PubMed1998

Use of sublingual nitroglycerin during head-up tilt-table testing in patients >60 years of age.

Previous work had demonstrated a reduced specificity associated with head-up tilt protocols using high-dose isoproterenol in patients between 20 and 50 years of age. We evaluated the specificity of head-up tilt testing using different isoproterenol infusion doses and administration of nitroglycerin in patients aged >60 years. In addition, whether the same protocols have impact on the sensitivity of the test was also assessed. One hundred sixty subjects were included in this study. Seventy-six were volunteers randomized to either head-up tilt test with low-dose, 3- and 5-microg/min of isoproterenol (group I) or to a protocol including 0.4 mg of sublingual nitroglycerin (group II). In addition, after an upright tilt drug-free state, 58 patients with a history of syncope underwent repeat head-up tilt with increasing doses of isoproterenol infusion, followed by sublingual nitroglycerin if the test result remained negative. The remaining 33 patients were subjected to the nitroglycerin protocol after the drug-free state phase. In the control groups, the incidence of false-positive responses was 88% and 95%, respectively. In patients with syncope after a negative test result during 5 microg of isoproterenol infusion, nitroglycerin administration increased the number of positive responses from 45% to 79%. The percentage of positive tilt in patients undergoing nitroglycerin administration after the drug-free state part of the protocol was 78%. Administration of nitroglycerin was the most significant predictor of a positive upright tilt in patients with syncope. In subjects aged >60 years, head-up tilt protocols with high-dose isoproterenol infusion and nitroglycerin maintained an adequate specificity. In this subset of patients, nitroglycerin seemed to provide a better sensitivity than isoproterenol.

Administration, Sublingual↗
PubMed2003

Venous response to nitroglycerin is enhanced in young, healthy carriers of the 825T allele of the G protein beta3 subunit gene (GNB3).

OBJECTIVE: The ultimate mode of action by which nitroglycerin elicits vasodilation remains elusive. Animal studies point to an involvement of pertussis toxin-sensitive G proteins. The 825T allele of the GNB3 C825T polymorphism in the gene encoding the G protein beta3 subunit is associated with enhanced signal transduction via pertussis toxin-sensitive pathways in vitro. We hypothesized that G proteins have a role in nitroglycerin-mediated vasodilation and that carriers of the 825T allele would exhibit a stronger response to nitroglycerin. METHODS: We used the linear variable transducer technique to compare dorsal hand vein compliance in 28 young, healthy men with and without the T allele (n = 15 CC, n = 8 CT, and n = 5 TT). After individual dose-response curves to phenylephrine had been established, veins were preconstricted to 70% of the maximal phenylephrine-induced constriction. Nitroglycerin was then infused in ascending doses (0.02-2000 ng/min), and the vasodilatory response was measured. RESULTS: The vasodilatory response to nitroglycerin was significantly greater in carriers of the 825T allele. The maximal response to nitroglycerin was 102% +/- 6% venodilation in the CT/TT group and 78% +/- 5% in the CC control group (P =.0045) (mean difference, -24% +/- 8%; 95% confidence interval, 8%-40%). Comparison of the nitroglycerin dose-response curves by ANOVA confirmed an enhanced nitroglycerin-induced venodilation in 825T-allele carriers (P <.0001). CONCLUSION: Our results suggest that the GNB3 C825T polymorphism determines venous response to nitroglycerin and that G proteins may be involved in the signal transduction pathway.

Adult↗
PubMed1997

Lack of cross-tolerance to short-term linsidomine in forearm resistance vessels and dorsal hand veins in subjects with nitroglycerin tolerance.

BACKGROUND: Therapy with nitroglycerin is widely used in the treatment of angina pectoris, but development of tolerance is a major problem. Nitrovasodilators other than nitroglycerin may be less prone to induce vascular tolerance. This investigation was designed to test whether the alternative nitric oxide donor linsidomine maintains its vasodilator effects in the presence of nitroglycerin tolerance. METHODS: We tested the vascular effects of nitroglycerin and linsidomine (SIN-1) in forearm resistance arteries (venous occlusion plethysmography) and hand veins (venous compliance technique) using a randomized, double-blind placebo-controlled regimen in 33 healthy subjects (age range, 22 to 38 years; mean age, 26 years) before and after 7 days of assignment to either 1 week of nitroglycerin administration (0.83 mg/hr) for induction of tolerance or placebo administration. RESULTS: Vascular responses of both vascular beds to nitroglycerin (in veins: mean difference, 42.3%; confidence interval [CI], 3% to 81.7%; p < 0.05; in arteries: mean difference, 65.0%; CI, 38.9% to 91.1%; p < 0.01) but not to linsidomine (in veins: mean difference, -13.8%; CI, -53.5 to 25.8%; not significant; in arteries: -19.7%; CI, -33.7% to -5.6%; not significant) were attenuated in the nitroglycerin patch group, whereas the placebo group showed no differences to either nitroglycerin (in arteries: mean difference, -7.5%; CI, -44.6% to 29.6%; in veins: -10.6%; CI, -58.2% to 36.9%) or linsidomine (in arteries: 4.5%; CI, -12.8% to 21.7%; in veins: -13.1%; CI, -4.5% to 29.8%). CONCLUSION: These results suggest that short-term administration of sydnonimines can overcome the loss of vascular relaxation associated with long-term nitroglycerin therapy.

Adult↗
PubMed2001

Tetrahydrobiopterin improves endothelium-dependent vasodilation in nitroglycerin-tolerant rats.

Tolerance to nitroglycerin is caused by a nitroglycerin-mediated increase in vascular superoxide anion production. Administration of tetrahydrobiopterin (co-factor for endogenous nitric oxide (NO) formation) may potentially influence nitroglycerin tolerance in at least two different ways. Firstly, tetrahydrobiopterin may act as a scavenger of the nitroglycerin-mediated production of superoxide anions. Secondly, tetrahydrobiopterin may protect endothelial NO synthesis from the deleterious effects of increased oxidative stress. This study investigates whether in vivo nitroglycerin tolerance is affected by tetrahydrobiopterin supplementation and assesses the in vivo role of tetrahydrobiopterin in endogenous NO-mediated vasodilation in normal and nitroglycerin-tolerant rats. The results show that tetrahydrobiopterin does not affect nitroglycerin-derived, NO-mediated vasodilation, but reduces baseline mean arterial blood pressure (by 8 mm Hg, P<0.05) and normalizes endothelium-dependent responses to N(G)-monomethyl-L-arginine (L-NMMA) (from 7+/-1 to 22+/-4 mm Hg, P<0.05) in nitroglycerin-tolerant rats. It is concluded that altered bioavailability of tetrahydrobiopterin is involved in the pathophysiology of endothelial dysfunction seen in nitroglycerin tolerance.

Animals↗
PubMed1999

The cardioprotective effects of nitroglycerin-induced preconditioning are mediated by calcitonin gene-related peptide.

Previous investigations have shown that endogenous calcitonin gene-related peptide (CGRP) may play an important role in the mediation of ischemic preconditioning and that nitroglycerin evokes the release of CGRP. In the present study, we examined whether nitroglycerin provides a preconditioning stimulus, and whether the cardioprotective effects of nitroglycerin-induced preconditioning involve endogenous CGRP. Thirty minutes of global ischemia and 30 min of reperfusion caused a significant impairment of cardiac contractile function and an increased release of creatine kinase. Pretreatment with nitroglycerin at the concentration of 3x10(-7) or 10(-6) M for 5 min produced a significant improvement of cardiac function and a decrease in the release of creatine kinase. The content of CGRP-like immunoreactivity in coronary effluent was increased during nitroglycerin perfusion. However, the cardioprotection afforded by nitroglycerin was abolished by CGRP-(8-37) (10(-7) M), a selective CGRP receptor antagonist. Pretreatment with capsaicin (50 mg/kg, s.c.), which specifically depletes the transmitter content of sensory nerves, also abolished the protective effects of nitroglycerin and markedly reduced the release of CGRP from the heart during nitroglycerin perfusion. These findings suggest that nitroglycerin-induced preconditioning is related to stimulation of CGRP release in rat hearts.

Animals↗