[Methemoglobin formation in nitroglycerin infusions. Remarks on the work of The, G.S., G. Spring: Nitroglycerin poisoning after controlled hypotension].
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Humans↗
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Proceedings: Nitroglycerin and nitroglycerin-phenylephrine-induced reduction in ischaemia during acute myocardial infarction in man.
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Drug Therapy, Combination↗
Stability of nitroglycerin as nitroglycerin concentrate for injection stored in plastic syringes.
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Drug Stability↗
Buccal versus sublingual nitroglycerin administration in the treatment of angina pectoris: a multicentre study.
Buccal (Suscard) was compared with sublingual nitroglycerin (Nitromex) in 126 patients with stable angina pectoris. Following a dose adjustment period they were randomized to cross-over treatment, two weeks on sublingual and buccal nitroglycerin, respectively. The dosage of buccal nitroglycerin was 2.5 mg in 49% and 5.0 mg in 51%. The total number of treated acute anginal attacks was 31% less during the buccal compared to the sublingual nitroglycerin period (P less than 0.001) despite a reported physical activity level which was significantly higher during the buccal nitroglycerin period. The use of sublingual nitroglycerin and buccal nitroglycerin was considered equally simple by 67%, sublingual nitroglycerin easier by 19% and buccal nitroglycerin easier by 14% of the patients. Sublingual nitroglycerin was used prophylactically on 806 occasions and buccal nitroglycerin on 929 occasions (P less than 0.05) with success in 66% of the sublingual nitroglycerin-attempts and 74% of the buccal nitroglycerin-attempts (P less than 0.05). Considering only prophylactic use, buccal nitroglycerin was preferred by 81% and sublingual nitroglycerin by 4% (P less than 0.05). When given the opportunity only to select one of the two nitroglycerin formulations, 65% (P less than 0.05) preferred buccal nitroglycerin and 19% sublingual nitroglycerin. In conclusion, buccal nitroglycerin seems to be more efficacious than sublingual nitroglycerin. The explanation is probably that the two formulations are comparable in the treatment of acute anginal attacks, while buccal nitroglycerin has a more pronounced prophylactic effect due to its longer duration of action.
Administration, Buccal↗
Altered peripheral vasodilator profile of nitroglycerin during long-term infusion of N-acetylcysteine.
OBJECTIVES: The aim of this study was to compare the short- and long-term effects of intravenous nitroglycerin plus placebo and nitroglycerin plus N-acetylcysteine on peripheral arteries, veins and microcirculation in humans. BACKGROUND: The thiol donor N-acetylcysteine may potentiate the hemodynamic response to nitrates in nitrate-tolerant and nontolerant patients. The vascular changes responsible for this effect are not clear. METHODS: Eight male volunteers were treated with nitroglycerin (0.1 microgram/kg per min) combined with N-acetylcysteine (2 g intravenously, followed by 5 mg/kg per h) or placebo for 23 h in a double-blind, randomized, crossover study. Venous volume, the diameter of the radial and temporal arteries, calf blood flow and subcutaneous blood flow were measured at baseline and repeated after 1 and 23 h of infusion. RESULTS: Prolonged coadministration of N-acetylcysteine and nitroglycerin potentiated the acute venodilator effect of nitroglycerin as estimated by changes in venous volume (nitroglycerin plus N-acetylcysteine, 4.45 +/- 0.36 ml/100 g; nitroglycerin plus placebo, 3.65 +/- 0.46 ml/100 g, mean +/- SEM, p < 0.05) and prevented development of tolerance as seen after 23 h of treatment with nitroglycerin plus placebo (4.35 +/- 0.25 vs. 3.47 +/- 0.41 ml/100 g, p < 0.05). N-acetylcysteine had no effect on nitroglycerin-induced changes in arterial diameters (p > 0.05) but significantly increased microcirculatory subcutaneous blood flow after 1 h (nitroglycerin plus N-acetylcysteine: 6.3 +/- 1.3 ml/100 g per min vs. nitroglycerin plus placebo: 3.5 +/- 0.3 ml/100 g per min, p < 0.05) and after 23 h (4.4 +/- 0.6 vs. 3.1 +/- 0.5 ml/100 g per min, p < 0.05). CONCLUSIONS: The results suggest that coadministration of nitroglycerin and N-acetylcysteine in humans 1) potentiates and preserves nitroglycerin-induced venodilation and 2) augments the effect of nitroglycerin on small resistance vessels (regulating subcutaneous blood flow) without affecting the response to nitroglycerin in middle-sized arteries. Both the development of nitrate tolerance and the administration of N-acetylcysteine significantly change the normal vasodilator profile of nitroglycerin in humans.
Acetylcysteine↗
Dissociation of coronary vascular tolerance and neurohormonal adjustments during long-term nitroglycerin therapy in patients with stable coronary artery disease.
OBJECTIVES: We sought to examine whether long-term nitroglycerin treatment causes tolerance in large coronary arteries and whether the loss of vascular effects parallels neurohormonal adjustments. BACKGROUND: Nitroglycerin therapy is associated with increased plasma renin activity and aldosterone levels and a decrease in hematocrit. It is assumed that nitroglycerin tolerance results in part from these neurohormonal adjustments and intravascular volume expansion. METHODS: Three groups were studied: group I (n = 10), no prior nitroglycerin therapy; and group II (n = 10) and group III (n = 8), 24- and 72-h long-term nitroglycerin infusion (0.5 micrograms/kg body weight per min), respectively. Coronary artery dimensions were assessed using quantitative angiography. Plasma renin activity, plasma aldosterone and vasopressin levels and hematocrit were monitored before and during nitroglycerin infusions. RESULTS: In group I, increasing intravenous concentrations of nitroglycerin caused a dose-dependent increase of the midportion of the left anterior descending coronary artery (baseline diameter 2.13 +/- 0.07 mm [mean +/- SEM], maximally by 22 +/- 2%) and left circumflex coronary artery (baseline diameter 2.08 +/- 0.07) mm, maximally by 22 +/- 3%). An intracoronary nitroglycerin bolus (0.2 mg) caused no further significant increase in diameter, indicating maximal dilation. In group II (n = 10), the baseline large coronary artery diameter under ongoing nitroglycerin was significantly larger than that in group I (left anterior descending artery 2.61 +/- 0.08 mm, left circumflex artery 2.57 +/- 0.08 mm). Additional intravenous and intracoronary nitroglycerin challenges did not cause further dilation, indicating maximally dilated vessels. At the same time, plasma renin activity, plasma aldosterone and vasopressin levels were significantly increased, and hematocrit significantly decreased. In group III patients, the baseline diameter of the left anterior descending artery and the left circumflex artery did not differ from that in patients without nitroglycerin pretreatment, indicating a complete loss of nitroglycerin coronary vasodilative effects. These patients showed no significant increase in circulating neurohormonal levels but a significant decrease in hematocrit. CONCLUSIONS: Within 24 h of continuous nitroglycerin treatment, the coronary arteries were maximally dilated despite neurohormonal adjustments and signs of intravascular volume expansion. Within 3 days of nitroglycerin infusion, tolerance developed in the absence of neurohormonal activation. The dissociation of neurohormonal adjustments and tolerance in large coronary arteries indicates that after long-term nitroglycerin treatment, true vascular tolerance, perhaps from an intracellular tolerance step, may have developed.
Aldosterone↗
Mechanisms responsible for the heterogeneous coronary microvascular response to nitroglycerin.
Nitroglycerin dilates large (greater than or equal to 100 microns) but not small coronary arterial microvessels, and a putative metabolite of nitroglycerin, S-nitroso-L-cysteine, has been shown in vitro to dilate both large and small coronary microvessels. Based on this evidence, we tested the hypothesis that the lack of response of small coronary microvessels was due to an inability of small coronary microvessels to convert nitroglycerin into its vasoactive metabolite and examined possible explanations for this phenomenon. We studied left ventricular epicardial microvessels in vivo using video microscopy and stroboscopic epi-illumination in anesthetized, open-chest dogs. Diameters were determined while the epicardium was suffused with nitroglycerin, S-nitroso-L-cysteine, or S-nitroso-D-cysteine (all 10 microM) and nitroglycerin in the presence of L- or D-cysteine (100 microM). None of the agents affected systemic hemodynamics. Nitroglycerin dilated large arterioles (20 +/- 2%) but not small arterioles (1 +/- 1%). Both S-nitroso-L-cysteine and S-nitroso-D-cysteine were potent dilators of all size classes of microvessels. Concomitant application of L-cysteine and nitroglycerin evoked dilation in small microvessels (22 +/- 4%, p less than 0.5 versus nitroglycerin alone) and larger microvessels (27 +/- 6%, p = NS versus nitroglycerin alone). D-Cysteine did not alter the microvascular response to nitroglycerin in either small (7 +/- 4%, p = NS versus nitroglycerin alone) or large (18 +/- 3%, p = NS versus nitroglycerin alone) microvessels. Neither L-cysteine nor D-cysteine had a direct effect on microvascular diameter. These findings suggest that 1) sulfhydryl groups are required for the conversion of nitroglycerin to its vasoactive metabolite; 2) the interaction between nitroglycerin and sulfhydryl residues is a stereospecific process, indicating either an intracellular mechanism or a membrane-associated enzymatic reaction; and 3) a lack of available sulfhydryl groups may be responsible for the lack of response of small coronary arterioles to nitroglycerin.
Analysis of Variance↗
Captopril potentiates the effects of nitroglycerin in the coronary vascular bed.
OBJECTIVES: This study was designed to examine the effects of captopril on the coronary vascular responses to nitroglycerin. BACKGROUND: The vasodilator effects of nitroglycerin are mediated by sulfhydryl-dependent bioconversion and influenced by local and systemic neural and hormonal counter-regulatory factors. METHODS: In patients with angina pectoris, the effects of 10 days of treatment with the sulfhydryl-containing angiotensin-converting enzyme inhibitor captopril on the coronary vasodilator responses to intracoronary nitroglycerin (1- to 20-micrograms doses) were examined utilizing a double-blind, placebo-controlled, randomized design. The effects of captopril on the induction of nitroglycerin tolerance were also examined after a 20-h intravenous infusion of nitroglycerin. RESULTS: Captopril reduced mean arterial pressure at rest by 8 mm Hg compared with 3 mm Hg in the placebo group (p = NS) and did not affect baseline coronary blood flow (168 vs. 144 ml/min in the placebo group, standard error of the differences of means (SED) 26) or coronary vascular resistance (53 vs. 57 dynes.s.cm-5, SED 9). Intracoronary nitroglycerin increased coronary blood flow in a dose-dependent fashion in both the captopril and placebo groups (p < 0.001). However, captopril potentiated the effects of all doses of nitroglycerin and shifted the dose-response relationship to the left (p < 0.001). At the maximal dose of 20 micrograms, intracoronary nitroglycerin increased the coronary blood flow by a further 60% in the captopril group compared with placebo. After 20 h of intravenous nitroglycerin (24 +/- 3 micrograms/min), the coronary vasodilator responses to intracoronary nitroglycerin were attenuated (p < 0.02) in the placebo group. However, the responses to intracoronary nitroglycerin in the captopril group, remained similar to the responses observed before intravenous nitroglycerin exposure. CONCLUSIONS: Captopril potentiates the coronary vasodilator responses of nitroglycerin in both the absence and the presence of nitroglycerin tolerance. The mechanisms and therapeutic implications of this interaction require further exploration.
Aged↗
Nitroglycerin to facilitate fetal extraction during cesarean delivery.
OBJECTIVE: To determine the efficacy of nitroglycerin in easing fetal extraction in elective cesarean deliveries in comparison with placebo and to collect maternal and fetal pharmacologic data after administration of nitroglycerin. METHODS: This randomized, double-blind clinical and descriptive pharmacokinetic study was carried out at the gynecology departments at Virchow Hospital and Charité Hospital (both university hospitals of Humboldt University, Berlin, Germany) between June 1994 and July 1996 in patients scheduled for elective cesarean delivery under general anesthesia. At the time of the uterine puncture incision, either 0.25 mg or 0.5 mg of nitroglycerin or a physiologic saline solution was administered as an intravenous bolus. Intraoperatively, maternal and neonatal pulse rates and blood pressure were monitored closely. The surgeons estimated reduction in uterine tone and the ease of fetal extraction by means of defined scales. Plasma concentrations of nitroglycerin and its metabolites were measured in maternal venous blood and from umbilical blood. RESULTS: Ninety-seven patients were included in the statistical evaluation of the study; 32 received 0.25 mg of nitroglycerin, 34 received 0.5 mg of nitroglycerin, and 31 received placebo. The evaluation of the surgeons' estimation revealed no significant difference in ease of fetal extraction (statistical power 0.7) and no significant reduction in uterine tone under treatment with both nitroglycerin dosages in comparison with placebo. Only substance-specific maternal side effects were noted. The neonates' conditions were not affected by administration of nitroglycerin. The median fetal-maternal ratio of venous nitroglycerin plasma levels was approximately 1:400 in the 0.25-mg nitroglycerin group and 1:160 in the 0.5-mg nitroglycerin group. Approximately 11-12 times more nitroglycerin was detected in the venous umbilical branch than in the arterial branch. CONCLUSION: Administration of nitroglycerin leads to no clinically relevant easing of fetal extraction, at least not in elective cesarean deliveries after the 34th week of gestation. With regard to pharmacokinetics, the measured median fetal-maternal venous nitroglycerin concentration was 1:400 in the 0.25-mg group and 1:160 in the 0.5-mg group.
Adult↗
N-acetylcysteine does not modify nitroglycerin-induced tolerance in canine vascular rings.
The mechanism whereby nitroglycerin initiates relaxation in vascular smooth muscle remains unclear. One hypothesis states that nitroglycerin oxidizes critical sulfhydryl groups in smooth muscle to initiate relaxation, and that repeated exposure to nitroglycerin results in tolerance. In the current study, N-acetylcysteine, a sulfhydryl-reducing agent, was used to explore the sulfhydryl hypothesis by assessing whether or not tolerance to nitroglycerin was reversed by N-acetylcysteine in canine dorsal pedal artery rings. Two nitroglycerin dose-response curves were performed (n = 18)--one before (1st dose-response curve, from 10(-9) to 1.1 X 10(-5) M nitroglycerin) and one after (2nd dose-response curve, from 10(-9) to 5 X 10(-7) M nitroglycerin) incubation with 10(-5) M nitroglycerin for 105 min. At 5 X 10(-7) M nitroglycerin there was 50.7 +/- 10.0% relaxation during the first dose-response curve. During the second dose-response curve, tolerance to nitroglycerin was evident, as demonstrated by a 6.8 +/- 4.8% relaxation (p less than 0.001) at 5 X 10(-7) M nitroglycerin. A 10-min treatment with 10(-3) M N-acetylcysteine (n = 10) during the second nitroglycerin dose-response curve was performed after the 5 X 10(-7) M concentration of nitroglycerin; the second dose-response curve was then completed up to 1.1 X 10(-5) M nitroglycerin. The dose of 10(-3) M N-acetylcysteine was chosen since higher concentrations (i.e., 1.3 X 10(-2) and 1.2 X 10(-1) M N-acetylcysteine) produced 20.3 +/- 8.4 and 43.6 +/- 11.6% relaxation in vascular rings (n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)
Acetylcysteine↗
Effects of inhalation of nitroglycerin on hypoxic pulmonary vasoconstriction.
Recent studies suggest that nitric oxide (NO) may play an important role in the pathophysiology of pulmonary hypertension. Nitroglycerin is metabolized to NO, which is a potent vascular smooth muscle relaxant. The aim of the present study was to compare the effects of inhaled and infused nitroglycerin on pulmonary hemodynamics and gas exchange in anesthetized, artificially ventilated dogs. Nitroglycerin was administrated either by inhalation or by infusion. Systemic blood pressure (SBP), pulmonary arterial pressure (PAP), and pulmonary capillary wedge pressure (PCWP) were measured, and cardiac output was estimated by an electromagnetic flowmeter. Blood gas measurements were performed during hypoxic gas exposure (FiO2; 0.1) with a continuous inhalation or infusion of nitroglycerin (1, 2.5 micrograms/kg/min). Inhaled (n = 4) and infused (n = 4) nitroglycerin (1 microgram/kg/min) did not produce any detectable effects on the hemodynamics. Inhaled nitroglycerin (2.5 micrograms/kg/min) reduced SBP, PAP and calculated pulmonary vascular resistance (PVR) in all dogs. Cardiac output did not change. In addition, inhaled nitroglycerin increased PaO2. In contrast, the continuous infusion of nitroglycerin (2.5 micrograms/kg/min) did not change in PAP, whereas infused nitroglycerin decreased the mean SBP. Infused nitroglycerin did not alter cardiac output and calculated PVR. A decreased PaO2 was noted in 2 dogs on nitroglycerin infusion. These findings indicate that inhaled nitroglycerin effects the pulmonary circulation relatively more than infused nitroglycerin, which tends to have more of a general effect on the systemic circulation. The effects of inhaled nitroglycerin may thus be comparable to the effects of NO inhalation.
Administration, Inhalation↗
Pharmacokinetic-hemodynamic studies of transdermal nitroglycerin in congestive heart failure.
Ten patients with chronic congestive heart failure were studied to assess the hemodynamic effects and bioavailability of a transdermal nitroglycerin delivery system. Nitrate sensitivity was defined by a prior 20 minute infusion of nitroglycerin, 21 micrograms/min. Five patients with a satisfactory hemodynamic response to intravenous nitroglycerin received two nitroglycerin patches of 10 cm2 each and five patients who did not achieve a satisfactory response to intravenous nitroglycerin (that is, greater than or equal to 25% reduction in left ventricular filling pressure) received larger doses of transdermal nitroglycerin. In the five nitrate-sensitive patients who received 20 cm2 of transdermal nitroglycerin, one study was terminated at 90 minutes, at which point there was no detectable hemodynamic response or arterial plasma nitroglycerin evident. Two patients had a minimal hemodynamic response and a peak plasma concentration of 1 ng/ml. A fourth patient had a short-lived hemodynamic response at 60 and 120 minutes and a plasma nitroglycerin concentration of 1 ng/ml at 60 minutes. A fifth patient had a hemodynamic response persisting for 24 hours and plasma concentrations between 0.6 and 1.1 ng/ml. The remaining five patients showed little or no hemodynamic response despite doses of transdermal nitroglycerin from 40 to 60 cm2. The highest plasma concentration achieved in these patients was 2 ng/ml and there was no relation between dose administered and plasma concentration achieved. In 4 of the 10 patients who subsequently received nitroglycerin ointment, there were a greater decrease in left- and right-sided filling pressures and greater increase in plasma nitroglycerin concentrations (from 1.6 to 4.8 ng/ml) than those that occurred with transdermal nitroglycerin.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Cutaneous↗
Interpretation of nitrate plasma concentrations. Effect of cardiac output on nitroglycerin pharmacokinetics in experimental animals.
We tested the hypothesis that the pharmacokinetics of nitroglycerin might be governed by haemodynamics, viz: cardiac output. The steady state pharmacokinetics of nitroglycerin, both in arterial and in venous plasma, were investigated in 11 rats after sequential infusions either of nitroglycerin alone (10 micrograms kg-1 min-1) or of nitroglycerin plus vasopressin (the latter at 5.5 mU kg-1 min-1). Cardiac output was estimated twice in each animal using 85Sr and 141Ce microspheres. Nitroglycerin systemic clearance in arterial plasma was found to be correlated strongly with cardiac output (r = 0.784, N = 22, P less than 0.001). Using the distribution ratio of nitroglycerin between red blood cells and plasma, we determined the systemic clearance of nitroglycerin in arterial blood to be about 3/4 of cardiac output. Vasopressin co-infusion decreased both the cardiac output and the arterial nitroglycerin clearance, but it also increased the arteriovenous extraction of nitroglycerin. Thus, vasopressin had no net effect on the venous plasma clearance of nitroglycerin. In animals infused with nitroglycerin alone, cardiac output also significantly correlated with nitroglycerin venous plasma clearance (P less than 0.01) and arteriovenous extraction (P less than 0.05). These data indicate that haemodynamic alterations may have profound effects on the observed plasma concentrations of nitroglycerin. These parameters need to be standardized and controlled if meaningful plasma concentrations of organic nitrates are to be obtained and interpreted.
Animals↗
Nitroglycerin-induced release of calcitonin gene-related peptide from sensory nerves attenuates the development of nitrate tolerance.
The present study was designed to determine if endogenous calcitonin gene-related peptide (CGRP) affects the process of nitrate tolerance development in blood vessels. Rat aortic rings were suspended in organ chambers and relaxations to nitroglycerin (10(-9) -10(-6) M) were obtained in nitrate tolerant and nontolerant rings contracted with norepinephrine (10(-7) M). Tolerance was induced by incubating the rings with (tolerant) or without (nontolerant) nitroglycerin (10(-4) M) for 90 minutes, followed by repeated rinsing for 1 hour. Some rings were treated with CGRP8-37 (10(-6) M), glyburide (10(-6) M), or iberiotoxin (10(-7) M) during the 90-minute desensitization period with nitroglycerin (10(-4) M), and were then washed out during the 1-hour rinsing period. Other rings were treated with capsaicin (10(-5) M) prior to the 90-minute desensitization period. Calcitonin gene-related peptide release was measured by radioimmunoassay. Relaxation to nitroglycerin was markedly reduced in tolerant rings, as compared with nontolerant. Incubation with CGRP8-37 (10(-6) M) specifically during the 90-minute desensitization period with nitroglycerin resulted in even greater impairment in the response to nitroglycerin in tolerant rings, even though the calcitonin gene-related peptide antagonist had been washed out before completion of the nitroglycerin dose-response curve. Similar results were obtained following depletion of calcitonin gene-related peptide stores in sensory nerves by treatment with capsaicin (10(-5) M) prior to the 90-minute desensitization period with nitroglycerin. Prior treatment with CGRP8-37 or capsaicin had no effect on the response to nitroglycerin in nontolerant rings. Incubation with glyburide (10(-6) M), but not iberiotoxin (10(-7) M), specifically during the 90-minute desensitization period, mimicked the effect of CGRP8-37 and capsaicin in tolerant rings, suggesting a role for KATP channels in the effect of calcitonin gene-related peptide. Nitroglycerin (10(-4) M) caused a greater than twofold increase over basal levels in calcitonin gene-related peptide release in nontolerant rings, which was abolished in rings treated with capsaicin and in nitrate tolerant rings. These results suggest that nitroglycerin releases calcitonin gene-related peptide from sensory nerves during the process of desensitization to nitrovasodilators, and that interference with either the release or action of endogenous calcitonin gene-related peptide during this period enhances the extent to which nitrate tolerance occurs. The finding that nitroglycerin-induced release of calcitonin gene-related peptide from sensory nerves attenuates the desensitizing effect of nitroglycerin represents a heretofore unknown event in the development of nitrate tolerance, and demonstrates a novel role for calcitonin gene-related peptide in the vasculature.
Animals↗
[Nitroglycerin and angina with angiographically normal coronary vessels. Clinical effects and effects on esophageal motility].
In order to determine whether the presence of a retrosternal pain sensitive to nitroglycerin is predictive of the finding of esophageal dyskinesia in patients with normal coronary angiography and negative methylergonovine test, we administered 0.8 mg of a nitroglycerin spray during esophageal manometry and after a methylergonovine or edrophonium provocation test. The effects of nitroglycerin on esophageal motility were recorded and compared with clinical data. Forty patients (21 men, 19 women, mean age 54 +/- 8 years) entered the study. In 22 of them (55 p. 100) the retrosternal pain was relieved by nitroglycerin within less than 5 minutes; the provocation test was positive in 10 cases (25 p. 100). In all patients nitroglycerin produced a highly significant decrease in the duration and amplitude of esophageal contractions. Among the 10 patients with esophageal dyskinesia, the duration of contractions was significantly more reduced (p less than 0.005) in those with nitroglycerin-sensitive pain (6 patients) than in those with nitroglycerin-resistant pain. These 6 patients, therefore, could be regarded clinically and manometrically as "responders" to nitroglycerin. Two of them had gastro-esophageal reflux. In contrast, among patients without induced esophageal dyskinesia the effects of nitroglycerin on manometry were the same irrespective of whether or not pain was usually relieved by nitroglycerin. The fact that pain was nitroglycerin-sensitive had no predictive value concerning the finding of esophageal dyskinesia by the provocation test (non-significant X2 test). We conclude that the clinical and manometric effects of nitroglycerin were concordant only in patients with induced esophageal dyskinesia; patients who responded to nitroglycerin could have a gastro-esophageal reflux.(ABSTRACT TRUNCATED AT 250 WORDS)
Angina Pectoris↗
Does alcohol intensify the hemodynamic effects of nitroglycerin?
To evaluate the combined effects of alcohol and nitroglycerin on cardiovascular hemodynamics, M-mode echocardiography and sphygmomanometric blood pressure measurements were performed on two groups of normal subjects, before and after the administration of nitroglycerin, both in the sober state and during alcohol intoxication. In the first part of the study, 0.5 mg of nitroglycerin was given sublingually to 10 healthy volunteers 5-10 minutes after they had ingested 1 g/kg body weight of ethanol within a 30-minute period. Control experiments substituted juice for ethanol. The combined effects of ethanol and nitroglycerin on left ventricular diameters, systolic blood pressure, and wall stress were not significantly different from those of juice and nitroglycerin; heart rate and diastolic blood pressure were increased more (p less than 0.01) by ethanol and nitroglycerin. In the second part of the study, 1.0 mg of nitroglycerin was administered to a second group of 10 healthy volunteers, first in the control state and again 60 minutes after the subjects had ingested 1 g/kg body weight of ethanol within a 60-minute period. Systolic blood pressure and wall stress were significantly lower (p less than 0.01) after ethanol and nitroglycerin than after nitroglycerin before ethanol intake. We conclude that the nitroglycerin-induced reductions in left ventricular preload and afterload are not increased by alcohol during the very early phase of intoxication. However, 1 hour or more after alcohol ingestion nitroglycerin may decrease left ventricular afterload to a level significantly lower than that seen after nitroglycerin in the sober state.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Dose dependent pharmacokinetics of nitroglycerin after multiple intravenous infusions in healthy volunteers.
Evaluation of the pharmacokinetics of nitroglycerin has been hindered in the past by the lack of specific and sensitive analytical procedures, and the unavailability of parenteral nitroglycerin and infusion sets which did not adsorb nitroglycerin. The purpose for this present study was to determine the pharmacokinetic parameters of nitroglycerin and the dinitrate metabolites after multiple intravenous infusions of nitroglycerin in healthy volunteers. Six volunteers received variable infusion rates of nitroglycerin. Generally, at 0, 40, 80, and 120 min, the infusion rates were adjusted to 10, 20, 40, and 10 micrograms/min, respectively. Plasma samples were drawn and analyzed for nitroglycerin and its 1,2- and 1,3-dinitrate metabolites using capillary GC. Steady-state nitroglycerin plasma concentrations attained at 10, 20, 40, and 10 micrograms/min were 0.44 +/- 0.31, 1.32 +/- 0.71, 4.23 +/- 1.50 and 1.04 +/- 0.43 ng/ml, respectively. As the infusion rate was increased, the steady-state concentrations increased disproportionately. When the dose was decreased from 40 to 10 micrograms/min, the steady-state nitroglycerin concentrations were always higher than those at the initial low infusion rate. Thus, in the majority of subjects, a hysteretic type of response was present. The hysteresis observed in the dose versus steady-state concentration curve may be explained by either end-product inhibition or saturable binding of nitroglycerin to blood vessels. The clearance values (5.5 to 711/min) were very high and far exceed the maximum possible hepatic clearance suggesting that nitroglycerin is metabolized by organs other than liver. Clearance was not directly related to plasma concentrations but was found to decrease to a constant value (approximately 11 +/- 6 l/min) as nitroglycerin concentrations initially increased.
Adsorption↗
Effect of therapy with an angiotensin-converting enzyme inhibitor on hemodynamic and counterregulatory responses during continuous therapy with nitroglycerin.
OBJECTIVES: We sought to characterize the reflex counterregulatory responses throughout a 6-day period of continuous nitroglycerin therapy and to examine the effect of concurrent administration of a non-thiol angiotensin-converting enzyme inhibitor (benazepril) on the nature of those responses. BACKGROUND: Therapy with nitroglycerin has been shown to be associated with reflex counterregulatory responses. METHODS: Standing systolic blood pressure, hormonal responses, urinary sodium and hematocrit levels were monitored during 6 days of continuous transdermal nitroglycerin therapy in normal volunteers. Using a double-blind randomized parallel design, 11 subjects received placebo and 9 received benazepril. Hemodynamic responses to sublingual nitroglycerin administration were evaluated before and after sustained therapy with transdermal nitroglycerin. RESULTS: Attenuation of the hypotensive response to transdermal nitroglycerin was rapid in the group receiving placebo and the group receiving benazepril. There were no significant hormonal responses to transdermal nitroglycerin in either group, and sodium retention was modest and transient. Hematocrit levels decreased after transdermal nitroglycerin therapy and remained depressed for the duration of nitroglycerin therapy, a finding that suggests plasma volume expansion. Blood pressure responses to sublingual nitroglycerin in both groups were similar before and after continuous transdermal nitroglycerin therapy. CONCLUSIONS: These data suggest that plasma volume expansion plays a more important role than neurohormonal responses in the loss of nitrate effects during sustained therapy. That therapy with an angiotensin-converting enzyme inhibitor did not modify the hemodynamic responses to continuous nitroglycerin therapy supports this conclusion. Further investigation will be necessary to confirm whether therapy with an angiotensin-converting enzyme inhibitor has any role in the prevention of nitrate tolerance.
Administration, Cutaneous↗