Action Of Nitroglycerin Research Articles

Bilateral action of nitroglycerin in coronary artery stenosis in dogs

Bilateral action of nitroglycerin in coronary artery stenosis in dogs

Direct evidence for nitric oxide formation from glyceryl trinitrate during incubation with intact bovine pulmonary artery.

It has been proposed that the mechanism of the vasodilator action of glyceryl trinitrate (GTN) involves biotransformation to nitric oxide. A sensitive chemiluminescence method for nitric oxide determination was used to test this hypothesis. In four experiments, bovine pulmonary artery (BPA) was incubated with GTN (0.1 mM) in Krebs' solution (2 mL) containing 30 mM KCl, and in anaerobic conditions using 95% Ar - 5% CO2, in a sealed micro-Fernbach flask (6.2-mL volume). After incubation for 2, 5, 10, or 20 min at 37 degrees C, 400-microL aliquots of headspace gas were removed and injected into a redox chemiluminescence detector. Nitric oxide formation was first measurable at 5 min (76 +/- 53 pmol/g wet wt. BPA), and increased with incubation time (174 +/- 46 pmol/g wet wt. BPA after 10 min and 310 +/- 67 pmol/g wet wt. BPA after 20 min). This is the first direct chemical measurement of nitric oxide formation during interaction of GTN with vascular smooth muscle. These data support the concept that GTN is a nitrovasodilator prodrug acting via the formation of nitric oxide.

Selected Issues From an Overview on Nicorandil

Nicorandil exerts its pharmacodynamic effects through two different modes of action: increase of cyclic GMP and activation of K+ channels of smooth muscle cells. The latter mechanism could explain the lack of development of tolerance that had been demonstrated clearly in various animal experiments. Therefore, it was attempted to elucidate this mechanism in humans. In 16 healthy subjects, the acute hemodynamic effects of a single oral dose of 40 mg nicorandil were compared with those of a single sublingual dose of 0.8 mg nitroglycerin. Thereafter, the subjects were treated with 30 mg isosorbide-5-mononitrate (IS-5-MN) slow release t.i.d. for 7 days to induce nitrate tolerance. Two hours after the last dose of IS-5-MN, hemodynamic measurements were repeated before and after administration of nicorandil and nitroglycerin, respectively. Recordings obtained from impedance cardiography and finger plethysmography as well as measurements of systolic time intervals provided evidence that nicorandil in the state of IS-5-MN tolerance continued to exert hemodynamic effects similar to those exerted after the first dose. The hemodynamic actions of nitroglycerin were no longer observed after chronic treatment with IS-5-MN. The duration of action of nicorandil was investigated in 22 patients with coronary artery disease (CAD). After a 2-week run-in period on placebo, patients had to perform a symptom-limited bicycle exercise tolerance test (ETT) on two separate days in which the reproducible anginal threshold had to be proven. After qualification, patients were allocated randomly to receive double-blind 10 or 20 mg nicorandil b.i.d. for 4 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Ouabain, na +-free and k +-free solutions and relaxations to nitric oxide and nitrovasodilators

1. 1. Experiments were designed to determine the effect of inhibition of Na +, K + ATPase by ouabain, Na +-free and K +-free solutions on the relaxations induced by nitric oxide, nitroglycerin and sodium nitroprusside in coronary smooth muscle. 2. 2. Rings without endothelium of canine left anterior descending coronary artery were suspended for isometric tension recording in modified Krebs-Ringer bicarbonate solution, in the presence of indomethacin, propranolol, and phenoxybenzamine. The rings were incubated with ouabain, Na +-free or K +-free solutions prior to contractions with prostaglandin F 2α. 3. 3. Nitric oxide induced transient relaxations which were significantly depressed by ouabain but were not affected by Na +- or K +-free solutions. Thus, the inhibitory effect of ouabain on relaxations to nitric oxide is not due to inhibition of the Na +, K + pump. 4. 4. The relaxation induced by sodium nitroprusside was impaired both in the presence of ouabain and after incubation in Na +- or K +-free solution, suggesting that it may involve in part activation of Na +, K + pumping. 5. 5. Only high concentration of ouabain and Na +-free solution decreased the relaxation evoked by nitroglycerin, indicating that the mechanism of action of nitroglycerin on vascular smooth muscle does not involve the Na +-K + pump.

Endothelium modulation of the effects of nitroglycerin on blood vessels from dogs with pacing‐induced heart failure

1. The relaxant actions of nitroglycerin (previously considered to be an endothelium-independent relaxing agent) and acetylcholine (an endothelium-dependent relaxing agent) were compared on 4 vascular preparations (dorsal pedal artery, saphenous vein, left anterior descending coronary artery and circumflex coronary artery) from dogs with and without pacing-induced congestive heart failure (CHF). 2. Responses of the coronary arteries to acetylcholine were unaltered in endothelium-intact rings from dogs with and without heart failure. Similarly no such changes were observed in the peripheral vessels. The maximum relaxation produced by acetylcholine was always greater in the coronary vessels compared to the peripheral vessels. 3. Before heart failure, the coronary vessels were more sensitive and reactive to nitroglycerin compared to the peripheral vessels. 4. Removal of the endothelium in both the control (dogs without CHF) and experimental (dogs with CHF) rings enhanced the relaxant effects of nitroglycerin, such that the EC50 for nitroglycerin became significantly lower in all denuded rings, with the exception of the saphenous vein and the left anterior descending coronary artery, before the development of CHF. 5. When CHF was maximally developed, vascular sensitivity to nitroglycerin was increased in peripheral vessels with an intact endothelium, but not in the coronary vessels. 6. These findings indicate that relaxation produced by nitroglycerin cannot be considered as entirely endothelium-independent but should be considered endothelium-modulated.

Nitrate Tolerance Induced by Nicorandil or Nitroglycerin is Associated with Minimal Loss of Nicorandil Vasodilator Activity

In the current study, the vasodilator and tolerance-inducing actions of a recently developed organic nitrate vasodilator, nicorandil, were compared to nitroglycerin (NTG) in an isolated coronary artery preparation. The order of potency for relaxing U46619-constricted bovine-isolated coronary artery rings was NTG greater than isosorbide dinitrate (ISDN) greater than nicorandil. NTG was approximately 250-fold more potent than nicorandil (mean EC50 values for relaxation; 0.044 and 11.2 microM, respectively; n = 6-8). Coronary artery rings preexposed for 60 min to NTG (30 microM) were subsequently markedly less responsive to the relaxant effects of NTG (7.5-fold increase in mean EC50 value, 68.4% decrease in Emax; p less than 0.001) and ISDN (14.1-fold increase in mean EC50 value; p less than 0.001), although only marginally less responsive to nicorandil (1.75-fold increase in mean EC50 value; p less than 0.05). Thus, the coronary artery relaxant actions of nicorandil were significantly less affected by NTG-induced tolerance than were the relaxant actions of the related organic nitrate compounds, NTG and ISDN. To compare the tolerance-inducing actions of NTG and nicorandil, the relaxant actions of a series of nitric oxide (NO)-containing vasodilators were determined in control coronary artery rings and in rings preexposed for 60 min to either 30 microM NTG or 5,000 microM nicorandil. Quantitatively, similar changes in coronary artery ring responsiveness were produced by tolerance induced by NTG and nicorandil; marked attenuation of responsiveness to NTG and to the nonnitrate compound 3-morpholinosydnonimine (SIN-1), but only marginal attenuation of responsiveness to nicorandil and NO.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanisms of nitrate tolerance: A review

With the increased use of long-acting nitroglycerin preparations, there has been greater recognition of the problem of nitrate tolerance. In recent years extensive research has broadened our understanding of the mechanisms of nitroglycerin action and the mechanisms of drug attenuation. This paper reviews the current state of knowledge regarding nitroglycerin tolerance, with an emphasis on the concepts of cellular and neurohumoral mechanisms of drug attenuation. The discussion includes potential approaches to prevent nitrate tolerance, including the introduction of a nitrate-free interval, or concomitant administration of sulfhydryl donors or neurohumoral blocking agents.

Coronary stenosis dilation by low dose intravenous nitroglycerin

In a randomized double-blind study, 40 patients with coronary heart disease received either 0.025 mg nitroglycerin or placebo intravenously. Before and 2-3 min after injection, the aortic and left ventricular pressures were recorded and coronary angiography was performed. Mean heart rate, systolic and diastolic aortic pressure, left ventricular filling pressure and the pre- and poststenotic coronary artery diameters, as well as the diameters of representative distal coronary artery segments showed no significant changes. Coronary artery stenosis diameters remained unchanged after placebo (1.01 +/- 0.5 to 1.13 +/- 0.49 mm; n.s.) but increased significantly after nitroglycerin from 1.15 +/- 0.68 to 1.32 +/- 0.73 mm (P less than 0.01). Since it has been demonstrated, on the other hand, that the same dose of nitroglycerin reveals antianginal activity, it can be hypothesized from these results that dilatation of coronary stenoses plays an important role in the antianginal action of nitroglycerin. Strong haemodynamic effects do not appear to be a prerequisite of the beneficial effects of nitroglycerin.

Endothelium- and sydnonimine-induced responses of native and cultured aortic smooth muscle cells are not impaired by nitroglycerin tolerance

Tolerance to the cyclic GMP-mediated vasodilator action of nitroglycerin develops with prolonged exposure and may be mediated either by formation of less nitric oxide from nitroglycerin or by desensitization of soluble guanylate cyclase to activation with nitric oxide. In the latter case, smooth muscle cells tolerant to nitroglycerin should show cross-tolerance to nitric oxide released from sydnonimines and endothelial cells (endothelium-derived relaxing factor). Therefore cultured smooth muscle cells from rabbit aorta were pretreated for 1 h with vehicle or high concentrations (0.55 mM) of nitroglycerin or the sydnonimine SIN-1. The formation of cyclic GMP induced by subsequent small doses of nitroglycerin, sydnonimine SIN-1 and endothelium-derived relaxing factor (released from cultured endothelial cells) was compared with the changes in activation of soluble guanylate cyclase, cyclic GMP formation and vasodilation in response to the same stimuli in similarly pretreated segments from rabbit thoracic aortae. Both cultured and native smooth muscle cells remained responsive to stimulation with sydnonimine SIN-1 and endothelium-derived relaxing factor after pretreatment with nitroglycerin, vehicle, or sydnonimine SIN-1, even though they were tolerant to nitroglycerin after pretreatment with nitroglycerin. In contrast, activation of soluble guanylate cyclase by nitroglycerin and sydnonimine SIN-1 was attenuated in homogenates of nitrate-tolerant aortae. The findings suggest that nitroglycerin tolerance in intact cells does not involve desensitization of soluble guanylate cyclase, because in intact cells nitrate tolerance can be overcome by direct activators of soluble guanylate cyclase.

Comparison of the Effects of Nifedipine and Nitroglycerin on Hemodynamic Determinants of Myocardial Oxygen Consumption and Supply During Exertional Angina

To investigate the antianginal action of nitroglycerin and nifedipine, systemic and right heart pressures, cardiac output, oxygen consumption, and radionuclide left ventricular ejection fraction and volume were measured in 14 men with stable effort angina and a positive exercise electrocardiogram. Exercise tests were performed on a semiupright bicycle ergometer on no therapy and after intravenous nitroglycerin and sublingual nifedipine, which lowered mean arterial pressure by 20 mm Hg. Exercise tolerance improved from 50 +/- 4 to 61 +/- 5 W on nifedipine and to 79 +/- 4 W on nitroglycerin (p less than 0.01, nitroglycerin vs. nifedipine). At submaximal workloads, both drugs decreased arterial pressure and ventricular volumes, but heart rate was higher on nifedipine. At peak exercise on nitroglycerin (79 W), oxygen consumption, cardiac index, heart rate, and rate-pressure product were significantly increased over peak control and nifedipine values, while systolic pressure and end-diastolic volume were unchanged. Nitroglycerin reduced pulmonary wedge pressure more and systemic diastolic pressure less than nifedipine, so the coronary perfusion gradient was reduced by nifedipine and maintained by nitroglycerin. Also, there was less angina and ST-segment depression after nitroglycerin compared to control or nifedipine, and the left ventricular diastolic pressure-volume relationship was improved only by nitroglycerin. This suggests that the action of nitroglycerin in reducing ischemia is not only due to reduced myocardial oxygen demand, but that myocardial oxygen delivery may also be increased.

Differential Inhibitory Effects of Nitroglycerin on Contractile Responses to the a-Adrenoceptor Agonists, Methoxamine and Clonidine, in Rabbit Aorta

The vasoinhibitory action of nitroglycerin was examined on contractile responses to methoxamine and clonidine in isolated rabbit aorta. Nitroglycerin at 10(-5) M, but not 10(-6)-10(-8) M, shifted the concentration response curve for methoxamine to the right. Nitroglycerin (10(-8)-10(-5) M), however, noncompetitively inhibited responses to clonidine in a concentration dependent manner. Nitroglycerin (10(-5) M) had no effect on responses to potassium (10-70 mM), but slightly inhibited responses to Ca2+ (0.1-5 mM) in a Ca2+-free medium containing potassium. Nifedipine (10(-6) and 10(-5) M), however, almost abolished responses to both potassium and Ca2+ but had no effect on responses to either methoxamine or clonidine. Agonist-antagonist interactions using prazosin and yohimbine revealed that responses to both methoxamine and clonidine were due to activation of alpha 1-adrenoceptors. Results with phenoxybenzamine suggested that the aorta has more receptor reserve for methoxamine than for clonidine. Furthermore, in tissues pretreated with phenoxybenzamine, nitroglycerin (10(-5) M) inhibited the maximal contractile response to methoxamine (3 x 10(-4) M). The maximal response to clonidine in tissues pretreated with phenoxybenzamine was not affected by nitroglycerin (10(-8) M). Nitroglycerin (10(-9)-10(-4) M) had greater inhibitory effect on residual responses to clonidine (10(-5) M) than that to methoxamine (10(-5) M) in a Ca2+-free medium containing EGTA. The contractile responses to Ca2+ (2 mM) in a Ca2+-free medium containing EGTA, nifedipine, and either methoxamine (5 x 10(-7) M) or clonidine (3 x 10(-7) M) were inhibited by nitroglycerin (10(-9) - 10(-5) M). The effect of nitroglycerin was greater on responses in the presence of clonidine than methoxamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Tolerance and Cross-Tolerance Between SIN-1 and Nitric Oxide in Bovine Coronary Arteries

The molecular mechanism of tolerance development to nitrovasodilators, most prominent with nitroglycerin, associated with desensitization of guanylate cyclase is still unclear. Nitric oxide (NO) appears to be the common denominator of this group of drugs that leads to guanylate cyclase activation, followed by increases in levels of cyclic GMP and relaxation. It was therefore decided to study whether NO itself, which causes some tolerance, interferes with the actions of (a) SIN-1 and sodium nitroprusside, both of which are thought to act directly by NO formation, which explains why they cause little tolerance; and (b) with the actions of nitroglycerin, which stimulates cyclic GMP formation only in the presence of cysteine and causes pronounced (large) tolerance. Experiments were performed in circular strips of isolated de-endothelialized bovine coronary artery by measuring isotonic changes in length and cyclic GMP determined by radioimmunoassay. When the strips were treated with submaximal effective concentrations of NO, some tolerance was observed, as shown by moderate attenuation of the rises in cyclic GMP, and a rightward shift of the dose-response curve of the relaxing effects by a dose factor of 10 (DF = 10). Exposure to nitroglycerin, SIN-1, or sodium nitroprusside rendered the strips cross-tolerant to NO to a comparable extent as NO itself, suggesting that under these conditions the NO component of all of these drugs that caused similar tolerance is displayed. When the strips were treated with NO and subsequently challenged with nitroglycerin, SIN-1, or sodium nitroprusside, the NO cross-tolerance was uniformly lower than the tolerance to the challenging agent.(ABSTRACT TRUNCATED AT 250 WORDS)

Endothelium-derived nitric oxide: pharmacology and relationship to the actions of organic nitrate esters.

Vascular smooth muscle relaxation elicited by various endogenous substances results from their interaction with vascular endothelial cells to triger the formation of endothelium-derived relaxing factor (EDRF). EDRF from pulmonary and peripheral arteries and veins and from cultured and freshly harvested aortic endothelial cells has been identified pharmacologically and chemically as nitric oxide (NO) or a labile nitroso compound. Endothelium-derived NO (EDNO) and authentic NO activate the cytoplasmic form of guanylate cyclase by heme-dependent mechanism and thereby stimulate intracellular cyclic GMP accumulation in cells including vascular smooth muscle and platelets. Cyclic GMP functions as a second messenger to cause vascular muscle relaxation and inhibition of platelet aggregation and adhesion to vascular endothelial surfaces. EDNO is synthesized from L-arginine and perhaps arginine-containing peptides by an unidentified calcium-requiring process coupled to the occupation of extracellular endothelial receptors. The biological actions of EDNO are terminated by spontaneous oxidation to NO2- and NO3-. The biological half-life of the very lipophilic EDNO is only 3-5 sec and this allows EDNO to function locally as an autacoid. Nitroglycerin and other organic nitrate esters elicit endothelium-independent relaxation after entering vascular smooth muscle cells and undergoing denitration and formation of NO. The pharmacological actions of nitroglycerin are therefore essentially the same as those of EDNO, and the endogenous NO receptor is the heme group bound to soluble guanylate cyclase. EDNO may serve a biological role to modulate local blood flow and platelet function.

Effects of sulfhydryl-containing compounds on nitroglycerin-induced coronary dilatation in isolated working rat hearts

The effects of various compounds on the time course of the coronary dilating response to nitrovasodilators were studied in working rat hearts. Continous administration of 100 μM glyceryl trinitrate (GTN) to the perfusate induced a rapid increase in coronary flow. The flow decreased to about 40% of the initial flow rise within 20 min and remained constant during the following 40 min. The flow increase induced by 100 μM SIN 1 (3-morpholino-sydnonimine), however, remained constant throughout the 60-min perfusion period. The decay of the GTN action was reduced in the presence of the thiol-containing agents L-homocysteine, L- and D-cysteine and to a lesser extent, reduced glutathione, while the initial response to GTN was only slightly enhanced. However, N-acetyl-L-cysteine caused a significant increase of the maximum response to GTN whereas the subsequent loss of GTN action was not greatly altered, suggesting that this agent exerts a potentiating action without altering tolerance. Dithiothreitol elicited a slight increase in the maximum effect of GTN, followed by a complete attenuation of the effect. These data suggest that SH group donors could exert different effects on the action of GTN while GTN tolerance is only influenced by L- and D-cysteine, L-homocysteine and reduced glutathione.

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.

Preferential venoconstriction by cyclooxygenase inhibition in vivo without attenuation of nitroglycerin venodilation.

Because prostacyclin is a rather potent venodilator in vivo, we analyzed the effect of cyclooxygenase inhibition on venous tone in 14 anesthetized dogs during ganglionic and beta-adrenergic blockade and atraumatic conditions. Effective vascular stiffness (a reciprocal of effective vascular compliance) as a variable of integrated venous tone was 0.30 +/- 0.01 mm Hg.kg/ml (n = 35) and was augmented up to twofold by diclofenac (1, 3, and 10 mg/kg i.v.), ibuprofen (6 and 60 mg/kg), or indomethacin (5 mg/kg) parallel to augmentations in central venous pressure, while the rise in arterial pressure was less than half of the increase induced by equivenoconstrictor dosages of norepinephrine. After preconstriction by indomethacin or diclofenac, nitroglycerin (1.5 micrograms/kg/min) lowered effective vascular stiffness (by 24 +/- 2% or 23 +/- 5%, respectively), similarly as during preconstriction by norepinephrine (by 24 +/- 4%). Long-term cyclooxygenase inhibition (diclofenac 2 x 1 mg/kg/day for 4 days) did not modify arterial pressure, heart rate, or hematocrit levels in conscious dogs at rest, but it lowered plasma volume to 52.5 +/- 1.9 ml/kg (sham treatment: 59.1 +/- 1.6 ml/kg, p less than 0.05, n = 4). In conclusion, venoconstriction by clinical dosages of cyclooxygenase inhibitors does not interfere with the venodilator action of nitroglycerin and is compensated chronically by adjustments of plasma volume.

8-Bromo cyclic GMP mimics the actions of nitroglycerin in modulating responses produced by full and partial alpha-adrenoceptor agonists in canine saphenous vein.

The purpose of the present study was to determine whether 8-bromo cyclic GMP (8-Br cGMP) mimics the actions of nitroglycerin (GTN) in inhibiting alpha-1 versus alpha-2 adrenoceptor-mediated constrictor responses in canine saphenous vein. Phenylephrine (PE) and L-dobutamine were used as full and partial alpha-1 adrenoceptor agonists, respectively, and B-HT 920 was employed as a selective alpha-2 adrenoceptor agonist. The ability of 8-Br cGMP and GTN to inhibit vasoconstrictor responses to a standard agonist concentration of PE, L-dobutamine and B-HT 920 was determined. 8-Br cGMP like GTN produced a selective antagonism of alpha-2-mediated responses of B-HT 920 and had minimal effects on alpha-1-induced constrictor responses of phenylephrine. However, when a portion of the alpha-1-adrenoceptor pool was inactivated by phenoxybenzamine (POB) (5 x 10(-8) M, 1 x 10(-7) M) 8-Br cGMP like GTN produced a significant depression of responses to PE. In addition, contractions produced by L-dobutamine, a selective partial alpha-1 adrenoceptor agonist (no alpha receptor reserve), were highly sensitive to inhibition by 8-Br cGMP and GTN. These results suggest that the presence of a large alpha-1-adrenoceptor reserve to PE concealed an underlying functional antagonism to alpha-1-adrenoceptor-mediated responses by GTN and 8-Br cGMP. The similarity in the efficacy and potency of these two agents (8-Br cGMP and GTN) suggests that the effects of GTN in canine saphenous vein may be the result of an increase in the intracellular concentration of cGMP.

Effects of intracoronary nitroglycerin on coronary vascular volume in man, assessed by a double-indicator dilution technique.

The effects of 0.2 mg nitroglycerin administered directly into the left coronary artery were studied in 7 patients with coronary artery disease. A multipurpose catheter designed for simultaneous measurement of coronary sinus flow and great cardiac vein flow by thermodilution and for addition recording of dye dilution curves by a fiberoptic method was introduced from a right antecubital vein into the coronary sinus and advanced with its tip to the great cardiac vein/anterior cardiac vein juncture. Coronary sinus flow and great cardiac vein flow were measured using the constant infusion technique. Selective bolus injections of indocyanine green dye were measured using the constant infusion technique. Selective bolus injections of indocyanine green dye were performed into the left coronary system via a 8 French Judkins catheter and dye dilution curves were recorded in the upper great cardiac vein. From these curves, coronary transit time was assessed and coronary vascular volume was calculated as great cardiac vein flow times coronary transit time. Intracoronary nitroglycerin led to a transient drop in regional coronary resistance that was associated with an almost parallel increase in intravascular volume. Since this increase in coronary vascular volume exceeded the well-known dilatory effect on the epicardial arteries, and lasted slightly longer than the drop in regional resistance, these data imply that the vasodilatory action of nitroglycerin is different in magnitude as well as in time course in different parts of the coronary circulation.

Hemodynamic studies of nitroglycerin in dogs using an open loop method.

Nitroglycerin is considered to decrease both preload and afterload. To elucidate the actions of nitroglycerin on afterload, venous return was kept constant in this experiment. Three different doses of nitroglycerin, 0.3 microgram/kg/min, 1.0 microgram/kg/min, 3.0 micrograms/kg/min were administered into the ascending aorta of 6 mongrel dogs weighing over 20 kg. These doses of nitroglycerin were randomized in each of six procedures. The plasma concentration of nitroglycerin increased during 10 min of infusion, then it decreased exponentially. Heart rate, cardiac output and left atrial pressure did not change significantly at any dose of nitroglycerin. Systolic blood pressure and systemic vascular resistance (as indices of afterload) decreased significantly during nitroglycerin infusion, especially with the 3 micrograms/kg/min dose. These data suggest that nitroglycerin decreases the afterload. The effects appeared rapidly with administration and disappeared rapidly after cessation of the infusion.

Historical aspects of nitrate therapy.

The exciting story of the development of nitrates as drugs in clinical medicine is briefly reviewed. Glyceryl trinitrate (nitroglycerin) was synthesised by Sombrero in 1847. Amyl nitrite was discovered a few years later and was used by Guthrie in 1859. The first report on the action of glyceryl trinitrate and amyl nitrite was published by Brunton in 1867, and further papers were published by Murell in 1879. Organic nitrates appeared in the 1930s. Krantz and co-workers synthesised and used mannide dinitrate, which was longer acting than the nitrates that had been used previously. Research on a similar drug, isosorbide dinitrate, was initiated by Porjé in Stockholm. The drug was first marketed in Sweden in 1946. Isosorbide dinitrate was independently synthesised in the United States by Harris and colleagues in the 1950s. The drug was used fairly extensively on both sides of the Atlantic. However, there was a temporary decrease in popularity around 1970 when Needleman and colleages reported oral nitrates to be of questionable value, as they underwent rapid biotransformation during first-pass metabolism in the liver. This opinion was later altered and today the drug enjoys worldwide acceptance in different formulations. Also, in recent years one of the active metabolites, isosorbide 5-mononitrate, has been marketed as an effective antianginal drug.