Fumiya Yoneyama

COMPARISON OF THE EFFECTS OF THE NOVEL VASODILATOR FK409 WITH THOSE OF NITROGLYCERIN IN ISOLATED CORONARY ARTERY OF THE DOG

1 The vasorelaxant effects of FK409, a new nitrovasodilator synthesized from a microbial product, were compared with those of nitroglycerin in isolated coronary artery rings of the dog contracted with U46619 (10−7 m). 2 FK409 (10−11–10−5 m) and nitroglycerin (10−9–10−4 m) each produced a concentration‐dependent relaxation. Comparison of EC50 values showed that FK409 was about 25 times more potent than nitroglycerin. 3 Submaximum concentrations of nitroglycerin (10−6 m) and FK409 (3 × 10−8 m) elevated guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) levels, effects associated with vasorelaxation. Adenosine 3′: 5′‐cyclic monophosphate (cyclic AMP) levels were unaffected. 4 The concentration‐relaxation curves for nitroglycerin and FK409 were shifted to the right by methylene blue (3 × 10−6–3 × 10−5 m), an inhibitor of soluble guanylate cyclase, and to the left by M&B22,948 (3 × 10−6–3 × 10−5 m), an inhibitor of cyclic GMP phosphodiesterase. 5 After exposure of coronary arteries to the maximally‐effective concentration of nitroglycerin (10−4 m), the mean EC50 value of FK409 did not change significantly, although that of nitroglycerin increased about 60 fold. After exposure to the maximally‐effective concentration of FK409 (10−5 m), the mean EC50 value of FK409 increased about 6 fold and that of nitroglycerin about 11 fold. 6 These results suggest that the vasorelaxant effect of FK409, like that of nitroglycerin, is due to activation of soluble guanylate cyclase and a resultant increase in intracellular cyclic GMP. However, compared with nitroglycerin, there was less self‐tolerance to the relaxant effects of FK409 and relatively little cross‐tolerance between the two agents.

Nicorandil increases coronary blood flow predominantly by K-channel opening mechanism

SummaryNicorandil has a hybrid property between nitrates and potassium (K)-channel openers. In order to clarify which mechanism of action is responsible for its effect in increasing coronary blood flow, we investigated how this effect was antagonized by glibenclamide, which was recently found to behave as a pharmacologic antagonist of K-channel openers. Cromakalim, one of the most specific K-channel openers currently available, and nitroglycerin were used as reference drugs. In isolated, blood-perfused papillary muscle preparations of dogs, intraarterial injections of nicorandil and cromakalim increased (coronary) blood flow, and at high doses a negative inotropic effect and ventricular fibrillation occurred. Dose-response curves for the increase in coronary blood flow produced by nicorandil or cromakalim were shifted to the right in a parallel manner and to similar extents by glibenclamide given intravenously to support dogs. Schild analysis yielded pA2 values of 6.08 and 6.34 for glibenclamide versus nicorandil and cromakalim, respectively. Nitroglycerin injected intraarterially produced only an increase in coronary blood flow. This effect was not affected by glibenclamide. These results indicate that the effect of nicorandil in increasing coronary blood flow, like that of cromakalim, is predominantly due to its mechanism of action as a K-channel opener. The negative inotropy and ventricular fibrillation seen with high doses of nicroandil and cromakalim were also antagonized by glibenclamide, indicating that these effects are also due to K-channel opening.

Vasodepressor mechanisms of 2-(1-octynyl)-adenosine (YT-146), a selective adenosine A2 receptor agonist, involve the opening of glibenclamide-sensitive K+ channels

The vasodepressor mechanism of 2-(1-octynyl)-adenosine (YT-146), a selective adenosine A2 receptor agonist, was compared with that of adenosine in spinally anaesthetized dogs whose blood pressure was kept elevated with i.v. infusion of noradrenaline. Cumulative i.v. administration of YT-146 (1-1000 nmol/kg) caused a slowly developing and long-lasting decrease in mean blood pressure (MBP) and a small decrease in heart rate (HR) at high doses, whereas single i.v. administration of adenosine caused short-lived decreases in MBP and HR. In dogs given glibenclamide (6 mumol/kg i.v.) or theophylline (30 mumol/kg i.v.) dose-response curves for decrease in MBP due to YT-146 underwent parallel rightward shifts. The ED50 values for YT-146 were increased about 5.5-fold with glibenclamide and about 11.9-fold with theophylline. However, no further rightward shifts of the curves were obtainable in dogs given glibenclamide plus theophylline; the increase in ED50 values for YT-146 was about 6.8-fold, being close to the increase obtained with theophylline alone. The ED50 values for adenosine to lower MBP increased about 1.6-fold with theophylline but not with glibenclamide. Glibenclamide and theophylline failed to antagonize the negative chronotropic effects of both drugs. These results suggest that the vasodepressor effect of YT-146 involves two mechanisms following stimulation of adenosine A2 receptors; one is probably a cyclic AMP-dependent mechanism and the other is the opening of glibenclamide-sensitive K+ channels.

Cardioprotective effect of TY-12533, a novel Na+/H+exchange inhibitor, on ischemia/reperfusion injury

The effects of 6,7,8, 9-tetrahydro-2-methyl-5H-cyclohepta[b]pyridine-3-carbonylguanidine maleate (TY-12533) on myocardial ischemia/reperfusion injury were evaluated in rats. Inhibitory effects of TY-12533, TY-50893 (the 9-chloro derivative of TY-12533) and cariporide on the platelet Na(+)/H(+) exchanger in vitro were almost equal at pH 6.2 and decreased at pH 6.7; but TY-12533 was four times more potent than TY-50893 and cariporide at pH 6.7. TY-12533, TY-50893 and cariporide administered before ischemia (0.01-1 mg/kg, i.v.) suppressed the ischemia/reperfusion-induced arrhythmias to the same extent in vivo; but TY-12533 was more effective than cariporide and TY-50893 when they were administered during ischemia (0.1-1 mg/kg). Similar results were obtained for the inhibitory effects of these drugs administered before ischemia (0.03-0.1 mg/kg, i.v.) and during ischemia (0.1-1 mg/kg) on the ischemia/reperfusion-induced myocardial infarction. These differences between TY-12533 and the other drugs in vitro and in vivo may be ascribed to the pK(a) values of the guanidinium moiety of TY-12533 (6.93), TY-50893 (6.35) and cariporide (6.28).

Specific but differential antagonism by glibenclamide of the vasodepressor effects of cromakalim and nicorandil in spinally‐anaesthetized dogs

1 Whether the vasodepressor effects of cromakalim and nicorandil, potassium channel openers, were differentially antagonized by glibenclamide, a supposed specific antagonist of potassium channel openers, was investigated in spinally‐anaesthetized dogs in which arterial pressure was maintained elevated by i.v. infusion of noradrenaline. 2 Cumulative administration of cromakalim (3–100 μg kg−1, i.v.), nicorandil (30–1000 μg kg−1, i.v.), diltiazem (3–300 μg kg−1, i.v.) and nitroglycerin (0.3–100 μg kg−1, i.v.) caused dose‐dependent decreases in mean arterial pressure. In dogs which received glibenclamide (3 mg kg−1, i.v.), the dose‐vasodepressor response curves for cromakalim and nicorandil were located on the right in parallel to the respective curves determined in control dogs, but those for diltiazem and nitroglycerin were not different. ED50% values increased about 6.7 fold for cromakalim and 2.2 fold for nicorandil. 3 The depression of LV dP/dtmax produced by a high dose of cromakalim (100 μg kg−1 i.v.) was abolished by glibenclamide and that produced by nicorandil was not only antagonized but converted to an increase. 4 These results suggest that the vasodepressor action of cromakalim is due predominantly to potassium channel opening, but that of nicorandil involves not only potassium channel opening but its action as a nitrate.

The group at C2 of N-ethylnicotinamide determines the vasodilator potencies and mechanisms of action of nicorandil and its congeners in canine coronary arteries

SummaryThe relaxant mechanisms of action of nicorandil and its congeners (SG-86, SG-103, SG-209 and SG-212) on large coronary arteries were investigated in isolated canine circumflex arteries contracted with 25 mmol/l KCl or 10−7 mol/l U46619, a thromboxane A2 analogue. SG-212, SG-86, SG-209 and SG-103 were obtained by replacement of the nitroxy group of nicorandil by bromine, the hydroxy, acetoxy and nicotinoyloxy groups, respectively.Nicorandil (10−6–10−3 mol/l), SG-212 (3 × 10−4 –10−2 mol/l),SG-209 (10−4–10−2 mol/l), SG-103 (3 × 10−4–10−2 mol/l), and SG-86 (10−3–10−2 mol/l) all produced a concentration-dependent relaxation in KCl- or U46619-contracted arteries. The order of relaxant potency was as follows: Nicorandil » SG-209 > SG-212 = SG-103 > SG-86. The relaxant effect of nicorandil was not affected by glibenclamide but antagonized by methylene blue. In the presence of glibenclamide, the concentration-relaxation curves for SG-209 underwent rightward parallel shifts. The relaxant effect of SG-209, however, was not affected by methylene blue. The concentration-relaxation curves for SG-212 underwent rightward parallel shifts only to a limited extent in the presence of glibenclamide, but they were not affected by methylene blue. The relaxant effect of SG-103 was affected by neither glibenclamide or methylene blue. The relaxant effect of SG-86 was not affected by glibenclamide. The relaxant effect of nicorandil accompanied an increase in cyclic-GMP levels but that of SG-209 did not. These results indicate that the group at C2 of the parent structure of nicorandil and its congeners, i.e., N-ethylnicotinamide determines not only the vasodilator potency but the vasodilator mechanism of action of the compound.

Cardiac versus coronary dilator effects of SD-3211, a new nondihydropyridine calcium antagonist, in isolated, blood-perfused dog hearts

SummaryCoronary and cardiac effects of SD-3211 were compared in isolated, blood-perfused sinoatrial (SA) node, atrioventricular (AV) node, and papillary muscle preparations of dogs. SD-3211 was administered intraarterially. In all preparations SD-3211 produced an increase in coronary blood flow. In SA node preparations, the drug produced a decrease in sinus rate, and in high doses atrial standstill occurred. The dose that produced a 15% decrease in sinus rate was about 5.6 times the dose that doubled coronary blood flow. In AV node preparations, when injected into the artery supplying the AV node, the drug produced an increase in AV conduction time, and in high doses second- or third-degree AV block occurred. The dose that produced a 15% increase in AV conduction time was about 1.6 times the dose that doubled coronary blood flow. In the same preparations the drug slightly increased AV conduction time only at high doses when injected into the artery supplying the His-Purkinjeventricular system. In paced papillary muscle preparations, the drug produced a decrease in the force of contraction. The dose that produced a 50% decrease in the force of contraction of the paced papillary muscle was about 50 times the dose that doubled coronary blood flow. The drug was virtually ineffective on ventricular automaticity. In short, in doses that doubled coronary blood flow, SD-3211 depressed only AV nodal conduction. This cardiovascular profile differs from those of diltiazem and verapamil, which do not discriminate between coronary vasculature and the SA and the AV node.

Amelioration of ischemia/reperfusion-induced myocardial infarction by the 2-alkynyladenosine derivative 2-octynyladenosine (YT-146).

The present study was aimed at determining whether the novel adenosine A2-agonist YT-146 may have cardioprotective effects against ischemia-reperfusion injury. Anesthetized open-chest dogs underwent 90-min occlusion of the left anterior descending artery and subsequent 300-min reperfusion. The animals were randomly assigned to receive vehicle, 3, or 10 μg/kg YT-146 or ischemic preconditioning (4 episodes of 5 min occlusion followed by 5 min of reperfusion). Blood pressure, heart rate, and regional myocardial blood flow throughout the experiment were measured, as was the myocardial infarct size after reperfusion. The infarct size of the vehicle-treated dog was 56.2%±2.7% (n=5), whereas that of 3 or 10 μg/kg YT-146-treated dog was smaller (ie, 29.5%±8.7% or 20.2%±7.0%, respectively; n=5). The infarct size of the dog treated with 10 μg/kg YT-146 was reduced to a degree similar to that of the ischemic preconditioning (19.2%±6.3%, n=5). YT-146 at both doses elicited a dose-dependent increase in acute hyperemic coronary flow immediately after reperfusion. The cardioprotective effect may be attributed to the limitation of the infarct size, probably via A2-receptor-mediated coronary artery dilatation during the early period of reperfusion.

TY-12533, a novel Na+/H+ exchange inhibitor, prevents myocardial stunning in dogs

Anesthetized open-chest dogs were subjected to 15-min myocardial ischemia followed by 2-h reperfusion to induce myocardial stunning. A novel Na(+)/H(+) exchange inhibitor 6,7,8,9-tetrahydro-2-methyl-5H-cyclohepta[b]pyridine-3-carbonylguanidine maleate (TY-12533), administered 10 min before or 10 min after start of ischemia (3 mg/kg/10 min, i.v.), did not affect reductions in regional myocardial wall thickening, blood flow and pH during ischemia, but it significantly improved recovery of the wall thickening and blood flow after reperfusion. These results indicate that TY-12533, even when administered during ischemia, could prevent myocardial stunning without affecting myocardial dysfunction or acidosis induced by brief ischemia.

A further study of the vasodilator and negative inotropic mechanisms of action of nicorandil and its congeners in the canine heart.

SummaryThe vasodilator and negative inotropic mechanisms of action of nicorandil and its congeners (SG-209, SG-103, and SG-86) were investigated in isolated canine papillary muscle preparations cross-circulated through the anterior septal artery with support dogs. SG-209, SG-103, and SG-86 were obtained by replacement of the nitroxyl group of nicorandil by acetoxyl, nicotinoyloxyl, and hydroxyl groups, respectively. Nicorandil (0.03–10 µmol), SG-209 (0.1–10 µmol), SG-103 (1–30 µmol), and SG-86 (3–100 µmol) all produced an increase in coronary blood flow through the anterior septal artery. Both nicorandil and SG-209 produced a near-maximal increase in coronary blood flow, the latter being about 5.5 times less potent than the former. SG-103 and SG-86 were far less potent than SG-209 in that order. The vasodilator actions of nicorandil and SG-209 were antagonized by glibenclamide given IV to support dogs, but those of SG-103 and SG-86 were not. The pKB values of glibenclamide were 6.34 toward nicorandil and 6.49 toward SG-209. Developed tension of the papillary muscle was reduced by nicorandil, SG-209, and SG-103, but not by SG-86. In this respect SG-209 was about 4.7 times less potent than nicorandil, and SG-103 was much less potent than SG-209. The negative inotropic effects of nicorandil and SG-209 were antagonized by glibenclamide, but that of SG-103 was not. These results indicate that both nicorandil and SG-209 act as K-channel openers in coronary resistance vessels and in ventricular myocardium, and that the nitroxyl and the acetoxyl group at C2 of the parent structure of nicorandil and its congeners, i.e., N-ethylnicotinamide, play a pivotal role in making these compounds act as K-channel openers. In this respect, the nitroxyl group is about five times more potent than the acetoxyl group.