Comparative study of coronary vasodilator and cardiac effects of nitrendipine by use of isolated, blood-perfused dog heart preparations

The coronary vasodilator and cardiac effects of 3-ethyl-5-methyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl) -3,5-pyridinedicarboxylate (nitrendipine, Bay e 5009) were compared in isolated, blood-perfused sinoatrial (SA) node, atrioventricular (AV) node and papillary muscle preparations of dogs with i.a. administration. In all preparations nitrendipine increased (coronary) blood flow. In SA node preparations nitrendipine reduced sinus rate but the reduction remained only about 13% of the basal value even at the highest dose. The dose estimated to produce a 15% (nearly a half maximum) decrease in sinus rate was about 8 times the dose which doubled coronary blood flow. In AV node preparations nitrendipine prolonged AV conduction time when injected into the artery supplying the AV node but the prolongation remained only about 12% of the basal value even at the highest dose. The dose estimated to produce a 15% (nearly a half maximum) increase in AV conduction time was about 11 times the dose which doubled coronary blood flow. When injected into the artery supplying the His-Purkinje ventricular system of AV node preparations, nitrendipine was entirely ineffective on AV conduction. In paced papillary muscle preparations nitrendipine reduced force of contraction. The reduction, however, remained less than 50% of the basal value even at the highest dose. The dose estimated to reduce force of contraction by half was about 11 times the dose which doubled coronary blood flow. Nitrendipine was entirely ineffective on ventricular beating rate of spontaneously beating papillary muscle preparations. These results indicate that nitrendipine is highly vasoselective, and warrant its high efficacy as an antianginal drug.     

Profile of cardiac and coronary vasodilator effects of MS-857, a novel cardiotonic agent, assessed in isolated, blood-perfused heart preparations of the dog

MS-857 is a novel orally active nonglycoside and nonsympathomimetic cardiotonic agent. Cardiovascular properties of MS-857 were assessed in isolated, blood-perfused papillary muscle, sinoatrial (SA) node, and atrioventricular (AV) node preparation of the dogs. MS-857 (0.3-100 nmol) was injected intraarterially (i.a.). In paced papillary muscles, the drug produced a dose-dependent increase in developed tension. In spontaneously beating papillary muscles, MS-857 was ineffective on the ventricular automaticity. The drug increased sinus rate in SA node preparations and shortened AV conduction time by accelerating AV nodal conduction in AV node preparations. In all preparations, MS-857 increased coronary blood flow. The drug produced no arrhythmia in all doses tested. At doses which MS-857 produced a 50% increase in developed tension of papillary muscle, the drug also produces coronary vasodilatation with minimal chronotropic and dromotropic effects. In having such a cardiovascular profile, MS-857 resembles both milrinone and MCI-154 among few cardiotonic agents.     

Cardiac and coronary vasodilator effects of the novel cardiotonic agent, MCI-154, assessed in isolated, blood-perfused dog heart preparations

MCI-154 is a potent nonglycoside and non-sympathomimetic cardiotonic agent with a pyridazinone structure. We assessed its cardiac and coronary vasodilator effects by use of isolated, blood-perfused papillary muscle, sinoatrial (SA) node, and atrioventricular (AV) node preparations of dogs. The drug (1-100 nmol) was injected intraarterially. MCI-154 increased the force of contraction of paced and unpaced papillary muscles but failed to affect the rate of automaticity of the latter. It increased sinus rate and shortened AV conduction time by accelerating AV nodal conduction, but in all doses examined it produced no arrhythmias. In all preparations, it increased blood flow. All the effects were long-lasting (1-2 h). MCI-154, however, was not homogeneously effective on these cardiovascular variables. The drug was nearly equieffective in producing a positive inotropic effect and coronary vasodilatation, but less effective in producing positive chronotropic and dromotropic effects. In having such a cardiovascular profile, MCI-154 most resembles milrinone among new cardiotonic agents, although unlike milrinone, its main mechanism of cardiotonic action is believed to be the sensitization of the contractile proteins to Ca2+. Whatever mechanisms are involved, the revealed cardiovascular profile of MCI-154 justifies its clinical trial in the treatment of heart failure.     

Cardiac versus coronary vasodilator actions of KB-944, a new calcium antagonist, assessed in isolated, blood-perfused heart preparations of dogs

We compared the cardiac and coronary vasodilator actions of a new calcium-antagonistic vasodilator, KB-944, in isolated, blood-perfused heart preparations of dogs. In all preparations KB-944 injected intra-arterially produced an increase in blood flow. In sinoatrial (SA) node preparations KB-944 decreased sinus rate and in large doses produced atrial standstill. In atrioventricular (AV) node preparations KB-944 increased AV conduction time and in large doses produced second- or third-degree AV block only when injected into the artery supplying the AV node. In the same preparations KB-944 had virtually no effect on AV conduction when injected into the artery supplying the His-Purkinje-ventricular system. In papillary muscle preparations KB-944 in medium and large doses depressed force of contraction, the depressant action being greater at high rates of contraction. In the same kind of preparations KB-944 affected automaticity slightly and inconsistently. Depression by KB-944 of SA nodal automaticity and AV nodal conduction occurred pari passu with coronary vasodilation, whereas force of contraction was depressed to a lesser extent in coronary vasodilator doses. In these respects, KB-944 resembles verapamil and diltiazem rather than nifedipine and nicardipine.     

Coronary vasodilator compared to cardiac effects of PY 108-068, a new dihydropyridine vasodilator, on isolated, blood-perfused dog-heart preparations

We evaluated coronary vasodilator and cardiac effects of PY 108-068 on isolated, blood-perfused sinoatrial (SA) node, atrioventricular (AV) node, and papillary muscle preparations of dogs. PY 108-068 was administered intra-arterially (i.a.). PY 108-068 increased (coronary) blood flow in all preparations. In SA node preparations, the drug produced a decrease in sinus rate and, in large doses, atrial standstill. In AV node preparations, the drug produced an increase in AV conduction time. Large doses caused second- or third-degree AV block, but only when injected into the artery supplying the AV node. The doses producing a 15% (nearly half maximum) decrease in sinus rate or a 15% (nearly half maximum) increase in AV conduction time were two to three times the doses that doubled coronary blood flow. In paced papillary muscle preparations, the drug produced a decrease in the force of contraction. However, the dose required to reduce the force of contraction of the papillary muscle by 50% was about 30 times the dose that doubled coronary blood flow. The drug was entirely ineffective on rate of ventricular automaticity. We conclude that PY 108-068 is not likely to produce reflex tachycardia when administered systemically in coronary vasodilator doses.     

Presynaptic inhibitory actions of lignocaine in canine isolated, blood-perfused atrial preparations

1. Cardiac effects of lignocaine on sinoatrial nodal pacemaker activity and atrial contractility were investigated in five canine isolated, blood-perfused right atria that were perfused with heparinized blood from support dogs. The effects of lignocaine on responses to intracardiac nerve stimulation and administered acetylcholine and noradrenaline were also examined. 2. Lignocaine was injected into the support dog intravenously or administered selectively to the sinus node artery of the isolated atrium. At doses that did not produce significant depressor action (0.3, 1.0 and 3.0 mg/kg), lignocaine produced no significant changes in heart rate. A large dose of 10 mg/kg lignocaine caused significant depressor effects and slight bradycardia. Direct administration of lignocaine (0.3, 1.0, 3.0, 10.0 and 30.0 mumol) into the sinus node artery of the isolated atrium consistently caused slight negative chronotropic and rather marked negative inotropic effects. 3. After treatment with a relatively large dose of lignocaine, electrical stimulation-induced negative chronotropic and inotropic responses were significantly inhibited in a dose-related manner, but positive chronotropic and inotropic responses were slightly depressed only at an extremely high dose of lignocaine (10.0 mumol). 4. Noradrenaline-induced positive chronotropic and inotropic effects were not modified by any doses of lignocaine used (0.3, 1.0, 3.0 and 10.0 mumol). Acetylcholine-induced negative chronotropic and inotropic effects were slightly, but significantly, depressed by 10 mumol lignocaine. 5. These results suggest that a relatively large dose of lignocaine has a dominant presynaptic inhibitory action, particularly on the parasympathetic component.     

The first demonstration of CGRP-immunoreactive fibers in canine hearts: coronary vasodilator, inotropic and chronotropic effects of CGRP in canine isolated, blood-perfused heart preparations

CGRP-immunoreactive nerve fibers were histologically stained in the endocardium and perivascular layer of coronary vessels of canine hearts. To examine the physiological role of the CGRP in the heart function, effects of exogeneous CGRP on the hearts were studied using canine isolated, blood-perfused heart preparations. CGRP exerted dose-related potent vasodilator effects with a minimal increase in the developed tension of the papillary muscle, but slightly decreased the sinoatrial rate. The vasodilator effects were unaffected by the pretreatment of either atropine or propranolol. These specific functional effects on the coronary artery are well in accordance with the anatomical localization of CGRP. Taken together, CGRP seems to play an important role in the regulation of coronary vascular tone, while it has only a small functional role in inotropism and chronotropism in canine hearts.     

Chronotropic, inotropic, dromotropic and coronary vasodilator effects of bisaramil, a new class I antiarrhythmic drug, assessed using canine isolated, blood-perfused heart preparations.

The cardiovascular effects of a new class I antiarrhythmic drug, bisaramil, were examined using canine isolated, blood-perfused heart preparations. Bisaramil exerted negative chronotropic, inotropic and dromotropic effects as well as coronary vasodilator action, which are qualitatively the same as those of classical class I drugs. The selectivity of bisaramil for the intraventricular conduction vs the other cardiac variables was compared with that of disopyramide and flecainide. Bisaramil was the most selective for intraventricular conduction, while it was the least selective for ventricular muscle contraction. We conclude that bisaramil may become a useful antiarrhythmic drug with less cardiac adverse effects.     

Profile of cardiovascular effects of NKH477, a novel forskolin derivative, assessed in isolated, blood-perfused dog heart preparations: comparison with isoproterenol.

Cardiac and coronary vasodilator effects of NKH477, a novel water-soluble forskolin derivative, and isoproterenol, a nonselective beta-adrenoceptor full agonist, were compared in isolated, blood-perfused papillary muscle, sinoatrial (SA) node, and atrioventricular (AV) node preparations of dogs. Both agents were injected intraarterially. The two agents increased the force of contraction of the paced papillary muscle and of the unpaced muscle, and the rate of automaticity of the latter. They increased sinus rate and accelerated AV nodal conduction. In producing these cardiac effects, both agents were similar, although NKH477 was 120-350 times less potent than isoproterenol; however, NKH477 differed distinctly from isoproterenol in that the former increased coronary blood flow more greatly than the latter. Thus, NKH477 is more coronary vasodilatory than positive inotropic, and more positive inotropic than positive chronotropic. Such a cardiovascular profile of NKH477 was similar to that of forskolin, except for the duration of actions; NKH477 was longer-acting than forskolin.     

Pharmacologic analysis of ketamine-induced cardiac actions in isolated, blood-perfused canine atria

Effects of ketamine were investigated on atrial rate and contractile force in the isolated, blood-perfused canine atrium. When a relatively small dose (3 micrograms) of ketamine was injected into the sinus node artery, positive chronotropic and inotropic responses were consistently observed. With doses of 10-300 micrograms i.a., biphasic (i.e., negative followed by positive) chronotropic and inotropic responses were induced. An extremely large dose of ketamine frequently produced biphasic chronotropic and only negative inotropic responses. The negative effects of ketamine were not affected by atropine pretreatment. After treatment with propranolol or imipramine, the positive effects were significantly suppressed. The effects were not influenced by tetrodotoxin. These results suggest that ketamine has (a) indirect cardioexcitatory properties mediated by a release of catecholamines which is due to a tyramine-like action, and (b) direct cardioinhibitory properties by which high doses depress the contractility rather than the pacemaker activity.     

Effects of tetrodotoxin and imipramine on the cardiac responses to nicotine in isolated, blood-perfused canine heart preparations.

The effects of nicotine on the sinus rate and atrial or left ventricular contractile force were investigated in the isolated, blood-perfused dog right atrium and left ventricle. Nicotine (3-300 nmol) in the right atrium induced dose-dependent negative followed by positive chronotropic and inotropic responses, whereas nicotine caused only a positive inotropic response in the left ventricle. The negative responses to nicotine were blocked by atropine, hexamethonium (C6), and tetrodotoxin (TTX). The positive effects of nicotine were abolished by propranolol and C6. TTX significantly inhibited the positive responses to nicotine by about 50% in the atrial preparation and totally suppressed them in the left ventricle. Imipramine inhibited the positive cardiac responses to nicotine and tyramine, but potentiated the responses to noradrenaline (NA) in atrial and ventricular preparations. These results suggest that (a) nicotine induces negative and positive cardiac effects mediated by parasympathetic ganglionic nicotinic receptors and presynaptic nicotinic receptors of the postganglionic sympathetic nerves, respectively, in the dog heart; (b) there are few parasympathetic ganglionic cells in the dog left ventricle; (c) the positive cardiac responses to nicotine are caused by both TTX-sensitive and TTX-insensitive NA release mechanisms; and (d) imipramine inhibits the positive cardiac responses to nicotine at the presynaptic nicotinic receptor sites of the postganglionic sympathetic nerves.     

Direct cardiac effects of a novel vesamicol receptor ligand, m-iodobenzyl-trozamicol, assessed in the canine isolated, blood-perfused heart preparations

MIBT, m-(iodobenzyl)trozamicol, is a recently discovered vesamicol analogue that can be used as a functional marker of cholinergic activity in the heart as well as the brain. The purpose of this study was to assess the effects of MIBT on sinus node automaticity, ventricular contraction, and coronary blood flow in addition to the action-potential duration of the ventricle by using canine isolated, blood-perfused sinoatrial node and papillary muscle preparations. Intracoronary administration of MIBT (1-300 microg) exerted negative chronotropic, inotropic, and coronary vasodilator effects in a dose-related manner. Pretreatment of the preparations with the muscarinic receptor antagonist atropine did not change these effects of MIBT. Moreover, MIBT had little effect on the repolarization phase of the ventricular action potential. Because the doses of MIBT needed for imaging cardiac cholinergic function were much lower than those affecting the cardiovascular system, MIBT may be used safely in future clinical applications.     

Chronotropic and inotropic effects of kampo extracts in the canine isolated, blood-perfused heart preparations

Cardiac effects of drugs used for circulatory disorders in traditional Japanese medicine based on ancient Chinese medicine (Kampo Medicine): Saikoka-ryukotsu-borei-to, Oren-gedoku-to, Toki-shakuyaku-san, Shimbu-to, Moku-boi-to, Ryo-kei-jutsu-kan-to, Sha-kanzo-to, Keishi-ninjin-to, Toki-to and Ryo-kan-kyo-mi-shin-ge-nin-to were investigated using canine isolated, blood-perfused sinoatrial node and papillary muscle preparations. Single injections of small doses of Oren-gedoku-to, Moku-boi-to and Ryo-kan-kyo-mi-shin-ge-nin-to (0.1 to 3 mg) dose-dependently increased the sinoatrial rate and the developed tension of papillary muscle, while other drugs showed almost no effect on these parameters. All the drugs had almost no effect on the blood flow through the nutrient arteries of each preparation. The positive chronotropic and inotropic effects induced by Oren-gedoku-to, Moku-boi-to and Ryo-kan-kyo-mi-shin-ge-nin-to did not show tachyphylaxis and were not affected after pharmacological denervation by tetrodotoxin treatment or by reserpine pretreatment, but were significantly suppressed by atenolol. These results indicate that these three drugs act as beta-adrenoceptor agonists to produce clinically useful cardiac effects.     

Acadesine attenuates ischemic cardiac dysfunction in the isolated blood-perfused rabbit heart

Acadesine (AICA-riboside) is a nucleoside analog with cardioprotective properties. Most previous studies demonstrating cardioprotection with acadesine have been conducted in buffer-perfused hearts, and no study has investigated the dose-response relationship to acadesine in a blood-perfused model. The objective of this study was to investigate the dose-related cardioprotective effects of acadesine in donor-perfused, isolated rabbit hearts subjected to 12 × 3 min episodes of global ischemia with intervening periods of reperfusion of 5 min duration. Five groups of hearts were studied: saline control and four treatment groups of acadesine, 0.1, 0.2, 0.5, 2.0 gm/kg/min (0.4, 0.8, 2.0, 8.0 μmol/kg/min) constant intravenous infusion to the support animal. Left ventricular (LV) pressure and coronary blood flow (CBF) in the isolated hearts were measured. In control hearts, baseline LV developed pressure averaged 129 ± 7 mmHg and declined to 43 ± 3% of baseline after 12 periods of ischemia and reperfusion. Acadesine significantly improved recovery of function at the lower doses tested, i.e., hearts treated with 0.1, 0.2, and 0.5 mg/kg/min (0.4, 0.8, 2.0 μmol/kg/min) recovered 61 ± 5%, 67 ± 7%, and 65 ± 7% of LV pressure, respectively (P < 0.05 vs. saline). This protective effect was not observed with the highest dose of acadesine, 2.0 mg/kg/min (8.0 μmol/kg/min) (52 ± 6%). The greatest recovery of function corresponded to plasma acadesine concentrations of 27 ± 6.0 μM, but the beneficial effect was lost when plasma concentrations reached 205 ± 28 μM. These results suggest that repetitive episodes of ischemia and reperfusion induced stunning in isolated blood-perfused rabbit hearts, and that the severity of this dysfunction is attenuated by treatment with acadesine. © 1994 Wiley-Liss, Inc.     

Cardiac effects of clinically available Kampo medicine assessed with canine isolated, blood-perfused heart preparations

Cardiac effects of 10 kinds of clinically available Kampo medicines were investigated: Kakkon-to (TJ-1), Dai-saiko-to (TJ-8), Boi-ogi-to (TJ-20), Chorei-to (TJ-40), Rokumi-gan (TJ-87), Tsu-do-san (TJ-105), Gosha-jinki-gan (TJ-107), San'o-shashin-to (TJ-113), Sairei-to (TJ-114) and Inchin-gorei-san (TJ-117). Chronotropic and inotropic effects were studied using canine isolated, blood-perfused heart preparations, while subcellular mechanisms were analyzed by measuring the drug-induced changes of the adenylate cyclase activity in the canine ventricular membrane preparation. Intracoronary injections of TJ-1, TJ-20, TJ-105 and TJ-113 increased the sinoatrial rate and developed tension of papillary muscle in a dose-related manner, which was significantly attenuated by the pretreatment of the preparations with beta-blocker propranolol. Meanwhile, the other extracts hardly affected these parameters. TJ-1, TJ-20 and TJ-113 increased the adenylate cyclase activity in a dose-related manner, but their potency was significantly less compared with that by an equivalent concentration of isoproterenol. Moreover, TJ-105 did not increase the adenylate cyclase activity. These results suggest that the positive chronotropic and inotropic effects of TJ-1, TJ-20, TJ- 105 and TJ-113 may be exerted through the direct stimulation of the beta-adrenoceptor and/or the norepinephrine release from the postganglionic nerve terminals in the heart.     

The effects of aminophylline on adenosine and ATP actions on sinoatrial conduction in the isolated, blood-perfused dog atrium

The effects of adenosine and adenosine triphosphate (ATP) on sinus cycle length (SCL) and sinoatrial conduction time (SACT) estimated by constant atrial pacing were studied in isolated, blood-perfused canine right atria. Adenosine and ATP were infused into the sinus node artery at a rate of 1, 2 and 4 micrograms/min. Both adenosine and ATP caused an increase in SCL and SACT in a dose-dependent manner and decreased atrial developed tension. There was no significant difference between the effect of adenosine and that of ATP on SCL and SACT. The prolongation of SACT induced by 4 micrograms/min of adenosine and ATP was significantly inhibited by a single injection of 1 to 3 mg of aminophylline, although this dose level of aminophylline did not significantly suppress the prolongation of SCL produced by adenosine and ATP. From these results it is concluded that both adenosine and ATP lengthen SCL and SACT in a dose-related manner, and that aminophylline blocks the increase in SACT much more easily than that in SCL.     

Inotropic versus chronotropic, dromotropic, and coronary vasodilator actions of DPI 201-106, a novel positive inotropic agent, in the dog heart

Inotropic versus chronotropic, dromotropic, and vascular effects of DPI 201-106 were assessed in isolated, blood-perfused papillary muscle, sinoatrial (SA) node, and atrioventricular (AV) node preparations of dogs. DPI 201-106 was administered intraarterially. In paced papillary muscles the drug produced an increase in developed tension. In spontaneously beating papillary muscles the drug slightly decreased the beating rate. In SA node preparations the drug decreased sinus rate, and atrial standstill ensued from the highest dose. In AV node preparations the drug affected AV conduction only when administered into the AV node artery, and in high doses second- or third-degree AV block occurred. In all preparations the drug increased blood flow. DPI 201-106 at the dose that produced a 50% increase in the force of contraction of ventricular muscle increased coronary blood flow by 8.4%, AV conduction time by 7.6%, and decreased sinus rate by 2.6%, indicating its high selectivity for force. When infused into the AV node artery, the drug in high doses produced dose-dependent prolongations of both the AV nodal conduction time and the functional refractory period of the AV node, which were pronounced with elevation of the pacing rate. These effects of DPI 201-106 are very similar to those of calcium channel blockers.     

A Na+/Ca2+ exchanger inhibitor, KB-R7943, caused negative inotropic responses and negative followed by positive chronotropic responses in isolated, blood-perfused dog heart preparations

Effects of a Na+/Ca2+ exchanger inhibitor, KB-R7943 (2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl] isothiourea methanesulfonate), on the sinoatrial nodal pacemaker activity, atrial contractility and ventricular contractility were investigated in the isolated and blood-perfused right atrium and left ventricle of the dog. KB-R7943 (0.03- 3 micromol) induced negative inotropic effects and negative followed by positive chronotropic effects in the right atrium and negative inotropic effects in the left ventricle. Neither atropine nor hexamethonium affected the cardiac responses to KB-R7943. Propranolol attenuated the positive chronotropic response to KB-R7943 but imipramine did not. Tetrodotoxin potentiated the positive chronotropic response to KB-R7943 in 6 of 11 isolated atria. When NaCl infusion increased atrial contractile force and atrial rate, KB-R7943-induced negative inotropic and chronotropic responses were attenuated in a dose-dependent manner. CaCl2 infusion potentiated the negative chronotropic response to KB-R7943 but did not affect the inotropic response significantly. On the other hand, ouabain (17 nmol) attenuated the negative inotropic response, but not chronotropic response, to KB-R7943. These results suggest that KB-R7943-induced cardiac effects relate to the Na+ activity, probably mediated through the Na+/Ca2+ exchanger, and the Na+/Ca2+ exchanger modifies the pacemaker activity and myocardial contractility in the dog heart.     

The chronotropic actions of guanethidine and reserpine on the isolated dog heart

Summary Administration of reserpine to a heart-lung preparation about 140 min after the addition of guanethidine, when the chronotropic action of the latter had levelled off, produces a rise in heart rate with a peak equal to that observed when reserpine is given alone. Addition of reserpine to a heart-lung prepared from reserpinized dogs after partial repletion of the stores with noradrenaline does not increase the heart rate in contrast to the action of guanethidine which under the same conditions results in a marked increase in rate. These experiments indicate that guanethidine and reserpine act on different sites and lend further support to the concept that at least two noradrenaline stores exist.With 2 Figures in the Text