Effects of the new dihydropyridine derivative 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl 6-(5-phenyl-3-pyrazolyloxy)hexyl ester on the cardiohemodynamics and the energy metabolism of ischemic myocardium

To characterize the effects of a new calcium antagonist of the dihydropyridine type, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic++ + acid methyl 6-(5-phenyl-3-pyrazolyloxy) hexyl ester (CV-159) on the cardiovascular system, experiments were performed in the anesthetized open-chest dogs and in the heart-lung preparation with a support dog in comparison with those of nicardipine. In the anesthetized dog CV-159 (1-30 micrograms/kg) produced a dose-related decrease in mean blood pressure with a decrease in total peripheral resistance, and an increase in coronary flow. There was a reflex increase in heart rate, aortic flow and left ventricular dP/dtmax. Nicardipine (1-30 micrograms/kg) produced qualitatively similar changes in these parameters, although the onset of action was quicker and the duration shorter. Hypotensive effects of CV-159 were approximately three times less potent than those of nicardipine. In doses above 3 micrograms CV-159 produced a long-lasting increase in coronary flow and slight negative inotropic and chronotropic effects in the heart-lung preparation. In doses above 1 microgram nicardipine produced an increase in coronary flow without producing any change in the cardiac functions. The increase in coronary flow produced by these two compounds was not associated with an increase in myocardial oxygen consumption. Studies conducted with 31P-NMR in the isolated perfused heart preparation of the rat demonstrated no improvement of the ischemic derangement of the myocardial energy metabolism with doses of CV-159 and nicardipine producing an increase in coronary flow rate, but no change in myocardial oxygen demand as assessed by heart rate X left ventricular pressure.     

Pharmacological analyses of hydralazine-induced cardiac action in intact dogs and isolated, blood-perfused canine atria

The effects of hydralazine (HYD) on heart rate and blood pressure in the intact dog and on atrial rate and contractile force in the isolated atrium were investigated. HYD (0.1-1 mg) injected into the sinus node artery produced double peaked positive inotropic and negative chronotropic effects in a dose-related manner. The initial positive inotropic and negative chronotropic responses were not affected by propranolol and atropine, respectively. The second positive inotropic response was inhibited by propranolol or reserpine, but it was not suppressed by imipramine or tetrodotoxin. When HYD (0.1-1 mg/kg) was administered intravenously to the donor dog, an initial increase followed by a decrease in blood pressure and an increase in heart rate were observed. In the isolated atrium, an increase in contractile force was induced. The increases of blood pressure and heart rate in the donor dog and the positive inotropic effect in the isolated atrium after HYD treatment were suppressed by reserpine. These results suggest that HYD has direct positive inotropic and negative chronotropic effects and indirect cardiac stimulating effects caused by a release of catecholamines from sympathetic nerve terminals, and that HYD-induced catecholamine release is not mediated by a tyramine-like action or via nerve excitation.     

The inotropic and chronotropic responses of isolated canine atrium to 5-(3-tert.-butylamino-2-hydroxy)propoxy-3,4-dihydrocarbostyril hydrochloride (carteolol)

Direct effects of 5-(3-tert.-butylamino-2-hydroxy) propoxy-3,4-dihydrocarbostyril hydrochloride (carteolol) on chronotropic and inotropic activity were investigated in seventeen isolated atrium preparations which were suspended in a bath and perfused with arterial blood from the heparinized donor dog. Carteolol has little adrenergic beta-receptor stimulating effect in doses which block prominent positive chronotropic and inotropic effects of norepinephrine. At relatively larger doses, however, carteolol produced a long-lasting positive chronotrophic and inotropic effect. At extremely larger doses, carteolol produced a negative inotropic effect with little or slight negative chronotropic effect. In propranolol-treated preparations, carteolol induced less positive effects. Propranolol-induced negative chronotropic and inotropic effects were significantly reduced by treatment with carteolol. From these results, carteolol has not only potent beta-adrenoceptor blocking property but also sympathomimetic activity, and different beta 1-type cardiac adrenergic receptors may probably be suggested.     

Effects of ketanserin on the pacemaker activity and contractility in the isolated, blood-perfused dog atrium

Effects of ketanserin on the pacemaker activity and atrial contractility and on 5-hydroxytryptamine (5-HT)-induced cardiac responses were investigated in the isolated, blood-perfused dog atrium. Ketanserin (1-300 micrograms) injected into the sinus node artery evoked a transient positive followed by a negative chronotropic effect, and a dose above 30 micrograms of ketanserin produced a dose-dependent negative inotropic effect with a little positive one. Ketanserin-induced negative chronotropic and inotropic effects were not affected by atropine in a dose which blocked ACh-induced responses. Propranolol inhibited positive inotropic responses to ketanserin and norepinephrine and significantly augmented the negative chronotropic and inotropic responses to ketanserin. Imipramine did not affect the transient positive followed by negative chronotropic and the negative inotropic responses to ketanserin but it induced the positive cardiac responses following the negative ones. Tetrodotoxin, phentolamine, and diphenhydramine did not modify the effects of ketanserin. From these results, it is concluded that ketanserin might induce the direct negative chronotropic and inotropic effects and the indirect effects by catecholamine release. Ketanserin-induced catecholamine release might not be due to tyramine-like or nicotine-like action. Ketanserin significantly inhibited a low dose (3 micrograms) of 5-HT-induced negative chronotropic and inotropic effects, suggesting the possibility of 5-HT2 receptors in the isolated dog atrium.     

Beta-adrenoceptor blocking effects of a selective beta 2-agonist, mabuterol, on the isolated, blood-perfused right atrium of the dog.

1. Effects of (+/-)-1-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-tert.- butylamino-ethanol hydrochloride (mabuterol) on pacemaker activity and atrial contractility were investigated in the isolated and blood-perfused right atrium of the dog. 2. Mabuterol, injected into the sinus node artery of the isolated atrium, dose-dependently increased atrial rate and contractile force at doses of 0.01-10 nmol but the responses to over 10 nmol of mabuterol gradually decreased and mabuterol at higher doses induced biphasic cardiac responses, i.e., negative followed by positive cardiac responses. 3. The maximal increases in atrial rate and contractile force induced by mabuterol were 41.4% and 12.9%, respectively, of the maximal chronotropic and inotropic effects of isoprenaline. 4. Positive chronotropic and inotropic responses to mabuterol were dose-dependently inhibited by a selective beta 2-adrenoceptor antagonist, ICI 118,551. These responses were only slightly attenuated by atenolol. 5. Mabuterol (1-300 nmol) dose-dependently inhibited both dobutamine- and procaterol-induced positive chronotropic and inotropic responses. 6. These results indicate that mabuterol causes weak positive chronotropic and inotropic effects on the perfused canine right atrium by activating beta 2-adrenoceptors, and that higher concentrations non-selectively block both beta 1-and beta 2-adrenoceptors.     

Electroencephalographic and cardiovascular effects of milnaciplan hydrochloride (TN-912), a novel antidepressant]

The electroencephalographic (EEG) and cardiovascular effects of milnaciplan hydrochloride (TN-912) were compared with those of imipramine (IMP) and maprotiline (MPT) in rats, guinea pigs and dogs. In conscious rats with chronic electrode implants, TN-912 (10-100 mg/kg, p.o.) had little effect on either the EEG activity or the EEG arousal response to auditory stimulation (2000 Hz). Both IMP (10-100 mg/kg, p.o.) and MPT (10-100 mg/kg, p.o.) tended to increase the drowsy EEG pattern period in the cortical and hippocampal EEG and inhibited the EEG arousal response to auditory stimulation. In conscious rats with a chronic arterial catheter, TN-912 (100 mg/kg, p.o.) slightly elevated the mean blood pressure (MBP) and decreased the heart rate (HR), while both IMP (10-100 mg/kg, p.o.) and MPT (10-100 mg/kg, p.o.) dose-dependently increased MBP and HR. In anesthetized dogs, i.v. injection of TN-912 (1-10 mg/kg), IMP (0.3-10 mg/kg) and MPT (1-20 mg/kg) produced a dose-dependent fall in MBP. IMP and MPT but not TN-912 dose-dependently increased HR. TN-912 did not show typical effects on femoral blood flow. TN-912 (30 mg/kg) had little effect on lead II electrocardiogram (ECG), while IMP and MPT markedly increased height of the T-wave on ECG. In the in vitro study with the isolated guinea pig atrium, TN-912 caused a slight positive inotropic and negative chronotropic effect, while both IMP and MPT showed marked negative inotropic and chronotropic actions. These results suggest that TN-912 has less EEG effect and cardiac toxicity, indicating that TN-912 may be safe in clinical use.     

Selective impairment of atrioventricular conduction by 2-(2-pyridyl)-ethylamine and 2-(2-thiazolyl)-ethylamine, two histamine H1-receptor agonists.

To further characterize the receptor mediating histamine-induced impairment of atrioventricular conduction, the effects of two selective histamine H1-receptor agonists, 2-(2-pyridyl)-ethylamine (PEA) and 2-(2-thiazolyl)-ethylamine (ThEA), were investigated using the isolated guinea pig heart. These effects were compared with those of histamine and other selective agonists. PEA and ThEA produced a weak stimulation of cardiac rate and contractility; however, they produced a marked prolongation of atrioventricular conduction. The orders of relative potencies observed substantiate the hypothesis that H2-receptors mediate the positive inotropic and chronotropic effects and H1-receptors mediate the negative dromotropic effect of histamine.     

Effects of disopyramide on SA nodal pacemaker activity and contractility in the isolated blood-perfused atrium of the dog.

The isolated blood-perfused preparations of canine atrium were suspended in a bath and perfused with arterial blood led from the carotid artery of the heparinized donor dog. Disopyramide caused dose-related negative chronotropic and inotropic effects in a dose range of 30-1000 microgram when injected directly into the cannulated sinus node artery of the isolated atrium. The order of potencies for inducing the negative chronotropic effect in isolated atrium preparations was verapamil greater than propranolol greater than lidocaine = quinidine greater than phenytoin greater than or equal to disopyramide greater than procainamide. On the other hand, the order of potencies for inducing the negative inotropic effect was verapamil = propranolol greater than lidocaine greater than or equal to phenytoin greater than disopyramide greater than procainamide greater than or equal to quinidine. When disopyramide (1 mg/kg or 3 mg/kg) was administered i.v. into the jugular vein of the donor dog, the systemic blood pressure of the donor dog was markedly decreased. However, the tension developed and sinus rate of the isolated atrium were only slightly decreased. Disopyramide produced greater suppression at higher frequencies and slightly depressed the calcium chloride-induced positive inotropic effects.     

Inhibition by glibenclamide of negative chronotropic and inotropic responses to pinacidil, acetylcholine, and adenosine in the isolated dog heart.

The blocking effects of glibenclamide on the chronotropic and inotropic responses to K+ channel openers pinacidil (ATP-sensitive) and acetylcholine (ACh) or adenosine (receptor-operated) were investigated in the isolated, blood-perfused canine atrium or ventricle. Glibenclamide (0.1-3 mumol) induced no significant cardiac effects. Cumulative administration of pinacidil (0.03-3 mumol) dose-dependently decreased sinus rate much less than the contractile force of the atrial and ventricular muscles. Glibenclamide similarly inhibited the negative chronotropic and inotropic responses to pinacidil in a dose-related manner. A high dose of glibenclamide (3 mumol) slightly but significantly attenuated the negative chronotropic and inotropic responses to ACh and adenosine but not to verapamil. These results demonstrate that glibenclamide inhibits the negative chronotropic and inotropic responses to the ATP-sensitive K+ channel opener pinacidil and the receptor-operated K+ channel openers ACh and adenosine but more selectively antagonizes the responses to pinacidil in the dog heart and suggest that in contrast to ACh and adenosine, an ATP-sensitive K+ channel opener has a greater effect on the ventricle than on the sinoatrial node.     

Histamine H2-receptor antagonistic action of N-(3-[3-(1-piperidinylmethyl)phenoxy]propyl)acetoxyacetamide hydrochloride (TZU-0460)

The antagonism of histamine H2-receptor by N-(3-[3-(1-piperidinylmethyl)phenoxy)propyl)acetoxyacetamide hydrochloride (TZU-0460) was estimated on isolated guinea-pig right atrium and rat uterus in vitro and on gastric acid secretion in dog with Heidenhain pouch. The concentration-response curves for the positive chronotropic effect of histamine and dimaprit (S-[3-(N,N-dimethylamino) propyl]isothiourea) on atrium were displaced to the right in parallel without change in the maximum response by TZU-0460 with pA2 values of 6.56 and 6.74 and also for the relaxant effect on uterus with pA2 values of 6.81 and 6.65, respectively. There was no significant difference between the estimated pA2 values for TZU-0460 on the different tissues against the same agonist, and also between the pA2 values on the same tissue against the different agonists. The slope of the regression line of log (DR-1) against log TZU-0460 concentration on either tissue was not significantly different from unity; 0.98 (95% confidence limits, 0.81-1.14) on atrium, 0.95 (0.56-1.34) on uterus. These results indicate that TZU-0460 is a competitive antagonist of histamine and dimaprit in vitro. In Heidenhain pouch dog, TZU-0460 also competitively antagonized the stimulation of acid secretion by histamine with pA2 of 6.59 and by dimaprit with pA2 of 6.52, calculated on infused rates. These results indicate that TZU-0460 was about 6 times more potent than cimetidine.     

Sympathetic nerve stimulation activates both beta 1- and beta 2-adrenoceptors of SA and AV nodes in anesthetized dog hearts.

We investigated blocking effects of the selective beta 1-adrenoceptor blocker atenolol (0.1-100 micrograms/kg, i.v.), the selective beta 2-adrenoceptor blocker ICI 118,551 (1-1000 micrograms/kg, i.v.) and the combination of the two drugs on positive chronotropic and dromotropic responses to norepinephrine (NE) released by stimulation of the sympathetic nerves in anesthetized, neurally decentralized, open-chest dogs after atropine was given. Stimulation of the intracardiac sympathetic nerves to the SA nodal region or to the AV nodal region selectively increased heart rate or decreased AV conduction time, respectively. ICI 118,551 inhibited the chronotropic or dromotropic response to each stimulation in a dose-dependent manner, but its inhibition of the dromotropic response was less than that of the chronotropic response. Atenolol similarly inhibited either the positive chronotropic or dromotropic response to each stimulation in a dose-related manner. The combination of atenolol and ICI 118,551 attenuated the responses to each stimulation more than atenolol alone. These data indicate that sympathetic nerve stimulation activates both beta 1- and beta 2-adrenoceptors of the SA and AV nodes and that the proportion of beta 2-adrenoceptor-mediated effects on the AV node is less than that on the SA node. These results suggest that neurally released NE in part controls physiological functional cardiac responses mediated through beta 2-adrenoceptors, in addition to the responses predominantly mediated through beta 1-adrenoceptors.     

In vivo and in vitro assessment of the cardiovascular effects of 8-(benzylthio)-N6-n-butyl-cyclic AMP

In the canine heart-lung preparation (HLP) and the anesthetized open-chest dog, both 8-(Benzylthio)-N6-n-butyl-cyclic AMP (BTB-cyclic AMP) (10 times more potent) and dibutyryl-cyclic AMP (DB-cyclic AMP) produced a definite positive inotropic effect (PIE) and an increase in the coronary blood flow with either no change (HLP) or a slight increase (anesthetized animal) (BTB-cyclic AMP) and a definite increase in the heart rate (DB-cyclic AMP). In the isolated atrial preparations of the guinea pig (AG), BTB-cyclic AMP produced a slight PIE at 3 X 10(-5) M and a negative chronotropic effect at 3 X 10(-4) M. Aminophylline reversed the latter to the positive one, while potentiating the former. At 10(-3) M marked positive inotropic and chronotropic effects were observed. DB-cyclic AMP was without effects. In the right ventricular papillary muscle preparations of the guinea pig (PMG), both compounds produced PIE. BTB-cyclic AMP initiated a contraction (AG) and a "slow" action potential (PMG) in partially depolarized preparations. Both of these effects were abolished by diltiazem. BTB-cyclic AMP (10(-3) M) suppressed the heart rate increase induced by isoproterenol in right AG. It was concluded that BTB-cyclic AMP was a cardiotonic agent with a relatively weak positive chronotropic effect and that the cardiotonic effect was ascribable to the initiation of slow action potentials and related contractions.     

Novel positive inotropic agents: synthesis and biological activities of 6-(3-amino-2-hydroxypropoxy)-2(1H)-quinolinone derivatives.

A series of 6-(3-amino-2-hydroxypropoxy)-2(1H)-quinolinones has been synthesized and evaluated for positive inotropic activity on the canine heart. Some of these derivatives have a potent activity with none or negative chronotropic effect in isolated, blood-perfused dog heart preparations. They also display a high selectivity for positive inotropic effect over chronotropic and vasodilatory effects in anesthetized dogs. (+/-)-6-[2-Hydroxy-3-[(3-methoxybenzyl)amino]propoxy]-2(1H)-quinolinone (39) and (+/-)-6-[3-(3,4-dimethoxybenzyl)amino]-2-hydroxypropoxy]-2 (1H)-quinolinone (40) were further investigated in conscious dogs. After iv administration, they did not affect heart rate or mean blood pressure at the dose producing a 50% increase in the peak of the first derivative of the left ventricular pressure. The compounds (39, OPC-18750, and 40, OPC-18790) are the most promising agents with desirable biological activities, and now are currently undergoing clinical evaluation.     

Suppression of strychnine on the chronotropic and inotropic effects in the isolated, blood-perfused canine atrium

In the isolated, blood-perfused dog atrium, strychnine evoked dose-dependent decreases in atrial rate and contractile force, and the negative cardiac effects were not influenced by atropine. Strychnine suppressed dose-dependently the negative chronotropic and inotropic responses to intramural parasympathetic nerve stimulation, but not the response to acetylcholine. These results suggest that strychnine has direct cardiac depressant properties and inhibits the release of acetylcholine from parasympathetic nerve terminals in isolated dog atrium.     

Comparison of the Arrhythmogenic Actions of (-)-Isoprenaline, Dobutamine and the selective beta 1-adrenoceptor agonist, (+/-)-(1-[3',4'-dihydroxyphenoxy] -2-hydroxy-[3",4"-dimethoxy phenethylamino]-propane)-oxalate (Ro 363)

In guinea-pig left atrial preparations, concentrations of (-)-isoprenaline and (+/-)-(1-[3',4'-dihydroxyphenoxy] -2-hydroxy-[3",4"-dimethoxyphenethylamino]-propane)-oxalate (Ro 363) causing maximal inotropic responses produced small reductions in effective refractory period. Dobutamine had little effect on the refractory period except at supramaximal inotropic concentrations, when increases in effective refractory period were produced. Isolated perfused heart preparations from guinea-pigs developed arrhythmic contractions following the administration of (-)-isoprenaline, Ro 363 and dobutamine in doses producing 70-100% of their maximal chronotropic responses. The arrhythmogenic activity of the three agonists paralleled their respective beta 1-receptor stimulant properties. In chloralose-anaesthetized cats, the 3 agonists, (-)-isoprenaline, Ro 363 and dobutamine, when compared to epinephrine (adrenaline), were essentially devoid of arrhythmogenic activity in animals in which cardiac sensitization was induced by 3-dimethylamino-2-methyl-2-phenoxypropiophenone hydrochloride (U-0882) or halothane. However, all 3 agonists elicited ventricular arrhythmias following the administration of subarrhythmic doses of ouabain and increased the number of subauricular escape beats which occurred during vagal nerve stimulation in non-ouabain treated animals. In all cases the arrhythmogenic activity of the drugs paralleled their relative activity for eliciting rises in heart rate.     

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.     

2-[(二乙胺)乙酰]-1,2,3,4-四氢-6,7-二甲氧基-1-[1′-(6″-甲氧-2″-萘)乙基]-异喹啉对离体豚鼠乳头状肌和心房的抑制作用(英文)

目的:研究2-[(二乙胺)乙酰]-1,2,3,4-四氢-6,7-二甲氧基-1-[1′-(6″-甲氧-2″-萘)乙基]-异喹啉(CPU57)对心脏的作用并与硝苯地平进行比较,着重于其作用机制的研究.方法:测量并记录以下参数:1)豚鼠右心房自发收缩的节律及张力;2)电刺激左心房和右室乳头状肌的等长收缩力.结果:CPU57象经典的钙拮抗剂硝苯地平一样,在0.01-100 μmol·L~(-1)浓度范围内对离体豚鼠心脏具有浓度依赖的负性频率和负性肌力作用,而前者明显弱于后者,且其对心脏的抑制作用比硝苯地平弱.将正常胞外Ca~(2 )浓度从1.5 mmol·L~(-1)降低至0.3或增高至7.5 mmol·L~(-1)可分别增强或减弱CPU57对电刺激左心房收缩的抑制作用.CPU57(1—10 μmol·L~(-1))还抑制CaCl_2所致电刺激左心房的量—效收缩曲线,pD_2′值为4.77.结论:CPU57对豚鼠心脏具有钙拮抗作用.     

Antihypertensive and cardiovascular effects of the new dihydropyridine derivative methyl (E)-3-phenyl-2-propen-1-yl-1,4-dihydro-2,6-dimethyl- 4-(3-nitrophenyl)pyridine-3,5-dicarboxylate

The hypotensive and cardiovascular effects of a newly synthetized dihydropyridine derivative, methyl (E)-3-phenyl-2-propen-1-yl-1,4-dihydro-2,6-dimethyl-4-(3- nitrophenyl)pyridine-3,5-dicarboxylate (FRC-8411) were investigated in rats, guinea pigs, and rabbits, in comparison with nifedipine, nicardipine, and diltiazem. In conscious hypertensive rats, FRC-8411 (0.3-3 mg/kg p.o.) was found to be an orally effective antihypertensive agent and its effect lasted for more than 7 h. This effect was gradual and yet much more potent and longer than those of other reference drugs. An accompanied tachycardia was observed after oral administration of FRC-8411 and other dihydropyridine derivatives. In anesthetized rats, FRC-8411 (3-30 micrograms/kg i.v.) also showed a gradual, potent and long-lasting hypotension with a tachycardia. FRC-8411 (up to 3 mg/kg i.v.) had no effect on the PQ interval of the ECG in anesthetized rats. In isolated guinea pig atria, FRC-8411 (10(-9) - 3 X 10(-8) mol/l) showed a negative chronotropic effect, but a higher dose of the drug was needed for induction of the negative inotropic effect. In K+-depolarized rabbit aorta and guinea pig taenia coli, FRC-8411 (3 X 10(-9) - 3 X 10(-7) and 10(-7) - 3 X 10(-7) mol/l) showed a dose-dependent inhibition of the calcium-induced contraction, and its pA2 value was 8.4 and 7.1, respectively. FRC-8411 had a much higher sensitivity to the aorta than the taenia coli, though it was less potent than nifedipine and nicardipine in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiovascular profile of Ro 13-6438, a novel positive inotropic agent with vasodilating properties

The cardiovascular properties of Ro 13-6438 (R-6-chloro-1,5-dihydro-3- methylimidazo -[2,1-b] quinazolin -2[ 3H]-one), a novel nonglycoside , noncatechol cardiotonic agent, were investigated in vitro and in vivo by both intravenous and oral administration. Ro 13-6438 increased tension development of isolated guinea pig left atria in a concentration-dependent manner with an EC50 of 30 microM, but had no stimulant effect on the spontaneous rate of right atria. The positive inotropic effect of Ro 13-6438 was additive to that of ouabain (0.1 microM); Ro 13-6438 suppressed the arrhythmogenic activity of high concentrations of ouabain (10 microM). IN anesthetized open-chest dogs 10-300 micrograms/kg Ro 13-6438 i.v. produced a significant and dose-dependent increase in myocardial force, with a duration of action exceeding 60 min following the highest dose. It also slightly increased heart rate, cardiac output, and blood flow. Ro 13-6438 decreased systolic and diastolic blood pressure, left ventricular end-diastolic pressure, and total peripheral resistance. Thus, the direct positive inotropic effects of Ro 13-6438 were supported by a decrease in preload and afterload. In chronically instrumented, conscious dogs Ro 13-6438 increased myocardial contractility after administration of 0.03-0.3 mg/kg i.v. or 3-10 mg/kg p.o. The effects persisted for greater than 8 h after oral administration of 10 mg/kg. The inotropic effects were accompanied by a modest increase in heart rate, which, however, had a clearly shorter duration of action than the former.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of 1-ethyl-4-(2-morpholinoethyl)-3, 3-diphenyl-2-pyrrolidinone hydrochloride hydrate (doxapram) on the transmural stimulation and reactiontonicotine of the isolated guinea pig heart atrium]

It has been reported that doxapram exhibits a remarkable stimulating effect on respiration in humans and various experimental animals. The present experiment was an attempt to investigate whether or not doxapram inhibits an atrial arrest induced by transmural stimulation and exogenously applied nicotine. Doxapram and dimorpholamine used as comparative agents showed transient and slightly positive responses followed by a negative one in the atrium preparation. Transmural stimulation under a condition of 30 V intensity with 0.3 msec duration at a frequency of 10 Hz for 2 sec caused an atrial arrest for about 3 sec followed by negative chronotropic and inotropic responses, and a positive one. All responses caused by transmural stimulation were hardly affected by pretreatment with doxapram at a concentration of 10(-5) g/ml or less, while dimorpholamine at a high concentration (10(-5)g/ml) showed an inhibition of atrial arrest and following negative responses. Negative chronotropic and inotropic responses caused by an application of nicotine were significantly inhibited by pretreatment with doxapram or dimorpholamine. Both doxapram and dimorpholamine at higher concentrations also inhibited the positive responses of the atrium caused by nicotine. Neither doxapram nor dimorpholamine affected the ACh-induced responses. NA-induced responses were uneffected by pretreatment with doxapram, while the responses were slightly potentiated by dimorpholamine. The action mechanisms of doxapram and dimorpholamine are discussed.