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Biomedical subjects

Y Ogiwara

Publications and source records attributed to Y Ogiwara.

At least 19 recordsLinked to original sources
PubMed1991

K+ channel blocking and anti-muscarinic effects of a novel piperazine derivative, INO 2628, on the isolated dog atrium.

The effects of a novel piperazine derivative, INO 2628, on the negative inotropic and chronotropic responses to intracardiac parasympathetic nerve stimulation and carbachol, to adenosine and to the K+ channel openers, pinacidil and nicorandil, were investigated in isolated, blood-perfused dog heart preparations. INO 2628 (0.1-10 mumol) injected into the sinus node artery of the isolated atrium induced negative chronotropic and small positive inotropic responses in a dose-dependent manner. INO 2628 antagonized the negative chronotropic and inotropic responses to intracardiac vagus stimulation and carbachol in a dose-dependent manner, whereas INO 2628 did not antagonize the negative cardiac responses to adenosine. Pinacidil and nicorandil caused dose-dependent negative inotropic and small negative chronotropic responses in isolated atria and ventricles, suggesting that pinacidil-related K+ channels are much sparser in SA nodal pacemaker cells than in cardiac muscle cells. INO 2628 dose dependently antagonized the negative inotropic responses to pinacidil and nicorandil, but it did not modify the nicardipine-, pentobarbital- or G-strophanthin-induced cardiac responses. These results suggest that INO 2628 inhibits the negative cardiac effects of acetylcholine at muscarinic receptors and directly inhibits K+ channels in the isolated dog heart.

Adenosine↗
PubMed1989

Differential vagal inhibition of the positive chronotropic and inotropic responses to cardiotonics in the isolated dog atrium.

The effects of vagal nerve stimulation on the chronotropic and inotropic responses to norepinephrine (NE), dobutamine, forskolin, 3-isobutyl-1-methylxanthine (IBMX) and Bay k 8644 were investigated in the isolated, blood-perfused right atrium of the dog. Electrical stimulation of intramural vagal nerves evoked decreases in the sinus rate and atrial contractile force, which were maintained at almost constant levels during stimulation. Vagal stimulation consistently attenuated both the positive chronotropic and inotropic responses to NE, dobutamine, forskolin and IBMX. The vagal inhibition of the chronotropic response to each substance was greater than that of the inotropic one except that to Bay k 8644. Vagal stimulation did not depress the positive chronotropic and inotropic responses to Bay k 8644. These results, therefore, suggest that, under parasympathetic tonic conditions, NE, dobutamine, forskolin and IBMX induce a positive chronotropic effect much less than a positive inotropic effect in the isolated dog atrium. Our results also suggest that the vagal inhibition of the chronotropic response to a beta-adrenoceptor agonist is induced at intracellular sites in the cyclic AMP cascade proximal to the Ca channel activation and also at a site proximal to the catalytic unit of adenylate cyclase.

1-Methyl-3-isobutylxanthine↗
PubMed1989

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.

1-Methyl-3-isobutylxanthine↗
PubMed1989

Comparative study of cardiovascular effects of clonidine and alinidine in cross-perfused dog atrial preparations.

Cross-perfused canine atrial preparations were used to investigate the direct and indirect cardiac actions of clonidine and alinidine. Intravenous injections of clonidine (0.1-3 micrograms/kg) produced an initial brief pressor response and bradycardia followed by hypotension in the intact dog. Chronotropic and inotropic responses were absent in the isolated atrium perfused with the intact dog's blood. Intravenous clonidine (10-300 micrograms) also induced negative chronotropic and inotropic effects in isolated atria. On the other hand, alinidine, at doses which caused a depressor action and bradycardia in the intact dog, consistently produced negative chronotropic and inotropic effects in the isolated atrium. Therefore, it was confirmed that a relatively small dose of clonidine has a selective vascular action, while alinidine has direct cardiac depressant properties at all effective doses. Negative chronotropic and inotropic effects of peripheral vagal stimulation, carbachol and adenosine were not significantly modified by 100 or 300 micrograms doses of intraarterial clonidine. On the other hand, the effects of vagal stimulation and carbachol were significantly inhibited by 100 and 300 micrograms of alinidine, without affecting adenosine-induced cardiac actions. Therefore, it was demonstrated that alinidine has anti-muscarinic properties.

Animals↗
PubMed1989

Beta-2 adrenoceptor-mediated effects on sinus rate and atrial and ventricular contractility on isolated, blood-perfused dog heart preparations.

Changes in the sinus rate, right atrial contractile force and left ventricular contractile force in response to isoproterenol, epinephrine, dobutamine, salbutamol and procaterol were studied in isolated, blood-perfused right atrial or left ventricular cardiac preparations of the dog. Each substance elicited dose-dependent increases in the three parameters and the ranking of the potency (ED50) for each effect was isoproterenol greater than epinephrine greater than dobutamine greater than or equal to salbutamol greater than or equal to procaterol. The ED50 of procaterol for changing sinus rate was lower than for altering atrial and ventricular contractile force, whereas the ED50 of dobutamine for changing sinus rate was higher. Ranking on the basis of the ratio of increase in sinus rate to increase in atrial tension induced by the agonists gave the following order: procaterol greater than or equal to salbutamol greater than epinephrine greater than or equal to isoproterenol greater than dobutamine. Procaterol-induced increases in sinus rate and atrial contractile force were dose-dependently inhibited by the beta-2 adrenoceptor antagonist, ICI 118,551, but only attenuated slightly by the beta-1 antagonist, atenolol. On the other hand, the positive chrono- and inotropic effects on the right atrium induced by dobutamine and isoproterenol were blocked completely by atenolol. The epinephrine- or salbutamol-induced positive chrono- and inotropic responses in the right atrium were inhibited moderately by both antagonists, but ICI 118,551 inhibited sinus rate increases more effectively than the atrial tension increases.(ABSTRACT TRUNCATED AT 250 WORDS)

Albuterol↗
PubMed1988

Different antagonism of the positive chronotropic and inotropic responses of the isolated, blood-perfused dog atrium to Bay k 8644 by nicardipine and verapamil.

The effects of Bay k 8644, a dihydropyridine calcium agonist, on sinoatrial (SA) node pacemaker activity and atrial contractility and its interaction with the calcium antagonists, nicardipine and verapamil, were investigated in the isolated, blood-perfused dog atrium. Bay k 8644 (0.03-30 micrograms) increased sinus rate and atrial contractility dose dependently. Norepinephrine (NE) and CaCl2 dose dependently increased the sinus rate and contractility but the positive chronotropic effect of CaCl2 was much less than that of the other drugs. The positive chronotropic effect of Bay K 8644 (0.3-1 microgram) was dose dependently depressed by nicardipine at doses of 1-10 micrograms but the inotropic effect was depressed only by a large dose of 10 micrograms. After sinus arrest induced by nicardipine (10-30 micrograms), SA node pacemaker activity was readily restored by Bay k 8644 or NE. Verapamil (1-3 micrograms) also depressed the positive chronotropic effect of Bay k 8644 more effectively than the inotropic effect although it did not attenuate the chronotropic effect of NE. The inotropic interaction could not be evaluated at higher doses of antagonists because of sinus arrest. Propranolol (3 micrograms) suppressed both positive chronotropic and inotropic effects of NE but did not depress the Bay k 8644-induced responses. These results show that the antagonism between Bay k 8644 and calcium antagonists is predominant on SA node pacemaker activity in cardiac tissues.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1988

Cardiovascular effects of dibutyryl cyclic AMP in the intact dog heart and the isolated cross-perfused right atrium.

This study used an isolated right atrial preparation, cross-perfused with arterial blood from a support dog. We investigated the effects of dibutyryl cyclic AMP (DBcAMP) on heart rate and arterial blood pressure of the support dog and on the sinus rate and atrial contractile force of the isolated perfused atrium. DBcAMP was injected into the external jugular vein of the support dog or into the sinus node artery of the isolated atrium. DBcAMP to the support dog induced a small increase and/or decrease in arterial blood pressure at a dose of 3 or 10 mg/Kg i.v. It produced a decrease, with or without an increase in blood pressure, at a dose of 30 mg/Kg i.v., and a dose-dependent increase in heart rate in the support dog. In the isolated atrium, positive chronotropic and inotropic effects were observed. Direct injection of DBcAMP (3-30 mg) into the sinus node artery of the isolated atrium induced positive chronotropic and inotropic effects, after initial brief negative effects, in a dose-dependent manner. DBcAMP did not change norepinephrine-induced positive chronotropic and inotropic effects in the isolated atrium. These results demonstrate that DBcAMP induces a decrease in systemic arterial blood pressure with increases in sinus rate and atrial contractile force, and acts additively with the norepinephrine-induced positive cardiac effects in the dog heart.

Animals↗
PubMed1988

Bradycardic effects of AQ-A 39 (falipamil) in situ and in isolated, blood-perfused dog hearts. Comparison with alinidine and verapamil.

The cardiovascular effects of a specific bradycardic agent, AQ-A 39, were investigated in intact donor dogs and isolated and cross-perfused dog heart preparations. Intravenous administration of AQ-A 39 (10-1000 micrograms/kg) to the donor dog caused a dose-dependent heart rate decrease in the donor dog and a decreased atrial rate in the isolated atrium perfused by the donor's blood. The arterial blood pressure of the donor dog and contractile force of the atrial preparation were unchanged or slightly decreased. The direct injection of AQ-A (1-300 micrograms) into the sinus node artery of the isolated atrium caused dose-dependent negative chronotropic and slight, transient positive inotropic responses. Alinidine and verapamil caused marked negative chronotropic and inotropic responses. The negative chronotropic effect of AQ-A 39 was not modified by atropine. However, it was enhanced slightly but significantly by propranolol, indicating that AQ-A 39-induced bradycardia was antagonized partly by beta-adrenoceptor function. These results confirmed that AQ-A 39 selectively reduced sinus rate by a direct action on the sinus node. Furthermore, the potency of the bradycardiac action, compared with the decrease in contractility, was greater than for alinidine or verapamil. AQ-A 39 (300 micrograms) tended to depress norepinephrine (NE)-induced positive chronotropic but not inotropic effects in isolated atria. By contrast, verapamil (3-10 micrograms) significantly depressed the NE-induced positive inotropic but not the chronotropic effect, and propranolol (10 micrograms) suppressed both cardiac effects of NE. These data suggest that the AQ-A 39-induced, selective attenuation of the NE-induced chronotropic effect is not due to either calcium channel blockade or beta-adrenoceptor antagonism.

Animals↗
PubMed1988

Negative chronotropic and positive inotropic effects of a unique cardioactive agent, N,N'-dicyclopropyl methyl piperazine (bis) hydrochloride (INO 2628), in isolated, blood-perfused dog atria.

The effects of a novel piperazine derivative (INO 2628) on sinus node pacemaker activity and atrial contractile force were investigated in isolated, blood-perfused dog atrium. Injections of INO 2628 (0.03-100 mumol) into the sinus node artery of the isolated atrium induced a dose-dependent decrease in sinus rate and an increase in contractile force. The positive inotropic effects at more than 10 mumol were accompanied by a transient negative inotropism. Propranolol did not affect the positive inotropic response to INO 2628, but it significantly suppressed positive chronotropic and inotropic responses to norepinephrine. Atropine at a dose which completely blocked negative chronotropic and inotropic responses to carbachol, produced a slight but significant depression of INO 2628-induced negative chronotropic responses; inotropic responses were unaffected. These results suggest that INO 2628 induces noncholinergic negative chronotropic and nonadrenergic positive inotropic responses in isolated dog atria.

Animals↗
PubMed1988

Fade responses at neuroeffector junction to vagal stimulation in the isolated, blood-perfused dog atrium.

Effects of physostigmine and of beating rate on the negative chronotropic and inotropic responses to tonic intramural parasympathetic nerve stimulation at a frequency of 5 Hz for 2 min were investigated, using the isolated, blood-perfused dog atrium which was pretreated with propranolol. The responses to stimulation reached a maximum, and then "faded" back toward the control levels during stimulation. Before physostigmine, the fade of the inotropic response was consistently observed but the fade of the chronotropic response was minimal. Both the maximum effect and the fade of the chronotropic response were augmented dose-dependently by physostigmine in spontaneously beating atria. Physostigmine increased the maximum chronotropic response to infusion of acetylcholine (ACh) but did not potentiate the fade response. These results suggest that the potentiation of the fade of the chronotropic response to stimulation after physostigmine is due to decreases in the amount of ACh at the neuroeffector junction. The maximum negative inotropic responses were dose-dependently potentiated similarly by physostigmine in isolated spontaneously beating or paced atria. The fade of the inotropic response in spontaneously beating atria was decreased along with reduction of the rate by physostigmine, whereas the fades in paced atria at 2 and 3 Hz were not changed, showing that decreases in rate during stimulation influenced the reduction of the fade. Increases in contractile force induced by infusion of CaCl2 did not alter the maximum and fade responses to stimulation in 2 Hz paced atria. The blood flow into an isolated atrium was not changed detectably during stimulation. These results suggest that the fade of the inotropic response to parasympathetic nerve stimulation is related subsidiarily to acetylcholinesterase or washout of ACh at the neuroeffector junction in isolated perfused atria.

Acetylcholine↗
PubMed1987

Time dependent impairment of vagally mediated inhibition of noradrenaline release in the dog heart.

The effects of right vagal nerve stimulation on changes in heart rate, mean coronary sinus blood flow, and noradrenaline overflow rate induced by right cardiac sympathetic nerve stimulation were investigated in anaesthetised decentralised, open chest dogs, when autonomic nerve fibres were stimulated tonically at a frequency of 4 or 5 Hz for 2.5 min. Sympathetic nerve stimulation produced a mean(SEM) increase in each of the variables (50(7.0)% in heart rate, 48(6.3)% in coronary sinus blood flow, and 87.0(12.3) ng.min-1 in noradrenaline overflow rate into coronary sinus blood at 30 s), and the increments remained almost constant during continued stimulation. Vagal nerve stimulation induced a decrease of 34(3.4)% in heart rate and of 22(4.5)% in coronary sinus blood flow and a slight reduction (-9(3.2) ng.min-1) in noradrenaline overflow rate at 30 s. Only the decrease in heart rate faded slightly with time. Combined stimulation of the sympathetic and parasympathetic nerves induced a decrease of 19(5.0)% in heart rate and 4(7.5)% in coronary sinus blood flow and an increase of 34.3(12.0) ng.min-1 in noradrenaline overflow rate at 30 s. The decrease in heart rate and coronary sinus blood flow faded, and noradrenaline overflow rate increased significantly to 86.4(17.3) ng.min-1 at 120 s. The temporal changes in heart rate, coronary sinus blood flow, and noradrenaline overflow rate caused by combined nerve stimulation were readily inhibited by treatment with atropine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Cardiovascular responses to a newly developed cardiotonic agent, ZSY-39 [4-methyl-5-(4-pyridinyl)-thiazole-2-carboxyamide] in dog cross-circulated atrial and ventricular preparations.

The cardiovascular effects of ZSY-39 [4-methyl-5-(4-pyridinyl)-thiazole-2-carboxyamide] were investigated in isolated and blood-perfused atrial and ventricular muscles perfused with donor's arterial blood. When ZSY-39 was given i.v. to the intact donor dog, hypotension with a slight tachycardia was induced at a dose range of 30-1,000 micrograms/kg. At the same time, slight positive chronotropic and inotropic responses appeared in isolated, perfused atria at i.v. doses of 300 and 1,000 micrograms/kg ZSY-39, indicating a relatively dominant inotropic action. Direct injection of ZSY-39 into the cannulated sinus node artery of the isolated atrium produced positive chronotropic and inotropic responses in a dose-related manner (1 to 300 micrograms). ZSY-39 also induced a dose-dependent increase in developed tension in the isolated ventricle. The positive chronotropic and inotropic effects of ZSY-39 were not modified by an adequate dose of propranolol which completely blocked norepinephrine-induced positive chronotropic and inotropic responses. From these results, it is concluded that ZSY-39 has mild cardiotonic properties, showing relatively selective positive inotropic activity.

Animals↗
PubMed1987

Cardiovascular effects of a new phenoxyalkylamine derivative, 2-isopropyl-5-[3-(2-methoxyphenoxy)propylamino]-2-(3,4,5-trimethoxy phenyl) valeronitrile fumarate (HV-525), in cross-circulated dog atrial preparations.

A newly developed phenoxyalkylamine derivative, 2-isopropyl-5-[3-(2-methoxyphenoxy)propylamino]-2-(3,4, 5-trimethoxyphenyl)-valeronitrile fumarate (HV-525), was investigated in intact dogs and in isolated dog atria perfused with anesthetized donor dog's arterial blood. When 0.3 mg/kg of HV-525 was intravenously administered to the donor dog, a depressor effect without significant changes in heart rate was observed in donor dogs and a decrease in developed tension was observed in the isolated atrium. At 1 mg/kg, HV-525 caused a depressor response in donor dogs and decreases in developed tension and atrial rate in isolated atria. The decrease in systemic blood pressure seen following 1 mg/kg of HV-525 was between 15-40 mmHg. These effects continued for about 60 min. When HV-525 was administered into the cannulated sinus node artery of the isolated atrium, dose related negative inotropic and chronotropic actions were observed. Occasionally, HV-525 induced slight, brief positive chronotropic and inotropic effects followed by long-lasting negative effects. The threshold dose for inducing the negative chronotropic effect was approximately 3 micrograms while the negative inotropic one was approximately 1 microgram. A large dose of 100 micrograms of HV-525 caused a profound deceleration but not atrial arrest. The order of potencies for inducing a negative chronotropic effect in dog atria was verapamil greater than propranolol much greater than HV-525 greater than or equal to lidocaine greater than or equal to quinidine greater than phenytoin greater than disopyramide greater than procainamide, and that for inducing a negative inotropic effect was verapamil greater than or equal to propranolol greater than HV-525 greater than lidocaine greater than phenytoin greater than disopyramide greater than procainamide greater than or equal to quinidine. HV-525 did not induce a significant effect on sinoatrial conduction time. HV-525 at the doses studied, uniformly suppressed the frequency-force relationship, while verapamil, one of the phenoxyalkylamine derivatives, caused a marked depression of high frequency-induced contraction. Thus, it is concluded that HV-525 has mild depressant properties on the cardiovascular system and may have characteristics different from those of verapamil.

Animals↗
PubMed1987

Cardiac effects of piretanide and furosemide on intact anesthetized dogs and on isolated atria.

The effects of piretanide and furosemide on systemic arterial blood pressure and heart rate were examined in the anesthetized dog and the effects on atrial rate and contractile force were assessed in isolated atrial muscle perfused with heparinized arterial blood from a donor dog. When piretanide was administered intravenously to intact dogs, the depressor and bradycardic responses were produced dose-dependently. There were no significant simultaneous chronotropic or inotropic changes in the isolated atrium. On the other hand, furosemide (1-3 mg/kg) did not induce significant changes in either systemic blood pressure or heart rate in the intact dog. The atrial rate and developed tension were also not affected in the isolated atrium. A potent beta-adrenoceptor blocking agent, propranolol (1 mg/kg i.v.), consistently produced a significant depressor response and a profound negative chronotropic effect in the intact dogs; significant negative chronotropic and inotropic effects were also observed in the isolated atrium. When large doses of piretanide and furosemide were injected intraarterially into the sinus node artery of the isolated atrium, atropine-insensitive negative chronotropic and inotropic effects were induced dose-dependently. The potency of the negative chronotropic effect of piretanide was slightly greater than that of furosemide, but the negative inotropic effect of piretanide was slightly smaller than that of furosemide. These data indicate that piretanide has a depressor effect without significant cardiac influences. However, a high dose of piretanide has negative chronotropic and inotropic effects. These effects were not observed with the doses of furosemide (1-3 mg/kg) employed in this study.

Animals↗
PubMed1987

Effects of DJ-7141, a new alpha-2 agonist, 2-(2-chloro-6-fluorophenyl)-2,3,5,6-tetra-hydro-1H-imidazo[1,2-a] imidazole hydrochloride, on the isolated atrium, cross-perfused with blood from a support dog.

The effects of DJ-7141, a new alpha-2 agonist, on an isolated atrial preparation cross-perfused with arterial blood from a support dog were investigated. In the isolated atrium, a selective injection of DJ-7141 (1-100 micrograms) into the sinus node artery induced dose-dependent positive chronotropic and inotropic effects. The positive cardiac effects of DJ-7141 were not only inhibited by propranolol and by imipramine, but reversed to negative effects, whereas the positive cardiac effects of norepinephrine were blocked by propranolol and potentiated by imipramine. Tetrodotoxin (TTX) did not modify the cardiac responses to DJ-7141. After propranolol treatment, the negative chronotropic and inotropic responses to DJ-7141 were not influenced by atropine, which completely blocked acetylcholine-induced cardiac responses. When DJ-7141 was injected into the support dog at a dose of 10-300 micrograms/Kg i.v., it induced a brief increase in femoral arterial blood pressure and a long-lasting decrease in heart rate in the support dog and increases in atrial rate and contractile force in the isolated atrium. These results suggest that the new alpha-2 agonist, DJ-7141, induces indirect positive chronotropic and inotropic effects due to a tyramine-like action and direct negative cardiac effects in the isolated dog heart, and that the tyramine-like effect may be partially responsible for the increase in blood pressure seen with DJ-7141 in in situ dogs.

Adrenergic alpha-Agonists↗
PubMed1987

Pharmacological analysis of chrono- and inotropic responses to diazepam in the isolated, blood-perfused canine atrium.

Effects of diazepam on the pacemaker activity and atrial contractility were investigated using the isolated and blood-perfused canine atrium. When diazepam in a dose range of 3-300 micrograms was injected directly into the sinus node artery, biphasic (negative followed by positive) chrono- and inotropic responses were dose-relatedly evoked. These responses were not affected by atropine in a dose which blocked ACh-induced negative ones. Propranolol inhibited positive chrono- and inotropic responses to diazepam, and prolonged the duration of the negative responses. Imipramine, in a dose which blocked tyramine-induced positive responses, significantly augmented the positive inotropic responses to diazepam. From these results, it is suggested that diazepam induces direct negative chrono- and inotropic effects, the mechanism of which remains to be defined, and indirect positive effects by catecholamine release from the sympathetic nerve terminals, though not mediated by a tyramine-like action. Diazepam tended to potentiate negative chrono- and inotropic effects of adenosine but not significantly, suggesting that diazepam plays a minor role as an adenosine potentiator in the dog right atrium.

Acetylcholine↗