PubMed Health⌕ Search

Biomedical subjects

R Yorikane

Publications and source records attributed to R Yorikane.

At least 19 recordsLinked to original sources
PubMed1996

Possible involvement of altered Na+ -Ca2+ exchange in negative inotropic effects of class I antiarrhythmic drugs on rabbit and rat ventricles.

We investigated the way in which Na+ channel blocking class I antiarrhythmic drugs, lidocaine (30 mu M), flecainide (30 mu M), and RS-2135 (100 mu M) affected contractions elicited by several protocols in rat and rabbit ventricular strips. Rabbit ventricles showed a positive force-frequency relation, and antiarrhythmic drugs inhibited the contraction, flattening the force-frequency curve. In contrast, rat ventricles showed a negative force-frequency relation, and the drugs shifted the force-frequency curve downward. Rapid-cooling contracture (RCC) also showed a positive or negative dependence on the frequency of preceding stimulation in rabbit or rat ventricles, respectively. All drugs inhibited the RCC, suggesting that they reduced the Ca2+ content in the sarcoplasmic reticulum. Ryanodine (1 mu M) abolished the RCC in both muscles and the contraction in rat muscles, but partially decreased contractions at high frequencies in rabbit ventricles. Antiarrhythmic drugs caused a further inhibition of contractions in the presence of ryanodine in rabbit ventricles. These results indicate that inhibition of Na+ channels by antiarrhythmic drugs alters Na+ -Ca2+ exchange, resulting in a decrease in the Ca2+ content in the sarcoplasmic reticulum (SR) and the Ca2+ entry through the exchanger.

Animals↗
PubMed1996

Antianginal effect of RS-5773, a diltiazem congener, in the methacholine-induced anginal model in rats.

The antianginal effect of RS-5773 ((2S,3S)-3-acetoxy-8-benzyl-2,3-dihydro-5-[2-(dimethylamino)- ethyl]-2-(4-methoxyphenyl)-1,5-benzothiazepine-4-(5H)-one hydrochloride), a newly developed benzothiazepine derivative, was evaluated in an angina model rat. Close-coronary artery injections of methacholine in anesthetized rats evoked ischemic electrocardiographic (ECG) changes (S wave elevation of about 0.6 mV). The ECG changes produced by methacholine were reproducible for as long as 6 hr. Intravenous and intraduodenal administration of RS-5773, diltiazem or clentiazem produced dose-dependent suppressions of the ischemic ECG changes. RS-5773 exceeded the other two agents both in the maximum suppressive effect on S wave elevation and in the duration of action after intravenous administration. The antianginal potency expressed as AUC (area under the curve), i.e., the percent suppression of S wave elevation integrated over time, revealed that RS-5773 was 16 times and 7 times more potent than diltiazem and clentiazem, respectively. A similar order of potency difference was observed after intraduodenal administration, and RS-5773 sustained its effect for about 6 hr at 3 mg/kg. In addition, RS-5773 did not cause excessive hypotension or depression of atrioventricular conduction. These results suggest that RS-5773 has a preferable profile as an antianginal agent.

Angina Pectoris, Variant↗
PubMed1995

Altered production of endothelin-1 in the hypertrophied rat heart.

Although endothelin-1 (ET-1) has been shown to have potent hypertrophic effects in cultured cardiac myocytes, there is no evidence that the production of ET-1 is altered in the hypertrophied heart in vivo. We investigated mRNA and peptide levels of ET-1 in the rat heart hypertrophied due to pressure or volume overload. One week after surgery of abdominal aortic banding (AB) or aortic valve regurgitation (AR; the aortic valve was destroyed by a polyethylene catheter), the rats were sacrificed. Control sham-operated rats were also studied (AB-sham and AR-sham). The left ventricular (LV) weight to body weight ratio was significantly higher in AB rats than in AB-sham rats. It was also significantly higher in AR rats than in AR-sham rats. Therefore, AB rats and AR rats developed LV hypertrophy due to pressure and volume overload, respectively. The expression of ET-1 mRNA in the LV was markedly higher in AB rats than in AB-sham rats. The peptide level of ET-1 was also significantly higher in the LV of AB rats than in that of AB-sham rats. However, the expression of ET-1 mRNA in the LV of AR rats was similar to that of AR-sham rats. The present findings suggest that the production of ET-1 in the heart differs between pressure and volume overload-induced hypertrophy in rats.

Animals↗
PubMed1994

Effects of RS-2135, a novel class I antiarrhythmic agent, on sustained ventricular tachycardia after coronary embolization in conscious dogs.

To assess the ability of RS-2135, a novel class I antiarrhythmic agent to suppress ischemia-induced ventricular arrhythmias, we produced myocardial infarction (MI) by introducing a glass bead into the coronary artery of the dog (bead model). Ventricular arrhythmias after coronary embolization were as severe and long-lasting as those that occur after two-stage coronary artery ligation as described by Harris. RS-2135 (1.25 and 2.5 mg/kg intravenously, i.v.) suppressed sustained ventricular tachycardia (SVT) 24 h after coronary embolization in the bead model. The antiarrhythmic effects of i.v. administration of RS-2135 were more potent and more long-lasting than those of lidocaine (5 and 10 mg/kg i.v.), mexiletine (5 and 10 mg/kg i.v.), disopyramide (2.5 and 5 mg/kg i.v.), and flecainide (2.5 and 5 mg/kg i.v.). The antiarrhythmic effects of oral (p.o.) administration of RS-2135 were evaluated 48 h after coronary embolization. RS-2135 (10 mg/kg p.o.) was equipotent to flecainide (10 mg/kg p.o.) and twice as potent as disopyramide (20 mg/kg p.o.) and mexiletine (20 mg/kg p.o.). Onset of antiarrhythmic effects after p.o. RS-2135 was slower than that of other drugs. These data suggest that the bead model is as useful as the Harris model for evaluation of the antiarrhythmic potential of chemicals and that RS-2135, either i.v. or p.o., is effective against SVT after acute MI.

Administration, Oral↗
PubMed1994

Possible involvement of endothelin-1 in cardiac hypertrophy.

In an attempt to ascertain a possible involvement of endothelin-1 (ET-1) in the development of cardiac hypertrophy induced by hemodynamic overloads in vivo, the expression of prepro ET-1 mRNA in the cardiac tissue and the plasma level of ET-1 were determined in rats undergoing various treatments for inducing cardiac hypertrophy. One week after aortic banding (AB), the rat exhibited left ventricular hypertrophy characterized by ventricular wall thickening, i.e. concentric hypertrophy. In contrast, the aortic regurgitation (AR) produced left ventricular enlargement without wall thickening 1 week after the operation, i.e. eccentric hypertrophy. Monocrotaline treatment (s.c.) also caused marked hypertrophy in the right ventricle (concentric hypertrophy) 3 weeks later, which was accompanied by a severe pulmonary hypertension (MCT-PH). A Northern blot analysis revealed that AB and MCT-PH markedly increased the expression of prepro ET-1 mRNA in the left and right ventricles, respectively. The rats with MCT-PH but not with AB displayed a significant higher level in their plasma ET-1 levels compared with control animals. In contrast, the rats undergoing AR surgery exhibited no significant elevation in either prepro ET-1 mRNA in the heart or the plasma ET-1 concentration. The results of the present study suggest that ET-1 is involved at least in part in the development of concentric but probably not eccentric cardiac hypertrophy induced by hemodynamic overloads.

Animals↗
PubMed1993

Increased production of endothelin-1 in the hypertrophied rat heart due to pressure overload.

Endothelin-1 (ET-1) has been demonstrated to induce hypertrophy in cultured cardiac myocytes. We investigated the production of ET-1 in the heart of aorta-banded rats in vivo. Seven days after the banding of the abdominal aorta, rats developed a significant left ventricular hypertrophy. The tissue content of mature ET-1 and the level of expression of prepro ET-1 mRNA were higher in the left ventricle of aorta-banded rats than in those of sham-operated rats. The expression of prepro ET-1 mRNA in the right ventricle was not different between the two groups. These findings indicate that the production of ET-1 increased in the hypertrophied left ventricle, thereby suggesting the possible involvement of endogenous ET-1 in the development of cardiac hypertrophy due to pressure overload.

Animals↗
PubMed1993

Effects of RS-2135, a new antiarrhythmic agent, on the kinetics of use-dependent decrease in maximum upstroke velocity in guinea pig ventricular myocardium.

The use-dependent decrease in maximum upstroke velocity (Vmax) caused by RS-2135, a new antiarrhythmic compound was analyzed in isolated papillary muscles of guinea pigs. RS-2135 3 and 10 microM decreased Vmax of action potential (AP) in a concentration-related manner without affecting resting membrane potential (RMP). Vmax decay in the presence of RS-2135 was exponential at stimulation rates > 0.5 Hz. This use-dependent block of Vmax was enhanced at higher stimulation frequencies. The time constants and onset rates per action potential of the use-dependent block were 10.7-26.9 s and 0.021-0.041 AP-1, respectively. The time constants of recovery from use-dependent block were 57.9 and 63.6 s, respectively, in the presence of 3 and 10 microM RS-2135. The predicted half-time of the recovery process calculated by physicochemical parameters of RS-2135 agreed well with the observed values. These results suggest that RS-2135 is a sodium channel blocking agent with slow kinetics and that the physicochemical properties underlie these characteristics.

Action Potentials↗
PubMed1993

Altered expression of ETB-receptor mRNA in the lung of rats with pulmonary hypertension.

To investigate the pathophysiologic role(s) of endothelin-1 (ET-1) in pulmonary hypertension, we studied the expression of ETB-receptor mRNA in the lung and venous plasma concentrations of ET-1 in rats with monocrotaline-induced pulmonary hypertension (PH). Three weeks after s.c. injection of monocrotaline (60 mg/kg), rats (PH rats, n = 6) were sacrificed. Vehicle-injected rats (n = 6) served as controls. The right ventricular systolic pressure of PH rats [58.0 +/- 4.7 mm Hg (mean +/- SEM)] was significantly higher than that in the vehicle-treated control rats (29.2 +/- 2.1; p < 0.01). Northern blot analysis showed that the expression of ETB-receptor mRNA decreased in the lung of PH rats. The venous plasma concentration of ET-1 measured by a sandwich-enzyme immunoassay was significantly higher in PH rats than in control rats (5.1 +/- 0.7 versus 1.3 +/- 0.2 pg/ml; p < 0.01). The present findings suggest that the expression of ETB-receptor mRNA decreases in the lung of PH rats, which might be closely related to the increase in plasma ET-1 concentration in these rats.

Animals↗
PubMed1993

Contribution of endogenous endothelin-1 to the progression of cardiopulmonary alterations in rats with monocrotaline-induced pulmonary hypertension.

Endothelin-1 (ET-1) is known to have potent contractile and proliferative effects on vascular smooth muscle cells and is known to induce myocardial cell hypertrophy. We studied the pathophysiological role of endogenous ET-1 in rats with monocrotaline-induced pulmonary hypertension. Four-week-old rats were given a single subcutaneous injection of 60 mg/kg monocrotaline (MCT rats) or saline (control rats) and were killed after 6, 10, 14, 18, and 25 days. In the MCT rats, right ventricular systolic pressure progressively increased and right ventricular hypertrophy developed in a parallel fashion. The venous plasma ET-1 concentration also progressively increased, and this increase preceded the development of pulmonary hypertension. The isolated pulmonary artery exhibited a significantly weaker response to ET-1 in the MCT rats on day 25 but not on days 6 and 14. In the MCT rats, the expression of prepro ET-1 mRNA as measured by Northern blot analysis significantly increased in the heart on days 18 and 25, whereas it gradually decreased in the lungs. The peptide level of ET-1 in the lungs also significantly decreased in the pulmonary hypertensive stage. The expression of prepro ET-1 mRNA had increased by day 6 only in the kidneys. Continuous infusion of BQ-123, a selective ETA receptor antagonist, by an osmotic minipump (14.3 mg per day per rat for 18 days) significantly inhibited the progression of both pulmonary hypertension (right ventricular systolic pressure, 77.8 +/- 4.2 [mean +/- SEM] mm Hg [n = 10] versus 52.3 +/- 2.4 mm Hg [n = 7]; P < .01) and right ventricular hypertrophy (right ventricle/[left ventricle +/- septum], 0.56 +/- 0.03 [n = 10] versus 0.41 +/- 0.02 [n = 7]; P < .01). Histological examination revealed that BQ-123 also effectively prevented pulmonary arterial medial thickening. The inhibition of right ventricular hypertrophy by BQ-123 may be partly ascribed to the blockade of excessive stimulation of the heart by ET-1, in addition to the prevention of pulmonary hypertension. The present findings suggest that endogenous ET-1 contributes to the progression of cardiopulmonary alterations in rats with MCT-induced pulmonary hypertension.

Animals↗
PubMed1992

Synthesis and biological action of the aminotetrahydroisoquinocarbazoles and related compounds: a new class of compounds with antiarrhythmic activity.

A series of 12-aminotetrahydroisoquinocarbazoles and related compounds were synthesized using an intramolecular Diels-Alder reaction and screened for antiarrhythmic activity in chloroform-induced ventricular arrhythmias in mice. Several compounds showed more potent activity than disopyramide. There was some correlation between substituents on aromatic ring and angular position, and antiarrhythmic activity. An amino group or some functional groups containing an amino group on C-12 seemed to be essential to exhibit the activity. Ring size also influenced the activity. The compound (+)-10 (RS-2135) had the most favorable combination of antiarrhythmic activity and toxicity and was selected for further evaluation.

Action Potentials↗
PubMed1992

Electrophysiologic effects of RS-2135, a new antiarrhythmic compound, on canine Purkinje fibers.

RS-2135 is the (+) isomer of a novel, fused carbazol derivative. The agent, when administered orally, shows long-lasting antiarrhythmic effects in several models of arrhythmia. We used standard microelectrode techniques to characterize the electrophysiological effects of the agent on canine Purkinje fibers. RS-2135 reduced the maximum upstroke velocity of the action potential (Vmax) and shortened the action potential duration (APD) in a concentration-related manner (0.3-3 microM). RS-2135 decreased Vmax at lower concentrations than disopyramide, flecainide, and mexiletine. RS-2135 shortened the effective refractory period (ERP), but significantly increased the ratio of ERP to APD90. Additionally, the effects of the (-) optical isomer of RS-2135 were compared with those of RS-2135, the (+) enantiomer. The (-) isomer was much less potent than RS-2135 in decreasing Vmax. These data suggest that RS-2135 belongs to the class I or "local anesthetic" type of antiarrhythmic agent and that the stereochemistry of the drug molecule is an important determinant of Na channel blocking activity.

Action Potentials↗
PubMed1991

Electrophysiological effects of endothelin-1 on canine myocardial cells.

Endothelin-1 (ET-1) has been shown to induce severe ventricular arrhythmias associated with myocardial ischemia. However, ET-1 may have a direct arrhythmogenic action that is not related to myocardial ischemia. To examine this possibility, we studied the electrophysiological effects of ET-1 on cardiac tissues. The right bundle branch, false tendon, ventricular muscle, and atrial muscle were isolated from the dog, and transmembrane potentials were recorded by the conventional microelectrode technique. ET-1 prolonged the action potential duration (APD) in all of the tissues tested except in the atrial muscle, where the APD was shortened. Bay K 8644, a calcium channel agonist, prolonged the APD in all cardiac tissues. Spontaneous firing of the right bundle branch was suppressed by ET-1 but not Bay K 8644. The prolongation of the APD by ET-1 was far more marked in the right bundle branch than in other tissues, and it was followed by the development of early after depolarizations (EADs) only in the right bundle branch. The EADs induced by ET-1 or Bay K 8644 were abolished by nicardipine. These data suggest that L-type calcium current is involved in the genesis of EADs by ET-1, although other ionic mechanisms can not be ruled out. Since EADs underlie some types of arrhythmias, arrhythmias caused by ET-1 are at least partly attributable to the direct actions of the agent on myocardial cells.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1991

Antiarrhythmic and cardiovascular profiles of the fused indole compound (3aR,12R,12aR,12bS)-12-amino-2,3,3a,4,11,12,12a,12b-octahydro-10-hydrox yisoquino [2,1,8-lma]carbazol-5(1H)-one hydrochloride 1.5 hydrate.

Antiarrhythmic and cardiovascular profiles of a fused indole compound, (3aR,12R,12aR,12bS)-12-amino-2,3,3a,4,11,12,12a,12b -octahydro- 10-hydroxyisoquino [2,1,8-lma]carbazol-5(1H)-one hydrochloride 1.5 hydrate (RS-2135, CAS 133775-36-7), were investigated in anesthetized dogs. Class I antiarrhythmic agents such as disopyramide, lidocaine, mexiletine and flecainide were used as reference compounds. RS-2135 exerted more potent antiarrhythmic activity than reference compounds against ouabain-induced arrhythmias in dogs. The onset of action was slow, but the duration of action was longer than with the other compounds tested. The agent suppressed the conduction in the atrium, A-V node and ventricle more markedly than the reference compounds. RS-2135, however, did not change blood pressure and heart rate at a dose 5 times the dose for antiarrhythmic activity and decreased cardiac contractility to a lesser extent than the reference compounds.

Animals↗
PubMed1990

Evidence for direct arrhythmogenic action of endothelin.

We studied electrophysiological effects of endothelin on canine cardiac tissues. Endothelin prolonged action potential duration and decreased spontaneous firing rate of the right bundle branch cells. At a concentration of 2 x 10(-7)M the plateau phase of action potentials was flattened, followed by the abrupt occurrence of early afterdepolarizations (EADs). ET, at a concentration as low as 2 x 10(-9)M, was capable of inducing EADs although their incidence was low. The EADs were initiated from the membrane potential less negative than -30mV and were suppressed by nicardipine, suggesting the involvement of dihydropyridine-sensitive Ca2+ channels in the induction of EADs. Because EADs are considered to underlie certain types of arrhythmias endothelin per se may have arrhythmogenic action.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1990

The arrhythmogenic action of endothelin in rats.

Endothelin (ET) was administered into the coronary ostia at doses of 0.1-1 microgram/kg in anesthetized rats. The ST segment was depressed at doses below 0.5 microgram/kg and was transiently elevated at 1 microgram/kg. Ventricular arrhythmias developed at doses above 0.5 microgram/kg. The arrhythmias that developed at 1 microgram/kg were precipitated into ventricular fibrillation. At the time when the arrhythmias developed, the ischemic changes had already subsided. These results suggest that ET may have an arrhythmogenic action, which is not solely attributable to myocardial ischemia.

Animals↗
PubMed1988

Cardiovascular pharmacology of RS-1893, an orally active cardiotonic agent with arterial and venous vasodilator actions.

RS-1893, 2-[2-chloro-4-(2,3,4,5-tetrahydro-3-oxo-6-pyridazinyl)]-phenoxy-N- (2-(2-morpholinoethyl)-acetamide, is a newly synthesized compound whose structure is different from that of cardiac glycosides and beta-stimulants. The in vitro cardiotonic action of RS-1893 was about 3 times more potent than that of milrinone. This action is most likely due to inhibition of phosphodiesterase-III, as has been suggested for many other cardiotonic agents. In pentobarbital anesthetized dogs, RS-1893 (1-30 micrograms/kg, i.v.) produced dose dependent increases in left ventricular dP/dtmax and cardiac output and caused decreases in blood pressure and total peripheral resistance with a relatively small increase in heart rate. Central venous pressure decreased markedly, suggesting venous vasodilation. The in vivo cardiotonic action of RS-1893 was 3 times more potent than that of milrinone and was not affected in the presence of a large dose of propranolol. Oral administration of RS-1893 (0.03 and 0.1 mg/kg) also produced a dose-related increase in cardiac contractility in conscious beagles. The increase in LVdP/dtmax reached a maximum in 1-3 hr after administration and lasted for more than 8 hr. Thus, RS-1893 appeared to be an orally active cardiotonic agent with vasodilator properties, probably acting on both arterioles and veins.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1987

Enhancement by yohimbine of nicotine- and dimethylphenylpiperadinium-induced release of norepinephrine from cardiac sympathetic nerves of the dog: interaction of presynaptic alpha and nicotinic receptors.

The effect of yohimbine on nicotine- and dimethylphenylpiperadinium (DMPP)-induced release of norepinephrine (NE) from sympathetic cardiac nerves of the dog was examined in order to elucidate the interaction of presynaptic alpha and nicotinic receptors. Intracoronary infusion of nicotine (300 or 500 micrograms/min) or DMPP (100 or 300 micrograms/min) into the left circumflex artery increased coronary sinus output of NE (NE output), left ventricular dp/dt maximum (LV dp/dt max) and coronary sinus blood flow. The nicotine-induced increases in NE output, LV dp/dt max and coronary sinus blood flow were enhanced by simultaneous yohimbine infusion in doses of 10 and 30 micrograms/min into the same artery, and were attenuated by the drug in a dose of 100 micrograms/min. The DMPP-induced increases were enhanced by 10 micrograms/min of yohimbine infusion, but the enhancement was decreased by 30 and 100 micrograms/min. Yohimbine did not modify increases in NE output, LV dp/dt max and coronary sinus blood flow induced by intracoronary infusion of tyramine (100 micrograms/min). We have reported previously that yohimbine in the dose range used enhanced cardiac sympathetic nerve stimulation-induced increases in these parameters in a dose-dependent manner in the same preparation. The enhancement by yohimbine of nicotinic receptor-mediated NE release would be due to the blockade of presynaptic alpha-2 adrenoceptors. Therefore, it is suggested that presynaptic alpha-2 adrenoceptor-mediated feedback control operates on the process of NE release induced by nicotinic receptor activation as well as nerve stimulation. Although the mechanism of loss of the enhancement of the nicotinic effect by the large dose of yohimbine is not known, the possible mechanisms are discussed.

Animals↗