Inotropic Effect Of Bay Research Articles

Pharmacological Study of Isoproterenol and Diabetic Cardiomyopathies in Rat Right Ventricular Strips

The present study was undertaken to compare the cardiomyopathies induced by experimental diabetes mellitus and chronic isoproterenol (ISO) pretreatment on inotropic reactivity of right ventricular strips from rats. One month after initiation of treatment, cardiac muscle was isolated and challenged with either the beta-adrenoceptor agonist ISO or the calcium channel activator Bay K 8644. Sensitivity and responsiveness to these agonists were determined. Crude membrane preparations were obtained from residual ventricular muscle and beta-adrenoceptor density determined using iodocyanopindolol. Isolated right ventricular strips from diabetic and ISO-treated rats demonstrated hyperresponsiveness to the inotropic effects of Bay K 8644 but subsensitivity to ISO. Ventricular beta-adrenoceptor density was found to be significantly depressed in membrane preparations from both diabetic and ISO-treated groups relative to controls. These data indicate that both forms of cardiomyopathy may affect inotropic reactivity through similar alterations to beta-adrenoceptors and calcium utilization.

Differential Inhibitory Action of Phorbol-12,13-Dibutyrate on the Positive Inotropic Effect of Endothelin-1 and Bay K 8644 in the Isolated Rabbit Papillary Muscle

Endothelin-1 (ET-1) elicited a concentration-dependent positive inotropic effect on the rabbit isolated papillary muscle (electrically driven at 1 Hz at 37 degrees C). The duration of isometric contractions was prolonged by ET-1 in a concentration-dependent manner mainly by prolongation of relaxation time. A tumor-promoting phorbol ester, i.e., phorbol-12,13-dibutyrate (PDBu), inhibited selectively the positive inotropic effect of ET-1 at the concentration that it did not (10 nmol/L) or only slightly (10-20% at 100 nmol/L) reduced the basal force of contraction and the positive inotropic effect of Bay K 8644. The positive inotropic effect of 10 mumol/L of phenylephrine mediated via myocardial alpha 1-adrenoceptors (in the presence of 0.3 mumol/L of bupranolol) was likewise inhibited by PDBu in the same concentration range as it suppressed the ET-1-induced positive inotropic effect. PDBu at concentrations higher than 100 nmol/L inhibited the positive inotropic effects of Bay K 8644 and isoproterenol, and decreased the basal force of contraction in a concentration-dependent manner to a similar extent. Thus, PDBu exhibited selective and potent inhibitory action on the ET-1-induced and alpha 1-adrenoceptor-mediated positive inotropic effect (compared with that on the effect of the Ca2+ channel agonist Bay K 8644 and a beta-adrenoceptor agonist). The present findings indicate that ET-1 elicits a positive inotropic effect on the rabbit ventricular myocardium, the characteristics of which are similar to those of myocardial alpha-adrenoceptor activation, which may involve the phosphoinositide hydrolysis.

Interactions between peripheral-type benzodiazepine receptor ligands and an activator of voltage-operated calcium channels

The effects of the peripheral-type benzodiapine receptor (PBR) ligands Ro 5-4864 and PK 11195 were studied in the spontaneously beating guinea pig atrium and in a model for myocardial ischemia in the rat. In the former, Bay K 8644 produced positive chronotropic and inotropic responses; intracarotid administration of this agonist (5 or 10 micrograms kg-1) to anesthetized rats elicited a transient increase in mean arterial blood pressure accompanied by alterations in the ECG pattern. Ro 5-4864 and PK 11195 (10 microM) completely blocked the positive chronotropic effect of Bay K 8644 in the atrium, PK 11209, a structural analog of PK 11195 with a low affinity for PBR, was inactive, and the central benzodiazepine receptor ligand clonazepam had a marginal effect. Ro 5-4864 potentiated whereas PK 11195 inhibited the myocardial ischemia produced by Bay K 8644 in the rat. Furthermore, PK 11195 blocked the combined response to Bay K 8644 and Ro 5-4864. Addition of Ro 5-4864 (10 microM) to the organ bath potentiated the inotropic effect of Bay K 8644 in the atria; PK 11195 at the same concentration inhibited this effect. Clonazepam and PK 11209 were both inactive in this regard. Nifedipine, a potent calcium channel antagonist, completely blocked the inotropic and chronotropic responses to Bay K 8644. PK 11195 and Ro 5-4864 did not affect this action. These findings strongly suggest that there is a functional association between PBR and voltage-operated calcium channels in the guinea pig atrium and rat cardiovascular system.

Possible inhibition of canine ventricular sarcoplasmic reticulum by BAY K 8644

The calcium-channel agonist-antagonist racemic mixture of BAY K 8644 as well as the pure calcium-channel agonist enantiomer, converted rest potentiation in canine ventricular muscle to rest depression. The depressed postrest beats had increased action potential plateau heights and durations, suggesting that extracellular calcium entry was enhanced. BAY K 8644 did not alter the time to peak tension of either steady-state or postrest beats. Although BAY K 8644 slightly increased the amplitude of rapid-cooling contractures (RCC) immediately after an electrically evoked steady-state contraction (RCCss), the RCC amplitude rapidly decreased with increasing durations of rest. These results suggest that increased calcium influx because of BAY K 8644 increases the pool of releasable calcium during steady-state stimulation. However, they also indicate that BAY K 8644 causes acceleration of diastolic loss of calcium from the sarcoplasmic reticulum (SR). Scattered light intensity fluctuation measurements showed that the negative inotropic effect of BAY K 8644 on postrest contraction was not caused by calcium overloading of the SR, since BAY K 8644 reduced asynchronous myofilament motion. A negative relationship found between extracellular calcium and BAY K 8644-induced postrest depression also rules out the possibility that the latter effect is caused by intracellular calcium overload. BAY K 8644 seems to accelerate the loss of calcium from the SR during diastole by a pathway that does not appear to pass through the myofilaments.

Metabolic Requirement for the Inotropic Effects of Digitalis and BAY K 8644

The positive inotropic effects of ouabain and of BAY K 8644 are not apparent in rabbit atria suspended in substrate free medium or in a medium containing 5 mM pyruvate. Addition of glucose in graded concentrations (1-11 mM) during continued exposure of the preparations to the inotropic agents yields graded inotropic effects. The possible involvement of the glycolytic pathway to the development of the inotropic effect of ouabain and BAY K 8644 was tested by using inhibitors of glycolysis that act at two different steps. Iodoacetic acid completely blocks the inotropic effect of ouabain in atria at 0.1 mM and papillary muscles at 0.05 mM. The inotropic effect of BAY K 8644 was blocked partially in atria and papillary muscles. Iodoacetic acid did not change the inotropic effects of isoproterenol and Ca2+. Addition of 1 mM fluoride did not affect significantly the inotropic effect of either ouabain or BAY K 8644 in atria but partially blocked the effect of BAY K 8644 in papillary muscles. The response of atria to ouabain was not changed significantly when glyceraldehyde (10 mM) was substituted for glucose. We suggest that glycolytic ATP may be important for the full inotropic effect of ouabain and BAY K 8644.

The positive inotropic action of the nifedipine analogue, Bay K 8644, in guinea‐pig and rat isolated cardiac preparations

The inotropic effect of Bay K 8644 has been studied in rat and guinea-pig atria and ventricular strips stimulated at 1 Hz, in a medium containing CaCl2 1.8 mM. The positive inotropic effect at maximal effective concentrations of Bay K 8644 was in the following order: guinea-pig ventricle greater than rat ventricle greater than guinea-pig atria greater than greater than rat atria. In rat preparations, the tension recorded at maximum effective concentrations of Bay K 8644 was similar at three different calcium concentrations (0.7, 1.8, 3.0 mM). The amplitude of the positive inotropic effect evoked by Bay K 8644 increased when atrial and ventricular contractions were reduced by lowering the external calcium concentration. The contractile tension reached in the presence of maximum effective concentrations of Bay K 8644 (3 X 10(-7) -1 X 10(-6) M) was greater than that produced by the maximum effective concentration of external calcium (3 mM) in rat ventricles but not in rat atria. High doses of nifedipine (3 X 10(-7) -1 X 10(-6) M) depressed the contraction of rat atria more than the contraction of rat ventricles. In rat ventricles, nifedipine shifted to the right the inotropic dose-effect curve of Bay K 8644. It is concluded that the interaction between nifedipine and Bay K 8644 occurred at the same binding sites. These sites have some characteristics of the low affinity binding sites of nifedipine and other related dihydropyridines.