Positive Inotropic Effect Of Bay Research Articles

Investigation of the negative inotropic effects of 17 beta-oestradiol in human isolated myocardial tissues.

1. The aim of the present study was to evaluate the effects of 17 beta-oestradiol in human myocardium. The effects of 17 beta-oestradiol, progesterone and testosterone on force of contraction were investigated in electrically driven isolated atrial trabeculae and ventricular papillary muscles from human hearts in the presence and absence of Bay K 8644, a calcium channel agonist. In addition, the effects of 17 beta-oestradiol, progesterone and testosterone on binding of [3H]-PN 200 110 were assessed in membranes prepared from human ventricular myocardium. 2. 17 beta-Oestradiol elicited a negative inotropic effect in atrial (IC50: 7.1 mumol 1(-1), confidence interval 3.8 to 13.4, n = 3) and ventricular preparations (IC50: 4.6 mumol 1(-1)), confidence interval 2.2 to 9.4, n = 3) as compared with solvent controls. There was no significant difference (P > 0.05) of IC50 values in the absence and presence of isoprenaline (0.0 mumol 1(-1)) in atrial (IC50: 10.8 mumol 1(-1), confidence interval 9.1 to 12.9, n = 6) and ventricular preparations (IC50: 9.4 mumol 1(-1), confidence interval 7.3 to 11.9, n = 8). 3. 17 beta-Oestradiol at 30 mumol 1(-1) induced a significant rightward shift of the concentration-response curves for the positive inotropic effect of Bay K 8644 in atrial preparations (EC50: 0.13 mumol 1(-1), confidence interval 0.08 to 0.19, n = 6; EC50 with 17 beta-oestradiol: 0.58 mumol 1(-1), confidence interval 0.33 to 0.83, n = 6, P < 0.05) and ventricular preparations (EC50: 0.07 mumol 1(-1), confidence interval 0.04 to 0.11, n = 8; EC50 with 17 beta-oestradiol: 0.3 mumol 1(-1), confidence interval 0.18 to 0.49, n = 8, P < 0.05). Testosterone, progesterone at 30 mumol 1(-1) and the solvent control had no significant effect on the concentration-response curves to Bay K 8644. 4. In membranes prepared from human ventricular myocardium the effect of 17 beta-oestradiol on binding of [3H]-PN 200 110, an antagonist at the 1,4 dihydropyridine binding site, was not different from that observed with progesterone, testosterone or solvent controls. 5. In myocardial membranes no specific oestrogen receptors were demonstrated by [3H]-oestradiol binding studies. 6. Thus, the calcium antagonistic property of 17 beta-oestradiol cannot be attributed to a direct interaction with 1, 4 dihydropyridine binding sites.

Inotropic, chronotropic, and radioligand binding characteristics of leukotriene B 4 in cardiac myocyte, papillary muscle, and membrane preparations

Cardioprotective effects of dietary fish oil consumption have been attributed to the substitution of eicosapentaenoic acid (EPA) for arachidonic acid (AA) in cellular membranes. This substitution blocks the formation of leukotriene B 4 (LTB 4) which is elaborated locally in the area of ischemic myocardium. We studied the in vitro inotropic, chronotropic, and radioligand binding characteristics of LTB 4 to gain potentially important insights into the mechanisms involved in the cardioprotective effect of EPA. LTB 4 was a concentration-dependent and reversible negative inotrope in isolated papillary muscle preparations. LTB 4 significantly blocked the positive inotropic effect of Bay K 8644 (BK) (calcium channel regulator) on papillary muscles and the positive chronotropic effect of BK on spontaneously beating neonatal cardiac myocytes. LTB 4 had no direct effect on [ 3H]PN200-110 binding to cardiac sarcolemmal L-type calcium channels or [ 3H]ryanodine binding to cardiac SR calcium release channels. These studies support a potentially important indirect effect of LTB 4 on myocardial E-C coupling.

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.

Effect of selective agonists and antagonists on atrial adenosine receptors and their interaction with Bay K 8644 and [3H]‐nitrendipine

1. (-)-N6-phenylisopropyladenosine (R-PIA) and N6-cyclohexyladenosine (CHA), highly selective agonists at A1-adenosine receptors, 5'-N-ethyl-carboxamidoadenosine (NECA), a non-selective agonist at A1 and A2 receptors, and 2-phenylaminoadenosine (CV-1808), a selective A2 agonist, were compared in spontaneously beating and electrically driven atria. R-PIA, CHA and NECA inhibited contraction in both preparations. CV-1808 was not effective up to 500 nM. 2. 1,3-Dipropyl-8-cyclopentylxanthine (DPCPX), a new selective A1 receptor antagonist, competitively inhibited the effects of the adenosine agonists, at low concentrations (IC50 less than 1 nM). 3. CHA and NECA were able to inhibit the positive inotropic effect of Bay K 8644 both in spontaneously beating and in electrically driven atria. 4. R-PIA, CHA and NECA (agonists), 8-phenyltheophylline (PT) and DPCPX (antagonists), failed to influence [3H]-nitrendipine binding on microsomal membranes from guinea-pig atria and ventricles in a range of concentrations from 1 nM to 100 microM. 5. The data support the existence of A1 receptors in atrial tissue. No evidence for a direct interaction between adenosine analogues and Bay K 8644 was found at the level of slow calcium channels. Adenosine analogues appear to antagonize the effects of Bay K 8644 indirectly by activation of A1 receptors.

Antagonism between (–)‐N6‐phenylisopropyl‐adenosine and the calcium channel facilitator Bay K 8644, on guinea‐pig isolated atria

Antagonism between (-)-N6-phenylisopropyladenosine (PIA) and the dihydropyridine calcium channel facilitator Bay K 8644 was investigated in guinea-pig spontaneously beating or electrically driven isolated atria, taken from normal and from reserpine-treated animals. PIA (3-100 nM) produced a dose-dependent decrease in contractile tension and frequency in spontaneously beating atria being more effective in reserpinized preparations. Bay K 8644 (5-200 nM) produced an increase in contractile tension in both normal and reserpinized atria. In electrically driven left atria the positive inotropic effect of Bay K 8644 was similar to that in spontaneously beating preparations. The positive chronotropic effect of Bay K 8644 was slight and variable. PIA produced a rightward parallel shift of the concentration-response curves for the positive inotropic effects of Bay K 8644 in all experimental conditions. In spontaneously beating atria from normal guinea-pigs, the Schild regression plot was linear and its slope near to unity; pA2 of PIA 8.63 +/- 0.05 (IC50 2.35 +/- 0.25 nM). In electrically driven atria the antagonism by PIA of the effects of Bay K 8644 was apparently competitive, and the IC50 of PIA was 18.6 +/- 0.4 nM. PIA antagonized the positive chronotropic effect of Bay K 8644 in spontaneously beating preparations, both from normal and from reserpine-treated animals. Carbachol did not modify the positive inotropic effects of Bay K 8644. These data indicate that PIA may interact with Bay K 8644 at the level of the slow calcium channels, and may decrease the transmembrane calcium flux into the cell.

Positive inotropic effect of bay K 8644: cAMP-independence and lack of inhibitory effect of adenosine

The aim of the present study was to characterize the positive inotropic effect of the Ca2+ channel activator Bay K 8644. In isolated guinea-pig papillary muscles we investigated whether adenosine and the R site adenosine receptor agonist (-)-N6-phenylisopropyladenosine (PIA) were able to antagonize the positive inotropic effect of Bay K 8644. The effect of Bay K 8644 and adenosine or PIA on myocardial cAMP content was also measured. The influence of adenosine and PIA on the positive inotropic effect of the beta-adrenoceptor agonist isoprenaline and of the phosphodiesterase inhibitor amrinone was studied for comparison. Adenosine and PIA antagonized the positive inotropic effects of isoprenaline and amrinone in a concentration-dependent manner. In contrast, adenosine or PIA did not affect the positive inotropic effect of Bay K 8644. The positive inotropic effect of Bay K 8644 was not accompanied by a change in the cAMP content of the papillary muscles. Additionally applied adenosine or PIA also failed to affect the cAMP content. It is concluded that an increased myocardial cAMP content is not involved in the positive inotropic effect of Bay K 8644. Moreover, the results support the view that adenosine and PIA only antagonize the positive inotropic effects of drugs known to increase myocardial cAMP content and that an increased myocardial cAMP content is a prerequisite for the manifestation of a negative inotropic effect of the nucleosides in ventricular cardiac muscle.

Differential antagonism by Bay k 8644, a dihydropyridine calcium agonist, of the negative inotropic effects of nifedipine, verapamil, diltiazem and manganese ions in canine ventricular muscle.

Antagonism between either the dihydropyridine calcium agonist, Bay k 8644, or high external Ca2+ and the calcium antagonists, nifedipine, verapamil and diltiazem, and Mn2+ was investigated in canine isolated ventricular trabeculae. Bay k 8644 (10(-7)-10(-5)M) produced a slowly developing increase in developed tension which reached a maximum at 10(-6)M. A small decrease in the positive inotropic effect of Bay k 8644 at 10(-5)M was probably due to the negative inotropic effect of the solvent, 0.5% ethanol. Bay k 8644 (10(-7)-10(-5)M) produced a rightward parallel shift of the concentration-response curves for the negative inotropic effects of nifedipine (10(-8)-10(-5)M) and verapamil (10(-7)-3 X 10(-5)M). The slopes of the Schild plots were -0.92 for nifedipine (pA2 value = 6.58) and -0.48 for verapamil. Bay k 8644 (10(-6) and 10(-5)M) produced only a slight rightward shift of the concentration-response curves for the negative inotropic effect of diltiazem (10(-7)-3 X 10(-5)M) and did not affect the negative inotropic effect of Mn2+ (10(-4)-10(-2)M). Addition of 2.5 X 10(-3)M Ca2+ (5.05 X 10(-3)M Ca2+) to the medium produced a greater maximum positive inotropic effect than Bay k 8644. The concentration-response curves for the negative inotropic effects of nifedipine, verapamil and diltiazem obtained under these conditions were not essentially different from those under control conditions (2.55 X 10(-3)M Ca2+). 6 These results indicate that Bay k 8644, while producing a positive inotropic effect, antagonizes the negative inotropic effect of nifedipine by competing with the latter for the same site closely associated with the calcium channel. In contrast, Bay k 8644 antagonizes the negative inotropic effects of verapamil and diltiazem by interfering allosterically with the binding of these calcium antagonists to their sites of action. Bay k 8644 does not antagonize the negative inotropic effect of Mn2+. No pharmacological antagonism was observed between the three organic calcium antagonists and high external Ca2+_