Properties of the Inotropic Response in Rat Papillary Muscles to the Dihydropyridine “Ca‐Channel Activator” BAY K 8644

Abstract

The aim of the present study was 1) to characterize qualitatively the positive inotropic effect of the Ca-channel activator BAY K 8644 and to compare this response to response-types with known and different relationship to the cyclic AMP (cAMP) system (e.g. responses elicited through alpha- and beta-adrenergic receptor stimulation) and 2) to study the effect of simultaneous muscarinic cholinergic stimulation upon the BAY K 8644 response in order to further evaluate the role of the cAMP system in this response. The responses were evaluated in isolated, electrically paced, isometrically contracting papillary muscles from rat heart. Isometric tension (Tmax), rate of rise and decline of tension (first derivative = T') and rate of transition from tension rise to tension decline (negative part of second derivative = T") were recorded. In the presence of the alpha 1-adrenergic receptor blocker prazosin (10(-7) mol/l) and the beta-adrenergic receptor blocker timolol (10(-6) mol/l), the positive inotropic effect of 1.7 x 10(-6) mol/l BAY K 8644 developed rather slowly with a time to half maximal effect of about 4 minutes. Qualitatively the response was characterized by an almost proportional ("symmetrical") increase in all parts of the contraction-relaxation cycle with a small prolongation of time to peak tension and of the duration of the whole cycle. This response contrasted sharply with the cAMP-dependent response to beta-receptor stimulation (beta-type response with shortening of time to peak tension), but was very similar to the cAMP-independent response to alpha-receptor stimulation (alpha-type response).(ABSTRACT TRUNCATED AT 250 WORDS)

Positive inotropic and negative chronotropic effects of (−)‐cis‐diltiazem in rat isolated atria

“…The present study, however, did not support this assumption, because (-)-cis-diltiazem, unlike Bay K 8644 which is a dihydropyridine calcium agonist, did not produce the calcium agonistic action in the rat aortic strip (Figure 8). Bay K 8644 binds to the calcium channel that is open and increases the calcium influx (Bechem & Schramm, 1987), and therefore it produces contraction of the vascular smooth muscle and increases contractility of the heart without affecting cyclic AMP content (Skomedal et al, 1988). Never-theless, Bay K 8644 produces only a weak positive inotropic action in isolated rat left atria (Finet et al, 1985), while in the partially depolarized rat aortic strip it produced a large contractile response as shown in the present study.…”

SERCA2 activity is involved in the CNP‐mediated functional responses in failing rat myocardium

“…2+ channel activation, but not during maximal β-adrenoceptor stimulation the non-selective phosphodiesterase inhibitor IBMX to ensure maximal cAMP production, which will activate PKA and induce phosphorylation of downstream targets such as LTCC, PLB and TnI, causing both inotropic and lusitropic responses; (ii) Ca 2+ channel activation by BAY-K8644 (Kokubun and Reuter, 1984), which was previously shown not to cause LR (Skomedal et al, 1988) but to induce an inotropic response quantitatively comparable to that induced by β-adrenoceptor stimulation. In the presence of Iso + IBMX, CNP was unable to induce either a NIR [Δ(dF/dt)max = 0.2 ± 2.0% of basal, n = 4] or a LR (LRmax = 1.6 ± 1.3%, n = 4).…”

New 1,4-Dihydropyridines Endowed with NO-Donor and Calcium Channel Agonist Properties

“…After a 90 min equilibration period, cumulative concentration−response curves to Ca 2+ agonists were constructed by increasing doses by half-log units after each response had reached a plateau. To avoid indirect receptor-mediated effects of possibly released endogenous noradrenaline by the Ca 2+ -channel activators, the muscles were incubated in the presence of the β-receptor blocker propranolol (1 μM) and the α 1 -receptor blocker prazosin (0.1 μM) . The receptor blockers were introduced into the bath solution 15 min before addition of Ca 2+ -channel activator.…”

“…Functional Studies. Papillary muscles 16 and aortas were isolated from male Wistar rats weighing 200-250 g which had been anaesthetized with CO2 and killed by decapitation. All animals were treated humanely in accordance with recognized guidelines on experimentation.…”