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

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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 α‐ and β‐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 α1‐adrenergic receptor blocker prazosin (10−7mol/l) and the β‐adrenergic receptor blocker timolol (10−6mol/l), the positive inotropic effect of 1.7 × 10−6mol/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 β‐receptor stimulation (β‐type response with shortening of time to peak tension), but was very similar to the cAMP‐independent response to α‐receptor stimulation (α‐type response). Additional cholinergic muscarinic stimulation by carbacholdid notcounteract the effect of BAY K 8644, but rather increased the inotropic response. It is concluded that both the qualitative characteristics of the BAY K 8644 response and the effect of simultaneous cholinergic stimulation upon this response are those expected for a cAMP‐independent response. The results also support the assumption that the response type can be used as a first step in classifying whether an inotropic agent is dependent or independent upon activation of the cAMP system.

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