EFFECTS OF ACIDOSIS AND HYPOXIA ON THE RESPONSE OF ISOLATED FERRET CARDIAC-MUSCLE TO INOTROPIC AGENTS

Objective: The aim was to study the effects of acidosis and hypoxia on the response of cardiac muscle to inotropic agents which (a) act pred ominantly by increasing intracellular [Ca2+] (raising extracellular [C a2+], noradrenaline, isoprenaline) and (b) act partly (phenylephrine) or predominantly (EMD 57033) by increasing myofilament calcium sensiti vity. Methods: The experiments were performed on isometrically contrac ting, isolated ferret papillary muscles (n=45). For each intervention dose-response curves were performed in control solution (pH 7.35), in hypercapnic acidosis (pH 6.85), and in hypoxia (produced by replacing O-2 With N-2 in the superfusing solution). In some experiments, the ph otoprotein aequorin was microinjected into superficial cells of the pr eparation in order to measure intracellular [Ca2+] as well as force. R esults: The results were broadly similar for both classes of inotropic agent. Acidosis caused a shift of the pCa-tension curve to the right (desensitisation of the myofilaments to calcium), but had no significa nt effect on maximum force. A sufficient inotropic stimulus supplied b y either class of inotropic agent could completely reverse the negativ e inotropic effects of acidosis. The main difference between the two i notropic mechanisms was that the enhanced force produced by calcium se nsitisers was associated with a reduction in calcium transient amplitu de, while the other inotropes increased the amplitude. The main effect of hypoxia was to decrease maximum force. All the inotropes tested we re relatively ineffective in reversing the force depression due to hyp oxia. Conclusions: The negative inotropic effects of acidosis can be r eversed by a sufficiently large inotropic stimulus. Since calcium tran sient amplitude is already increased in acidosis, the results suggest that calcium sensitisers are likely to be less arrhythmogenic in this situation. The relative ineffectiveness of the inotropes in hypoxia in dicates that the main mechanisms causing reduced force in this situati on lie downstream of the mechanisms of action of the inotropic agents tested.