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 predominantly by increasing intracellular [Ca2+] (raising extracellular [Ca2+], noradrenaline, isoprenaline) and (b) act partly (phenylephrine) or predominantly (EMD 57033) by increasing myofilament calcium sensitivity. Methods: The experiments were performed on isometrically contracting, 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 photoprotein aequorin was microinjected into superficial cells of the preparation in order to measure intracellular [Ca2+] as well as force. Results: 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 significant effect on maximum force. A sufficient inotropic stimulus supplied by either class of inotropic agent could completely reverse the negative inotropic effects of acidosis. The main difference between the two inotropic mechanisms was that the enhanced force produced by calcium sensitisers was associated with a reduction in calcium transient amplitude, while the other inotropes increased the amplitude. The main effect of hypoxia was to decrease maximum force. All the inotropes tested were relatively ineffective in reversing the force depression due to hypoxia. Conclusions: The negative inotropic effects of acidosis can be reversed by a sufficiently large inotropic stimulus. Since calcium transient 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 indicates that the main mechanisms causing reduced force in this situation lie downstream of the mechanisms of action of the inotropic agents tested.