Is the Cardiotonic Effect of Aminopyridines and Aminopyrimidines in vitro A Consequence of Increased Extracellular pH?

This chapter discusses a study to analyze the cardiotonic effect of aminopyridines and aminopyrimidines. This study compares the effects of the strongly basic substances 4-aminopyridine (4-AP) and 2,4,6-triaminopyrimidine (TAP) with those of increased pH on tension responses and cyclic AMP levels in rabbit isolated electrically-driven (1 Hz) papillary muscles. Both 4-AP base and TAP base elicited concentration-dependent increases in contractile force. As the force of contraction increased, however, so too did the extracellular pH rising from a resting level of 7.2 to 9.6 at the highest concentration used. In contrast, Pymadin® (4-AP hydrochloride) or neutralized TAP were devoid of inotropic activity and did not significantly alter the pH of the bathing medium. Increasing the pH of the bathing solution from 7.0 up to 9.6 in the absence of either drug induced inotropic responses almost identical to those elicited by either 4-AP or TAP. These responses were highly reproducible and readily reversed to control tension levels on re-immersion in solution at pH 7.