Calcium entry blocking activity of dilazep and other adenosine potentiating compounds in guinea-pig atria

In potassium-depolarized guinea-pig left atria treated with isoproterenol, calcium entry blocking activities of adenosine and its potentiating compounds, dipyridamole, lidoflazine and dilazep were studied and compared to verapamil and diltiazem. pA2 values for various drugs were calculated using concentration-response curves for calcium (parallel shift to the right). The order of potency for the calcium entry blocking effect was: verapamil greater than diltiazem greater than adenosine greater than lidoflazine = dilazep greater than dipyridamole. Adenosine caused negative inotropic effects in depolarized left atria. The negative inotropic effect of adenosine was very quick in onset and was potentiated by erythro-6-amino-9(2-hydroxy-3-nonyl)-purine hydrochloride (EHNA), an adenosine deaminase inhibitor, suggesting that adenosine was being degraded. The effect of adenosine was quickly abolished by adenosine deaminase (ADA) and antagonized by 8-phenyltheophylline (8-PT), suggesting that the action of adenosine was most likely through the surface membrane receptor sites. The negative inotropic effects of dilazep and dipyridamole were only partially reversed by ADA and 8-PT, while that of lidoflazine was not affected by these agents. These findings suggest that the mechanism(s) of negative intotropic effect of lidoflazine was different from that of dilazep and dipyridamole. These data suggest that the negative intropic effect of dilazep is most likely due to a direct calcium entry blocking effect and in part due to its adenosine potentiating effect. However, the calcium entry blocking effect of lidoflazine is independent of adenosine.