Positive inotropic and chronotropic effects of trypsin and some other proteolytic enzymes in the guinea-pig heart.

1 In atrial preparations of the young guinea-pig (body weight 150-250 g), five proteolytic enzymes (trypsin, chymotrypsin, bacterial-Al-proteinase (nagarse), bromelain and kallikrein) produced concentration-dependent positive inotropic and chronotropic effects, while they exerted only minimal effects on the papillary muscle preparations. 2 To characterize the effects, further experiments were conducted in atrial preparations using trypsin. There was a strong tendency for tachyphylaxis: a second exposure to the same concentration of trypsin resulted in considerably smaller positive inotropic and chronotropic effects. The positive inotropic and chronotropic effects of this substance were not affected by propranolol (5 X 10(-7)M). However, an accumulation of cyclic AMP was observed and the positive inotropic and chronotropic effects were potentiated by aminophylline (10(-4)M) in association with an augmentation of the accumulation of cyclic AMP. In preparations partially depolarized with high K+ (22mM) medium (contractions ceased under this condition) trypsin 100 micrograms ml-1 reinstated the contraction. Treatment of the preparation with aprotinin (200 u ml-1) resulted in a strong inhibition of the positive inotropic and chronotropic effects. 3 Islet activating protein (IAP), a specific inhibitor of the 'inhibition specific' guanine nucleotide binding regulatory protein of the adenylate cyclase system, did not produce significant inhibition of the positive inotropic and chronotropic effects of trypsin, whereas it produced a complete inhibition of the negative inotropic and chronotropic effects of carbachol. 4. These results suggest that the positive inotropic and chronotropic effects ofproteolytic enzymes are intimately connected with the proteolytic activities through which adenylate cyclase is activated to produce an accumulation of cyclic AMP within the myocardium. The destruction of the 'inhibition specific' guanine nucleotide regulatory protein of the adenylate cyclase was not substantiated as a mechanism of activation of the adenylate cyclase.