Beta-1-adrenoceptor agonists with low adenylate cyclase activation--theoretical and clinical implications

Several partial beta-agonists such as TA-064, prenalterol, ICI 89,963 and ICI 119,033 possess pronounced positive inotropic effects but induce only limited activation of myocardial adenylate cyclase; this results in low cyclic AMP levels. Partial agonists, as compared to isoproterenol, need high receptor occupancy for maximal physiological response, and demonstrate inadequate coupling between receptor and adenylate cyclase. However, the biochemical mechanisms which generate the final biological effects originating from cyclic AMP are tissue-specific, and for that reason, can maintain a pronounced positive inotropic action. Clinical data with TA-064 and prenalterol have established positive inotropic effects without significant changes in heart rate. Partial beta-agonists with diminished cyclic AMP may be less arrhythmogenic than full beta-agonists. The clinical importance of partial beta-1-agonists remains to be established, particularly with relevance to long-term exposure and inherent beta blockade.