New positive inotropic substances--true inotropy or peripheral effects?

A large number of chemical substances increase contractility of isolated animal myocardial preparations. Their augmentation is the result of a number of mechanisms which ultimately increase the available calcium for contractile protein coupling. Although there is some research with drugs which activate calcium channels, present clinical research is mainly confined to agents whose major action on contraction is mediated by an increase in myocyte cyclic AMP. Species and age variations in the inotropic effect are common. These agents have additional cardiac effects (e.g. chronotropic, lusitropic) and non-cardiac actions. They are potent vasodilators. In isolated human myocardium obtained from patients without heart failure, they increase contractility at high concentrations. Generally this effect is attenuated in isolated myocardium obtained from patients and animals with chronic cardiac failure. In myocardium from patients with the most severe heart failure, even very high concentrations fail to increase contractility. Part of this attenuation may be due to reduced receptor number (or sensitivity) when the drug's effect is due to receptor-coupled adenylate cyclase activation. However, a reduced ability to produce and/or respond to cyclic AMP itself is suggested by impaired responses to phosphodiesterase inhibitors. In vivo, these agents have frankly harmful effects in patients with near normal cardiac function. Despite increasing contractility indices, they lower blood pressure, raise heart rate and impair myocardial lactate metabolism without increasing cardiac output. In patients with severe heart failure they produce beneficial resting haemodynamic changes; increased cardiac output and reduced filling pressures with only small changes in blood pressure and heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)