Stimulating G Protein–Coupled Receptors

Historically there has been intense interest in restoring to the failing heart the ability to improve contractility to normal levels. This concept, which has been pursued with almost religious zeal for the last half century, is based on the intuitive assumption that the defect in heart failure resides at the end point, which is defective myocyte contraction.This concept was given additional impetus by the observation by Chidsey et al1 that failing human hearts exhibit norepinephrine depletion. Over the last half century, the pharmaceutical industry has responded to this concept with a variety of β-adrenergic agonists designed to improve the contractility of the failing heart. For several years, isoproterenol was administered, which provided some short-term relief but was found to exert deleterious effects in most patients. Most likely, the isoproterenol-induced increases in cardiac rate, contractility, and oxygen consumption are maladaptive in patients with limited coronary reserve. This was followed by a series of β1-predominant or β1-selective agonists that induce enhanced contractility with little or no effect on heart rate or arterial pressure. Some of these agents were used for many years in clinical setting as well as under experimental conditions. It was not until carefully controlled long-term studies were carried out that it was found that mortality was increased in patients with heart failure on these drugs.2 3 4 The results of these studies suggest that agents that increase oxygen consumption over an extended period of time may …