Xamoterol, a β₁Adrenoceptor Partial Agonist: Pharmacology and Clinical Use

Abstract

The high prevalence of chronic congestive heart failure has encouraged the search for new orally active drugs. In the early stages of heart failure, when symptoms are confined to periods of work stress, the overriding objective of drug therapy is to improve cardiac contractile activity. As heart failure advances and vasoconstriction and increased activity of the neuroendocrine system results in salt and water retention, diuretics can be added. In the terminal stages of disease, the addition of angiotensin converting enzyme (ACE) inhibitors can be expected to benefit the patient (87).In 1948, Ahlquist (1) proposed the existence of two types of receptors in the adrenergic system, a-and P-receptors. Lands et al. (46) presented experimental evidence in 1967 that justified a subdivision of f3-adrenergic receptors into PI-and P,-adrenoceptors. In 1972, Furchgott described (31) the procedure for the characterization of a-and P-adrenoceptors. According to the earlier classification, the responses of the tissues could be classified as being mediated by either P,-or P,-adrenoceptors. Subsequently, PI-and P,-adrenoceptors have been found to coexist in various organs. For example, in the heart of some animals and in the human, we have both receptor types. The functional and pathophysiological roles of these receptors are not fully defined (4,(15)(16)(17)37,38,103).The pharmacological classification of P-adrenoceptors into PI-and &-subtypes has been based on the relative affinity of the receptors for the agonists and on the competition between selective antagonists and nonselective radiolabeled ligands. The P-adrenoceptors have been identified biochemically, and these two mammalian proteins possess identical molecular masses. The structures of PI-and P,-adrenoceptors have been proposed and their genes have been cloned. Recent data establish that the two receptors are products of different genes (30).When an agonist occupies the P-adrenoceptor, adenyl cyclase is activated through its interaction with the guanine nucleotide-binding regulatory proteins, G,. Cyclic AMP is an

Clinical and Pharmacological Effects of Denopamine, an Orally Active β1Agonist

“…A slightly weaker intrinsic activity (0.69) was reported for the chronotropic effect of denopamine in guinea pig right atrium (70). Based on these findings, denopamine has an agonistic potency equivalent to that of prenalterol (20) and is more potent than xamoterol (34,68,70). By intravenous as well as by oral administration denopamine consistently increased the maximal rate of rise of the left ventricular pressure (peak dP/dt) in situ (22,23,38,41).…”