Imidazoline receptor ligands:cardiovascular applications

Abstract

Hypertension, congestive heart failure and cardiac arrhythmias are very common cardiovascular diseases; e.g., the prevalence of hypertension has been estimated as approximately 10% of the adult population of industrial countries. The discovery and development of new antihypertensive drugs is justified by the fact that most of the available drugs act predominantly to reduce blood pressure alone and have only minimal effects on the risk factors associated with hypertension. The angiotensin converting enzyme (ACE) inhibitors were the first antihypertensive drugs to exhibit additional beneficial effects, such as a reduction in cardiac hypertrophy. Ligands selective for cerebral imidazoline-specific receptors are known to inhibit sympathetic activity and to restore sympatho-vagal balance. Rilmenidine and, more recently, moxonidine (representatives of the so-called second generation of centrally-acting cardiovascular drugs) were the first centrally-acting, imidazoline receptor-specific antihypertensive agents to be marketed as cardiovascular drugs. They may also be of benefit in the treatment of Syndrome X, through a combination of their antihypertensive and sympatho-inhibitory actions. Because the sympatho-vagal balance is also altered in congestive heart failure, imidazoline-like drugs are also expected to be of benefit in this prevalent disease. Imidazoline-like drugs have already been shown to prevent the occurrence of cardiac arrhythmias in animal models; such an anti-arrhythmic action occurring at doses below that necessary to exert an antihypertensive effect. Therefore, imidazoline-like drugs may also be of benefit as anti-arrhythmic drugs. The available imidazoline-like drugs are well tolerated. Existing therapies for cardiac arrhythmias and congestive heart failure suffer from deleterious side-effect profiles and/or minimal efficacy. Therefore, it is hoped that imidazoline-like drugs will lead to well-tolerated, efficacious drugs for the treatment of not only hypertension but also some of the risk factors associated with hypertension, in addition to cardiac arrhythmias and congestive heart failure. Whether the efficacy of such compounds in man will be more favourable than that of currently available therapies remains to be determined.