Stimulation of vascular dopamine receptors: status and future strategies

The ability to stimulate dopamine receptors in the heart and blood vessels with selective receptor agonists, such as fenoldopam, has been an important advance. Fenoldopam is a selective DA1 receptor agonist and is currently in clinical trials for cardiovascular disease therapy. An alternative approach to stimulating dopamine receptors, while at the same time blunting sympathetic nervous system activity, would be by inhibiting the enzyme dopamine beta-hydroxylase (D beta H), thus increasing the cardiovascular and renal ratio of dopamine to norepinephrine. SK&F 102698, (1-[3',5'-difluorobenzyl]-2-mercaptoimidazole), is a potent inhibitor of D beta H with a Ki of 40 nM against D beta H in vitro. In the spontaneously hypertensive rat SK&F 102698 100 mg/kg orally, increases the dopamine/norepinephrine ratio approximately 5-fold and lowers blood pressure approximately 30 mmHg to normotensive levels. Antihypertensive activity can be achieved with single daily oral administration and neither tolerance nor reflex tachycardia occur. Stimulation of dopamine receptors by inhibition of dopamine beta-hydroxylase is a unique approach toward cardiovascular and renal therapeutics.