Stimulation of Vascular Dopamine Receptors: Status and Future Strategies

Abstract

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 β-hydroxylase (Dβ), 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 DβH with a K_i of 40 nM against DβH in. vitro. In the spontaneously hypertensive rat SK&F 102698 100mg/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 β-hydroxylase is a unique approach toward cardiovascular and renal therapeutics.

Key Words:

• Dopamine Receptors
• Fenoldopam
• Dopamine β-hydroxylase inhibitors Catecholamines
• Blood Vessels
• Hypertension