L-arginine and tetrahydrobiopterin modulate endothelin-1A receptor activity in isolated rat aorta

Endothelin-1 (ET-1), is a potent endogenous vasoconstrictor secreted by endothelial cells. It acts as the natural counterpart of the vasodilator effect of nitric oxide (NO). ET-1 exert it is the vasoconstrictor activity through two types of receptors, ET-1A and ET-1B receptors that are located on vascular smooth muscle cells (VSMCs). The present study was designed to evaluate the effect of L-arginine (LA), tetrahydrobiopterin (BH4), and their combination on ET-1A receptor activity in rat aortic rings. The study involved pre-incubation of rat aortic rings with LA, BH4, and their combination. Then, the vascular response to a cumulative dose of the ET-1A receptor antagonist (BQ-123) and in the second set of experiment cumulative doses of Acetylcholine (ACh) were applied to each group. BQ-123 potency increased after LA pre-incubation, but LA and BH4 in combination significantly potentiated BQ-123 potency and maximum response. In the second set of experiment, ACh potency does not change, while ACh efficacy markedly increased during pre-incubation of LA, BH4, and their combination. In conclusion, LA and BH4 may offer some pharmacological tools to modulate the ET-1A receptor activity and treat cardiovascular disease beyond pulmonary arterial hypertension