Depletion of arterial L-arginine causes reversible tolerance to endothelium-dependent relaxation

This study examined the influence of lowered arterial levels of L-arginine on endothelium-dependent relaxation of isolated rings of bovine pulmonary artery. Incubation of arterial rings under tension for 24 hr in oxygenated Krebs bicarbonate solution at 37 degrees C resulted in the development of marked or complete tolerance to A23187 (calcium ionophore)- and acetylcholine-elicited relaxation. Relaxant responses to nitric oxide were unaffected. Addition of L-arginine did not relax control rings but did elicit marked endothelium-dependent relaxation of tolerant rings that was inhibited by oxyhemoglobin or methylene blue. L-Arginine also restored acetylcholine-elicited relaxation. Inclusion of L-canavanine in the 24 hr incubations protected against the development of tolerance. The tissue concentration of arginine was 3-fold lower in tolerant than control arterial rings and L-canavanine restored arterial arginine levels to control values. Therefore, depletion of arterial L-arginine causes reversible tolerance to endothelium-dependent relaxation.