Critical dependence of the NO-mediated component of cyclic AMP-induced vasorelaxation on extracellular L-arginine in pulmonary arteries of the rat.
A component of isoprenaline-mediated vasorelaxation in pulmonary arteries is mediated by nitric oxide (NO). We examined the effects of physiological concentrations (</=400 microM) of L-arginine on isoprenaline-induced relaxation in rat pulmonary arteries, and following inhibition of L-arginine uptake with L-lysine. In addition, we examined the role of the endothelium, and whether L-arginine affected acetylcholine (ACh)-induced relaxation. Isoprenaline-induced relaxation was potentiated by 400 microM L-arginine in pulmonary arteries; maximum relaxation was increased from 83+/-4% of initial tone to 94+/-4% (P<0.05). L-lysine (10 mM) not only abolished the potentiation by L-arginine, but suppressed relaxation compared to control (70+/-4%, P<0.05), even in the absence of L-arginine added to the bath. Blockade of NO synthase with 100 microM L-NMMA or removal of the endothelium inhibited isoprenaline-induced relaxation to the same extent as L-lysine, and under these conditions the presence or absence of 400 microM L-arginine made no difference. L-lysine had no additional effect when applied in combination with L-NMMA. The effect of extracellular L-arginine was concentration dependent, with an apparent EC(50) of approximately 1-7 microM. Relaxation to the membrane permeant cyclic AMP analogue CPT cyclic AMP was also potentiated by L-arginine and inhibited by L-lysine. There was however no difference in relaxation induced by acetylcholine (ACh) in the presence of L-arginine or L-lysine, and isoprenaline-induced relaxation of mesenteric arteries was unaffected by L-arginine or L-lysine. These results strongly suggest that extracellular L-arginine is critically important for development of the NO- and endothelium-dependent component of cyclic AMP-induced vasorelaxation in rat pulmonary arteries, but is not required for ACh-induced relaxation. As the apparent EC(50) for this effect is in the low micromolar range it is likely to be fully activated in vivo, as plasma L-arginine is >150 microM.
Hucks
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Department of Respiratory Medicine and Allergy, Guy's, King's and St Thomas' School of Medicine, King's College London, Guy's Campus, London SE1 9RT, UK.
Ward
J P
JP
D000818:Animals; D001120:Arginine / Q000494:pharmacology*; D000242:Cyclic AMP / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000502:physiology; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008239:Lysine / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000502:physiology; D052250:Nitric Oxide Synthase Type III; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D014664:Vasodilation / Q000187:drug effects*; D019323:omega-N-Methylarginine / Q000494:pharmacology
D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine; D000242:Cyclic AMP; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D008239:Lysine; D007545:Isoproterenol