Impairment of smooth muscle function of rat thoracic aorta in an endothelium‐independent manner by long‐term administration of N G ‐nitro‐ l ‐arginine methyl ester

In this study, we aimed to elucidate whether the daily hypertensive dose of long‐term N G ‐nitro‐ l ‐arginine methyl ester ( l ‐NAME) treatment, could make a difference between endothelial and smooth muscle functions in rat thoracic aorta. We test the hypothesis that high‐dose, long‐term l ‐NAME treatment has a depressive effect on vascular smooth muscle contractile activity which is not related with nitric oxide (NO) synthesis inhibition. After 14 days of treatment, isometric tension and 45 Ca 2+ influx were measured in aortic tissues isolated from l ‐NAME 10 and l ‐NAME 100 hypertensive (10 and 100 mg/kg/day, systolic blood pressures 167 ± 7 and 172 ± 10 mmHg, respectively) and control normotensive rats (132 ± 7 mmHg). In l ‐NAME 10 ‐ and l ‐NAME 100 ‐treated rats, acetylcholine‐induced relaxation in aortic rings was suppressed with no significant difference between the treatments. l ‐NAME 100 (but not l ‐NAME 10 ) treatment, significantly inhibited contractile responses to phenylephrine, angiotensin II, and K + (80 m m ) in endothelium‐intact tissues. The effect of l ‐NAME 100 on phenylephrine‐induced contractile responses was not observed after 3 days of treatment. In endothelium‐denuded aortic tissues of l ‐NAME 100 (but not l ‐NAME 10 )‐treated rats, phenylephrine (1 × 10 −6   m )‐ and K + (80 m m )‐induced contractions and 45 Ca 2+ influxes were significantly reduced. In Ca 2+ ‐free medium (0.1 m m EDTA), on the contrary, the transient contractions obtained by either phenylephrine (1 × 10 −6   m ) or caffeine (1 × 10 −2   m ), or the sustained contractions induced by 12‐ o ‐tetradecanoylphorbol‐13‐acetate (1 × 10 −6   m ; a protein kinase C activator) in endothelium‐denuded aortic rings, were not modified by both l ‐NAME treatments. These results indicate that in aortic rings from l ‐NAME hypertensive rats, low and high doses, long‐term l ‐NAME administration may be associated with equivalent inhibition in NO‐dependent vasodilator tone (corresponding to equivalent hypertension values); whereas only high‐dose, long‐term l ‐NAME administration produces an endothelium‐independent decrease in vasocontrictor activity, at least partly explained by a reduction in extracellular Ca 2+ influx.