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

Abstract

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 mm) 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 x 10(-6) m)- and K(+) (80 mm)-induced contractions and (45)Ca(2+) influxes were significantly reduced. In Ca(2+)-free medium (0.1 mm EDTA), on the contrary, the transient contractions obtained by either phenylephrine (1 x 10(-6) m) or caffeine (1 x 10(-2) m), or the sustained contractions induced by 12-o-tetradecanoylphorbol-13-acetate (1 x 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.

Barnidipine ameliorates the vascular and renal injury in l-NAME-induced hypertensive rats

“…L-NAME (60 mg/kg/day, p.o, 5 weeks) administration elevated SBP and reduced body weights of rats consistent with previous studies (Baylis et al, 1992;Lopez et al, 2004;Ribeiro et al, 1992;Sekiguchi et al, 2001).…”

“…In the current study, long term L-NAME treatment significantly reduced concentration-dependent contractions to noradrenaline, an Į-adrenoceptor agonist, both in the mesenteric and renal arteries which were restored by concomitant Barnidipine treatment. It has been previously speculated that reduced contractile reactivity following long term inhibition of NO synthesis might play a compensatory role against the enhanced stimulation of vasoconstrictor signalling pathways (Dowell et al,1996;Lopez et al, 2004). Supportively, it was notified that the pressor responses to sympathetic stimulation were augmented in L-NAME-treated rats due to increased adrenal catecholamine release (Elayan et al, 2002).…”

Diminished Contractile Responses of Isolated Conduit Arteries in Two Rat Models of Hypertension

“…This could contribute to the fact that this artery behaved differently from aorta and had no tendency to diminution of contractility in SHR in our study. In contrast to SHR, reduction in arterial contractile responses in rats made hypertensive with L-NAME treatment is present more globally in the vasculature (7,17). This finding may seem unexpected not only because of the hypertrophied arterial walls in these rats but also due to their markedly impaired vasorelaxation (28).…”

“…But in chronic conditions, when L-NAME is delivered to the organism for several weeks (especially in higher doses), the sustained inhibition of NO synthase has some additional long-term consequences on cardiovascular functions. Besides the adaptation to severe systemic hypertension due to suppressed NO-dependent vasorelaxation, long-term NO deficiency alone induces structural alterations in cardiovascular tissues like fibrotic lesions (19,23), lipid deposition in arterial wall (33), or functional changes of vascular smooth muscle cells resulting from decreased contractile protein expression or reduction in extracellular Ca 2+ influx (17,33) which indicate the loss of arterial contractile properties. This may affect smooth muscle function either directly, or also through the structural changes in the arterial wall, which constrain the transfer of muscular generated force, as was described above.…”

“…However, as stated by Mulvany and Halpern (22), by reason of methodological limitations, most of this information until the mid-1970s was obtained only from large elastic vessels, animal aorta being the most examined. Despite the fact that there are many techniques for investigating much smaller vessels today [with internal diameters down to around 100 µm; (22)], large arteries are still regularly being used in the study of functional and morphological alterations accompanying various cardiovascular diseases (17,27).…”