Effects of Aminoguanidine on Norepinephrine-Induced Vascular Contraction in Renovascular Hypertensive Rats / 대한신장학회잡지

BACKGROUND: It has been established that hypertension is characterized by a dysfunctional endothelium. Among the endothelial factors that cause vasorelaxation, nitric oxide has been most widely known, which is synthesized by the enzyme nitric oxide synthase. This study was aimed to evaluate the role of the inducible nitric oxide synthase in chronic two-kidney, one clip (2K1C) hypertensive rats. METHODS: 2K1C hypertension was made by clipping the left renal artery and age- matched rats received a sham treatment served as control. In vitro experiments were preformed on intact and endothelium-denuded isolated thoracic aortic rings from lipopolysaccharide (LPS)-treated rats, in the presence of aminoguanidine alone, considered to be a selective inhibitor of the inducible nitric oxide synthase and of aminoguanidine and the nonselective nitric oxide synthase inhibitor Nomega-nitro-L-arginine (L-NNA). RESULTS: LPS treatment induced a shift to the right of concentration-response curves to norepinephrine in aortic rings with or without endothelium from sham- clipped control rats, while it did not modify in 2K1C hypertensive rats. In aortic rings with endothelium, aminoguanidine caused a significant shift of the norepinephrine concentration-response curve to the left in LPS-treated control rats, but had no effect in hypertensive rats. L-NNA caused an additional shift of the concentration-response curve to norepinephrine in both control and hypertensive rats, although the magnitude was diminished in hypertensive rats. In the endothelium-denuded rings, norepinephrine-induced contractions were enhanced by aminoguanidine in LPS- treated control rats, whereas no significant changes were observed in hypertensive rats. LPS treatment inhibited the relaxation response to acetylcholine in aortic rings from control rats, while it was without effect in hypertensive rats. L-arginine caused a dose-dependent relaxation in endothelium-denuded rings from LPS-treated rats. The relaxation response to L-arginine was attenuated by aminoguanidine in control rats, but no significant changes were noted in hypertensive rats. CONCLUSION: These results provide indirect evidence for an impaired activity of the inducible nitric oxide synthase in 2K1C hypertension, although involvement of an altered activity of constitutive nitric oxide synthase in the endothelium cannot be excluded.

Altered Endothelial Modulation of Vasoconstriction in Chronic Two-Kidney, One Clip Hypertensive Rats / 대한신장학회잡지

It is well known that the endothelium plays an important role in the circulation by modulating contractile responses of vascular smooth muscle. This study was designed to investigate the alterations and the mechanisms of endothelial modulation in chronic 2-kidney, 1 clip(2K1C) hypertensive rats. 2K1C hypertension was made by clipping the left renal artery and age-matched control rats received a sham treatment. Aortic rings were mounted in tissue baths for measurement of isometric tension. In rings with endothelium, norepinephrine evoked concentration-dependent contraction. Endothelium removal markedly enhanced the contraction, and the responses were less pronounced in 2K1C rats than control rats. Similar fashion of the contractions by endothelium removal was observed with norepinephrine and the alpha1 drenoceptor agonist phenylephrine in control rats, while phenylephrine did not alter the contraction by endothelium removal in 2K1C rats. The alpha2 drenoceptor agonist clonidine also greatly enhanced the contraction after endothelium removal, however the endothelial inhibition was still shown in 2K1C rats. In contrast to norepinephrine-induced contractions, the enhancement of serotonin-or prostaglandin F2alpha - induced contractions after endothelium removal was small and similar in 2K1C and control rats. NG-nitro-L-arginine methyl ester enhanced the contraction induced by agonists in aortic rings with endothelium, which was similar to the response in rings without endothelium. The relaxation response to acetylcholine was attenuated in 2K1C rats, while the response to sodium nitroprusside remained unaltered. These results indicate the endothelium plays an inhibitory role against contractions in rat aorta by releasing nitric oxide, but the characteristics of the endothelial inhibition are not identical against various agonists. The negative endothelial modulation is more pronounced during alpha1 and alpha2 renoceptor- mediated contractions than during contractions mediated by other receptors. In addition, the inhibitory role of the endothelium against alpha1 drenoceptor agonist-induced contraction is impaired in 2K1C renal hypertension.