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  • Title: Mechanisms underlying the impairment of endothelium-dependent relaxation in the pulmonary artery of monocrotaline-induced pulmonary hypertensive rats.
    Author: Nakazawa H, Hori M, Ozaki H, Karaki H.
    Journal: Br J Pharmacol; 1999 Nov; 128(5):1098-104. PubMed ID: 10556948.
    Abstract:
    1. It has been reported that endothelium-dependent relaxation is impaired in pulmonary hypertensive vessels. The underlying mechanisms for this phenomenon, however, have not yet been identified. In this study, the mechanisms responsible for decreased endothelium-dependent relaxation in the pulmonary artery isolated from monocrotaline (MCT)-induced pulmonary hypertensive rat (MCT rat) were examined. MCT (60 mg kg-1), or its vehicle was administered by a single subcutaneous injection to 6-week-old male Sprague Dawley rats. 2. Endothelium-dependent relaxation induced by carbachol or ionomycin in the MCT rat artery was significantly smaller than that in vehicle-treated rat (control rat) artery. Cyclic GMP levels, measured by enzyme-immunoassay, under resting or stimulation with carbachol or ionomycin were also smaller in the MCT rat artery. However, sodium nitroprusside-induced cyclic GMP accumulation in the endothelium-denuded artery was similar in control and MCT rats. These results suggest that MCT treatment decreases endothelial nitric oxide (NO) production. 3. Resting endothelial Ca2+ levels ([Ca2+]i) in the fura-PE3-loaded MCT rat artery, were not different from those in the control rat. However, the increase in endothelial [Ca2+]i elicited by carbachol was attenuated in the MCT rat. 4. In quantitative RT - PCR analysis, the expression of mRNA encoding endothelial NO synthase was rather increased in the MCT rat artery, suggesting an up-regulation of eNOS expression. 5. These results provide evidence that impaired NO-mediated arterial relaxation in the MCT rat is due to dissociation between eNOS expression and NO production. This dissociation may be derived from an inhibition of receptor-mediated Ca2+ metabolism and also from the apparent decrease in Ca2+ sensitivity of eNOS.
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