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Mechanisms underlying the impairment of endothelium‐dependent relaxation in the pulmonary artery of monocrotaline‐induced pulmonary hypertensive rats
Author(s) -
Nakazawa Hiroshi,
Hori Masatoshi,
Ozaki Hiroshi,
Karaki Hideaki
Publication year - 1999
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0702878
Subject(s) - carbachol , medicine , enos , endocrinology , endothelium , pulmonary artery , ionomycin , sodium nitroprusside , nitric oxide , stimulation , nitric oxide synthase , chemistry
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. 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. Resting endothelial Ca 2+ levels ([Ca 2+ ] i ) in the fura‐PE3‐loaded MCT rat artery, were not different from those in the control rat. However, the increase in endothelial [Ca 2+ ] i elicited by carbachol was attenuated in the MCT rat. 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. 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 Ca 2+ metabolism and also from the apparent decrease in Ca 2+ sensitivity of eNOS.British Journal of Pharmacology (1999) 128 , 1098–1104; doi: 10.1038/sj.bjp.0702878