ANGIOTENSIN II-DEPENDENT DOWN-REGULATION OF VASCULAR NATRIURETIC PEPTIDE TYPE-C RECEPTOR GENE-EXPRESSION IN HYPERTENSIVE RATS

Biological actions of natriuretic peptide (NP) are determined by the c ondition of the receptor as well as that of the the hormone. Although we previously demonstrated in hypertensive rats the up-regulation of N P-A receptor that mediates various biological actions of NPs, the path ophysiologic significance of NP-C receptor, another subtype thought to be related to clearance of NPs and possibly to biological actions, re mains unknown. In the present study, we determined NP-C receptor messe nger RNA (mRNA) level in the aortic tissue of stroke-prone spontaneous ly hypertensive rats (SHR-SP/Izm) and in cultured aortic smooth muscle cells by ribonuclease protection assay. The aortic NP-C receptor mRNA level in SHR-SP/Izm was significantly lower than that in the control WKY/Izm. Oral administration of an angiotensin (Ang) II receptor (AT1) antagonist, TCV-116, but not a calcium channel blocker, manidipine, r eversed the down-regulated NP-C receptor mRNA in SHR-SP/Izm to the lev el in WKY/Izm, whereas the latter was more potent in decreasing the bl ood pressure. In cultured aortic smooth muscle cells, the NP-C recepto r was the predominant subtype. Ang II decreased the NP-C receptor mRNA level in a dose-dependent manner, but this effect was reversed by an AT1 antagonist, CV-11974. Neither the NP-A nor NP-B receptor mRNA leve l was altered by Ang II. These findings indicate that vascular NP-C re ceptor is down-regulated via Ang II-mediated mechanism in SHR-SP/Izm. The phenomenon, together with the up-regulation of the NP-A receptor, may play an important role in counteracting hypertension by enhancing the action of NPs.