SMOOTH-MUSCLE CELL RESPONSIVENESS TO NITROVASODILATORS IN HYPERTENSIVE AND NORMOTENSIVE RATS

Endothelium-derived relaxing factor and exogenous nitrovasodilators are thought to produce smooth muscle relaxation by activation of soluble guanylate cyclase. To investigate whether diminished cyclic GMP (cGMP) accumulation underlies the differences in vascular reactivity to nitrovasodilators between Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR), we determined cGMP formation in aortic smooth muscle cells from the two strains. Both cultured cells and aortic rings from 12- to 14-week-old SHR accumulated greater amounts of cGMP on stimulation with exogenous nitrovasodilators tie, sodium nitroprusside) than those from WKY rats, whereas there was no difference observed in cells from prehypertensive animals (5- to 6-week old) between the two strains. Responsiveness of smooth muscle cells to endothelium-derived relaxing factor was investigated in cocultures of bovine aortic endothelial cells (BAE) and smooth muscle cells from SHR and WKY rats. cGMP accumulation elicited by endothelium-derived relaxing factor released either basally or in response to bradykinin and the calcium ionophore A23187 was greater in smooth muscle from 12- to 14-week-old SHR than from age-matched WKY rats (80+/-17 versus 11+/-2 for basal; 152+/-12 versus 80+/-26 for A23187; 163+/-21 versus 40+/-12 pmol/mg protein per 15 minutes for bradykinin) in SHR/ BAE and WKY/BAE cocultures, respectively. Northern blot analysis of steady-state messenger RNA levels for the beta(1) subunit of soluble guanylate cyclase revealed higher levels of the message in SHR. These results indicate that smooth muscle cells from SHR accumulate greater amounts of cGMP than WKY cells in response to endogenous or exogenous nitric oxide, possibly because of increased levels of soluble guanylate cyclase.