Inhibition by cyclic AMP of basal and induced inositol phosphate production in cultured aortic smooth muscle cells from Wistar- Kyoto and spontaneously hypertensive rats

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Abstract
Objective To investigate inositol phosphate formation and its modulation by the cyclic AMP (cAMP) pathway in cultured aortic smooth muscle cells from spontaneously hypertensive rats (SHR). Methods Phenylephrine was used to stimulate inositol phosphate formation in cultured aortic smooth muscle cells from SHR and Wistar-Kyoto (WKY) rats. The smooth muscle cells from passages 6-14 were prelabelled with myo-[2-3H]-inositol (1.9x105Bq/ml for 24 h) and inositol phosphate formation was measured after exposure to agonist for 45min. (-)lsoproterenol or forskolin-induced cAMP formation was also evaluated using a radioimmunoassay method. Results The basal level of inositol phosphate formation in smooth muscle cells from SHR was higher than that observed in smooth muscle cells from WKY rats. Phenylephrine increased the formation of inositol phosphates in a concentration-dependent manner (0.1-100 μmol/l). In the presence of 100 μmol/l phenylephrine, the increase in inositol phosphate formation was significantly greater in smooth muscle cells from SHR (214±6%) than that observed in smooth muscle cells from WKY rats (156±8%). When the cells were pretreated with 1 mmol/l 8-bromoadenosine 3'5'-cyclic monophosphate or with 10 μmol/l forskolin for 45min, the basal production of inositol phosphates in smooth muscle cells both from SHR and from WKY rats was significantly and similarly decreased by about 20%. In the presence of 1 mmol/l 8-bromoadenosine 3'5'-cyclic monophosphate, 100 μmol/l phenylephrine-induced inositol phosphate formation was similarly decreased by 33±4 and 30±3% in smooth muscle cells from SHR and from WKY rats, respectively, whereas, in the presence of 10 μmol/l forskolin, inositol phosphate formation was reduced by 25±3 and 27±5%, respectively, in those cells. In contrast, isoproterenol induced less inhibition of phenylephrine-induced inositol phosphate formation in smooth muscle cells from SHR (14±2%) than it did in those from WKY rats (25±4.5%). Although there was no significant difference in basal or forskolin-induced cAMP accumulation between smooth muscle cells from SHR and those from WKY rats, (-)isoproterenol-induced cAMP accumulation was significantly lower in smooth muscle cells from SHR. Conclusion A marked inhibitory effect of cAMP on the α1-adrenoceptor-mediated inositol phosphate signal transduction pathway was demonstrated in smooth muscle cells of SHR and of WKY rats. Decreased cAMP formation with ß-adrenergic stimulation and increased inositol phosphate formation with α-adrenergic stimulation in SHR smooth muscle cells may both contribute to the dominant α1-adrenergic activity observed in SHR

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