G-proteins and adenylyl cyclase signalling in hypertension
Abstract The present studies were undertaken to examine if adenylyl cyclase activity and the levels of G-proteins (Gsα and Giα) are altered in cardiovascular tissues in hypertension. Adenylyl cyclase activity and its responsiveness to stimulatory and inhibitory hormones as well as the expression of G-proteins (Gs and Gi) were determined at protein and mRNA levels by using specific antibodies and cDNA probes in hearts and aorta from 12 week old spontaneously hypertensive rats (SHR) and their age-matched control Wistar Kyoto (WKY) rats. The stimulatory effects of guanine nucleotides, isoproterenol, glucagon etc. on adenylyl cyclase activity were decreased in SHR rats as compared to the WKY rats, whereas, the inhibitory hormones inhibited enzyme activity to a grater extent in SHR rats as compared to WKY rats. Furthermore, the levels of Giα-2 and Giα-3 proteins and Giα-2 and Giα-3 mRNA as determined by immunoblotting and Northern blotting techniques respectively were higher in SHR as compared to WKY rats. However, the levels of Gsa were unaltered in SHR. To further investigate if these alterations are the cause or effect of hypertension, the SHRs at various ages of the development of blood pressure (3–5 days, 2, 4 and 8 weeks) and their age-matched WKY were used for G-protein expression and adenylyl cyclase activity. The increased expression of Gi α−2 and Gi α−3 protein and mRNA levels in hearts and aorta were observed as early as in 2-weeks old SHR as compared to WKY, when the blood pressure was still normal. However, the levels of G sα in SHR were not different from WKY rats. In addition, the altered responsiveness of adenylyl cyclase to hormone stimulation and inhibition was also observed as early as in 2 week old SHR. These results suggest that the increased expression of Gi α−2 and Gi α−3 and decreased levels of cAMP precedes the development of blood pressure and may be one of the contributing factors in the pathogenesis of hypertension.
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