Impaired prostaglandin E-2/prostaglandin I-2 receptor-G(s) protein interactions in isolated renal resistance arterioles of spontaneously hypertensiverats

The protective effect of vasodilator agents linked to the cAMP pathway is l ess effective for buffering the vasoconstrictor effect of angiotensin II in young animals with genetic hypertension. To determine the underlying cellu lar mechanism, experiments were performed on freshly isolated preglomerular resistance arterioles obtained from kidneys of 7-week-old spontaneously hy pertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Specific hi gh-affinity saturable binding of H-3-prostaglandin (PG) E-2 revealed 1 rece ptor class in renal microvessels; PGE(2) receptor density was similar in SH R and WKY (106 versus 115 fmol/mg; P>0.8), as was receptor affinity (3.6 ve rsus 3.5 nmol/L; P>0.7). Basal cAMP activity was similar in renal arteriole s from SHR and WKY. A major finding was that PGE(2), PGI(2), and isoprotere nol produced weaker stimulation of cAMP formation in arteriolar cells of SH R (P<0.02). In contrast, GTP gamma s and forskolin stimulated cAMP generati on to a similar degree in both rat strains, which suggests normal adenylate cyclase activity in hypertension-prone SHR. Immunoblots revealed the prese nce of 3 classes of G proteins (G(s), G(i), and G(q)) in preglomerular arte rioles. The relative amounts of discernible G-protein alpha-subunits in ren al resistance vessels did not differ between SHR and WKY. These results ext end previous in vivo studies of abnormal renal vascular reactivity in SHR a nd more directly localize defective coupling of the prostaglandin and beta- adrenergic receptors to a stimulatory G protein and cAMP production in fres hly isolated preglomerular arteriolar cells of young SHR. This dysfunction may be due to an abnormal interaction between prostaglandin receptors and G (s) protein that leads to inefficient coupling of initiating steps in the c AMP-protein kinase A cascade during the development of hypertension.