Blunted cGMP response to ANF in vascular smooth muscle cells of SHR

Abnormalities in the coupling of atrial natriuretic factor (ANF) receptors with the guanosine 5'-cyclic monophosphate (cGMP) system in vascular smooth muscle cells (VSMCs) may play a role in the pathophysiology of hypertension in the spontaneously hypertensive rat (SHR). This concept was examined in cultured, aortic VSMCs (passages 6-10) from SHR, Wistar-Kyoto (WKY), and American Wistar (Wis) rats. Quiescent VSMCs of the SHR (serum deprived for 24 h) had higher ANF receptor density (B(max)) and lower affinity [i.e., increased equilibrium dissociation constant (K(d))] than cells from normotensive controls. Maximal binding (B(max)) (specific binding sites/cell) values for these cells were SHR 112,855 ± 6,951, WKY 48,650 ± 3,607, and Wis 36,122 ± 2,607 (means ± SE; P < 0.001 for SHR vs. both WKY and Wis). The K(d) values were (in nM) SHR 1.20 ± 0.098, WKY 0.657 ± 0.065, and Wis 0.37 ± 0.037 (P < 0.001 for SHR vs. both WKY and Wis). Despite their higher B(max), VSMCs of the SHR showed a substantially lower maximal stimulation of cGMP accumulation in response to ANF: 987 ± 29.3, 1,992 ± 574.2, and 2,019 ± 273.8 fmol·4 min^-1·10⁶ cells^-1 for SHR, WKY, and Wis, respectively (P < 0.01 for SHR vs. Wis and P < 0.02 for SHR vs. WKY). Further experiments demonstrated that the poor response of SHR VSMCs to the ANF was not due to a population of receptors that did not couple to the particulate guanylate cyclase. Such findings demonstrate a dissociation of the cGMP response to ANF from the binding of the hormone to its receptors in VSMCs of the SHR compared with controls. This appears to represent a primary and innate defect in these cells that may contribute to the hypertensive process in the SHR.