AJP - Cell Physiology, Vol 255, Issue 5 C573-C580, Copyright © 1988 by American Physiological Society
Blunted cGMP response to ANF in vascular smooth muscle cells of SHR
M. Nakamura, A. Nakamura, B. Fine and A. Aviv
Hypertension Research Center, University of Medicine and Dentistry of New Jersey, Newark 07103.
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 (Bmax) and lower affinity [i.e.,
increased equilibrium dissociation constant (Kd)] than cells from
normotensive controls. Maximal binding (Bmax) (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 less than 0.001 for SHR vs. both
WKY and Wis). The Kd values were (in nM) SHR 1.20 +/- 0.098, WKY 0.657 +/-
0.065, and Wis 0.37 +/- 0.037 (P less than 0.001 for SHR vs. both WKY and
Wis). Despite their higher Bmax, 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-1.10(6) cells-1 for
SHR, WKY, and Wis, respectively (P less than 0.01 for SHR vs. Wis and P
less than 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.
