Despite a high density ot atrial natriuretic factor (ANF) receptors, cultured vascular smooth muscle cells of the spontaneously hypertensive rat (SHR) manifest a blunted cyclic GMP (cGMP) response to ANF. We explored the role of cytosolic free Ca2++ ([Ca2+]¡) in the ANF-induced cGMP response of cultured aortic vascular smooth muscle cells from SHR and two normotensive rat strains: Wistar-Kyoto (WKY) and American Wistar. Exposure to 500nmol/l A23187 in Ca2+-containing but not in Ca2+-deficient medium resulted in a decline in the ANF-induced cGMP response at maximal ANF concentration (500nmol/l; SHR from 1004 ± 98 to 423 ±67,P< 0.001; WKY from 1791 ± 209 to 625 ±90,P< 0.001; American Wistar from 1496 ± 125 to 559 ± 96fmol/106cells/4min,P< 0.001). The same phenomenon was observed by depolarization with 50mmol/l KCI in Ca2 +-containing medium. There were no significant differences among the rat strains in basal levels of [Ca2 +]j. If Ca2+plays a role in the blunted cGMP response to ANF in vascular smooth muscle cells of the SHR, this effect may be exerted by a distinct pool of the ion in the submembrane domain which is associated with the particulate guanylate cyclase system