Essential hypertension in man and the genetically-determined hypertension of the Spontaneously Hypertensive Rat (Okamoto-Aoki strain) share many similarities, and the rat disorder is considered a useful model of the human disease. Calcium abnormalities occur in both syndromes, and many studies point to a plasma membrane defect involving decreased membrane binding of Ca and increased cytosolic Ca. In arterial smooth muscle cells this could result in increased tonus and peripheral resistance. Our laboratory has recently isolated an integral membrane calcium binding protein, IMCAL, which is widely distributed in rat tissues, dependent on vitamin D and dietary Ca, and highly correlated with Ca translocation in rat intestine. Immunochemical assays with monoclonal and polyclonal antibodies have demonstrated decreased content of IMCAL in tissues of SHR as compared to Wistar-Kyoto (WKy) controls. Accordingly, this research will test the hypothesis that the genetic defect in SHR which results in hypertension does so by decreasing membrane IMCAL. Tissues of suckling and weanling SHR and WKy will be assayed for IMCAL to establish whether the membrane change precedes the hypertension. IMCAL content of the tissues in other rat models of hypertension (Goldblatt 2 kidney/1 clip and DOCA-saline treatment) will be estimated. Regulation of tissue IMCAL in vivo by vitamin D and dietary Ca will be compared in SHR and WKy. IMCAL content of the mesenteric arterial wall and of primary cultures of smooth muscle cells derived from the arterial wall of SHR and WKy will be quantified. The possibility of regulation of the IMCAL content in cell cultures by ambient Ca or 1,25-dihydroxyvitamin D3 will be explored. Finally, a pilot project will compare the IMCAL content of the erythrocyte membrane of essential hypertension patients with those of matched controls. The studies will provide new information on the molecular basis of calcium homeostasis and hypertension in SHR and may lead to a biological marker of essential hypertension in man.
