Hypertension is a major health problem which accounts for a significant degree of morbidity and mortality in our population. Both structural and functional changes in the vasculature are believed to contribute to the genesis and maintenance of this disease. Reports of disturbances in Ca2+ homeostasis in several organ systems of both the essential hypertensive human and the spontaneously hypertensive rat (SHR) have served as the basis for the hypothesis that variations in the levels of serum 1,25 VitD, parathyroid hormone (PTH) or calcitonin alter functional properties of vascular muscle. Until recently, however, the vascular effects of these hormones had not been investigated. Our laboratory has found that 1,25 VitD increases 45Ca uptake in cultured aortic myocytes of the SHR and the Wistar Kyoto (WKY) control. 1,25 VitD and PTH were found to differentially modulate norepinephrine (NE)- induced changes in intracellular-free (Ca2+)i in resistance arteries of the SHR and WKY. 1,25 VitD has also been found to modulate growth of vascular myocytes in culture. Our findings have prompted the hypothesis that the calciotropic hormones 1,25 VitD and PTH as well as calcitonin and calcitonin gene-related peptide (CGRP) are modulators of vascular cell contractility, Ca2+ metabolism and growth. A derivative hypothesis is that vascular muscle of the SHR is differentially sensitive to these agents. These hypotheses will be experimentally tested. The effects of 1,25 VitD, PTH, calcitonin and CGRP on contractility and (Ca2+)i of mesenteric resistance arteries will be assessed using a wire myograph and the intracellular dye Fura-2. The effects of these hormones on cellular Ca2+ metabolism will be assessed using both primary and passaged cultures of mesenteric artery myocytes. Indices of Ca2+ metabolism that will be assessed include 45Ca uptake and agonist-induced changes in free (Ca2+)i. Calciotrophic hormone effects on cell growth will be assessed by measuring their effect on both basal and growth factor-induced proliferation. Cellular mechanisms to be examined which might underlie the growth- related actions of these hormones include generation of the inositol polyphosphates and induction of transient changes in free (Ca2+)i and pH. In summary, these experiments will examine metabolism and growth; the results may provide a basis for the development of new perspectives on blood pressure control.
Showing the most recent 10 out of 19 publications
