Persistent elevation of blood pressure or hypertension is a significant medical problem throughout the world, and a major cause of cardiovascular disease. Hypertension is a complex disease involving interactions between cardiovascular, nervous, renal and endocrine systems. While the etiology of certain isolated forms of hypertension is known, for the majority of cases -essential hypertension, the causative factor(s) remain unknown. Evidence suggests that interactions of genetic and environmental factors may predispose individuals to hypertension. Lead (Pb) is a persistent environmental contaminant that is known to affect the nervous system, kidney, and formed elements of the blood. Aside from occupational toxicity, exposure to Pb is typically highest during the early stages of development. Evidence suggests 1) that exposure to Pb during the early stages of life can have long-term health consequences, and 2) that chronic low-level exposure to Pb can cause small, though persistent and significant elevations in mean arterial blood pressure. Thus, early exposure to Pb may be a contributory factor to development of hypertension. The mechanisms by which this occurs are not known. The long-term goal of this proposal is to ascertain whether perinatal exposure to Pb causes sustained elevations in adult blood pressure or blood pressure control mechanisms and whether specific subgroups show differential sensitivity to the cardiovascular consequences of perinatal Pb exposure. The hypothesis of the current proposal is that alterations in intracellular Ca2+ signaling induced by Pb contribute to the hypertensive response directly by enhancing vascular contractility through actions on L-type Ca channels. This is based on observations that chronic exposure of cells to Pb increases the current carried through L-type voltage-gated Ca2+ channels, a critical source of Ca2+ entry into excitable cells such as smooth muscle cells, and an important path for activation of gene expression. Moreover, Pb induces heightened contractility in vascular smooth muscle by mechanisms that can be blocked by Ca2+ channel antagonists. To test this hypothesis a combination of in vivo and in vitro experiments are proposed. Rats will be treated with Pb during gestation and subsequent nursing. Daily measurements of blood pressure will be conducted subsequently in conscious, unrestrained rats using telemetry. Sensitivity of Pb -exposed rats to two groups of commonly used antihypertensive agents including Ca channel blockers will be tested to determine if sensitivity to these important antihypertensive agents is altered by chronic treatment with Pb. In vitro measurements of resting arterial tension and response to agents that alter vascular contractility will be made in arteries isolated from rats following Pb exposure. Whole cell and single L-type Ca channel currents from vascular smooth muscle will be examined to determine if Pb exposure increases Ca channel current density or properties. Results of this study should help increase our understanding of the role which environmental exposure to Pb plays in the etiology of hypertension as well as potential mechanisms by which this postulated increase occurs. ? ?
