A number of epidemiological studies have documented a direct correlation between intracellular sodium and blood pressure in Blacks, a characteristic not observed in non-Blacks. In addition, normotensive and hypertensive Black subjects more frequently manifest a pressor response to [Na] loading than corresponding White groups. Given that altered Na+ homeostasis marked by increased intracellular Na+ levels might be a phenotype marker for hypertension in Blacks; that Na+ metabolism by the kidney and vasculature is a greater factor in racial differences than is Na+ intake; that NaK- ATPase is responsible for maintaining cellular Na/K gradients; that depressed activity of NaK-ATPase is more common in Black as compared to White women; that products of the cytochrome P450 system have been implicated in animal and human hypertension and documented to depress activity of the [Na+] pump, we hypothesize that such products may be responsible for altered [Na+] pump activity and [Na+] handling, characteristic of salt sensitive Black female subjects (hypertensives and normotensives). This altered set point for elevated intracellular [Na+] then triggers a cascade of compensatory pathophysiologic events affecting other ion transporters leading to elevated intracellular Ca, altered vascular reactivity, salt sensitivity and eventually hypertension. We propose to test this hypothesis in a case controlled study with 200 normotensive and hypertensive females (50% Blacks/50% Whites).
One aim of this proposal is to determine the urinary excretion of the major products of cytochrome P450 dependent arachidonic acid metabolism, namely epoxyeicosatrienoic acids, their corresponding diols, omega-and omega-1- alcohols (20- and 19-HETE).
A second aim i s to correlate the pattern of P450 dependent arachidonic acid metabolism with a variety of metabolic parameters: {Ca2+] and [Na+], [Na+] pump activity, and BP responsiveness to sodium loading and depletion.
A third aim will be to screen for polymorphism of cytochrome P450 omega-hydroxylase mRNA expression in macrophages of patients displaying discrete phenotypes. These studies will involve post-menopausal women, as estrogen and progesterone affect the [Na+] pump. Such studies will yield important information on racial/ethnic patterns of blood pressure regulation and enhance our understanding of the genetic basis of salt sensitive hypertension in women, thus, setting the stage to design specific therapeutic approaches for control of subtypes of hypertension. These studies represent a logical outgrowth of studies on receptor/effector coupling supported by this PPG, wherein cytochrome P450 dependent arachidonic acid metabolites have been identified as important mediators of signalling by vasoactive hormones and modulators of ion transports through Ca mobilization and inhibition of Na,K-ATPase in a variety of tissues. These studies thus represent an important vehicle for evaluating the physiological relevance of this class of compounds on [Na+] and Ca metabolism and their clinical significance in human hypertension.
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