The overall goal of these proposed experiments is to investigate the role of NO in the peripheral and renal vasodilatory response to normal and hypertensive pregnancy. Immunohistochemical and molecular biology techniques will localize and quantitate the No synthases and arginine biosynthetic enzymes in normal pregnancy, pseudopregnancy and during hormonal manipulation. In vivo and in vitro experiments will also investigate glomerular function. BP, NO, arginine and cGMP activity in pregnancy during maneuvers which cause inhibition or stimulation of inducible or constitutive NO synthase; during arginine deficiency or supplementation and during acute manipulation of other vascular control systems to investigate interactions with NO in pregnancy. The role of NO will also be investigated in several models of hypertensive pregnancy: in the Spontaneously hypertensive rat (SHR) and renal ablation-induced hypertension, where pregnancy. Further extensive in vivo and in vitro studies will characterize the interaction between pregnancy and chronic No blockade induced hypertension, and will investigate interactions with other vascular control systems, i.e., renin/angiotensin, sympathetic nervous system, endothelin and cyclooxygenase products in NO blockade-induced hypertension. We already have good evidence that NO production is increased in pregnancy. These studies will determine how changes in NO synthases and arginine biosynthesis contributes tot he gestational rise in NO production; test the hypothesis that a constitutive NO synthase is activated in pregnancy; investigate the effect of manipulating the NO system on pregnancy; investigate the ability of pregnancy to increase NO production in various hypertensive states; and finally conduct extensive further studies on chronic No blockade induced hypertension. All experiments will be in rats employing 1) the conscious chronically catheterized preparation for measurement of renal function, renal vascular resistance and BP; 2) glomerular micropuncture in the anesthetized volume replete rat for measurement of glomerular hemodynamics, 3) Northern blot analysis and in situ hybridization measurement of NO synthase and arginine enzyme mRNA levels. Activity of the endogenous arginin-NO system will be assessed from arginine, nitrite/nitrate and cGMP levels. Hypertensive complications of pregnancy are a serious health concern for both mother and baby and the present studies will provide insight into, and suggest new treatments, for this disorder.
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