Date of Graduation

1999

Document Type

Dissertation/Thesis

Abstract

Nitric oxide (NO) has been implicated as a mediator of the normal renal and systemic hemodynamic changes of pregnancy. In study 1, we measured NO 3 + NO2 (=NOx) in plasma (PNOx) and 24 hour urinary excretion of NOx (UNOxV) and cGMP (UcGMPV) as well as tissue NOS activity in virgin (V), mid (MP) and late pregnant (LP) rats. The results from this study suggest that the soluble isoforms, NOS1 and/or NOS2, are the isoforms responsible for increased NO production during pregnancy. In study 2 we have evaluated PNOx, UNOxV, UcGMPV and tissue NOS activity in V, MP, and LP rats given chronic aminoguanidine (AG). Chronic AG inhibited the pregnancy induced increase in PNOx and UNOxV, without affecting the pregnancy induced increase in UcGMPV. Chronic AG also inhibited tissue sources of pregnancy induced increased NOS activity. In study 3, renal function and blood pressure (BP) was measured in V, MP and LP conscious chronically catheterized rats given chronic AG. Chronic inhibition of NOS2 with AG abolished the normal midterm renal vasodilation of pregnancy, and acute treatment with another NOS2 inhibitor, 1400W, further increased renal vascular resistance and decreased renal plasma flow. In study 4, we have evaluated PNOx, UNOxV, UcGMPV and tissue NOS activity in V, MP and LP 5/6th neprectomized (NX) rats. Virgin 5/6 th NX rats had decreased tissue NOS activity. 5/6th NX also attenuated the pregnancy induced increase in UNOxV and PNOx and inhibited tissue sources of pregnancy induced increased NOS activity. In study 5, conscious chronically catheterized rats were studied at stages of the estrous cycle which have maximal and minimal physiological levels of estradiol and were also studied while treated with the aromatase inhibitor, anastrazole (Arimidex), to inhibit synthesis of 17B-estradiol. The findings of this study suggest that estradiol has a vasodilatory role in the renal, but not the systemic, vasculature. However, inhibition of estradiol increased UNOxV and PNOx. In summary, during rat pregnancy there is increased NO production in a variety of tissues. A portion of these tissue sources of increased NO production in pregnancy can be inhibited by AG or 5/6th NX without affecting the pregnancy induced decrease in BP in the rat. Finally, these findings support the idea that measurements of total body NO production, as indexed by UNOxV and PNOx, do not provide an accurate representation of NOS activity and NO production at the level of individual tissues.

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