The chronically instrumental ewe: a model for studying vascular reactivity to angiotensin II in pregnancy.

Abstract

A B S T R A C T Vascular refractoriness to the systemic pressor effects of angiotensin II (AII) develops normally during human pregnancy. To ascertain if the ewe might provide a suitable anfomal model to study the mechanisms responsible for this response (unique to pregnancy) we studied this phenomenon in unanesthetized, chronically instrumented nonpregnant and pregnant sheep, 68-143 d gestation. In these studies dose-response curves were established for changes in both mean arterial pressure and uterine blood flow. The pressor response to continuous infusions of AII increases as a function of the dose of AII in both nonpregnant and pregnant animals (P < 0.001), R = 0.943 and 0.879, respectively. However, the pregnant animals were refractory to the pressor effects ofAII, requiring 0.016 ,ug ofAll/min per kg to elicit a 20 mm Hg rise in mean arterial pressure, in contrast to 0.009 for nonpregnant animals. The slope and intercept for the regression lines are different at P < 0.001. In pregnant animals the dose-response curve for uterine blood flow was also determined. Increases in uterine blood flow were observed at doses ofAII < 0.016 ,ug/min per kg, while larger doses resulted in a progressively greater reduction in blood flow. It appears likely that the ewe may serve as an animal model suitable for the further study of the unique pregnancy-modified systemic and uteroplacental vascular responses elicited by AII.

Evidence against the hypothesis that prostaglandins are the vasodepressor agents of pregnancy. Serial studies in chronically instrumented, conscious rats.

“…Indomethacin may promote antikaliuresis indirectly, by inhibition of the renin-angiotensin aldosterone axis (37). The attenuated systemic pressor response to exogenous vasoconstrictors that develops during pregnancy has been observed in many species (26,(47)(48)(49)(50)(51)(52), present study). The mechanism(s) is not clearly defined, and prereceptor, receptor, and/or postreceptor phenomena could contribute.…”

In vitro prostacyclin production by ovine uterine and systemic arteries. Effects of angiotensin II.

“…Normal pregnancy is associated with the development of relative vascular refractoriness to the systemic pressor effects of infused angiotensin II (ANG II)' in women (1)(2)(3), sheep (4,5), and several other species (6,7). This refractoriness is lost in women who develop pregnancy-induced hypertension (preeclampsia), and they become exquisitely sensitive to the pressor effects of infused ANG 11 (3,8).…”

“…We have demonstrated that the chronically instrumented sheep may serve as an excellent animal model in which to study the normal cardiovascular changes that occur in pregnancy (5,15). In these studies, the uterine vascular bed of late pregnant sheep was even less responsive to infused ANG II than the systemic vascular bed overall (16)(17)(18).…”

Myometrial angiotensin II receptor subtypes change during ovine pregnancy.

“…In contrast, pregnant women destined to develop preeclampsia lose this refractoriness and become increasingly sensitive to the pressor effects of infused ANG II (4); however, the mechanism(s) responsible for these changes is unknown. The pregnant ewe (5,6) and several other species (7, 8) also develop attenuated pressor responses to infused ANG II. Moreover, the dose ofANG II required to elicit a 20-mmHg rise in mean arterial pressure in pregnant and nonpregnant ewes is virtually identical to that required in normotensive pregnant and nonpregnant women, respectively (3)(4)(5).…”