During pregnancy, vascular reactivity of the uterine artery is characterized by decreased contraction to norepinephrine and increased relaxation to acetylcholine. We investigated whether 1) relaxation to A23187 is increased during pregnancy and 2) endothelium-derived relaxing factor (EDRF) and/or prostaglandins are responsible for the decreased uterine artery sensitivity to norepinephrine during pregnancy. Isolated rings of uterine and carotid arteries were obtained from pregnant and nonpregnant guinea pigs. Relaxation to sodium nitroprusside in uterine but not carotid artery was reduced during pregnancy. Relaxation of both uterine and carotid arteries to the calcium ionophore A23187 was unaffected by pregnancy. During pregnancy, contractions to norepinephrine were reduced in the uterine artery compared with arteries from nonpregnant animals. Indomethacin slightly enhanced the contractions of uterine artery to norepinephrine during pregnancy. However, indomethacin-treated uterine arteries from pregnant animals were still less responsive to norepinephrine than control uterine arteries from nonpregnant animals. Methylene blue enhanced the efficacy of norepinephrine in uterine arteries of nonpregnant animals as well as carotid arteries of pregnant and nonpregnant animals but not in uterine arteries of pregnant animals. In contrast, N-monomethyl-L-arginine, a specific inhibitor of EDRF synthesis, not only enhanced uterine and carotid artery responses to norepinephrine in both pregnant and nonpregnant animals but fully reversed the blunted potency of norepinephrine on uterine arteries of pregnant to that of nonpregnant animals.(ABSTRACT TRUNCATED AT 250 WORDS)

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Because platelet activation and serotonin have been implicated in preeclamptic hypertension, we investigated the effect of pregnancy on the contractile response to this agent. Prior studies have shown that the vascular contractions to norepinephrine, angiotensin II, and thromboxane are reduced during normal pregnancy by the altered release of endothelium-derived vasoactive substances. We hypothesized that the contraction to serotonin would also be reduced during pregnancy by an endothelium-dependent mechanism. Isolated ring segments from uterine and carotid arteries of near-term pregnant and nonpregnant guinea pigs were studied after stimulating a small amount of active tone with prostaglandin F2 alpha. Serotonin (10(-8) to 10(-5) M) contractile responses of both arteries were reduced by pregnancy. Regardless of pregnancy status, the contractile responses of the uterine artery to serotonin were severalfold greater than that of the carotid artery whose maximum averaged only 10% of the 120 mM KCl contraction. Denudation of uterine artery abolished acetylcholine-stimulated relaxation in vessels from pregnant and nonpregnant animals. However, serotonin-induced contractions were enhanced by denudation only in ring segments obtained from pregnant animals. Nitric oxide synthase inhibition by either NG-monomethyl-L-arginine (L-NMMA) or N omega-nitro-L-arginine and cyclooxygenase inhibition by indomethacin had no effect on serotonin-induced contraction of intact uterine artery regardless of pregnancy. L-NMMA modestly enhanced the intact carotid arterial response to 10(-5) M serotonin independent of pregnancy.(ABSTRACT TRUNCATED AT 250 WORDS)

Regional variation in the response of the thoracic aorta to contractile agonists has previously been demonstrated. Since the net contractile response reflects the interaction between smooth muscle activation and the release of endothelial substances, we hypothesize that agonist-stimulated release of endothelium-derived nitric oxide (NO) also varies along the length of the thoracic aorta. The distribution of thoracic aorta estrogen receptors is also regionalized. Since pregnancy augments the release of endothelium-derived NO by acetylcholine (ACh) in some arterial beds, we further hypothesize that pregnancy enhances the stimulated release of NO from the thoracic aorta. Aortae were removed from nonpregnant and near term pregnant guinea pigs and cut into ring segments numbered sequentially proximal to distal. The rings were suspended at their optimal passive tension and submaximally contracted with prostaglandin F_2α. Endothelium-derived NO-dependent relaxation to ACh increased moving proximal to distal along the aorta independent of pregnancy and ACh relaxation was unaffected by pretreatment with physostigmine to inhibit cholinesterase. The magnitude of the relaxation to carbachol among the different segments was similar to ACh. Pregnancy decreased the ED₅₀ for ACh of segments from the middle and distal segments of the thoracic aorta. Relaxation to the NO donor sodium nitropmsside and the nonreceptor-mediated endothelium-dependent relaxing agent A23187 was uniform along the length of the aorta and independent of pregnancy. These experiments demonstrate regional variation in the stimulated release of endothelium-derived NO in the guinea pig thoracic aorta which is increased by pregnancy.

SUMMARY. Chronically catheterized lambs (4-37 days postnatal age) (n =35) were studied to test the hypothesis that the products of angiotensin-converting enzyme activity are involved in renal and adrenal responses to normocapnic hypoxemia in immature lambs. Arterial angiotensin II (from 111.0 ± 38.8 to 71.0 ± 38.8 pg/ml, P < 0.01) and aldosterone (from 128.0 ± 98.0 to 62.1 ± 27.9 pg/ml, P < 0.01) concentrations were significantly decreased and vasopressor responses to angiotensin I were greater than 90% inhibited by continuous intravenous infusion of angiotensin-converting enzyme inhibitor (captopril, 2.5 /ig/kg/min, n =16). Baseline mean arterial pressure (64 ± 14 vs. 78 ± 9 mmHg) and urinary sodium excretion rate (UN 8 V 3.04 ± 2.83 vs. 15.00 ± 20.00 fiEq//min) were significantly (P < 0.05) decreased in captopril-treated lambs vs. control lambs. Baseline arterial plasma renin activity was significantly (P < 0.01) increased in captopril-treated vs. control lambs (8.6 ± 9.0 vs. 100.0 ± 64.0 ng/ml per hr). Normocapnic hypoxemia (P02 38 ± 6 torr for 30 minutes) during captopril infusion was associated with no significant (P > 0.05) changes in renal hemodynamics and function, including glomerular filtration rate (from 0.34 ± 0.24 to 0.35 ± 0.25 ml/min per g). Urinary prostaglandin E excretion rate (from 0.655 ± 0.703 to 1.310 ± 1.020 ng/min) and adrenal blood flow (from 2.67 ± 1.69 to 6.24 ± 3.73 ml/min per g) increased significantly (P < 0.05) under these conditions. Arterial epinephrine (from 0.11 ± 0.07 to 1.1 ± 1.8 ng/ml), norepinephrine (0.48 ± 0.38 to 3.2 ± 5.4 ng/ml), and arginine vasopressin (from 5.11 ± 2.20 to 10.70 ± 8.61 jiU/ml) also increased significantly (P < 0.05) in response to hypoxemia during angiotensin-converting enzyme inhibition with captopril. None of these responses to hypoxemia were significantly different from that of uninhibited (control) lambs (n=19). In contrast, cortisol response to hypoxemia was significantly (P < 0.05) less in captopril-treated lambs (captopril vs. control, -1.00 ± 1.90 vs. 3.40 ± 3.30 /ig/dl). These data suggest that the products of angiotensin-converting enzyme activity are not important regulators of renal responses to hypoxemia, but may be involved in cortisol responses to normocapnic hypoxemia in immature lambs. (Circ Res 52: 179-187, 1983)