Regionalization of endothelium-dependent relaxation in the thoracic aorta of pregnant and nonpregnant guinea pigs.

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 F2 alpha. 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 nitroprusside 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.

Pregnancy reduces serotonin-induced contraction of guinea pig uterine and carotid arteries.

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)

Endothelium-derived relaxing factor and indomethacin-sensitive contracting factor alter arterial contractile responses to thromboxane during pregnancy.

OBJECTIVES: Pregnancy reduces uterine artery contractile responses to norepinephrine and angiotensin II in many species, including the human and the guinea pig, by release of endothelium-derived relaxing substances. We hypothesized that vascular reactivity to thromboxane during pregnancy would also be reduced by a similar mechanism. STUDY DESIGN: Isolated ring segments of uterine and carotid arteries from nonpregnant and near-term pregnant guinea pigs were suspended in a myograph for the measurement of isometric tension. RESULTS: Uterine but not carotid artery sensitivity to cumulative addition of the thromboxane analog U46619 was decreased during pregnancy. The maximal contractile responses of both vessels were unaltered by pregnancy. N omega-nitro-L-arginine (10(-4) mol/L), an inhibitor of nitric oxide endothelium-derived relaxing factor synthesis, increased the sensitivity of uterine and carotid arteries to U46619 in both pregnant and nonpregnant animals. The maximal contractile response of uterine arteries from pregnant guinea pigs was also increased, but that of nonpregnant ones was not. The maximal U46619 contractile response of the carotid artery was not significantly altered by N omega-nitro-L-arginine. Indomethacin (10(-5) mol/L), a cyclooxygenase inhibitor, reduced both the sensitivity and the maximal response of U46619 in each vessel group. Removal of the endothelium from uterine artery of pregnant animals enhanced both sensitivity and maximal response to U46619. Pretreatment of the denuded segments with indomethacin reduced the sensitivity to U46619. However, indomethacin-treated denuded segments were still more sensitive to U46619 than controls. CONCLUSION: The sensitivity of guinea pig uterine artery but not carotid artery to thromboxane is reduced during pregnancy. Although the precise mechanism remains unclear, both endothelium-derived relaxing factor and an indomethacin-sensitive contracting factor are involved. If indomethacin-sensitive contracting factor is released by humans and disease alters that release, it is possible that any enhanced contractile response to thromboxane resulting from the loss of endothelium-derived relaxing agents such as prostacyclin and endothelium-derived relaxing factor would be offset by the loss of indomethacin-sensitive contracting factor.

Elimination of antithrombin III concentrate in healthy pregnant and preeclamptic women with an acquired antithrombin III deficiency.

The activity elimination half-life of heat-treated antithrombin III (AT III) concentrate was studied in 5 healthy pregnant and 5 preeclamptic women with a documented AT III deficiency. Healthy pregnant women received 1500 units over 20 minutes. Serial blood specimens were obtained over the next 12 hours. The mean (+/- SEM) activity elimination half-life of AT III was 29.4h +/- 3.4h. Preeclamptic subjects had a mean baseline AT III activity of 70.5 +/- 2% (range 61 to 75%). Their activity eliminator half-life after 3000 units of AT III concentrate was 8.5 +/- 1.2h. There was a direct relationship between the pre-concentrate AT III activity level and the AT III activity elimination half-life (r = 0.79, p = 0.01) for all subjects. Based upon parameters calculated from the first infusion, the AT III activity of preeclamptic subjects was maintained by a constant infusion at approximately 100% for 96h. At the conclusion of the infusion, the activity elimination half-life was again measured. A dramatic increase in the activity elimination half-life was demonstrated (433.6h). We conclude that the activity elimination half-life of AT III concentrate is increased during normal pregnancy and further increased in preeclamptic women with an acquired deficiency.

The effect of intravenously administered 2-chloroprocaine upon uterine artery blood flow velocity in gravid guinea pigs.

The purpose of the present study was to assess the effect of intravenously administered 2-chloroprocaine upon uterine artery blood flow velocity (UBFV) in gravid guinea pigs. Ten experiments were performed in ten chronically instrumented animals between 0.7 and 0.9 of timed gestation. Each animal received four solutions of 2-chloroprocaine in random order: 1) 0.67 mg/kg; 2) 1.34 mg/kg; 3) 2.0 mg/kg; and 4) 1.34 mg/kg, with epinephrine 0.2 microgram/kg. Six animals received a fifth solution, 0.2 ml of saline control. 2-Chloroprocaine 1.34 mg/kg significantly increased maternal mean arterial pressure (MMAP) at 30 s after injection, and 2-chloroprocaine 2.0 mg/kg significantly increased MMAP through 2 min. 2-Chloroprocaine 1.34 mg/kg, with epinephrine 0.2 microgram/kg, also significantly increased MMAP through 2 min. No other solution significantly altered MMAP. 2-Chloroprocaine 2.0 mg/kg significantly decreased UBFV at 30 s after injection. 2-Chloroprocaine 1.34 mg/kg, with epinephrine 0.2 microgram/kg, significantly decreased UBFV through 2 min. No other solution significantly altered UBFV. The authors conclude that iv administration of 2-chloroprocaine with epinephrine significantly decreased UBFV in pregnant guinea pigs. In contrast, only the largest dose (i.e., 2.0 mg/kg) of 2-chloroprocaine alone transiently decreased UBFV. These data suggest that, in doses up to 1.34 mg/kg, 2-chloroprocaine alone may not decrease uterine blood flow when used as a marker for intravenous injection in obstetric patients.

The effect of ephedrine upon uterine artery blood flow velocity in the pregnant guinea pig subjected to terbutaline infusion and acute hemorrhage.

The purpose of the present study was to determine the effect of intravenously administered ephedrine upon uterine artery blood flow velocity (UBFV) in the gravid guinea pig subjected to terbutaline infusion and acute hemorrhage. Ephedrine, 1.0 mg/kg, was administered intravenously to ten chronically instrumented pregnant guinea pigs near term, before and after intravenous infusion of terbutaline and acute hemorrhage. Before terbutaline and hemorrhage, ephedrine increased maternal mean arterial pressure (MMAP) by 30 +/- 1% (P = .0001) and 17 +/- 1% (P = .0001) at 30 s and at 1 min after injection, respectively; UBFV was decreased by 10 +/- 4% (P less than .01) and 14 +/- 4% (P less than .01) at 1 min and at 90 s after injection, respectively. Infusion of terbutaline (1.5-6.0 ug X kg-1 X min-1) increased maternal heart rate (MHR) by 22 +/- 1% (P = .0001), decreased MMAP by 13 +/- 2% (P = .0001), and decreased UBFV by 24 +/- 3% (P = .0001). During hypotension resulting from acute hemorrhage, ephedrine, 1.0 mg/kg, was superior to placebo in restoring MMAP and UBFV toward the prebleed values. The authors concluded that ephedrine, 1.0 mg/kg, results in a small, transient decrease in UBFV in the normotensive gravid guinea pig. However, ephedrine aids restoration of UBFV in the gravid guinea pig rendered hypotensive by acute hemorrhage during terbutaline infusion.

Effect of intravenous epinephrine on uterine artery blood flow velocity in the pregnant guinea pig.

The purpose of the present study was to determine the effect of intravenously administered epinephrine on the maternal cardiovascular response and uterine artery blood flow velocity (UBFV) in the pregnant guinea pig. Epinephrine (0.2, 0.5, and 1.0 micrograms/kg) and lidocaine (0.4 mg/kg, with and without 0.2 micrograms/kg of epinephrine) were administered intravenously to seven chronically instrumented pregnant guinea pigs near term. Lidocaine without epinephrine did not significantly alter maternal heart rate (MHR), maternal mean arterial pressure (MMAP), or UBFV. Epinephrine, with and without lidocaine, resulted in a transient decrease in MHR. Further, epinephrine, with and without lidocaine, resulted in significant elevations in MMAP and significant, dose-related reductions in UBFV. Mean (+/- SEM) UBFV was 72 +/- 4%, 56 +/- 4%, and 40 +/- 5% of baseline at 30 s after administration of epinephrine, 0.2, 0.5, and 1.0 micrograms/kg, respectively. It is concluded that these small intravenous boluses of epinephrine result in significant, although transient, reductions in UBFV in the pregnant guinea pig.