Thermoregulatory and acute-phase responses to endotoxin of full- term-pregnant rabbits.

Fever, a fall in the plasma level of iron (Fe), and rises in the levels of certain plasma glycoproteins (indexed by protein-bound-N-acetylneuraminic acid [NANA]) normally occur during infection; they are thought to be mutually enhancing in host defense. It has been reported that fever is suppressed at full term of pregnancy; however, it is not known whether the blood chemical changes are similarly affected. Also, the mechanism for the suppression of fever is controversial. Since uteroplacental blood flow is at its maximum near term, competition between the demands of the fetoplacental unit and of thermoregulatory effectors might result in underperfusion of thermogenic tissues and therefore provide a basis for the lack of fever. To examine these questions, the changes in colonic temperature (Tco) and regional blood flow induced by Salmonella enteritidis endotoxin (LPS, 2 micrograms/kg iv) were compared in conscious nonpregnant and 30-day-pregnant rabbits 35 min after injection, using 15-microgram radiolabeled microspheres. In different rabbits, the effects of LPS on Tco and plasma Fe and NANA levels were measured before mating and at term. LPS induced fevers similar in heights and courses in both nonpregnant and full-term pregnant rabbits It caused decreases in the blood flows to brain, tongue, mammary gland, small intestine, and ear and increases in the blood flows to masseter muscle, bone, liver (hepatic artery), and left ventricle; blood flows to the kidneys, spleen, right ventricle, ovaries, and myometrium did not change. There were no significant differences in these vascular responses between nonpregnant and 30-day-pregnant rabbits, except a 28% reduction in the blood flow to the placentas.

Thermal and acute-phase protein responses of guinea pigs to intrapreoptic injections of leukotrienes.

Although it seems probable that intrahypothalamic prostaglandin (PG) E2, a cyclooxygenase metabolite of arachidonic acid, modulates interleukin-1 (IL1)-induced fever, the evidence that it plays such a role is still only circumstantial; PGE2 does not, however, centrally mediate the fever-associated, acute-phase glycoprotein response. In this study, we investigated whether lipoxygenase products of arachidonic acid, viz. leukotriene (LT) B4, C4, D4 OR E4, injected intrapreoptically (2 ng/microliter, 1 microliter bilaterally) induces, like IL1, febrile and acute-phase glycoprotein responses in guinea pigs; controls received pyrogen-free saline, IL1 or PGE2. Measurements were: core temperature (Tco) and, as indices of acute-phase glycoproteins, plasma levels of copper (Cu) and protein-bound N-acetylneuraminic acid (NANA). Unlike IL1 or PGE2, no LT caused a febrile rise in Tco. Similar to PGE2 but unlike IL1, no LT produced increases in the plasma levels of Cu and NANA. These results indicate that intrapreoptic LTs probably are not involved in initiating the febrile or acute-phase glycoprotein responses characteristics of IL1.

Effects of muramyl dipeptide on sleep, body temperature and plasma copper after intracerebral ventricular administration.

Muramyl peptides are the monomeric components of bacterial cell wall peptidoglycans. Many muramyl peptides, such as muramyl dipeptide (MDP), (N-acetylmuramyl-L-alanyl-D-isoglutamine), are immune response modifiers, pyrogenic and somnogenic. The purposes of this study were to measure the somnogenic effects of MDP in conjunction with a biochemical measure of the host defense response, plasma Cu, and to determine if plasma Cu levels, like sleep, are regulated by a central nervous system process. MDP administered into a lateral cerebral ventricle induced a dose-dependent rise in plasma copper at 28 h postinfusion. This was usually associated with dose-dependent fevers, increases in SWS and reductions in rapid eye movement (REM) sleep during the first 6 h after infusion. Intravenous (i.v.) administration of the same amount of MDP did not affect any of these variables. We conclude that the syndrome induced by centrally administered MDP includes activation of the host defense response with respect to a rise in plasma copper in addition to fever and enhanced sleep.

Adhesion prevention by solutions of sodium carboxymethylcellulose in the rat. I.

Solutions of sodium carboxymethylcellulose (SCMC) were studied in rats to determine their longevity within the peritoneal cavity and their potential for prevention of postoperative intraperitoneal adhesions. In 18 rats, test solutions of SCMC and 10% dextran 40 were instilled at laparotomy. At 48 hours copious amounts of SCMC remained, whereas no 10% dextran 40 could be detected. In addition, standardized surgical injury was produced on the ceca of 100 rats at laparotomy. All control animals had significant adhesions at 2 weeks. Eighty-two percent of the 10% dextran 40 group had significant adhesions, while only 16% of the 0.9 wt% SCMC and 17% of the 1.0 wt% SCMC groups had significant adhesions. Solutions of SCMC were significantly more effective than 10% dextran 40 in the prevention of adhesions (P less than 0.001). Properties of SCMC and a possible mechanism for its striking effectiveness in adhesion prevention in this study are discussed.

Adhesion prevention by solutions of sodium carboxymethylcellulose in the rat. II.

In a rat model, sodium carboxymethylcellulose (SCMC) was compared with normal saline and 32% dextran 70 in the prevention of surgically induced intraperitoneal adhesions. The 32% dextran 70 was similar to normal saline in the initial prevention of adhesions, and both appeared less effective than SCMC. After lysis of the initial adhesions, SCMC was significantly more effective than 32% dextran 70 in the prevention of the reformation of adhesions. Possible mechanisms of action, complications of SCMC, and the need for further research in finding an ideal solution for use in adhesion prevention are discussed.

Activation of acute-phase responses by intrapreoptic injections of endogenous pyrogen in guinea pigs.

The acute-phase reaction (APR) is the concatenation of events that develops in response to infectious or other acute inflammatory stimuli. It includes fever and changes in plasma trace metal and glycoprotein levels. Endogenous pyrogen (EP) is believed to be the mediator of the APR. It acts within the preoptic-anterior hypothalamus (PO) to initiate fever; prostaglandins E (PGE) may modulate this action. To determine whether the nonfebrile responses to EP also are mediated by the PO and through PGE, guinea pigs were injected bilaterally intra-PO (iPO) with homologous EP (1 microliter) or PGE2 (0.1 microgram), and their colonic temperatures (Tco) and plasma iron (Fe), zinc (Zn), copper (Cu), and N-acetylneuraminic acid (NANA) levels were measured. For comparison, EP (2 ml) also was injected intraperitoneally (IP). Heat-denatured EP (delta EP) or pyrogen-free saline (PFS) was the corresponding control. Fevers were induced by IP EP (1.0 +/- 0.1 degrees C [mean +/- SD]), iPO EP (1.1 +/- 0.2 degrees C), and iPO PGE2 (1.4 +/- 0.2 degrees C); neither delta EP nor PFS was pyrogenic. Plasma Fe and Zn levels were decreased significantly after IP EP, but unchanged after iPO EP and PGE2. Plasma Cu and NANA levels were elevated significantly following both IP and iPO EP, but not after iPO PGE2. delta EP or PFS did not cause any changes, by either route. It appears, therefore, that EP-induced fever and rises in plasma Cu and NANA are mediated by the PO, while the decreases of plasma Fe and Zn are direct, peripheral effects. On the other hand, PGE2 appears to be involved only in the central febrile response. Indeed, guinea pigs, pretreated with indomethacin (5 mg/kg, IP), and injected iPO with EP or IP with S. enteritidis endotoxin (2 micrograms/kg), did not develop fever, but exhibited the rise in plasma Cu and NANA.

Hypothalamic opioids and the acute-phase glycoprotein response in guinea pigs.

Endogenous opioids (EO) probably do not modulate endotoxin (LPS)- or interleukin 1 (IL1)-induced fever because naloxone does not prevent its development. Yet, increases in CSF and hypothalamic levels of beta-endorphin have been reported during LPS-and IL1-induced fevers. Since IL1 also reduces the specific binding of opioids to their receptors in guinea pig brain, the opioids could be involved in modulating nonfebrile effects of IL1. To determine whether EO might have a role in the IL1-induced acute-phase glycoprotein response of guinea pigs, (1) naloxone (5 and 10 mg/kg, SC) was injected prior to LPS (S. enteritidis 2 micrograms/kg, IV; N = 5), and (2) morphine (MOR, 10 micrograms/microliter), [D-ala2]-met-enkephalinamide (DAME, 5 micrograms/microliter), or dynorphin A (DYN, 5 micrograms/microliter) was injected into the preoptic area (1 microliter, bilaterally; N = 8/treatment) or into the 3rd ventricle (N = 4/treatment); pyrogen-free saline was the control injection. Measurements were: core temperature (Tco) and, as indices of acute-phase glycoproteins, plasma levels of copper (Cu) and N-acetylneuraminic acid (NANA). Naloxone did not prevent the fever or the increases in plasma Cu and NANA levels evoked by LPS. The intracerebral administration of opioid agonists by either route induced variable rises in Tco, each with a different pattern, but no increases in plasma Cu and NANA levels. Thus, EO do not participate in the central modulation of acute-phase glycoprotein synthesis, but may have a role in influencing other nonthermal IL1 effects in the CNS.

Thermal stimulation of the hypothalamus does not evoke the acute-phase reaction.

Interleukin-1 (IL1) injected into the preoptic-anterior hypothalamus (POAH) induces, besides fever, the hepatic synthesis of acute-phase glycoproteins. Since the febrigenic action of IL1 may involve thermosensitive neurons in the POAH, this study examined whether such neurons also might mediate the acute-phase response (APR). The POAH of six adult NZW rabbits was cooled (Tpo = 34.4 +/- 0.4 degrees C [mean +/- SD]) or heated (40.6 +/- 0.2 degrees C) continuously for 2.5 hr (so as to mimic the mean febrile course following a bolus microinjection of IL1 into the POAH). The ambient temperature (Ta) was 23.5 +/- 1.0 degrees C. Expectedly, core temperature fell and skin temperature rose on POAH heating, and the opposite occurred on POAH cooling. However, no statistically significant changes in the plasma levels of Fe, Zn, Cu, and N-acetylneuraminic acid, as indices of the APR, were induced by these treatments. These results indicate, therefore, that the central actions of IL1 in inducing fever and the APR are separate, and that the APR is not mediated through stimulation of thermosensitive units in the POAH.

Suppression of fever after lesions of the anteroventral third ventricle in guinea pigs.

Endogenous pyrogen (EP), injected systemically or intracerebrally, evokes fever and certain changes in plasma trace metal and glycoprotein levels which are characteristic of the acute-phase reaction. It is generally assumed that EP enters the brain from the blood, although it has not yet been demonstrated that EP crosses the blood-brain barrier (BBB). The possibility that EP might penetrate the brain through the organum vasculosum laminae terminalis (OVLT), which is outside of the BBB and located in close proximity to the medial preoptic region (MPO, the primary site sensitive to locally applied EP), was investigated by making electrolytic lesions (3 mA, 20 sec, anodal) in the anteroventral wall of the third ventricle of guinea pigs (AV3V-X). After 10 days, their febrile and selected acute-phase responses (plasma iron, zinc, copper, and sialic acid levels) to endotoxin (LPS, S. enteritidis, 2 micrograms/kg, IP), which induces EP production by the host, were measured; controls were sham-operated guinea pigs. LPS did not induce in the AV3V-X animals either fever or rises in plasma copper and sialic acid levels; however, as in the controls, it caused hypoferremia and hypozincemia. To exclude damage to the MPO as a cause of these responses, sham and AV3V-X guinea pigs were administered homologous EP intrapreoptically (1 microliter bilaterally). Comparable fevers developed in both groups of animals. Hence, the integrity of the AV3V region including the OVLT seems to be critical for the EP-induced elevations of both body temperature and plasma levels of acute-phase proteins, but not for the fall of plasma iron and zinc levels. It may be that EP passes into the brain through the OVLT.

Effect of indomethacin and N omega-nitro-L-arginine methyl ester on the pressure/flow relation in isolated perfused hindlimbs from pregnant and nonpregnant rats.

OBJECTIVE: To compare the pressure/flow relationship and to assess the roles of prostaglandins and nitric oxide in flow-induced vasodilation in the nonpregnant and late-pregnant rat hindlimb vasculature. METHODS: Pressure/flow and conductance/flow relationships were determined in isolated, Krebs buffer-perfused, norepinephrine (0.5 mumol/L) preconstricted hindlimbs from nonpregnant and late-pregnant Wistar-Kyoto rats before and after inhibition of cyclo-oxygenase with indomethacin (20 mumol/L), or nitric oxide synthase with N omega-nitro-L-arginine methyl ester (300 mumol/L). RESULTS: There were no significant differences in baseline perfusion pressure between nonpregnant and pregnant rat hindlimbs perfused at 2 mL/min (20.6 +/- 0.8 and 19.7 +/- 1.1 mmHg, respectively) and norepinephrine increased perfusion pressure about twofold (40.8 +/- 2.0 and 34.8 +/- 1.8 mmHg, respectively). After constriction, perfusion pressure increased linearly as flow was increased in a stepwise manner to a maximum of 4 mL/min. The slope of the pressure/flow regression line for the pregnant rat hindlimbs (6.00) was significantly lower (P < or = .001) than that for the nonpregnant rat hindlimbs (8.44). Vascular conductance also increased as flow was increased, and was significantly greater at all flow rates in the pregnant compared to the nonpregnant rat hindlimbs. Indomethacin slightly decreased the constrictor response to norepinephrine and increased the pressure/flow regression line slope in nonpregnant, but not in pregnant rat hindlimbs. N omega-nitro-L-arginine methyl ester abolished flow-mediated vasodilation in nonpregnant and pregnant rat hindlimbs, and there was no longer any significant difference between the pressure/flow regression line slopes. CONCLUSION: These results suggest that flow-induced vasodilation, mediated by endothelium-derived nitric oxide, is enhanced during pregnancy allowing the maternal vasculature to accommodate increased blood flow without increased blood pressure.

Evidence of a nonendothelial source of nitric oxide in the isolated perfused hindlimb vasculature of the pregnant rat.

OBJECTIVE: This study was undertaken to further elucidate the roles of the vascular endothelium and nitric oxide (NO) in the regulation of vascular tone and constrictor responsiveness in pregnancy. METHODS: The perfusion pressure-flow relationship was measured in isolated, perfused, norepinephrine-constricted (1) endothelium-intact, (2) endothelium-denuded, and (3) N omega-nitro-L-arginine methyl ester (L-NAME)-treated hindlimbs from nonpregnant and term-pregnant rates. RESULTS: Baseline perfusion pressure at a flow rate of 2 mL/min was similar (approximately 20 min Hg) in all hindlimbs. Norepinephrine (0.5 muM) increased perfusion pressure in both nonpregnant (+21.6 +/- 2.4 mm Hg) and pregnant (+13.6 +/- 0.9 mm Hg) endothelium-intact rat hindlimbs. In nonpregnant rat hindlimbs, endothelium removal and L-NAME increased norepinephrine vasoconstriction similarly (+44.3 +/- 4.0 mm Hg and +46.4 +/- 8.6 mm Hg, respectively). In pregnant-rat hindlimbs, L-NAME increased norepinephrine vasoconstriction by 43.5 +/- 10.8 mm Hg, similar to that in nonpregnant-rat hindlimbs, but endothelium removal only increased norepinephrine vasoconstriction by 28.0 +/- 2.2 mm Hg. Perfusion pressure increased linearly as the flow rate was increased from 2 to 4 mL/min, and the slope of the regression line of the endothelium-intact pregnant-rat hindlimbs (7.0 +/- 0.6) was slightly, but not significantly, lower than that of the nonpregnant-rat hindlimbs (9.6 +/- 0.9). Endothelium removal increased the slopes of the regression lines, but that of pregnant-rat hindlimbs (12.8 +/- 1.6) was significantly lower (p < or = 0.05) than that of the nonpregnant-rat hindlimbs (23.8 +/- 1.8). L-NAME caused a similar increase in the pressure-flow slopes of nonpregnant-rat (36.5 +/- 3.4) and pregnant-rat (32.1 +/- 5.3) hindlimbs. CONCLUSIONS: These results suggest that nonendothelial nitric oxide production may be increased in the hindlimb resistance vasculature of the pregnant rat, which may play a role in the normal pregnancy blunting of constrictor responsiveness and reduction of vascular resistance.

Preeclampsia and related disorders. Clinical aspects and relevance of endothelin and nitric oxide.

Preeclampsia is a pregnancy-specific disorder believed to result from widespread endothelial dysfunction. Endothelin and NO are two potent vasoactive agents of endothelial origin and, as such, are postulated to play an important role in the pathogenesis of preeclampsia. If these agents are found to be important in preeclampsia, they will most likely exert their effects locally, rather than systemically. Future research on the autocrine and paracrine effects of endothelin and NO may yield important insights into the cause and pathogenesis of this enigmatic disease.

Endothelium-derived relaxing factor inhibition augments vascular angiotensin II reactivity in the pregnant rat hind limb.

OBJECTIVE: The purpose of our study was to determine whether endothelium-derived relaxing factor plays a role in the blunting of maternal vascular reactivity in pregnancy. STUDY DESIGN: We measured the concentration-pressor responses to norepinephrine (10(-8) to 10(-4) mol/L and angiotensin II (10(-10) to 10(-6) mol/L) in isolated, perfused hind limbs of nonpregnant and pregnant (postmating day 20 to 21) normotensive Wistar-Kyoto and spontaneously hypertensive rats. The hind limbs were perfused at 4 ml/min with Krebs-Ringer solution containing indomethacin (10(-5) mol/L to inhibit prostaglandin production and were either infused with N omega-monomethyl-L-arginine (10(-4) mol/L), a specific inhibitor of endothelium-derived relaxing factor synthesis, or 0.9% saline solution (untreated). RESULTS: Baseline perfusion pressure was similar in the nonpregnant and pregnant hind limbs of both strains, and N omega-monomethyl-L-arginine had no effect on perfusion pressure. Norepinephrine induced similar pressor responses in the nonpregnant and pregnant hind limbs of both strains, and N omega-monomethyl-L-arginine did not alter these responses. Angiotensin II pressor responses were significantly attenuated in the pregnant rat hind limbs compared with the nonpregnant rat hind limbs. N omega-monomethyl-L-arginine enhanced the angiotensin II responses in the pregnant, but not in the nonpregnant, rat hind limbs. CONCLUSION: The results suggest that rat pregnancy is not associated with generalized refractoriness to all vasoconstrictors and that endothelium-derived relaxing factor plays a role in attenuating vascular reactivity to angiotensin II.

The relationship between experimentally determined litter size and maternal blood pressure in spontaneously hypertensive rats.

Pregnancy lowers blood pressure in hypertensive rats. To evaluate the role of the conceptus in maternal blood pressure regulation, we measured the changes in systolic blood pressure b (by tail-cuff plethysmography) throughout gestation and mean arterial pressure, cardiac output, and organ blood flows (with radioactive microspheres) on postmating day 21 for calculation of total peripheral and organ vascular resistances in spontaneously hypertensive rats with litter size surgically adjusted to 0 to 10 conceptuses on postmating day 7. Blood pressure remained elevated in those rats with zero fetuses but decreased during the last week of pregnancy in those rats with three or more fetuses. The magnitude of the decrease was directly related to litter size. At term, cardiac output was positively correlated (r = 0.61; p less than 0.001), whereas mean arterial pressure and total peripheral resistance were negatively correlated (r = -0.74; p less than 0.001 and r = -0.79; p less than 0.001, respectively) with litter size. Resistances of all the vascular beds in the body, except the kidneys, spleen, and hepatic artery were also negatively correlated with fetal number. Thus pregnancy is characterized by a generalized maternal vasodilation, and the fetal/placental unit may play a significant role in modulating maternal vascular tone.

Effects of dietary lead and zinc on fetal organ growth.

In order to further understand the effects of ingested lead (Pb) on the fetus and the possible interaction of the trace element zinc (Zn) with Pb, groups of rats with dated pregnancies were fed 0, 10, 50, 100, 200 or 500 mg/L of Pb in water throughout pregnancy. Diet was provided ad libitum. A group pair fed with the 200 mg/L of Pb group and a group fed both Zn and Pb, 200 mg/L, were also studied. Placental weight remained constant, but cell division and total protein level were decreased while cell size increased markedly. Fetal carcass and liver weight, cell division, and protein were decrease while cell growth was unchanged. Brain weight decreased while cell division, growth, and protein were unchanged. Kidney weight, cell division and protein level were unchanged but cell growth was decreased. Organ dry weight varied with wet weight while the percentage of water was unchanged. Whether pair feeding and Zn supplements improve carcass and liver weight is questionabel.

Effects of dietary lead and zinc on pregnancy.

In order to further understand the effects of ingested Pb on pregnancy and the possible interaction of the trace element Zn with Pb, groups of dated pregnant rats were fed 10, 50, 100, 200, or 500 mg/L of Pb in water throughout pregnancy. A control group with no Pb, but diet ad lib, and a pair-fed control group with no Pb were also studied. Maternal average daily food consumption was significantly reduced at 50 mg/L of Pb and up. Total and net maternal weights were significantly reduced at 50 mg/L of Pb and up. Pair feeding at the 200 mg/L level improved maternal weight gain but not to control levels. Zn, 200 mg/L, supplement at the 200 mg/L of Pb level caused no improvement nor did ad lib diet with Pb removed after 16 days. Fetal weight decreased progressively as Pb levels were increased. Pair feeding at the 200 mg/L Pb of level and Zn, 200 mg/L, supplement with 200 mg/L of Pb significantly increased fetal weight but not to control levels. Placental weight was unchanged throughout. The results indicate that Pb-induced fetal growth retardation is due to reduced maternal food and energy intake, as well as to direct effect on the fetus. Excess dietary Zn improves fetal growth, probably by increasing maternal food consumption.

Cadmium uptake by the rat embryo as a function of gestational age.

Maternal blood, liver, kidney, and placental and fetal (embryo) accumulation of cadmium (Cd), a known embryotoxic trace element, was investigated following a single oral dose of various amounts of Cd (10 to 1,000 microgram/rat) as CdCl2 containing 109Cd at days 6, 10, 14, and 17 of gestation. Twenty-four hours after Cd administration the rats were killed and the various tissues were counted in a gamma well counter for determination of 109Cd activity. Maternal liver and kidneys were the main target organs of Cd accumulation at all stages of gestation. Embryo levels of Cd were highest prior to formation of the functional placenta. After placental formation, fetal Cd levels were decreased, while placental accumulation of Cd increased with increasing gestational age. The results indicate that the embryo accumulates the greatest percentage of ingested Cd between implantation and placentation, the early period of organogenesis. The placenta apparently protects the fetus from exposure to this element during the last third of gestation.

Effect of dietary restriction, during the last week only or throughout gestation, on cardiac output and uteroplacental blood flow in pregnant rats.

Cardiac output and uteroplacental blood flow were measured by using 15-microns radioactive labeled microspheres in ad libitum-fed nonpregnant female rats, and in pregnant rats: 1) fed ad libitum; 2) fed a 50% restricted diet from day 14 of gestation on; and 3) fed a 50% restricted diet from day 5 of gestation on. Dietary restriction induced fetal growth retardation regardless of duration. Cardiac output in both groups of diet-restricted dams was 30% less than that of the ad libitum-fed pregnant dams, and not significantly increased above that of the nonpregnant rats. Total uterine and placental blood flows in the dams fed the restricted diet during the last week of gestation were reduced 30-35% relative to the ad libitum-fed dams due to the reduced cardiac output. In the dams fed the restricted diet from day 5, total uterine and placental blood flows were reduced 60-65% due to both the reduced cardiac output and a decreased fractional distribution of cardiac output to the uterus. Dietary treatment had no effect on blood flow to the kidneys and ovaries. The results suggest that the reduced placental blood flow associated with maternal malnutrition-induced fetal growth retardation is caused by an inadequate expansion of maternal cardiac output, and, if malnutrition is severe enough, a fractional redistribution of cardiac output away from the uterus and developing conceptus occurs.

Fever and trace metal changes in endotoxin-challenged neonates.

During infections, plasma Fe and Zn generally fall, while body temperature and plasma Cu rise. However, infected neonates usually do not develop fever during the first week of postnatal life. While fever could not be evoked in neonatal guinea pigs by 2 micrograms/kg of S. enteritidis endotoxin until they were 8 days old, their plasma levels of Fe and Zn were lowered significantly from birth; plasma Cu tended to increase from 2 days postnatally. These results indicate that, contrary to the refractoriness to endotoxin of the fibrific system, the ability to alter trace metal levels exists from birth. Thus, fever and trace metal levels are not necessarily coupled for host defense during infection.

Enhanced endothelium-derived relaxing factor activity in pregnant, spontaneously hypertensive rats.

Pregnancy is normally associated with vasodilation that, in hypertensive animals such as the spontaneously hypertensive rat, causes a profound decrease in blood pressure. To test the possibility that enhanced basal endothelium-derived relaxing factor activity has a role in the vasodilation of pregnancy, we measured the changes in mean arterial pressure and heart rate induced by NG-monomethyl-L-arginine, a specific inhibitor of endothelium-derived relaxing factor synthesis, in conscious nonpregnant and pregnant (postmating day 20 to 21) normotensive Wistar-Kyoto and spontaneously hypertensive rats. NG-monomethyl-L-arginine caused similar dose-dependent increases in mean arterial pressure in nonpregnant and pregnant Wistar-Kyoto rats, but the accompanying decrease in heart rate was significantly greater in nonpregnant rats than in pregnant ones. In the spontaneously hypertensive rats, NG-monomethyl-L-arginine caused significantly greater dose-dependent increases in mean arterial pressure in pregnant compared with nonpregnant rats; there were no differences in the decreases in heart rate. These pressor responses were partially reversed by excess L-arginine but not D-arginine. Indomethacin had no effect on the pressor response to NG-monomethyl-L-arginine or the depressor response to L-arginine after NG-monomethyl-L-arginine. Therefore basal endothelium-derived relaxing factor plays a role in vascular tone and blood pressure regulation in vivo, and pregnancy may be associated with enhanced basal endothelium-derived relaxing factor activity in the hypertensive spontaneously hypertensive rats.