Roles of nitric oxide and angiotensin II in the impaired baroreflex gain of pregnancy

The present study tested the hypothesis that nitric oxide (NO) contributes to impaired baroreflex gain of pregnancy and that this action is enhanced by angiotensin II. To test these hypotheses, we quantified baroreflex control of heart rate in nonpregnant and pregnant conscious rabbits before and after: 1) blockade of NO synthase (NOS) with Nomega-nitro-L-arginine (20 mg/kg iv); 2) blockade of the angiotensin II AT1 receptor with L-158,809 (5 microg x kg(-1) x min(-1) iv); 3) infusion of angiotensin II (1 ng x kg(-1) x min(-1) nonpregnant, 1.6-4 ng x kg(-1) x min(-1) pregnant iv); 4) combined blockade of angiotensin II AT(1) receptors and NOS; and 5) combined infusion of angiotensin II and blockade of NOS. To determine the potential role of brain neuronal NOS (nNOS), mRNA and protein levels were measured in the paraventricular nucleus, nucleus of the solitary tract, caudal ventrolateral medulla, and rostral ventrolateral medulla in pregnant and nonpregnant rabbits. The decrease in baroreflex gain observed in pregnant rabbits (from 23.3 +/- 3.6 to 7.1 +/- 0.9 beats x min(-1) x mmHg(-1), P < 0.05) was not reversed by NOS blockade (to 8.3 +/- 2.5 beats x min(-1) x mmHg(-1)), angiotensin II blockade (to 5.0 +/- 1.1 beats x min(-1) x mmHg(-1)), or combined blockade (to 12.3 +/- 4.8 beats x min(-1) x mmHg(-1)). Angiotensin II infusion with (to 5.7 +/- 1.0 beats x min(-1) x mmHg(-1)) or without (to 8.4 +/- 2.4 beats x min(-1) x mmHg(-1)) NOS blockade also failed to improve baroreflex gain in pregnant or nonpregnant rabbits. In addition, nNOS mRNA and protein levels in cardiovascular brain regions were not different between nonpregnant and pregnant rabbits. Therefore, we conclude that NO, either alone or via an interaction with angiotensin II, is not responsible for decrease in baroreflex gain during pregnancy.     

Functional and molecular characterization of tachykinins and tachykinin receptors in the mouse uterus

The aim of this study was to analyze the function and expression of tachykinins, tachykinin receptors, and neprilysin (NEP) in the mouse uterus. A previous study showed that the uterotonic effects of substance P (SP), neurokinin A (NKA), and neurokinin B (NKB) in estrogen-treated mice were mainly mediated by the tachykinin NK1 receptor. In the present work, further contractility studies were undertaken to determine the nature of the receptors mediating responses to tachykinins in uteri of late pregnant mice. Endpoint and real-time quantitative RT-PCR were used to analyze the expression of the genes that encode the tachykinins SP/NKA, NKB, and hemokinin-1 (HK-1) (Tac1, Tac2, and Tac4); and the genes that encode tachykinin NK1 (Tacr1), NK2 (Tacr2), and NK3 (Tacr3) receptors in uteri from pregnant and nonpregnant mice. The data show that the mRNAs of tachykinins (particularly NKB and HK-1), tachykinin receptors, and NEP are locally expressed in the mouse uterus, and their expression changes during the estrous cycle and during pregnancy. The tachykinin NK1 receptor is the predominant tachykinin receptor in the nonpregnant and early pregnant mouse and may mediate tachykinin-induced uterine contractions in the nonpregnant mouse. The tachykinin NK2 receptor is predominant in the late pregnant mouse and is the main receptor mediating uterotonic responses to tachykinins at late pregnancy. The tachykinin NK3 receptor is expressed in considerable amounts only in uteri from nonpregnant diestrous animals, and its physiological significance remains to be clarified.     

Rat ovarian angiotensin II receptors, renin, and angiotensin I-converting enzyme during pregnancy and the postpartum period.

The ovarian renin-angiotensin system (RAS) has been studied extensively in the virgin cycling rat, but little information is available about this system in pregnant and postpartum rats. We show that renin and angiotensin I-converting enzyme (ACE)--the key enzymes involved in angiotensin II (Ang II) formation--and Ang II receptors, are present in pregnant and postpartum rat ovaries. From gestation Days 2-4 to 10-12, active ovarian renin ranged from 1.12 +/- 0.13 to 1.27 +/- 0.19 ng Ang I/h/mg and comprised between 68 and 86% of total (active+inactive) ovarian renin activity. Between Days 10-12 and Days 14-16 of pregnancy, ovarian active renin activity increased slightly, but inactive renin disappeared, suggesting its activation; the remaining active renin then decreased 62% by Days 18-20 (p < 0.05). On postpartum Day 2, both active and total ovarian renin activity exceeded that of Days 2-20 of pregnancy (p < 0.05); levels of both then declined sharply by postpartum Day 3 (p < 0.05). In pregnant rats, levels of ovarian Ang II receptors, identified by the specific binding of [125I]-[Sar1,Ile8]Ang II to ovarian membranes, were high between Days 2-4 and 10-12 of pregnancy, ranging from 12.8 +/- 1.7 to 15.7 +/- 3.4 fmol/mg, but steadily declined by 82% between gestation Days 10-12 and 18-20 (p < 0.05). Postpartum Ang II receptor levels on Days 2, 3, and 4 showed a gradual increase from low levels comparable to Days 18-20 of pregnancy. Ovarian ACE activity did not change throughout pregnancy or during the postpartum period.(ABSTRACT TRUNCATED AT 250 WORDS)     

125I[Sar(1)Ile(8)] angiotensin II has a different affinity for AT(1) and AT(2) receptor subtypes in ovine tissues

Iodinated angiotensin II (Ang II) and its analogues are often assumed to have equal affinities for AT(1) and AT(2) receptor subtypes. However, using saturation and competition binding assays in several tissues from pregnant, nonpregnant, and fetal sheep, we found the affinity of 125I[Sar(1)Ile(8)] Ang II for Ang II receptors was different (P<0.05) between tissue types. The dissociation constants (Kd) and half maximal displacements of [Sar(1)Ile(8)] Ang II (Sar IC(50)) were directly related (P<0.05) to proportions of AT(1) receptors, and inversely related (P<0.05) to proportions of AT(2) receptors in tissues from all groups combined, in tissues from individual groups (pregnant, nonpregnant or fetal), and in some individual tissues (uterine arteries and aortae). This suggests that 125I[Sar(1)Ile(8)] Ang II has a different affinity for AT(1) and AT(2) receptors in ovine tissues. The Kds of 125I[Sar(1)Ile(8)] Ang II for "pure" populations of AT(1) and AT(2) receptors were 1.2 and 0.3 nM, respectively, i.e. affinity was four-fold higher for AT(2) receptors. We corrected the measured proportions of the receptor subtypes using their fractional occupancies. In tissues which contained at least 10% of each receptor subtype, the corrected proportions were significantly altered (P<0.05), even in some tissues, to the extent of being reversed.     

Production of angiotensin II receptors type one (AT1) and type two (AT2) during the differentiation of 3T3-L1 preadipocytes.

During their development from progenitor cells, adipocytes not only express enzymatic activities necessary for the storage of triglycerides, but also achieve the capability to produce a number of endocrine factors such as leptin, tumor necrosis factor alpha (TNFalpha), complement factors, adiponectin/adipoQ, plasminogen activator inhibitor-1 (PAI-1), angiotensin II and others. Angiotensin II is produced from angiotensinogen by the proteolytic action of renin and angiotensin-converting enzyme; and several data point to the existence of a complete local renin-angiotensin system in adipose tissue, including angiotensin II receptors. In this study, we directly monitored the production of angiotensin II type one receptor (AT1) and angiotensin II type two receptor (AT2) proteins during the adipose conversion of murine 3T3-L1 preadipocytes by immunodetection with specific antibodies. AT1 receptors could be detected throughout the whole differentiation period. The strong AT2 signal in preadipocytes however was completely lost during the course of differentiation, which suggests that expression of AT2 receptors is inversely correlated to the adipose conversion program.     

Defining the differential sensitivity to norepinephrine and angiotensin II in the ovine uterine vasculature

The intact ovine uterine vascular bed (UVB) is sensitive to α-agonists and refractory to angiotensin II (ANG II) during pregnancy; the converse occurs in the systemic circulation. The mechanism(s) responsible for these differences in uterine sensitivity are unclear and may reflect predominance of nonconstricting AT(2) receptors (AT(2)R) in uterine vascular smooth muscle (UVSM). The contribution of the placental vasculature also is unclear. Third generation and precaruncular/placental arteries from nonpregnant (n = 16) and term pregnant (n = 23) sheep were used to study contraction responses to KCl, norepinephrine (NE), and ANG II (with/without ATR specific inhibitors) and determine UVSM ATR subtype expression and contractile protein content. KCl and NE increased third generation and precaruncular/placental UVSM contractions in a dose- and pregnancy-dependent manner (P ≤ 0.001). ANG II only elicited modest contractions in third generation pregnant UVSM (P = 0.04) and none in precaruncular/placental UVSM. Moreover, compared with KCl and NE, ANG II contractions were diminished ≥ 5-fold. Whereas KCl and ANG II contracted third generation>precaruncular/placental UVSM, NE-induced contractions were similar throughout the UVB. However, each agonist increased third generation contractions ≥ 2-fold at term, paralleling increased actin/myosin and cellular protein content (P ≤ 0.01). UVSM AT(1)R and AT(2)R expression was similar throughout the UVB and unchanged during pregnancy (P > 0.1). AT(1)R inhibition blocked ANG II-mediated contractions; AT(2)R blockade, however, did not enhance contractions. AT(2)R predominate throughout the UVB of nonpregnant and pregnant sheep, contributing to an inherent refractoriness to ANG II. In contrast, NE elicits enhanced contractility throughout the ovine UVB that exceeds ANG II and increases further at term pregnancy.     

Angiotensin II mediates uterine vasoconstriction through alpha-stimulation

Intravenous angiotensin II (ANG II) increases uterine vascular resistance (UVR), whereas uterine intra-arterial infusions do not. Type 2 ANG II (AT(2)) receptors predominate in uterine vascular smooth muscle; this may reflect involvement of systemic type 1 ANG II (AT(1)) receptor-mediated alpha-adrenergic activation. To examine this, we compared systemic pressor and UVR responses to intravenous phenylephrine and ANG II without and with systemic or uterine alpha-receptor blockade and in the absence or presence of AT(1) receptor blockade in pregnant and nonpregnant ewes. Systemic alpha-receptor blockade inhibited phenylephrine-mediated increases in mean arterial pressure (MAP) and UVR, whereas uterine alpha-receptor blockade alone did not alter pressor responses and resulted in proportionate increases in UVR and MAP. Although neither systemic nor uterine alpha-receptor blockade affected ANG II-mediated pressor responses, UVR responses decreased >65% and also were proportionate to increases in MAP. Systemic AT(1) receptor blockade inhibited all responses to intravenous ANG II. In contrast, uterine AT(1) receptor blockade + systemic alpha-receptor blockade resulted in persistent proportionate increases in MAP and UVR. Uterine AT(2) receptor blockade had no effects. We have shown that ANG II-mediated pressor responses reflect activation of systemic vascular AT(1) receptors, whereas increases in UVR reflect AT(1) receptor-mediated release of an alpha-agonist and uterine autoregulatory responses.     

肾素 - 血管紧张素 - 醛固酮系统阻滞的研究进展

肾素-血管紧张素-醛固酮系统起初被认为是较简单的神经体液调节机制之一。但是,这一想法随着RAAS阻滞剂:肾素阻滞剂、血管紧张素转换酶抑制剂(ACEI)、AT1受体拮抗剂及盐皮质激素受体拮抗剂的深入研究而受到挑战。因此,RAAS的组成、以上药物发挥作用的具体通路及副作用均得到重新定义。在RAAS阻滞剂的应用过程中,机体肾素水平升高,并刺激肾素原受体(即无活性的肾素前体,PRR),进而对机体造成不良影响。同理,在AT1受体拮抗剂的应用过程中,血浆血管紧张素II的水平升高,并与2型血管紧张素II(AT2)受体结合,进而对机体产生有利作用。此外,随着ACEI及ARB的应用,血管紧张素1-7水平升高,其与Mas受体结合,发挥心脏及肾脏保护的作用,还可通过刺激干细胞发挥组织修复作用。     

Sarcosine1,glycine8 angiotensin II is an AT1 angiotensin II receptor subtype selective antagonist

Studies predating the discovery of the two major subtypes of angiotensin II (Ang II) receptors, AT1 and AT2, revealed anomalous characteristics of sarcosine1,glycine8 Ang II (Sar1,Gly8 Ang II). It competed poorly for 125I-Ang II binding in bovine brain but potently antagonized dipsogenic responses to intracerebroventricularly administered Ang II. Subsequent recognition that bovine brain contains AT(2) receptors, while dipsogenic responses to Ang II are mediated by AT1 receptors, suggests that Sar1,Gly(8) Ang II is AT1 selective. Sar1,Gly8 Ang II competed for 125I-sarcosine1,isoleucine8 Ang II binding to AT1 receptors in pituitary, liver and adrenal (the latter with the AT2 selective antagonist PD 123,319) with Ki's of 0.66, 1.40 and 1.36 nM, respectively. In contrast, the Ki of Sar1,Gly8 Ang II for AT2 receptors in rat adrenal (with the selective AT1 antagonist losartan) was 52 nM. 125I-Sar1,Gly8 Ang II (0.5-3 nM) bound to AT1 receptors in pituitary, liver, heart, adrenal, and hypothalamic membranes with high affinity (Kd=0.43, 1.6, 2.3, 0.96 and 1.8 nM, respectively), but showed no saturable binding to the adrenal AT2 receptor. 125I-Sar1,Gly8 Ang II selectively labeled AT1 receptors in sections of adrenal using receptor autoradiography. Thus, binding studies reveal Sar1,Gly8 Ang II to be the first angiotensin peptide analog to show AT1 receptor selectivity. 125I-Sar1,Gly8 Ang II offers a new means to selectively radiolabel AT1 receptors and may help to characterize ligand docking sites and agonist switches for AT1 versus AT2 receptors.     

Involvement of AT(1) angiotensin receptors in the vasomodulatory effect of des-aspartate-angiotensin I in the rat renal vasculature

Angiotensin II is known to act primarily on the angiotensin AT(1) receptors to mediate its physiological and pathological actions. Des-aspartate-angiotensin I (DAA-I) is a bioactive angiotensin peptide and have been shown to have contrasting vascular actions to angiotensin II. Previous work in this laboratory has demonstrated an overwhelming vasodepressor modulation on angiotensin II-induced vasoconstriction by DAA-I. The present study investigated the involvement of the AT(1) receptor in the actions of DAA-I on angiotensin II-induced vascular actions in the renal vasculature of normotensive Wistar-Kyoto rats (WKY), spontaneously hypertensive rats (SHR) and streptozotocin (STZ)-induced diabetic rats. The findings revealed that the angiotensin receptor in rat kidney homogenate was mainly of the AT(1) subtype. The AT(1) receptor density was significantly higher in the kidney of the SHR. The increase in AT(1) receptor density was also confirmed by RT-PCR and Western blot analysis. In contrast, AT(1) receptor density was significantly reduced in the kidney of the streptozotocin-induced diabetic rat. Perfusion with 10(-9)M DAA-I reduced the AT(1) receptor density in the kidneys of WKY and SHR rats suggesting that the previously observed vasodepressor modulation of the nonapeptide could be due to down-regulation or internalization of AT(1) receptors. RT-PCR and Western blot analysis showed no significant changes in the content of AT(1) receptor mRNA and protein. This supports the suggestion that DAA-I causes internalization of AT(1) receptors. In the streptozotocin-induced diabetic rat, no significant changes in renal AT(1) receptor density and expression were seen when its kidneys were similarly perfused with DAA-I.     

Selective down-regulation of AT2 receptors in uterine arteries from pregnant ewes given 24-h intravenous infusions of angiotensin II

Previously, we showed that uterine arteries from late gestation pregnant ewes infused intravenously with angiotensin II (Ang II) for 24 h, displayed heightened responsiveness to Ang II in vitro. Furthermore, we found that a small population of ewes with a "preeclampsia-like" disorder also displayed this. Therefore, we have investigated the density and affinity of Ang II receptor subtypes in the uterine arteries from these groups. Ang II receptor binding was measured using 125I [Sar1Ile8] Ang II. Proportions of AT1 and AT2 receptors were determined by inhibiting 125I [Sar1Ile8] Ang II with losartan (AT1 antagonist) or PD 123319 (AT2 antagonist). Uterine arteries from 24-h Ang II-infused ewes had a lower proportion of AT2 receptors (56.2+/-2.3%) than control (saline-infused) ewes (84.1+/-1.0%; P<0.05). The density of AT2 receptors was reduced (P<0.05) while the density of AT1 receptors was not different. Thus, 24-h infusions of Ang II selectively down-regulated AT2 receptors in the uterine artery, resulting in heightened Ang II reactivity. By contrast, the binding properties of Ang II receptor subtypes in uterine arteries from ewes with the "preeclampsia-like" disorder were not different from control ewes.     

Changes in expression of angiotensin receptor subtypes in the rat aorta during development

Quantitative autoradiography was used to characterize angiotensin AT1 and AT2 receptors, in the rat aorta at three developmental ages; embryonic day 18 (E18), and postnatal weeks 2 and 8. The expression of angiotensin receptors was higher in the aorta of E18 and 2-week-old rat. A major proportion of the angiotensin receptors expressed in the aorta at these two ages was AT2 (84 and 81% respectively). Conversely, in the aorta of 8-week-old rats, AT1 was the predominant angiotensin receptor subtype (71%). In 8-week-old rats, the AT2 subtype was also present (28%). In pre- and postnatal rats, [125I]Sar1-angiotensin II binding to AT1 receptors was sensitive to GTP gamma S whereas binding to AT2 receptors was not. AT2 receptors may serve an important role during stages of rapid growth of the aorta, and also have a significant function in the adult vasculature.     

Nitric oxide synthase mRNA levels correlate with gene expression of angiotensin II type-1 but not type-2 receptors, renin or angiotensin converting enzyme in selected brain areas.

Recent data suggest that there is interaction between peripheral angiotensin II and nitric oxide. However, sparse information is available on the mutual interaction of these two compounds in the brain. The potential intercourse of nitric oxide with brain neuropeptides needs to be substantiated by assessing its local production and gene expression of the synthesizing enzymes involved. The aim of the present study was to evaluate whether the gene expression of brain nitric oxide synthase (bNOS) is related to the sites of gene expression of different components of the rat brain renin angiotensin system (renin, angiotensin converting enzyme (ACE) or angiotensin receptors of AT1 and AT2 subtypes). The levels of corresponding mRNAs were measured and correlated in nine structures of adult rat brain (hippocampus, amygdala, septum, thalamus, hypothalamus, cortex, pons, medulla and cerebellum). As was expected, positive correlation was observed between renin and angiotensin-converting enzyme mRNAs. Moreover, a significant correlation was found between brain NO synthase and AT1 receptor mRNAs, but not with mRNA of the AT2 receptor, ACE and renin. Parallel distribution of mRNAs coding for bNOS and AT1 receptors in several rat brain structures suggests a possible interaction between brain angiotensin 11 and nitric oxide, which remains to be definitely demonstrated by other approaches.     

Study of the fetal and maternal renin-angiotensin system and chorio-placental steroids in the guinea pig]

1.) Total renin, active renin, prorenin, angiotensin II, estradiol and progesterone were measured in maternal, placental and fetal blood and in trophoblastic and uterine tissues of the guinea pig. Furthermore, membrane angiotensin II receptors were measured in trophoblastic tissues. 2.) Blood and tissue concentrations of total renin, active renin, angiotensin II and steroids are shown to increase with gestational age. At the full term of pregnancy (70th post-coital day), tissue concentrations of total renin in chorion (23,900 +/- 2,752 ng/g of tissue/h), maternal placenta (14,210 +/- 1,131), fetal placenta (12,475 +/- 927) and uterus (7,677 +/- 798) are 100 time higher than those observed in placental, fetal and maternal blood. Distribution of blood and tissue prorenin (inactive renin) is similar to that found for total renin. Active renin/Total renin ratio reaches 1% in uterine, placental and chorion tissues and 9.3 +/- 1.0% in maternal, placental and fetal blood. 3.) Angiotensin II levels in systemic maternal blood (690 +/- 99 pg/ml) and in uterine blood (467 +/- 84) are higher than those found in placental blood (266 +/- 39) and in different trophoblastic tissues (between 200 and 400 pg/g). Angiotensin II receptor concentrations are highest in chorion. 4.) Regarding the steroid hormones, it is noted that placental and maternal blood contain more progesterone than trophoblastic tissues. The highest concentrations of estradiol are found in chorion tissue and uterine blood. 5.) A positive correlation is observed between angiotensin II and estradiol in uterine blood (r = 0.69, P less than 0.01) and in chorion (r = 0.71, P less than 0.01). These findings indicate that angiotensin II and estradiol could, by their interactions, play an important role in the physiology of pregnancy.     

Angiotensin II receptor type 1 (AT1) selective nonpeptidic antagonists--a perspective

Hypertension is a major risk factor for human morbidity and mortality through its effects on target organs like heart, brain and kidneys. More intensive treatment for the effective control of blood pressure significantly reduces the morbidity and mortality. The renin angiotensin system (RAS) is a coordinated hormonal cascade of major clinical importance in the regulation of blood pressure. The principal effector peptide of RAS is angiotensin II, which acts by binding to one of the two major angiotensin II receptors AT(1) and AT(2). Angiotensin II through AT(1) receptor mediates vast majority of biologically detrimental actions. Nonpeptidic angiotensin II (AT(1)) antagonists are the most specific means to block the renin angiotensin enzymatic cascade available presently. Majority of AT(1) antagonists are based on modifications of losartan structure, the first clinically used AT(1) antagonist. In this review, a comprehensive presentation of the literature on AT(1) receptor antagonists has been given.     

Endothelium and aortic contraction to endothelin-1 in the pregnant rat

Endothelium-derived factors modulate tone and may be involved in hyporeactivity to vasoconstrictors, such as norepinephrine or angiotensin II, as has been previously described during gestation. The endothelium produces endothelin-1, a major vasoconstrictor peptide, therefore aortic contractions to endothelin-1 (10(-10) to 3 x 10(-7) M) were used to assess the role of the endothelium in pregnant Wistar rats (at 20 days of gestation). Late pregnancy is characterized by a significantly diminished systolic blood pressure in conscious rats (-17 mmHg, P < 0.001, n = 14). In pregnant and in age-matched nonpregnant female rats, endothelin-1 induced aortic contraction was greater when endothelium was present (at least P < 0.01). Indomethacin significantly reduced this contraction in aortic rings with intact endothelium in all groups. In aortic rings that had endothelium physically removed, contraction to endothelin-1 was greater in pregnant rats than in nonpregnant ones. Indomethacin decreased contraction of aortic rings in pregnant rats only. These results suggest an enhanced synthesis of vasoconstrictors by cyclooxygenases in vascular smooth muscle during pregnancy. In vessels with intact endothelium, we did not find hyporeactivity to endothelin-1 during late pregnancy. Contraction to endothelin-1 involved ET(A) receptors because it was decreased by BQ-123, an ET(A) receptor antagonist, whereas there was no significant change when using BQ-788, an ET(B) receptor antagonist.     

Up-regulation of mesotocin receptors in the tammar wallaby myometrium is pregnancy-specific and independent of estrogen

The oxytocin-like peptide of most Australian marsupials is mesotocin, which stimulates uterine contractions and is important for normal birth in the tammar wallaby. Female marsupials have two uteri and, in monovular species such as the tammar, one uterus is gravid with a single fetus, whereas the contralateral uterus is nongravid. A significant increase in myometrial mesotocin receptor concentrations occurs only in the gravid uterus on Day 23 of the 26-day gestation. This study examined whether or not mesotocin receptors are present in the myometrium and are up-regulated at the equivalent stage of the luteal phase in unmated tammars. In contrast to the marked increase in mesotocin receptor mRNA and protein concentrations in the myometrium of the gravid uterus during pregnancy, receptors did not increase in the unmated animals. There were also no significant differences between the two uteri, except on Day 27. Plasma profiles of peripheral estradiol-17beta and progesterone did not differ significantly between pregnant and nonpregnant cycles. However, progesterone concentrations were significantly lower on Day 1 postpartum compared with Day 27 of the nonpregnant cycle. In pregnant tammars, the molar ratio of circulating estradiol-17beta to progesterone increased significantly between Day 25 of gestation and 1 day postpartum, but was not correlated with an increase in mesotocin receptor concentrations in either uterus. The data confirm that a local fetal influence is more important than systemic factors, such as estrogen, in the regulation of uterine mesotocin receptors in the tammar wallaby.     

Receptors for Arg8-vasopressin, angiotensin II, and atrial natriuretic peptide in the mesenteric vasculature of pregnant rats.

Blood pressure and sensitivity of blood vessels to vasoconstrictors are decreased in term-pregnant rats (20-21 days). To determine if changes in receptors for vasoactive peptides could account for these observations, receptor kinetics were measured for Arg8-vasopressin (AVP), angiotensin II (Ang II), and atrial natriuretic peptide (ANP) in the mesenteric vascular bed of the rat throughout pregnancy. Receptors for AVP were statistically similar in the five groups of animals (nonpregnant; pregnant 9, 15, and 21 days; and postpartum). The dissociation constant (KD) for [3H]AVP varied from 0.41 to 0.52 nmol/L (NS), while receptor density (Bmax) varied from 310 +/- 110 to 455 +/- 135 fmol/mg protein for six experimental measurements. Similar observations were made for Ang II receptors where KD of 125I-labelled Sar1, Ile8-Ang II was between 0.60 and 0.97 nmol/L and Bmax between 215 +/- 30 and 250 +/- 40 fmol/mg protein in the different groups. 125I-labelled ANP (101-126) receptors were markedly modified in terms of number of sites. Bmax was significantly increased during pregnancy (9 days, 429 +/- 86; 15 days, 541 +/- 54; 20 days, 438 +/- 72) and decreased in the postpartum period (133 +/- 21) by comparison with the nonpregnant group (245 +/- 35 fmol/mg protein), while KD was similar in the different experimental groups (57 to 82 pmol/L). Despite these increases in receptor density, the vasorelaxant effects of ANP was only increased at 9 days of pregnancy.(ABSTRACT TRUNCATED AT 250 WORDS)