Myogenic reactivity is reduced in small renal arteries isolated from relaxin-treated rats

Administration of the ovarian hormone relaxin to nonpregnant rats vasodilates the renal circulation comparable to pregnancy. This vasodilation is mediated by endothelin (ET), the ET(B) receptor, and nitric oxide. Furthermore, endogenous relaxin mediates the renal vasodilation and hyperfiltration that occur during gestation. The goal of this study was to investigate whether myogenic reactivity of small renal and mesenteric arteries is reduced in relaxin-treated rats comparable to the pregnant condition. Relaxin or vehicle was administered to virgin female Long-Evans rats for 5 days at 4 microg/h, thereby producing midgestational blood levels of the hormone. The myogenic responses of small renal arteries (200-300 microm in diameter) isolated from these animals were evaluated in an isobaric arteriograph system. Myogenic reactivity was significantly reduced in the small renal arteries from relaxin-treated compared with vehicle-treated rats. The reduced myogenic responses were mediated by the ET(B) receptor and nitric oxide since the selective ET(B) receptor antagonist RES-701-1 and the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester restored myogenic reactivity to virgin levels. The influence of relaxin was not limited to the renal circulation because myogenic reactivity was also reduced in small mesenteric arteries isolated from relaxin-treated rats. Thus relaxin administration to nonpregnant rats mimics pregnancy, insofar as myogenic reactivity of small renal and mesenteric arteries is reduced in both conditions.     

Impact of gender and endothelin on renal vasodilation and hyperfiltration induced by relaxin in conscious rats

Chronic administration of the hormone relaxin elicits renal vasodilation that is dependent on nitric oxide (NO) in both conscious intact and ovariectomized female rats. Our first objective was to test whether the hormone, when administered to approximate serum concentrations found in midterm pregnant rats, induces renal vasodilation in males. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) increased significantly, on average, by 33 and 49% over baseline, respectively, after 5 days of recombinant human relaxin (rhRLX) administration to 12 conscious male rats by subcutaneous osmotic minipump. There were also significant decreases in hematocrit, plasma osmolality, and sodium concentration. Another objective was to determine whether endogenous endothelin (ET; via the endothelial ET(B) receptor) mediates the NO-dependent renal vasodilation produced by relaxin. rhRLX or vehicle was administered to conscious female rats (n = 9 and 8 rats, respectively). On the fifth day, baseline GFR and ERPF were both increased, on average, by 20-30% in the rats administered rhRLX (P < 0.05 vs. vehicle). Next, the specific ET(B)-receptor antagonist RES-701-1 was infused intravenously over 4 h in both groups of rats. In response to RES-701-1, there was a significant decline in both GFR and ERPF in the rats receiving rhRLX such that renal function converged in the two groups of animals. We conclude 1) relaxin induces marked changes in the renal circulation and in osmoregulation regardless of gender and 2) relaxin-induced renal vasodilation and hyperfiltration are mediated by endothelin through the endothelial ET(B) receptor subtype and NO.     

Endothelin and nitric oxide mediate reduced myogenic reactivity of small renal arteries from pregnant rats

We tested the hypothesis that endothelin acting through the endothelial ET(B) receptor subtype and the nitric oxide (NO) pathway accounts for reduced myogenic reactivity of the renal resistance vasculature during pregnancy. Small renal arteries (100-200 microm) were isolated from virgin and midterm pregnant rats when gestational renal hyperfiltration and vasodilation are maximal in this species. Myogenic reactivity (the adjustment of arterial diameter in response to a change in transmural pressure) was assessed with a pressurized myograph system. A rapid increase in transmural pressure from 60 to 80 mmHg resulted in a 2.4% diameter increase in vessels from virgin compared with an 8.1% increase in arteries from midgestation rats (n = 8 each, P < 0.05). Thus myogenic reactivity is markedly reduced during pregnancy. Incubation with the NO synthase inhibitors, an ET(B) receptor subtype antagonist (RES-701-1), the nonselective ET(A/B) receptor blocker (SB-209670), or endothelial removal abrogated the reduced myogenic reactivity of vessels from gravid rats without affecting myogenic reactivity in arteries from virgin animals. Thus the endothelium mediates the reduced myogenic reactivity of small renal arteries of midgestation rats most likely through the ET(B) receptor subtype and NO pathway.     

Emerging role of relaxin in renal and cardiovascular function

Although traditionally associated with reproductive processes, relaxin is emerging as an important player in renal and cardiovascular function. Much of our recently acquired understanding of relaxin in this new context has arisen from studies of maternal renal and cardiovascular adaptations to pregnancy in rats where the hormone is turning out to be an important mediator. First, we highlight the influence of relaxin on renal hemodynamics and glomerular filtration rate, as well as on other peripheral circulations. Second, we discuss the effect of relaxin on both the steady and pulsatile systemic arterial load, as well as on the heart, in particular, coronary blood flow. Third, we consider the impact of the hormone on cultured endothelial and vascular smooth muscle cells. Fourth, we address the interaction of relaxin with renal and cardiac disease, as well as its role in angiogenesis. Finally, in Perspectives, we point out several key research questions in need of investigation that relate to a potential autocrine/paracrine role of relaxin in renal and cardiovascular tissues. Furthermore, on the basis of its potent vasodilatory and matrix-degrading attributes, we speculate about the therapeutic potential of relaxin in renal and cardiovascular diseases.     

Endothelium-dependent vascular relaxation induced by Globularia alypum extract is mediated by EDHF in perfused rat mesenteric arterial bed

The vasodilatory effect of Globularia alypum L. (GA) extract was evaluated in rat mesenteric arterial bed pre-contracted by continuous infusion of phenylephrine (2-4 ng/mL). Bolus injections of GA elicited dose-response vasodilation, which was abolished after endothelium removal. Addition of a nitric oxide synthase inhibitor, N(G)-nitro-l-arginine methyl ester (100 μmol/L), alone or in the presence of a cyclooxygenase inhibitor, indomethacin (10 μmol/L), did not significantly affect the vasodilation of the mesenteric arterial bed in response to GA extract. These results suggest that GA-induced vasodilation is endothelium dependent but nitric oxide and prostacyclin independent. In the presence of high K(+) (60 mmol/L), the GA vasodilatory effect was completely abolished, suggesting that the vasodilation effect is mediated by hyperpolarization of the vascular cells. Also, pre-treatment with atropine (a muscarinic receptors antagonist) antagonized the GA-induced vasodilation, suggesting that the vasodilatory effect is mainly mediated by the endothelium-derived hyperpolarizing factor through activation of endothelial muscarinic receptors.     

The secretory patterns of relaxin and human chorionic gonadotropin in human pregnancy

Relaxin and human chorionic gonadotropin (hCG) were simultaneously determined in the same serum samples obtained from pregnant women. Although the secretory pattern of relaxin, in general, appeared to parallel that of hCG during human pregnancy, several discrepancies were discerned in the secretory patterns of the two hormones. The mean hCG concentration significantly differed between weeks 4-7 and 8-11 of pregnancy, but the mean relaxin concentration did not. The mean relaxin concentration began to decrease at weeks 16-19 whereas that of hCG did so at weeks 12-15. The mean relaxin concentration at weeks 4-7 was significantly higher than that at weeks 24-27, though there was no significant difference between the mean hCG concentrations in the two periods. These differences in the secretory pattern of relaxin from that of hCG indicate that relaxin secretion in pregnancy is not determined only by the circulating level of hCG. The responsiveness of the corpus luteum of pregnancy to hCG stimulation of relaxin secretion may vary as a function of the age of the corpus luteum, and this may partially account for the differences between the secretory pattern of relaxin and that of hCG observed in the present study.     

Chronic Nicotine Exposure Abolishes Maternal Systemic and Renal Adaptations to Pregnancy in Rats

Pregnancy is characterized by maternal systemic and intrarenal vasodilation, leading to increases in the renal plasma flow (RPF) and glomerular filtration rate (GFR). These responses are mainly mediated by nitric oxide (NO) and relaxin. The impact of cigarette smoking on the maternal adaptations to pregnancy is unclear. Here we evaluated the effects of chronic exposure to nicotine on systemic and intrarenal parameters in virgin (V) and 14-day pregnant (P) Wistar rats. V and P groups received saline or nicotine (6 mg·kg^-1·day^-1) respectively, via osmotic minipumps for 28 days, starting 14 days before pregnancy induction. Nicotine induced a 10% increase in blood pressure in the V group and minimized the characteristic pregnancy-induced hypotension. Renal sympathetic nerve activity (rSNA) and baroreflex sensitivity were impaired by nicotine mainly in the P group, indicating that the effect of nicotine on blood pressure was not mediated by nervous system stimulation. Nicotine had no effect on GFR in the V rats but reduced GFR of the P group by 30%. Renal expression of sodium and water transporters was downregulated by nicotine, resulting in increased fractional sodium excretion mainly in the P group, suggesting that nicotine compromised the sodium and water retention required for normal gestation. There was a reduction in the expression of inducible NO synthase (iNOS) in both the kidney tissue and renal artery, as well as in the expression of the relaxin receptor (LGR7). These results clearly show that nicotine induced deleterious effects in both virgin and pregnant animals, and abolished the maternal capacity to adapt to pregnancy.     

Modulation of pulmonary endothelial endothelin B receptor expression and signaling: implications for experimental hepatopulmonary syndrome

The hepatopulmonary syndrome (HPS) results from intrapulmonary vasodilation in the setting of cirrhosis and portal hypertension. In experimental HPS, pulmonary endothelial endothelin B (ET(B)) receptor overexpression and increased circulating endothelin-1 (ET-1) contribute to vasodilation through enhanced endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) production. In both experimental cirrhosis and prehepatic portal hypertension, ET(B) receptor overexpression correlates with increased vascular shear stress, a known modulator of ET(B) receptor expression. We investigated the mechanisms of pulmonary endothelial ET(B) receptor-mediated eNOS activation by ET-1 in vitro and in vivo. The effect of shear stress on ET(B) receptor expression was assessed in rat pulmonary microvascular endothelial cells (RPMVECs). The consequences of ET(B) receptor overexpression on ET-1-dependent ET(B) receptor-mediated eNOS activation were evaluated in RPMVECs and in prehepatic portal hypertensive animals exposed to exogenous ET-1. Laminar shear stress increased ET(B) receptor expression in RPMVECs without altering mRNA stability. Both shear-mediated and targeted overexpression of the ET(B) receptor enhanced ET-1-mediated ET(B) receptor-dependent eNOS activation in RPMVECs through Ca(2+)-mediated signaling pathways and independent of Akt activation. In prehepatic portal hypertensive animals relative to control, ET-1 administration also activated eNOS independent of Akt activation and triggered HPS. These findings support that increased pulmonary microvascular endothelial ET(B) receptor expression modulates ET-1-mediated eNOS activation, independent of Akt, and contributes to the development of HPS.     

Aging attenuates the vasodilator response to relaxin

Relaxin, an insulin-like growth factor peptide, increases endothelium-dependent vasodilation and vascular compliance and decreases myogenic reactivity. These vascular effects significantly contribute to the physiological circulatory adaptations in pregnancy, particularly in the mesentery and kidney. Aging predisposes to vascular maladaptation and gestational hypertensive disease. We hypothesized that mild aging reduces the vascular responses to relaxin. In 20 young (10-12 wk) and 20 middle-aged (40-46 wk) female Wistar Hannover rats, vascular responses to chronic exposure of relaxin vs. placebo (5 days) were quantified in isolated mesenteric arteries and kidney. Vascular responses were evaluated using pressure-perfusion myograph, wire myograph, and an isolated perfused rat kidney model. Rxfp1 (relaxin family peptide) gene expression was determined by quantitative polymerase chain reaction. In young rats, relaxin stimulated nitric oxide (NO)-dependent flow-mediated vasodilation (2.67-fold, from 48 ± 9 to 18 ± 4 μl/min), reduced myogenic reactivity (from -1 ± 2 to 7 ± 3 μm/10 mmHg), and decreased mesenteric sensitivity to (28%, from 1.39 ± 0.08 to 1.78 ± 0.10 μM) but did not change compliance and renal perfusion flow (RPFF). In aged rats, relaxin did not affect any of the analyzed mesenteric or renal parameters. In aged compared with young placebo-treated rats, all mesenteric characteristics were comparable, while RPFF was lower (17%, from 6.9 ± 0.2 to 5.7 ± 0.1 ml·min?1·100 g?1) even though NO availability was comparable. Rxfp1 expression was not different among young and aged rats. Our findings suggest that moderate aging involves normal endothelial function but blunts the physiological endothelium-dependent and -independent vasodilator response to relaxin.     

Impaired vascular responses to relaxin in diet-induced overweight female rats

Relaxin mediates renal and mesenteric vascular adaptations to pregnancy by increasing endothelium-dependent vasodilation and compliance and decreasing myogenic reactivity. Diet-induced overweight and obesity are associated with impaired endothelial dysfunction and vascular remodeling leading to a reduction in arterial diameter. In this study, we tested the hypothesis that local vascular responses to relaxin are impaired in diet-induced overweight female rats on a high-fat cafeteria-style diet for 9 wk. Rats were chronically infused with either relaxin or placebo for 5 days, and vascular responses were measured in isolated mesenteric arteries and the perfused kidney. Diet-induced overweight significantly increased sensitivity to phenylephrine (by 17%) and vessel wall thickness, and reduced renal perfusion flow (RPFF; by 16%), but did not affect flow-mediated vasodilation, myogenic reactivity, and vascular compliance. In the normal weight rats, relaxin treatment significantly enhanced flow-mediated vasodilation (2.67-fold), decreased myogenic reactivity, and reduced sensitivity to phenylephrine (by 28%), but had no effect on compliance or RPFF. NO blockade by l-NAME diminished most relaxin-mediated effects. In diet-induced overweight rats, the vasodilator effects of relaxin were markedly reduced for flow-mediated vasodilation, sensitivity to phenylephrine, and myogenic response compared with the normal diet rats, mostly persistent under l-NAME. Our data demonstrate that some of the vasodilator responses to in vivo relaxin administration are impaired in isolated mesenteric arteries and the perfused kidney in diet-induced overweight female rats. This does not result from a decrease in Rxfp1 (relaxin family peptide receptor) expression but is likely to result from downstream disruption to endothelial-dependent mechanisms in diet-induced overweight animals.     

Relaxin depresses small bowel motility through a nitric oxide-mediated mechanism. Studies in mice

Gastrointestinal motility is reduced and the incidence of functional gastrointestinal disorders is increased in pregnancy, possibly due to hormonal influences. This study aims to clarify whether the hormone relaxin, which attains high circulating levels during pregnancy and has a nitric oxide-mediated relaxant action on vascular and uterine smooth muscle, also reduces bowel motility and, if it does, whether nitric oxide is involved. Female mice in proestrous or estrous were treated for 18 h with relaxin (1 microg s.c.) or vehicle (controls). Isolated ileal preparations from both groups were used to record contractile activity, either basal or after acute administration of relaxin (5 x 10(-8) M). Drugs inhibiting nitric oxide biosynthesis or neurotransmission were used in combination with relaxin. Expression of nitric oxide synthase isoforms by the ileum was assessed by immunocytochemistry and Western blot analysis. Relaxin caused a clear-cut decay of muscle tension and a reduction in amplitude of spontaneous contractions upon either chronic administration to mice or acute addition to isolated ileal preparations. These effects were significantly blunted by N(G)-nitro-L-arginine, but not by the neural blockers we used. Moreover, relaxin increased the expression of nitric oxide synthases II and III, but not synthase I. Relaxin markedly inhibits ileal motility in mice by exerting a direct action on smooth muscle through the activation of intrinsic nitric oxide biosynthesis.     

Serum relaxin in patients with invasive mole, choriocarcinoma and persistent trophoblastic disease

Human chorionic gonadotropin (hCG) is considered to be one of the factors which regulate relaxin secretion in humans. Serum immunoreactive relaxin levels are increased and are detectable by radioimmunoassay both in normal and molar pregnancy. Circulating hCG levels are increased in trophoblastic disease. In the present study, relaxin and hCG levels were sequentially measured in patients with invasive mole, choriocarcinoma and persistent trophoblastic disease. Serum relaxin levels were detectable by radioimmunoassay in these patients before treatment, though they were significantly lower than in normal pregnancy. The corpus luteum of pregnancy is the main source of circulating relaxin in normal pregnancy. The existence of a corpus luteum was confirmed in the 2 patients who underwent laparotomy. Consequently, the corpus luteum may also be the main source of circulating relaxin in trophoblastic disease. Parallel changes in hCG and relaxin levels were observed during the courses of trophoblastic disease. The finding suggests that relaxin secretion is dependent on hCG stimulation in trophoblastic disease in the presence of corpus luteum.     

Contribution of oxygen radicals to altered NO-dependent pulmonary vasodilation in acute and chronic hypoxia

Chronic hypoxia (CH) increases pulmonary arterial endothelial nitric oxide (NO) synthase (NOS) expression and augments endothelium-derived nitric oxide (EDNO)-dependent vasodilation, whereas vasodilatory responses to exogenous NO are attenuated in CH rat lungs. We hypothesized that reactive oxygen species (ROS) inhibit NO-dependent pulmonary vasodilation following CH. To test this hypothesis, we examined responses to the EDNO-dependent vasodilator endothelin-1 (ET-1) and the NO donor S-nitroso-N-acetyl penicillamine (SNAP) in isolated lungs from control and CH rats in the presence or absence of ROS scavengers under normoxic or hypoxic ventilation. NOS was inhibited in lungs used for SNAP experiments to eliminate influences of endogenously produced NO. Additionally, dichlorofluorescein (DCF) fluorescence was measured as an index of ROS levels in isolated pressurized small pulmonary arteries from each group. We found that acute hypoxia increased DCF fluorescence and attenuated vasodilatory responses to ET-1 in lungs from control rats. The addition of ROS scavengers augmented ET-1-induced vasodilation in lungs from both groups during hypoxic ventilation. In contrast, upon NOS inhibition, DCF fluorescence was elevated and SNAP-induced vasodilation diminished in arteries from CH rats during normoxia, whereas acute hypoxia decreased DCF fluorescence, which correlated with augmented reactivity to SNAP in both groups. ROS scavengers enhanced SNAP-induced vasodilation in normoxia-ventilated lungs from CH rats similar to effects of hypoxic ventilation. We conclude that inhibition of NOS during normoxia leads to greater ROS generation in lungs from both control and CH rats. Furthermore, NOS inhibition reveals an effect of acute hypoxia to diminish ROS levels and augment NO-mediated pulmonary vasodilation.     

Endothelin B receptor deficiency potentiates ET-1 and hypoxic pulmonary vasoconstriction

Endothelin (ET)-1 contributes to the regulation of pulmonary vascular tone by stimulation of the ET(A) and ET(B) receptors. Although activation of the ET(A) receptor causes vasoconstriction, stimulation of the ET(B) receptors can elicit either vasodilation or vasoconstriction. To examine the physiological role of the ET(B) receptor in the pulmonary circulation, we studied a genetic rat model of ET(B) receptor deficiency [transgenic(sl/sl)]. We hypothesized that deficiency of the ET(B) receptor would predispose the transgenic(sl/sl) rat lung circulation to enhanced pulmonary vasoconstriction. We found that the lungs of transgenic(sl/sl) rats are ET(B) deficient because they lack ET(B) mRNA in the pulmonary vasculature, have minimal ET(B) receptors as determined with an ET-1 radioligand binding assay, and lack ET-1-mediated pulmonary vasodilation. The transgenic(sl/sl) rats have higher basal pulmonary arterial pressure and vasopressor responses to brief hypoxia or ET-1 infusion. Plasma ET-1 levels are elevated and endothelial nitric oxide synthase protein content and nitric oxide production are diminished in the transgenic(sl/sl) rat lung. These findings suggest that the ET(B) receptor plays a major physiological role in modulating resting pulmonary vascular tone and reactivity to acute hypoxia. We speculate that impaired ET(B) receptor activity can contribute to the pathogenesis of pulmonary hypertension.     

Age impairs Flk-1 signaling and NO-mediated vasodilation in coronary arterioles

Impairment of flow-induced vasodilation in coronary resistance arterioles may contribute to the decline in coronary vasodilatory reserve that occurs with advancing age. This study investigated the effects of age on flow-induced signaling and activation of nitric oxide (NO)-mediated vasodilation in coronary resistance arterioles. Coronary arterioles were isolated from young (approximately 6 mo) and old (approximately 24 mo) male Fischer-344 rats to assess vasodilation to flow, vascular endothelial growth factor (VEGF), and ACh. Flow- and VEGF-induced vasodilation of coronary arterioles was impaired with age (P相似文献   

Vasodilator factors in the systemic and local adaptations to pregnancy

We postulate that an orchestrated network composed of various vasodilatory systems participates in the systemic and local hemodynamic adaptations in pregnancy. The temporal patterns of increase in the circulating and urinary levels of five vasodilator factors/systems, prostacyclin, nitric oxide, kallikrein, angiotensin-(1–7) and VEGF, in normal pregnant women and animals, as well as the changes observed in preeclamptic pregnancies support their functional role in maintaining normotension by opposing the vasoconstrictor systems. In addition, the expression of these vasodilators in the different trophoblastic subtypes in various species supports their role in the transformation of the uterine arteries. Moreover, their expression in the fetal endothelium and in the syncytiotrophoblast in humans, rats and guinea-pigs, favour their participation in maintaining the uteroplacental circulation. The findings that sustain the functional associations of the various vasodilators, and their participation by endocrine, paracrine and autocrine regulation of the systemic and local vasoactive changes of pregnancy are abundant and compelling. However, further elucidation of the role of the various players is hampered by methodological problems. Among these difficulties is the complexity of the interactions between the different factors, the likelihood that experimental alterations induced in one system may be compensated by the other players of the network, and the possibility that data obtained by manipulating single factors in vitro or in animal studies may be difficult to translate to the human. In addition, the impossibility of sampling the uteroplacental interface along normal pregnancy precludes obtaining longitudinal profiles of the various players. Nevertheless, the possibility of improving maternal blood pressure regulation, trophoblast invasion and uteroplacental flow by enhancing vasodilation (e.g. L-arginine, NO donors, VEGF transfection) deserves unravelling the intricate association of vasoactive factors and the systemic and local adaptations to pregnancy.     

Association between serum placental growth factor and vascular endothelial function in hyprtensive disorders complicating pregnancy

Hypertensive disorders complicating pregnancy (HDCP) is a systemic disease among pregnant women. Therefore, the prevention and prediction of hypertension during pregnancy are critical. This study aimed to clarify whether the vascular endothelial function of women with gestational hypertension was linked to placental growth factor. A total of 200 pregnant women were enrolled in our study and subsequently divided into two groups: the HDCP group and the normal pregnancy controls. The levels of serum placental growth factor, as well as plasma endothelin-1 and nitric oxide, between the two groups were measured. In addition, the endothelial function indexes, including pressure-strain elasticity coefficient (EP), the common carotid stiffness index (β), arterial compliance, single-point pulsed-wave velocity, and augment index (AI) of bilateral common carotid arteries, were compared between the HDCP and control groups using the echo tracking technique. In our study, the level of placental growth factor in the HDCP group was significantly lower than the control group. Furthermore, our results clarified that endothelin-1 increased while nitric oxide decreased in the HDCP group compared with the control group. On the other hand, we found that EP, β, pulsed-wave velocity and augment index values were significantly higher in the HDCP group than in the control group (P < 0.001). However, the value of arterial compliance was significantly decreased in patients of the HDCP group compared with the control group (P < 0.001). In conclusion, the association between serum placental growth factor and vascular endothelial function in HDCP could serve as a more accurate predictive factor of pregnant hypertension.     

Pregnancy and steroid hormones enhance the systemic and regional hemodynamic effects of calcitonin gene-related peptide in rats

Calcitonin gene-related peptide (CGRP) is a potent vasodilator neuropeptide known to be involved in the regulation of vascular resistance. Several lines of evidence suggest that CGRP plays a role in the vascular adaptations that occur during normal pregnancy; however, the effects of exogenous CGRP on systemic and regional hemodynamics during pregnancy remain unknown. Therefore, the purpose of this study was to determine the hemodynamic effects of systemically administered CGRP in adult pregnant (Day 19) and ovariectomized (ovx) rats using the radioactive microsphere technique. In addition, we also used ovariectomized rats treated for 3 days with estradiol (E2), progesterone (P4), E2 + P4 in sesame oil, or oil only to assess if these hormones regulate the CGRP-induced hemodynamic changes. On the day of study, catheters were inserted into the left cardiac ventricle (through the right carotid artery), right jugular vein, and caudal tail artery. Hemodynamic studies using radioactive microspheres were then performed in conscious rats 3 h after recovery from anesthesia. Blood pressure and heart rate were continuously monitored, and left ventricular pressure was determined immediately prior to each microsphere injection. Microspheres labeled with either (141)Ce or (85)Sr were injected prior to and 2 min following the i.v. bolus injection of CGRP (270 pmol/kg body weight [BW]). Mean arterial pressure (MAP) and total vascular resistance in pregnant rats was lower than in ovx rats, and this was further decreased with an i.v. bolus injection of 270 pmol CGRP/kg BW. Cardiac output was elevated with further increases upon CGRP administration in pregnant but not in ovx rats. The CGRP-induced changes in MAP, total vascular resistance, and cardiac output in E2 + P4 -treated rats were similar to that observed in Day 19 pregnant rats, indicating that CGRP effects on these parameters during pregnancy may be modulated by steroid hormones. Both pregnancy and E2 + P4 treatment in ovx rats caused significant decreases in CGRP-induced resistance in mesenteric, coronary, and renal vasculature. Thus, the vasodilatory sensitivity to CGRP during pregnancy may be mediated through decreased total vascular resistance, particularly to coronary, mesenteric, and renal vascular beds. Thus, CGRP-induced vasodilatory effects may play a role in mediating vascular adaptations that occur during pregnancy and that steroid hormones may modulate these CGRP effects.     

Dose-dependent effects of nitric oxide synthase inhibition on systemic and renal hemodynamics in conscious lambs.

The present experiments were carried out to determine the role of nitric oxide in influencing systemic and renal hemodynamics in conscious young sheep. Parameters of cardiovascular function were measured before and for 4 h after intravenous injection of either L-NAME (NG-nitro-L-arginine methyl ester) or D-NAME (N(G)-nitro-D-arginine methyl ester) at doses of 10, 20, or 40 mg/kg in 13 conscious, chronically instrumented young sheep aged 43 +/-5 days. Blood pressure increased and heart rate decreased in a dose-dependent manner following administration of L-NAME. Renal vascular resistance was increased for 10 min following a dose of 10 mg/kg of L-NAME and for 120 min following a dose of 40 mg/kg of L-NAME. The renal vasodilatory response to close arterial injection of 1 microg/kg of acetylcholine was attenuated by L-NAME in a dose-dependent manner. These experiments provide the first information that under normal physiological conditions in conscious young animals, nitric oxide influences systemic and renal hemodynamics.     

Pentoxifylline attenuation of experimental hepatopulmonary syndrome.

Hepatopulmonary syndrome (HPS) following rat common bile duct ligation results from pulmonary molecular changes that may be influenced by circulating TNF-alpha and increased vascular shear stress, through activation of NF-kappaB or Akt. Increased pulmonary microvascular endothelin B (ET(B)) receptor and endothelial nitric oxide synthase (eNOS) levels contribute to nitric oxide production and the development of experimental HPS. Pentoxifylline (PTX), a phosphodiesterase and nonspecific TNF-alpha inhibitor, ameliorates experimental HPS when begun before hepatic injury. However, how PTX influences the molecular events associated with initiation of experimental HPS after liver injury is established is unknown. We assessed the effects of PTX on the molecular and physiological features of HPS in vivo and on shear stress or TNF-alpha-mediated events in rat pulmonary microvascular endothelial cells in vitro. PTX significantly improved HPS without altering portal or systemic hemodynamics and downregulated pulmonary ET(B) receptor levels and eNOS expression and activation. These changes were associated with a reduction in circulating TNF levels and NF-kappaB activation and complete inhibition of Akt activation. In rat pulmonary microvascular endothelial cells, PTX inhibited shear stress-induced ET(B) receptor and eNOS expression and eNOS activation. These effects were also associated with inhibition of Akt activation and were reproduced by wortmanin. In contrast, TNF-alpha had no effects on endothelial ET(B) and eNOS alterations in vitro. PTX has direct effects in the pulmonary microvasculature, likely mediated through Akt inhibition, that ameliorate experimental HPS.