Endothelin and angiotensin mediate most glomerular responses to nitric oxide inhibition.
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BACKGROUND: Endothelin (ET) and angiotensin mediate glomerular responses to systemic nitric oxide (NO) inhibition. Acute systemic NO synthase (NOS) inhibition in the rat causes marked increases in both preglomerular (RA) and efferent arteriolar (RE) resistances and a fall in the glomerular capillary ultrafiltration coefficient (Kf). In contrast, local intrarenal NOS inhibition increases RA, but has no effect on RE while producing a similar Kf lowering effect as seen with systemic NOS inhibition. These studies were designed to assess whether the increase in RE during systemic NOS inhibition is mediated by endogenous ET and whether angiotensin II (Ang II) also contributes. METHODS: Micropuncture measurements were made before and during acute systemic NOS inhibition with N-monomethyl L-arginine (NMA) alone, NMA + the nonpeptide ETA and ETB receptor antagonist, bosentan, NMA + the Ang II type 1 receptor blocker, losartan, and NMA during combined bosentan and losartan. RESULTS: The falls in single nephron glomerular filtration rate (SNGFR) and glomerular plasma flow seen with systemic NOS inhibition were prevented by concomitant administration of bosentan and losartan alone and in combination. The increases in systemic blood pressure (BP), glomerular BP (PGC), RA, and RE and the reduction in Kf seen with systemic NOS inhibition were attenuated by either bosentan or losartan. An attenuation in the elevation in total renal vascular resistance seen with systemic NOS inhibition was also observed with bosentan. Combined ET and Ang II type 1 blockade completely prevented the increase in systemic BP, PGC, and RE and the fall in Kf with systemic NOS inhibition, leaving only a very attenuated rise in RA. CONCLUSIONS: These findings suggest that endogenous ET and Ang II partially mediate the glomerular hemodynamic responses (including the increased RE) to acute systemic NOS inhibition. The actions of ET and Ang II are mainly additive, and almost all of the vasoconstrictor responses to acute NOS inhibition are prevented when both vasoconstrictor systems are blocked. (+info)
Resveratrol inhibits MAPK activity and nuclear translocation in coronary artery smooth muscle: reversal of endothelin-1 stimulatory effects.
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In porcine coronary arteries, short-term treatment with resveratrol (RSVL) substantially inhibited MAPK activity (IC50 = 37 microM); and immunoblot analyses revealed consistent reduction in the phosphorylation of ERK-1/-2, JNK-1 and p38, at active sites. Endothelin-1 (ET-1), a primary antecedent in coronary heart diseases, enhanced MAPK activity, phosphorylation and nuclear translocation in a concentration-responsive but RSVL-sensitive manner. RSVL had no effect on basal or forskolin-stimulated cAMP levels, a known downregulator of the MAPK cascade. Likewise, inhibition of MAPK by RSVL was not reversed by the estrogen receptor blockers tamoxifen and ICI-182,780. Conversely, RSVL remarkably attenuated basal and ET-1-evoked protein tyrosine phosphorylation. Because MAPKs promote smooth muscle proliferation and contraction, their current inhibition may contribute to the putative protection by RSVL against coronary heart diseases. These effects apparently do not involve interaction with estrogen receptors. (+info)
Endothelin concentrations in monochorionic twins with severe twin-twin transfusion syndrome.
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The objective of this study was to determine endothelin (ET-1) concentrations in monochorionic twin fetuses with and without twin-twin transfusion syndrome (TTTS). Fourteen monochorionic twin pregnancies complicated by TTTS and six without TTTS were studied. Matched maternal and fetal blood samples were obtained both in utero and at birth. Amniotic fluid samples were also collected from twin pairs. ET-1 concentrations were measured by radio-immunoassay. ET-1 concentrations in recipient fetuses were higher than in the donors both in utero(P < 0.001) and at birth (P < 0.01). Fetal concentrations of ET-1 in donors were similar to non-TTTS twins. Plasma ET-1 concentrations were significantly higher (P < 0.01) in recipient fetuses with severe hydrops than those with mild/no hydrops. Maternal concentrations of ET-1 were comparable in the two groups. Endothelin concentrations in recipient twins were 2(1/2) times higher than in their co-twins and this was related to the severity of hydrops. (+info)
Effects of endothelin-1 on airway and parenchymal mechanics in guinea-pigs.
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The contributions of the airways and the parenchyma to the overall lung mechanical response to endothelin-1 (ET-1) have not been systematically studied. In this investigation, the ET-1 induced changes on lung mechanics in guinea-pigs were separated into airway and parenchymal components. Pulmonary impedance (ZL) data were collected between 0.5 and 21 Hz in six anaesthetized, paralysed, open-chest animals by introducing small-amplitude pseudorandom oscillations into the trachea through a wave tube. ZL was calculated before and following intravenous boluses of ET-1, with doses doubled from 0.125-2 microg x kg of body weight(-1). A model containing an airway resistance (Raw) and inertance (Iaw) and tissue damping (G) and elastance (H) was fitted to the ZL spectra in each condition. Parenchymal hysteresis (eta) was calculated as G/H. After each dose, ET-1 induced significant increases in Raw (at peak response mean+/-SEM: 424+/-129%), G (400+/-80%), H (95+/-22%) and eta (156+/-33%), whereas Iaw decreased following the two highest doses (-291+/-77%). These data suggest that the parenchymal constriction was accompanied by inhomogeneous constriction of the peripheral airways. (+info)
Mechanism of endothelin-1-(1-31)-induced calcium signaling in human coronary artery smooth muscle cells.
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We have found that human chymase produces a 31-amino acid endothelin [ET-1-(1-31)] from the 38-amino acid precursor (Big ET-1). We examined the mechanism of synthetic ET-1-(1-31)-induced intracellular Ca2+ signaling in cultured human coronary artery smooth muscle cells. ET-1-(1-31) increased the intracellular free Ca2+ concentration ([Ca2+]i) in a concentration-dependent manner (10(-14)-10(-10) M). This ET-1-(1-31)-induced [Ca2+]i increase was not affected by phosphoramidon, Bowman-Birk inhibitor, and thiorphan. The ET-1-(1-31)-induced [Ca2+]i increase was not influenced by removal of extracellular Ca2+ but was inhibited by thapsigargin. ET-1-(1-31) at 10(-12) M did not cause Ca2+ influx, whereas 10(-7) M ET-1-(1-31) evoked marked Ca2+ influx, which was inhibited by nifedipine. ET-1-(1-31) also increased inositol trisphosphate formation. These results suggest that the ET-1-(1-31)-induced [Ca2+]i increase at relatively low concentrations is attributable to the release of Ca2+ from inositol trisphosphate-sensitive intracellular stores, whereas Ca2+ influx into the cells evoked by high concentration of ET-1-(1-31) probably occurs through voltage-dependent Ca2+ channels. We concluded that the physiological activity of ET-1-(1-31) may be attributable to Ca2+ mobilization from intracellular stores rather than influx of Ca2+ from extracellular space. (+info)
Effects of sustained low-flow perfusion on the response to vasoconstrictor agents in postnatal intestine.
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This laboratory has previously reported that sustained reduction of blood flow in newborn intestine causes a triphasic increase in vascular resistance that occurs over 3-4 h and that these changes are mediated, in part, by loss of endothelial nitric oxide (NO) production. This study examines the effects of exposure to sustained low-flow perfusion on the subsequent response to three contractile agonists: ANG II, norepinephrine (NE), and endothelin-1 (ET-1). Gut loops from 3- and 35-day-old swine were exposed to low-flow conditions in vivo (i.e., reduction of flow to approximately 50% of baseline) for 30 min or 5 h. Thereafter, they were removed to an extracorporeal perfusion circuit for in vitro hemodynamic assessment; alternatively, the mesenteric artery perfusing the gut loop was removed and cut into rings for assessment of isometric tension development. Gut loops from 3-day-old subjects exposed to low-flow conditions demonstrated significantly increased contractile responses to ANG II, NE, and ET-1; also, mesenteric artery rings from these gut loops demonstrated a significant reduction of the ED50 for all three agonists. Similar changes were not observed in intestine or mesenteric artery rings from older subjects. Sustained blockade of endogenous NO synthesis with NG-monomethyl- L-arginine duplicated the effects of exposure to sustained low-flow perfusion. It appears that sustained reduction of blood flow in newborn intestine decreases constitutive NO production, which in turn causes a generalized enhancement of the contractile efficacy of ANG II, NE, and ET-1. (+info)
Characterization of natriuretic peptide production by adult heart atria.
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The cardiac polypeptide hormones atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) are synthesized and costored by atrial cardiocytes and share receptors and many biologic properties. Although some aspects of their synthesis and release are specific for each peptide, it is not clear whether they share intracellular sorting and secretory mechanisms. In the present work we take advantage of a stable isolated rat atrial preparation that allows, for the first time, long-term study of synthesis, trafficking, targeting, and secretion of ANF and BNP by adult atrial muscle. Three model stimuli of secretion were used: increased intra-atrial pressure, endothelin-1 (ET-1), and phenylephrine (PE), representing mechanical, hormonal, and alpha1-adrenergic stimuli, respectively. To gain further insight into the secretory process under basal and agonist-induced secretion, we employed agents known to inhibit protein synthesis (cycloheximide) or to interfere with the vectorial transport of protein targeted for secretion (brefeldin A and monensin). All these agents induced significant changes in ANF and BNP release. Cycloheximide decreased natriuretic peptide secretion under basal and stimulated conditions. Brefeldin A dramatically increased basal as well as stimulated secretion of ANF and BNP. Monensin partially decreased basal ANF and BNP secretion and completely blocked stimulated secretion. None of these agents modified proteolytic processing as assessed by reverse-phase HPLC analysis. Double-label pulse-chase experiments using [3H]- and [14C]leucine demonstrated that the secretory response to ET-1, in contrast to the response to muscle stretch, is based on peptide other than newly synthesized or relatively newly stored ANF. It is concluded that, in adult atrial cardiocytes, ANF and BNP are sorted to constitutive and regulated pathways in a manner that is substantially unique for atrial cardiocytes. In particular, it appears that basal and stimulated ANF and BNP secretion may have a large "constitutive-like" component, as previously defined in other endocrine systems. This type of secretion is based on the preferential release of hormone through vesicles arising from immature secretory granules. The capacity of the atria to release ANF and BNP in response to stimuli, therefore, may depend more on stimulation of the rate of formation of immature granules than on the amount of stored hormone. (+info)
Plasma endothelin-1 level in chronic obstructive pulmonary disease: relationship with natriuretic peptide.
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BACKGROUND AND OBJECTIVE: Endothelin-1 (ET-1) is a potent vasoconstrictor peptide produced by the vascular endothelium. The purpose of this study was to elucidate the pathophysiological role of ET-1 in patients with pulmonary hypertension secondary to chronic obstructive pulmonary disease (COPD). METHOD: We measured plasma ET-1 levels during right heart catheterization both at rest and during exercise on room air and while breathing oxygen in patients with COPD. In addition, we simultaneously measured plasma levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). RESULTS: Plasma ET-1 levels at rest were significantly higher in 21 patients with COPD than in 16 control subjects (p < 0.001). For COPD patients, there was no correlation between the plasma ET-1 level and pulmonary arterial pressure or pulmonary vascular resistance at rest. On the other hand, there was a significant negative correlation between plasma ET-1 level and mixed venous oxygen tension (r = -0. 503, p < 0.05). Also, the plasma ET-1 level was positively correlated with those of ANP (r = 0.540, p < 0.05) and BNP (r = 0. 533, p < 0.05) at baseline. Oxygen administration significantly decreased plasma ET-1 levels at rest (p < 0.05). Plasma ET-1 levels did not change significantly with exercise despite the progression of pulmonary hypertension and hypoxemia. In contrast, plasma ANP and BNP levels both increased markedly with exercise (p < 0.01). CONCLUSION: We conclude that in patients with COPD, the plasma ET-1 level is not affected by acute progression of pulmonary hypertension and hypoxemia during exercise, and persistent hypoxemia may be associated with an increase in the plasma ET-1 level. In addition, our findings suggest that ANP and BNP may modulate the pulmonary vascular tone by interacting with ET-1 in these patients. (+info)