Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although it is clear that vascular endothelial cells synthesize and release endothelin (ET), the contribution of this vasconstrictor peptide to the regulation of vascular tone appears limited in normal conditions. One possibility to explain this moderate effect is that continuous production of nitric oxide (NO) may permanently inhibit the release and the vasoconstrictor effects of ET. In these conditions, inhibition of NO synthesis might unmask a vasopressor response to ET. Thus, we tested whether bosentan (3 mg/kg i.v.), a non-peptide antagonist of ETA and ETB receptors, or BQ-123 (3 mg/kg), an antagonist of ETA receptors, affected the hypertensive response induced by the NO synthase inhibitors NG-nitro-L-arginine methyl ester (L-NAME 3 mg/kg) or NG-nitro L-arginine (3 mg/kg) in anesthetized, normotensive rats. Bosentan or BQ-123 did not affect blood pressure. L-NAME significantly increased mean arterial pressure (% increase from baseline: 25 +/- 5%), and this was reduced by bosentan (13 +/- 3%; p < 0.05) or by BQ-123 (14 +/- 5%; p < 0.01). In contrast, bosentan did not affect the pressor response to phenylephrine. The response to L-NAME (3 mg/kg) was also reduced by bosentan in ganglion-blocked (chlorisondamine: 2.5 mg/kg; controls 89 +/- 10; bosentan: 45 +/- 7%) or pithed rats (controls: 165 +/- 9; bosentan 85 +/- 12%; p < 0.01). Bosentan also inhibited the pressor response to NG-nitro L-arginine (3 mg/kg-1) in normal (controls 24 +/- 5, bosentan 10 +/- 3%; p < 0.01) or ganglion-blocked rats (controls 86 +/- 13; bosentan 25 +/- 8; p < 0.01). Finally, L-NAME induced a modest increase in plasma levels of ET-1 (controls: 26.8 +/- 4.1; L-NAME: 38.5 +/- 3.3 pg/ml; p < 0.05). Thus, acute inhibition of NO synthesis unmasks a tonic vasopressor influence of ET.
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PMID:[Demonstration of a vasopressor role of endogenous endothelin after inhibition of nitric oxide synthesis in rats]. 857 76

Acute nitric oxide blockade not only potentiates the vasoconstrictor actions of endothelin but also enhances the synthesis and release of endothelin. To investigate whether the vasoconstrictor actions of acute nitric oxide blockade are modulated by endothelin, studies were conducted in the conscious, chronically catheterized rat. Renal function was measured before and during acute nitric oxide blockade with nitro-L-arginine methylester (L-NAME), L-NAME + endothelin blockade with the endothelin-converting enzyme inhibitor phosphoramidon, or L-NAME + the nonpeptide ETA and ETB receptor antagonist Bosentan. The increases in blood pressure and RVR seen with acute nitric oxide blockade were attenuated by either method of concomitant endothelin blockade. The falls in RPF and GFR were not blunted because endothelin blockade produced parallel reductions of both pressor and renal vasoconstrictor responses to acute nitric oxide blockade. Endothelin blockade alone with either endothelin-converting enzyme inhibitor or the nonpeptide ETA and ETB receptor antagonist had little effect on blood pressure, RPF, or RVR, but increases in urinary sodium excretion and a small decline in GFR were observed with Bosentan. These observations indicate that endogenous endothelin exerts a tonic antinatriuretic action in the normal conscious rat and partially mediates the pressor actions of acute nitric oxide blockade.
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PMID:Endothelin modulates the pressor actions of acute systemic nitric oxide blockade. 858 26

1. The effect of endothelin antagonists on endothelium-dependent contractions was studied in conditions of stimulated endothelium-derived contracting factor (EDCF) release and with exogenous activation of thromboxane A2-endoperoxide receptors in the rat aorta. 2. The incubation of aortic rings with N omega-nitro-L-arginine methyl ester (L-NAME) led to EDCF-mediated contraction upon stimulation with acetylcholine (24 +/- 3% of KCl contraction). When vessels were preincubated with bosentan, an endothelinA- and endothelinB-receptor antagonist, in addition to L-NAME, acetylcholine-induced contraction was reduced to 8 +/- 2% (P < 0.01) of KCl contractions. PD147953, a selective endothelinA-receptor antagonist, reduced the contraction to 14 +/- 4% (P < 0.05) of KCl contractions. 3. Bosentan preincubation produced a significant parallel rightward shift of the contractions to U46619, a selective thromboxane A2 receptor agonist. In contrast, PD147953 failed to exhibit any inhibitory effect on U46619 contractions. 4. These results suggest that endothelin antagonists inhibit EDCF-mediated contractions by blocking endothelinA receptors and that, in addition, bosentan antagonizes the direct stimulation of thromboxane A2 receptors.
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PMID:Effect of endothelin antagonists on the responses to prostanoid endothelium-derived contracting factor. 883 68

Hypoxic pulmonary vasoconstriction (HPV) is an important mechanism for maintaining oxygenation, which may be altered by endotoxin. We determined that acute endotoxemia alters the HPV response secondary to changes in endothelium-derived vasoactive products. Rats were treated with Salmonella typhimurium lipopolysaccharide (LPS; 15 mg/kg i.p.) either 1 to 6 h before lung isolation and compared with control rats (no LPS). Additional 6-h LPS-treated and control rats were pretreated with either indomethacin (15 mg/kg i.p.), a cyclooxygenase inhibitor, or bosentan (10 mg/kg po), a nonselective endothelin-receptor antagonist. The rats lungs were isolated and challenged with 3% O2 for 10 min to elicit HPV responses before and after nitric oxide (NO) synthase inhibition with N omega-nitro-L-arginine methyl ester (L-NAME; 100 microM). LPS (6 h) significantly increased the peak HPV responses by 108%. L-NAME had no significant effect in LPS-treated lungs but increased the peak HPV response in control lungs to levels equal to LPS-treated lungs. Bosentan increased the peak HPV response in all lungs, and indomethacin increased the peak HPV in LPS-treated lungs. The HPV response was sustained in control lungs at 10 min and in additional 20-min studies. In contrast, in LPS-treated lungs the HPV response faded after 10 min to levels equal to control, and in 20-min studies it faded by 82% to levels significantly less than in control lungs. The 10-min fade in LPS-treated lungs was attenuated by indomethacin (51%) and bosentan (80%) but not by L-NAME. In conclusion, acute endotoxemia with LPS increased the peak HPV response, but this effect was not sustained and by 20 min was nearly abolished. Inhibition of endogenous NO by LPS may explain the increased peak HPV response, but NO is not involved in the fade. The fade is at least partially due to increased vasodilating cyclooxygenase products and endothelins.
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PMID:Endotoxin alters hypoxic pulmonary vasoconstriction in isolated rat lungs. 888 69

To test whether endothelins are involved in the regulation of portal resistance after endotoxin pretreatment and whether their effects are modulated by nitric oxide (NO), rats received intraperitoneal injections of Escherichia coli lipopolysaccharide (LPS, 1 mg/kg body wt) or saline. Six and twenty-four hours later, livers were isolated and perfused. Analyses of portal pressure-flow (P-Q) relationships and epifluorescence microscopy were performed before and after administration of 1) the NO synthesis inhibitor N omega-nitro-L-arginine methyl ester (L-NAME, 10(-3) M), followed by L-arginine (2 x 10(-3) M), or 2) the endothelin ETA/ETB-receptor antagonist bosentan (2 x 10(-4) M), followed by L-NAME (10(-3) M). LPS pretreatment increased all measures of resistance, which included total portal resistance, zero flow, incremental resistance (slopes of P-Q relationship), and sinusoid resistance. L-NAME had no effect in sham controls but increased all measures of resistance at 6 h after LPS and increased total and incremental resistance 24 h after LPS. L-Arginine reversed these changes. Bosentan reduced total and sinusoid resistance slightly in control livers and caused substantial reductions in all measures of resistance at 6 and 24 h after LPS; these were partially reversed after L-NAME at 6 but not at 24 h. Our data support the hypothesis that a critical balance between endothelin-mediated vasoconstrictor influences and NO-mediated vasodilator influences controls portal resistance after endotoxin pretreatment.
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PMID:A time-dependent balance between endothelins and nitric oxide regulating portal resistance after endotoxin. 894 14

Because nitric oxide inhibits the synthesis and vasoconstrictor effect of endothelin-1, the effect of endothelin-1 may be enhanced under conditions of chronic inhibition of nitric oxide synthesis. We studied the effect of chronic therapy with bosentan, a combined endothelin-A/endothelin-B receptor antagonist, on blood pressure and vascular function and structure of small arteries as well as on the reactivity of the aorta in N(omega)-nitro-L-arginine methyl ester (L-NAME)-induced hypertension. Six-week-old Wistar-Kyoto rats were randomly treated for 6 weeks with placebo (control), L-NAME (70 mg/kg per day), or L-NAME plus bosentan (100 mg/kg per day). The treatments were stopped 2 to 3 days before the in vitro experiments so that only the long-term effects of the drugs could be observed. L-NAME increased systolic blood pressure: bosentan did not prevent this effect although the initial blood pressure rise was delayed (P=NS versus L-NAME group). Bosentan administration did not modify the structural alteration of the resistance vessels induced by L-NAME, nor did it improve endothelium-dependent relaxation of resistance vessels or the aorta. However, bosentan therapy markedly increased endothelium-dependent contraction to acetylcholine, which was slightly enhanced by L-NAME. In contrast, bosentan inhibited aortic endothelium-dependent contractions when applied acutely in vitro. This observation, together with the increased maximal vasoconstriction to the thromboxane A2 receptor agonist U46619 after 2 weeks of bosentan administration, suggests that bosentan also interacts with the receptors mediating endothelium-dependent contractions. In conclusion, our experiments suggest a minor role of endothelin in chronic L-NAME-induced hypertension as well as in the concomitant alterations of vascular structure.
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PMID:Blood pressure and vascular effects of endothelin blockade in chronic nitric oxide-deficient hypertension. 905 93

Nitric oxide (NO) has been shown to down regulate its own synthesis in vitro. We tested the hypothesis that NO inhalation (30 ppm under normoxic conditions) could decrease the release of endogenous endothelial NO, and thus alter pulmonary vasoreactivity. Pulmonary vasoreactivity was assessed in isolated perfused rat lungs immediately or 6 h after a 48 h NO inhalation period, and compared with a control group. NO inhalation resulted in an increase in pulmonary vasoconstrictor reactivity to angiotensine II and U-46619, a reduction in the potentiation by the eNOS inhibitor L-NAME of the angiotensine II response, a decrease in endothelium-dependent vasodilation to arginine vasopressin, whereas non-endothelium-dependent vasodilation to sodium nitroprusside remained unaltered. These alterations returned to control values in the group studied 6 h after the end of NO inhalation, and were not prevented by inhibition of the prostanoid synthesis, or by pretreatment with the endothelin receptors antagonist Bosentan. These results indicate that NO inhalation over 2 d induces a reversible alteration of pulmonary vasoreactivity in relationship with a decrease in endogenous NO release. Inhibition of eNOS could be involved.
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PMID:Effect of 48 hours of nitric oxide inhalation on pulmonary vasoreactivity in rats. 927 26

Nitric oxide (NO) impairs endothelin (ET) formation and/or action in isolated vessels. We hypothesized that ET may magnify the consequences of NO formation blockade on receptor-operated dilation of resistance coronary vessels in conscious dogs. In conscious instrumented dogs, graded intracoronary (IC) doses of acetylcholine (ACh) were delivered before IC administration of Nomega-nitro-L-arginine methyl ester (L-NAME), after L-NAME, and after L-NAME plus IC bosentan, an ETA/ETB receptor blocker. Before L-NAME, ACh (100 ng. kg-1. min-1) increased coronary blood flow (CBF) by 43+/-4% from 47+/-6 mL. min-1. After L-NAME, ACh failed to increase CBF (-3+/-2% from 50+/-7 mL. min-1). CBF responses to ACh were partially restored (+10+/-2% from 50+/-7 mL. min-1, P<0.01) after the addition of bosentan. Bosentan alone (without L-NAME) did not alter CBF responses to ACh. Blockade of ETA (Ro 61-1790) but not ETB (Ro 46-8443) receptors partially restored CBF responses to ACh after L-NAME. Myocardial immunoreactive ET levels in the perfusion territories of the circumflex and left anterior descending coronary arteries did not differ. ETA-dependent tone magnified the inhibitory effects of blockade of NO formation on receptor-operated dilation to ACh in resistance coronary vessels. Presumably, stimulated NO release has an inhibitory action on endogenous ET production and/or action at the level of resistance coronary vessels.
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PMID:Endothelin-dependent tone limits acetylcholine-induced dilation of resistance coronary vessels after blockade of NO formation in conscious dogs. 982 42

The endothelins (ET) are potent 21-amino-acid vasoconstrictor peptides produced in many different tissues, particularly in the endothelium of blood vessels. ET-1 is the main endothelin secreted by the endothelium, and acts in a paracrine or autocrine fashion on blood vessels by interacting with ETA or ETB receptors on smooth muscle to stimulate contraction or on ETB receptors on endothelial cells to induce the release of vasorelaxants (nitric oxide and prostacyclin). Production of ET-1 is enhanced in several experimental models of hypertension in the rat, such as sodium-sensitive forms, e.g. deoxycorticosterone acetate (DOCA)-salt hypertensive, DOCA-salt-treated spontaneously hypertensive rats (SHR) and Dahl salt-sensitive rats, as well as other models such as stroke-prone SHR, angiotensin II-infused rats and fructose-fed rats, and possibly 1-K 1C Goldblatt hypertensive rats. In contrast, SHR, 2-K 1C Goldblatt hypertensive rats and nitric oxide-deficient (L-NAME-treated) hypertensive rats do not exhibit an ET-1 component. Endothelin dependency is manifested by excessive vascular growth, particularly in small arteries, and blood pressure lowering and regression of vascular growth after treatment with endothelin antagonists. The latter may be combined ETA/ETB or selective ETA antagonists, of which several are orally active and already in clinical development. In humans, endothelin-dependent vascular tone has been shown in studies of forearm blood flow. Enhanced expression of ET-1 mRNA has been demonstrated in the endothelium of small arteries of patients with moderate to severe hypertension. In a 4-week trial the combined ETA/ETB antagonist bosentan reduced the blood pressure of essential hypertensive patients equally to enalapril. Bosentan improved hemodynamics in patients with heart failure in acute and 2-week-long studies. Endothelin antagonists also offer promise in a rapidly fatal condition, primary pulmonary hypertension. Thus, the endothelin system appears to be involved in different forms of cardiovascular disease in experimental animals and humans, and its interruption offers great promise as a new therapeutic intervention in hypertension, heart failure and other diseases.
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PMID:Endothelin and endothelin antagonists in hypertension. 988 74

The present study was designed to determine the role of endogenous endothelin peptides and nitric oxide on angiotensin II (All) responses in the isolated nonpregnant rat uterine smooth muscle. AII (10, 20, or 50 ng/ml) increases rhythmic oscillations dose dependently (32.7 +/- 8.9, 55.96 +/- 10.3, and 62.78 +/- 17.7% increase, respectively). L-arginine methyl ester (L-NAME; 10(-5) M) did not affect the increase in rhythmic oscillations induced by All (10, 20, or 50 ng/ml) (17.5 +/- 12.1, 31.5 +/- 18.3, and 52.5 +/-11.8% increase, respectively, n = 6, p > 0.05). It reduced the contractile responses to AII (10 ng/ml: from 4.63 +/- 0.6 to 1.8 +/-0.7 cm2, p < 0.05: and 20 ng/ml: from 5.59 +/- 0.8 to 2.11 +/- 0.4 cm2, p < 0.05, n = 6). L-arginine (10 mM) decreased the contractile response obtained by AII (10 or 20 ng/ml) (1.93 +/- 1.05, p < 0.05 and 2.14 +/- 0.7 cm2, p < 0.05, respectively, n = 6). BQ 485 (50 ng/ml) decreased both the number of rhythmic oscillations and the contractility increased by AII. Bosentan (10(-5) M) induced an increase in the number of rhythmic oscillations but decreased the contractile responses to the higher concentrations of All. These data show that endogenous NO and endothelin peptides contribute to the motility changes induced by AII and may play an important role in the pathophysiological events of the uterine function.
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PMID:The contribution of nitric oxide and endothelins to angiotensin: II. Evoked responses in the rat isolated uterus smooth muscle. 1052 68


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