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

We determined the role of nitric oxide (NO) and endothelins (ETs) in the regulation of hepatic blood flow during resuscitation from hemorrhagic shock (HS) in anesthetized rats. Volume resuscitation restored systemic hemodynamics and increased hepatic arterial and portal venous flow above baseline in the vehicle group. Presence of N omega-nitro-L-arginine methyl ester (L-NAME, 1 mg/kg) during resuscitation increased systemic vascular resistance (SVR) above baseline, prevented the restoration of hepatic arterial flow, and abolished portal hyperemia. Although the ETA+B-receptor antagonist bosentan (10 mg/kg) did not alter the systemic hemodynamic response, it abolished the hepatic arterial and portal hyperemia. The ETA-receptor antagonist BQ-610 (150 micrograms/kg) reduced SVR below baseline, allowed hepatic arterial hyperemia to occur, and further enhanced the portal venous hyperemia. This indicates that 1) NO reduces SVR and acts to preserve hepatic blood flow during resuscitation from HS; 2) ETA-receptor-mediated vasoconstriction counteracts the systemic and portal hemodynamic effects of NO; and 3) simultaneous ETB-receptor stimulation enhances blood flow to the liver and may serve to modulate the ETA-receptor-mediated vasoconstrictive effects of ETs.
 ...
PMID:Regulation of hepatic blood flow during resuscitation from hemorrhagic shock: role of NO and endothelins. 922 53

1. Endothelin (ET) is a potent vasoconstrictor peptide which has been shown to have an important role in the regulation of systemic and renal haemodynamics. In order to elucidate the role of endogenous ET in the kidney, we examined the effects of ET receptor antagonists on systemic and renal vasculature in normotensive anaesthetized rats. 2. Intravenous injection of a selective ETA receptor antagonist, FR139317 (0.5 mumol kg-1, for 20 min) induced a very small fall in blood pressure. Similarly, a non-selective ETA/ETB receptor antagonist, TAK-044 (12.5 mumol kg-1, for 20 min) slightly decreased blood pressure. A selective ETB receptor antagonist, BQ-788 (0.5 mumol kg-1, for 20 min) had no effect of blood pressure. 3. FR139317 and TAK-044 did not affect renal blood flow or calculated renal vascular resistance. In contrast, BQ-788 significantly reduced renal blood flow by 18.2 +/- 2.4% and increased renal vascular resistance. Furthermore, the renal vascular action of BQ-788 was not observed when combined with FR139317. 4. Pretreatment with a nitric oxide (NO) synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME, 37 mumol kg-1, i.v.) and a cyclo-oxygenase inhibitor ibuprofen (44 mumol kg-1, i.v.) completely abolished the BQ-788-mediated renal vasoconstriction. 5. These results indicate that activation of ETB receptors by endogenous ET acts as a physiological brake for the ETA-mediated renal vasoconstriction; this effect appears to be mediated by stimulation of NO and/or vasodilator prostaglandin(s) release.
 ...
PMID:Renal vascular effects of the selective endothelin receptor antagonists in anaesthetized rats. 929 31

The bronchoconstrictor response after systemic administration of endothelins (ETs) in the guinea pig is indirectly mediated by thromboxane A2 (TxA2) release through ETB receptor activation. ETs also trigger the release of nitric oxide (NO) in endothelial cells by activation of ETB receptors. A growing body of evidence indicates that endogenous NO plays a key role in the regulation of pulmonary function. In this study we investigated the effect of an NO synthase inhibitor, L-NAME, on the release of TxA2 from the isolated, perfused guinea pig lung induced either by ET-1, the selective ETB receptor agonist IRL-1620, bradykinin (BK), or a TxA2-mimetic, U 46619. A 30 min intra-arterial (intra-arterial) infusion of L-NAME (300 microM) potentiated the TxA2 release with ET-1, IRL 1620, and BK (5, 50, and 50 nM, respectively) infused for 3 min (i.a.). U 46619 (10 nM) was ineffective as a stimulant of pulmonary eicosanoid release. Interestingly, L-NAME did not potentiate the release of prostacyclin (PGI2) triggered by ET-1, IRL 1620, or BK. Our results suggest a predominant role of ETB receptor activation in the release of TxA2. Furthermore, we suggest that NO in the guinea pig lung is a potent modulator of the TxA2 releasing activity of ET-1, IRL 1620, and BK, three agonists known to stimulate the release of NO.
 ...
PMID:L-NAME potentiates endothelin-stimulated thromboxane release from guinea pig lung. 959 14

Some endothelin (ET) receptor antagonists have been reported to elevate plasma immunoreactive endothelin-1 (irET-1). However, there is no information regarding the effects of ET receptor antagonists on cerebrospinal fluid (CSF) levels. To better understand the regulation of circulating and CSF ET-1, the effects of several nonpeptide antagonists with high, intermediate, or low affinity at the ETB receptor, as well as the potent ETB selective agonist sarafotoxin 6c (S6c), were characterized and compared. The effects of SB209670 (Ki ETA = 0.2 nM; Ki ETB = 12 nM), SB217242 (Ki ETA = 1.1 nM; Ki ETB = 111 nM), SB234551 (Ki ETA = 0.1 nM; Ki ETB = 500 nM), SB247083 (Ki ETA = 0.4 nM; Ki ETB = 467 nM), and S6c (Ki ETA = 950 nM; Ki ETB = 1 nM) on plasma irET-1 were determined by ELISA in the anesthetized dog after i.v. administration. Systemic administration of equivalent doses of the nonpeptide ET receptor antagonists produced dose-related elevations in plasma irET-1 which were correlated (p = 0.019) with affinity at the ETB receptor. There was no significant correlation with affinity at the ETA receptor. In addition, the plasma irET-1 and ET antagonist concentrations were linearly correlated (r = 0.98) throughout the time course after antagonist administration. There was no evidence of densensitization after three bolus administrations performed at 2-h intervals (SB209670, 1 and 3 mg/kg i.v.). Elevations in plasma irET-1 (four- to fivefold) were also observed after systemic administration of S6c (1 nmol/kg i.v.). The administration of L-NAME (200 micrograms/kg/min for 30 min), an inhibitor of nitric oxide (NO) synthase, increased blood pressure (33%) but did not alter plasma irET-1. In contrast, systemic administration of the ET receptor antagonists had little or no effect on the on irET-1 in the CSF. However, intracerebroventricular (i.c.v.) administration of SB209670 produced a dose-related (3-100 micrograms) increase in cisternal CSF levels of irET-1 without altering plasma irET-1. Systemic administration of ETB receptor antagonists and agonists rapidly increased plasma irET-1. These ETB receptor antagonist effects correlate linearly with affinity at the cloned human ETB receptor, do not exhibit desensitization, and do not appear to reflect inhibition of ETB-mediated NO production. The endothelial ETB receptor may represent a high-capacity storage/clearance site for circulating ET-1. ET receptor antagonists may also act extravascularly/abluminally to increase irET-1 in the CNS.
 ...
PMID:Plasma- and cerebrospinal fluid-immunoreactive endothelin-1: effects of nonpeptide endothelin receptor antagonists with diverse affinity profiles for endothelin-A and endothelin-B receptors. 959 25

At present, there is no information on endothelin-1 (ET-1)-mediated vascular effects in the human spleen. The objectives of this study were to investigate the in vitro vascular responses to ET-1 using pharmacologic probes (selective ET receptor agonists/antagonists) and to characterize the ET receptor population in the human spleen. Spleens (n = 6) were removed from patients for treatment of underlying disease. The organs were perfused with warmed (37 degrees C), oxygenated (95% O2/5% CO2) Krebs solution at constant flow, with continuous recording of splenic arterial perfusion pressure (SAPP). The increases in SAPP caused by injection of ET-1 (ETA/ETB agonist) were markedly reduced in the presence of the selective ETA antagonist FR-139317, whereas those induced by IRL-1620 (an ETB agonist) and norepinephrine (NE) were unchanged. The increases in SAPP induced by intra-arterial bolus injections of NE and ET-1 were significantly (p < 0.05) potentiated by indomethacin [INDO; a cyclo-oxygenase (COX) inhibitor] alone and the responses to both peptides (ET-1 and IRL-1620) were significantly (p < 0.05) potentiated by INDO and L-NAME [a nitric oxide (NO) synthase inhibitor] together. We conclude that ET-1 contributes to the regulation of vascular tone in human spleen through activation of both ETA and ETB receptors and that these responses are modulated by concomitant release of prostaglandins and NO.
 ...
PMID:Characterization of endothelin receptors in isolated, perfused human spleen. 959 40

We measured the activity of mitogen-activated protein (MAP) kinases, enzymes believed to be involved in the pathway for cell proliferation, in rat aortic strips with or without endothelium, and examined effects of angiotensin receptor antagonists, endothelin receptor antagonists and nitric oxide (NO)-related agents. Endothelium removal produced an activation of MAP kinase activity in the strips, whereas the enzyme activity was not affected in the adventitia. The MAP kinase activation was inhibited by either the angiotensin AT1 receptor antagonist losartan or the endothelin ETA receptor antagonist BQ 123. The combination of both antagonists caused an additive inhibition. The angiotensin AT2 receptor antagonist PD 123,319 and the endothelin ETB receptor antagonist BQ 788 did not affect the MAP kinase activation. The NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) caused an activation of MAP kinase in the endothelium-intact aorta and the MAP kinase activation was inhibited by losartan or BQ123. The NO releaser nitroprusside inhibited the MAP kinase activation induced by endothelium removal or angiotensin II. These results suggest that even in isolated arteries, NO of endothelial origin tonically exert MAP kinase-inhibiting effects and endogenous angiotensin II and endothelins in the media are tonically released to cause MAP kinase-stimulating effects in medial smooth muscle.
 ...
PMID:Evidence that angiotensin II, endothelins and nitric oxide regulate mitogen-activated protein kinase activity in rat aorta. 965 1

1. Coronary vascular tone is a vital factor that regulates the delivery of oxygen to cardiac muscle. We tested the hypothesis that basal coronary tone may depend on the release of an endogenous vasoconstrictor peptide, endothelin (ET). 2. Using an isolated, Krebs solution-perfused rat heart we measured the changes in coronary flow following the administration over a 30 min period of the ET antagonists Ro61-0612 (mixed ETA/ETB), PD155080 (ETA) and BQ788 (ETB). 3. In a second series of experiments, hearts were randomly assigned to perfusion with plain Krebs solution, or with Krebs solution to which L-NAME and/or indomethacin had been added. The effect on coronary flow following the addition of Ro61-0612 was then measured. 4. Perfusion with Ro61-0612 (10-4 M) alone increased coronary flow by 57.8 % vs. control (P = 0.00001). PD155080 (10-4 M) increased coronary flow by 28.9 % (P = 0.009), whereas BQ788 had no effect on coronary flow. 5. In the second series of experiments, Ro61-0612 increased coronary flow by 6.6 +/- 0.8 ml min-1 in hearts perfused with plain Krebs solution, by 3.8 +/- 0.8 ml min-1 in hearts to which both L-NAME and indomethacin had been added, by 3.3 +/- 0.7 ml min-1 in hearts to which L-NAME had been added, and by 6. 9 +/- 0.5 ml min-1 in hearts to which indomethacin had been added to the Krebs buffer. 6. In hearts perfused with Krebs solution alone, nitric oxide (NO) release into the coronary sinus increased from 219. 8 to 544.9 pmol min-1 g-1 following the addition of Ro61-0612 (P = 0. 06). There was no detectable release of NO from hearts perfused with L-NAME alone or in combination with indomethacin either before or after the addition of Ro61-0612. 7. We conclude that endogenous ET plays a role in coronary tone mediated via ETA receptors. This vasodilatation is partially due to an increase in endogenous NO release. However, a significant vasodilatation is still seen following the inhibition of NO synthesis. We propose that basal coronary tone depends on a balance between the endogenous release of vasodilators such as NO and vasoconstrictors such as ET.
 ...
PMID:Role of endogenous endothelin in the regulation of basal coronary tone in the rat. 970 30

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.
 ...
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.
 ...
PMID:Endothelin and endothelin antagonists in hypertension. 988 74

1. The purpose of this work was to investigate whether endothelin-1 (ET-1) was able to induce the release of an inhibitory factor from the airway epithelium in isolated human bronchi and to identify this mediator as well as the endothelin receptor involved in this phenomenon. 2. In intact bronchi, ET-1 induced a concentration-dependent contraction (-logEC50 = 7.92+/-0.09, n = 18) which was potentiated by epithelium removal (-logEC50 = 8.65+/-0.11, n = 17). BQ-123 , an ET(A) receptor antagonist, induced a significant leftward shift of the ET-1 concentration-response curve (CRC). This leftward shift was abolished after epithelium removal. 3. L-NAME (3 x 10(-3) M), an inhibitor of nitric oxide (NO) synthase, induced a significant leftward shift of the ET-1 CRC, and abolished the potentiation by BQ-123 (10(-8) M) of ET-1-induced contraction. 4. In intact preparations, the ET(B) receptor antagonist BQ-788 induced only at 10(-5) M a slight rightward shift of the ET-1 CRC. In contrast, in epithelium-denuded bronchi or in intact preparations in the presence of L-NAME, BQ-788 displayed a non-competitive antagonism toward ET-1-induced contraction. 5. IRL 1620, a selective ET(B) receptor agonist, induced a contraction of the isolated bronchus (-logEC50=7.94+/-0.11, n= 19). This effect was not modified by epithelium removal or by BQ-123. BQ-788 exerted a competitive antagonism against IRL 1620 which was similar in the presence or absence of epithelium. 6. These results show that ET-1 exerts two opposite effects on the human airway smooth muscle. One is contractile via ETB-receptor activation, the other is inhibitory and responsible of NO release which counteracts via ETA-receptor activation the contraction.
 ...
PMID:Modulation of ET-1-induced contraction of human bronchi by airway epithelium-dependent nitric oxide release via ET(A) receptor activation. 1007 48


<< Previous 1 2 3 4 5 6 Next >>