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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelins (ET) are 21-aminoacid peptides produced ubiquitously, which were discovered originally as endothelial products. These peptides may play important roles in cardiovascular physiology and pathophysiology. As the pathophysiologic roles of endothelins in cardiovascular disease become increasingly apparent, the potential therapeutic use of endothelin antagonists or endothelin converting enzyme inhibitors is recognized. The main endothelin produced by the endothelium is ET-1. Endothelin-1 is overexpressed in the vascular wall of salt-dependent models of hypertension, such as DOCA-salt hypertensive rats, DOCA-salt-treated spontaneously hypertensive rats (SHR) and Dahl salt-sensitive rats, and in stroke-prone SHR, angiotensin II-infused rats and 1-kidney 1 clip Goldblatt hypertensive rats, but not in SHR, 2-K 1C hypertensive rats or L-NAME-treated rats. The vasoconstrictor effect of ET-1 may contribute to blood pressure elevation and its growth-promoting action to vascular hypertrophy in the hypertensive models which overexpress ET-1 in blood vessels. In rats without generalized activation of the endothelin system, expression of ET-1 is often enhanced in coronary arteries, which suggests a role for ET-1 in myocardial ischemia in hypertension. In rats overexpressing ET-1, ETA/B and ETA-selective antagonists lowered blood pressure slightly, and significantly reduced vascular growth, particularly of small arteries, suggesting that ET-1 has a direct effect on growth. Protection from renal injury and from stroke has also been demonstrated in hypertensive rats treated with endothelin antagonists. In normotensive human subjects endothelin-dependent tone can be shown in the forearm. In a study of mild hypertensive patients, the ETA/B antagonist bosentan reduced blood pressure similarly to an ACE inhibitor. Moderate to severe hypertensive patients presented enhanced expression of ET-1 mRNA in the endothelium of subcutaneous resistance arteries. In blacks with familial hypertension increased plasma levels of endothelin have been found. Thus, ET-1 may play a role in some experimental hypertensive models and in human hypertension. In summary, endothelial ET-1 may be overexpressed in the more severe forms of hypertension, and in certain special populations which may respond particularly well to endothelin antagonism. Endothelin antagonists may prove to be effective disease-modifying agents if in future clinical trials they are shown clinically to blunt vascular growth and endothelial dysfunction, reduce stroke and exert the cardioprotective and renal protective effects already reported in experimental hypertension. These agents could contribute to reduce the long-term complications of hypertension, which remains to be demonstrated in humans.
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PMID:Endothelin: role in hypertension. 983 May 7

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

Endothelin-1 (ET-1) is an important mediator of vascular tone in humans, and a number of endothelin receptor antagonists are currently in clinical development as vasodilator agents. While the vasoconstrictor role of the ETA receptor is undisputed, the role of the ETB receptor remains unclear. Hemodynamic effects of systemic doses of the ETB-selective antagonist BQ-788 were investigated in 5 healthy male volunteers (age range, 33 to 48 years) in a placebo-controlled, four-way crossover study. After a 15-minute infusion of BQ-788 (3, 30, or 300 nmol/min) or placebo, plasma ET-1 and big ET-1, blood pressure, heart rate, cardiac index, and stroke index were measured. Total peripheral vascular resistance was calculated from cardiac index and mean arterial pressure. Hemodynamic data are expressed as maximum, placebo-corrected, percentage change from baseline following BQ-788 (300 nmol/min) and were examined by ANOVA. Plasma ET-1 increased by 3.7+/-1.2 pg/mL (maximum at 15 minutes, P=0.02), whereas there was no significant change in plasma big ET-1. Although BQ-788 had no effect on mean arterial pressure, there was a reduction in heart rate (13+/-7% at 50 minutes; P=0.002), cardiac index (17+/-5% at 40 minutes; P<0. 0001), and stroke index (8+/-4% at 40 minutes; P=0.002) and an increase in total peripheral vascular resistance (24+/-5% at 40 minutes; P<0.0001). The selective ETB receptor antagonist BQ-788 causes peripheral vasoconstriction in healthy volunteers, suggesting that the overall balance of effects of endogenous ET-1 at the vascular ETB receptor favors vasodilatation. Further investigation is now clearly required to address whether selective ETA or combined ETA/ETB receptor blockade will be more effective in the clinical setting.
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PMID:Systemic blockade of the endothelin-B receptor increases peripheral vascular resistance in healthy men. 993 Nov 69

Endothelin-1 (ET-1) is a positive inotrope in normal hearts; however, the direct cardiac effects of endogenous ET-1 in congestive heart failure (CHF) are unknown. We evaluated the cardiac responses to endogenous ET-1 using an ETA and ETB receptor blocker (L-754,142) in seven conscious dogs before and after pacing-induced CHF. Before CHF, when the plasma ET-1 was 7.3 +/- 1.7 fmol/ml, L-754,142 caused no significant alterations in heart rate, left ventricular (LV) end-systolic pressure, total systemic resistance, and the time constant of LV relaxation (tau). LV contractile performance, measured by the slopes of LV pressure (P)-volume (V) relation (EES), dP/dtmax-end-diastolic V relation (dE/dtmax), and stroke work-end-diastolic V relation, was also unaffected. After CHF, when the plasma ET-1 was significantly increased to 14.1 +/- 3.0 fmol/ml (p <.05), L-754,142 produced a significant decreases in LV end-systolic pressure (101 +/- 11 versus 93 +/- 8 mm Hg) and total systemic resistance (0.084 +/- 0.022 versus 0.065 +/- 0.15 mm Hg/ml/min). The tau (42 +/- 12 versus 38 +/- 10 ms), mean left atrial P (22 +/- 5 versus 18 +/- 4 mm Hg) (p <.05), and minimum LVP were also significantly decreased. After CHF, the slopes of P-V relations, EES (3.4 +/- 0.4 versus 4.8 +/- 0.8 mm Hg/ml), dE/dtmax (42.4 +/- 7.8 versus 50.0 +/- 7.8 mm Hg/s/ml), and stroke work-end-diastolic V relation (58.1 +/- 3.3 versus 72.4 +/- 5.2 mm Hg) (p <.05) all increased after L-754,142, indicating enhanced contractility. Before CHF, low levels of endogenous ET-1 have little cardiac effect. However, after CHF, elevated endogenous ET-1 produces arterial vasoconstriction, slows LV relaxation, and depresses LV contractile performance. Thus, elevated endogenous ET-1 may contribute to the functional impairment in CHF in this canine model.
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PMID:Endogenous endothelin-1 depresses left ventricular systolic and diastolic performance in congestive heart failure. 1002 61

Intracerebroventricular injections of endothelin-1 (ET-1) are reported to cause dose-related increases in sympathetic nerve activity and blood pressure in anesthetized normotensive rats. These studies were performed to determine the following: which endothelin receptor, A or B, is involved in mediating sympathetic and cardiovascular effects of ET-1 injected centrally; whether central endothelin tonically participates in blood pressure regulation in normotensive rats; and whether the altered endothelin system in the central nervous system contributes to blood pressure elevation in hypertensive rats. ET-1, ET-A antagonist (BQ-123), or ET-B antagonist (RES-701-1) was injected into the lateral cerebral ventricle (i.c.v.) of urethane-anesthetized normotensive Wistar and Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHRs), and stroke-prone SHRs (SHR-SPs). In Wistar rats, i.c.v. injections of ET-1 (1, 5, 10 pmol) consistently increased sympathetic nerve activity, thereby elevating blood pressure in a dose-related manner. The pressor responses induced by i.c.v. ET-1 were abolished after intravenous pretreatment with phentolamine. Neither ET-A nor ET-B antagonist, when injected centrally, altered basal levels of sympathetic nerve activity, heart rate, or blood pressure in Wistar rats. However, sympathetic activation and pressor responses induced by i.c.v. injection of endothelin were completely abolished after i.c.v. pretreatment with ET-A antagonist but were unaffected after pretreatment with ET-B antagonist. Although i.c.v. injections of ET-1 increased sympathetic nerve activity and blood pressure in WKY rats, SHRs, and SHR-SPs, the magnitudes of these responses did not differ among these three groups. In contrast, i.c.v. injections of ET-A antagonist decreased sympathetic nerve activity, blood pressure, and heart rate only in SHR-SPs, but not in WKY rats and SHRs. In addition, the depressor effects of i.c.v. ET-A antagonist in SHR-SPs were ascertained while these rats were awake. In summary, i.c.v. injections of ET-1 increased sympathetic nerve activity and blood pressure via ET-A receptors but not via ET-B receptors. Central ET might tonically activate sympathetic nerve activity to thereby contribute to blood pressure elevation in SHR-SPs, but not in WKY rats and SHRs.
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PMID:Central effects of endothelin and its antagonists on sympathetic and cardiovascular regulation in SHR-SP. 1036 90

We have demonstrated previously that endothelin-1 (ET-1) mRNA expression is increased in hypertensive rats. The aim of the study reported here was to elucidate the effects of the endothelin (ET) receptor antagonist on the hemodynamic and biochemical parameters in stroke-prone spontaneously hypertensive rats (SHRSPs/Izm). The endothelin-A- and -B- (ETA/ETB) receptor antagonist (TAK-044, Takeda Chemical Industries, Osaka, Japan) was administered subcutaneously at a dose of 10 mg/kg/day from the age of 8 weeks for 4 weeks. Blood samples and tissues of the kidney, heart and brain were obtained at the age of 12 weeks. Tissue expression of ET-1 mRNA was determined by reverse transcriptase-polymerase chain reaction (RT-PCR) followed by Southern blot analysis. Treatment with TAK-044 resulted in a significant decrease in systolic blood pressure (SBP), blood urea nitrogen (BUN), serum creatinine concentration, plasma aldosterone level, heart weight, and kidney weight. In addition, ET-1 contents and mRNA expression level in the kidney, heart and brain were significantly decreased by the treatment with TAK-044. These results suggest that the ET receptor antagonist TAK-044 is able to attenuate ET-1 gene expression in addition to its specific antagonism of the biological actions of ET via the receptors.
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PMID:Hemodynamic and biochemical effects of endothelin-A- and -B-receptor antagonist TAK-044 in stroke-prone spontaneously hypertensive rats. 1107 13

The single oral administration of a mixed endothelin-A-and -B- (ETA/ETB) receptor antagonist, J-104132 (L-753,037) decreased the blood pressure in conscious spontaneously hypertensive rats (SHR), stroke-prone SHR (SHRSP) and Dahl salt-sensitive hypertensive rats fed high-salt diet (DS-H) at doses of 3 and 10 mg/kg, with a duration of approximately 24 h. The magnitude of the antihypertensive effects was greater in DS-H than in SHR and SHRSP Preproendothelin-1 mRNA expression in the kidney and aorta was greater (about twofold) in DS-H than that in nonnotensive Dahl salt-resistant rats fed high-salt diet (DR-H), while there was no difference in preproendothelin-1 mRNA expression between SHR and Wistar Kyoto rats (WKY). An AT1-receptor antagonist, MK-954 (Losartan), also attenuated hypertension in SHR and SHRSP at oral doses of 3 and 10 mg/kg, but bad no effect in DS-H. The concomitant treatment with MK-954 and J-104132 showed additive antihypertensive effects in SHR and SHRSP. In DS-H, MK-954 potentiated the antihypertensive effects of J-104132. From these results, we suggest that: (1) the contribution of endothelin (ET) to the maintenance of hypertension is greater in salt-sensitive hypertensive models than in SHR and SHRSP; (2) the antihypertensive efficacy of ETA/ETB blockade is augmented by AT1-receptor blockade; (3) ET blockers alone or in combination with AT1 antagonists could be useful in the treatment of hypertension for patients who do not respond adequately to renin-angiotensin system inhibitors alone.
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PMID:Antihypertensive effects of a mixed endothelin-A- and -B-receptor antagonist, J-104132, were augmented in the presence of an AT1 -receptor antagonist, MK-954. 1107 14

Evidence suggests that endothelin receptor antagonists may have therapeutic potential for the chronic treatment of heart failure. In the current study, the effects of an orally active mixed endothelin-A/endothelin-B (ETA /ETB ) receptor antagonist (enrasentan) were assessed in a model of cardiac hypertrophy and dysfunction (spontaneously hypertensive stroke prone rats) maintained on a high-salt/high-fat diet. Echocardiography was used to quantify cardiac performance and left ventricular dimensions. Enrasentan (1,200 and 2,400 parts per million in the high-salt/high-fat diet) had no significant effects on body weight and systolic blood pressure. However, increases in heart rate were not observed in the enrasentan-treated groups at 12 weeks (p < 0.05). Enrasentan-treated groups exhibited significantly improved survival (90-95% vs. 30% [control rats] at 18 weeks; p < 0.001). Enrasentan treatments also increased stroke volume (at 8, 12, and 16 weeks) and cardiac index (at 8 and 16 weeks) 33-50% and 45-63%, respectively. Enrasentan treatments reduced the relative wall thickness (14-27% at 8 and 12 weeks), ratio of left ventricular mass to body weight (20% at 12 weeks), and ratio of terminal heart weight to body weight (16-23%, p < 0.05). Finally, circulating aldosterone concentration (54-57%) and proANF fragment (33%) were reduced in enrasentan-treated groups (54-57% and 33%, respectively). Mixed ETA /ETB receptor antagonism improves cardiac performance and attenuates ventricular remodeling and premature mortality in an aggressive hypertension model.
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PMID:Enrasentan improves survival, limits left ventricular remodeling, and preserves myocardial performance in hypertensive cardiac hypertrophy and dysfunction. 1158 31

Upon maintained on a 1% NaCl drinking solution beginning at 7 weeks of age, the stroke-prone spontaneously hypertensive rat (SHRsp) developed severe hypertension and stroke; most died by 16 weeks. The mechanism by which these diseases evolve remains unclear. Endothelin-1 (ET-1) is a potent, peptidic vasoconstrictor and is implicated in the pathogenesis of various cardiovascular, renal, and central nervous system diseases. The purpose of the present study was to compare the binding of [125I]ET-1 to the brain, heart, kidney, liver, and spleen membrane preparations of 16-week-old SHRsp and age-matched normotensive Wistar-Kyoto rats (WKY). The KD values for [125I]ET-1 binding to the corresponding tissues of the two strains were not significantly different, except in the brain (SHRsp: 17 +/- 1 pM; WKY: 24 +/- 1 pM). In contrast, the Bmax values measured in the brain, heart, kidney, and liver of SHRsp were 1.5- to 2.1-fold greater than those of their WKY counterparts. Competition of [125I]ET-1 binding to the membrane preparations by the specific ETA receptor antagonist BQ-123 or the specific ETB receptor agonist sarafotoxin S6c revealed a similar proportion of ETA and ETB receptor subtypes in the corresponding tissues of the two rat strains. These results indicate that ET-1 binding is upregulated in SHRsp and suggest that ET-1 may play a pathophysiological role in this animal model of genetic hypertension.
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PMID:Upregulation of endothelin-1 binding in tissues of salt-loaded stroke-prone spontaneously hypertensive rats. 1205 55

Changes in blood pressure and sympathetic nerve activity induced by local injection of endothelin-1 into the rostroventrolateral medulla were studied in narcotized stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive WKY rats. Endothelin-1 produced similar biphasic response in both rat strains: a transient increase in blood pressure and sympathetic nerve activity followed by progressive hypotension and bradycardia. Pretreatment with ETB-receptor antagonist BQ788 inhibited sympathetic activation induced by endothelin-1, while pretreatment with the ETA-receptor antagonist N-acetyl-[D-Trp16]-endothelin-1 abolished the subsequent hypotension. The antihypotensive effect of ETA-receptor blockade was most effective in normotensive rats. Our findings suggest that cardiovascular disorders in SHRSP rats can be related to peculiarities in the rostroventrolateral medullar endothelin system.
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PMID:Effects of central endothelin-1 in normotensive and spontaneously hypertensive rats. 1280 90


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