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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We showed recently that endothelin (ET)A receptors are involved in the salt sensitivity of ANG II-induced hypertension. The objective of this current study was to characterize the role of endothelin ETB receptor activation in the same model. Male rats on fixed normal (2 meq/day) or high (6 meq/day) salt intake received a continuous intravenous infusion of ANG II or salt only for 15 days. During the middle 5 days of the infusion period, rats were given either the selective ETB receptor antagonist A-192621 or the nonselective endothelin receptor antagonist A-182086 (both at 24 mg x kg(-1) x day(-1) intra-arterially). Infusion of ANG II caused a greater rise in arterial pressure in rats on high-salt intake. The administration of A-192621 increased arterial pressure further in all rats. The chronic hypertensive effect of A-192621 was not significantly affected by salt intake or ANG II. The administration of A-182086 lowered arterial pressure chronically only in rats on normal salt intake receiving ANG II. Thus the salt sensitivity of ANG II-induced hypertension is not caused by changes in ETB receptor function.
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PMID:Role of endothelin ETB receptor activation in angiotensin II-induced hypertension: effects of salt intake. 1166 86

Three endothelin family peptides (endothelin-1, -2 and -3) exert an extremely potent and long-lasting vasoconstrictor action as well as other various actions through stimulating two subtypes of receptor (ETA and ETB). Vascular endothelial cells produce only endothelin-1. Although the pharmacological actions of exogenous endothelin-1 have been extensively analyzed, the physiological roles of endogenous endothelin-1 have long been obscure. Using potent and selective receptor antagonists, endothelin-1 has been demonstrated to contribute slightly to the maintenance of regional vascular tone. In gene-targeted mice, endothelin family peptides and their receptors have been shown to play an important role in the embryonic development of neural crest-derived tissues. In addition to its potent vasoconstrictor action, endothelin-1 has direct mitogenic actions on cardiovascular tissues, as well as co-mitogenic actions with a wide variety of growth factors and vasoactive substances. Endothelin-1 also promotes the synthesis and secretion of various substances including extracellular constituents. These effects of endogenous endothelin-1 would appear to be naturally concerned with the development and/or aggravation of chronic cardiovascular diseases, e.g. hypertension, pulmonary hypertension, vascular remodeling (restenosis, atherosclerosis), renal failure, and heart failure. A great many non-peptide and orally active endothelin receptor antagonists have been developed, and shown to exert excellent therapeutic effects in animal models as well as human patients with these diseases.
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PMID:Basic and therapeutic relevance of endothelin-mediated regulation. 1172 53

The endothelium can greatly influence vascular tone and structure. The main endothelium-derived factor is nitric oxide (NO), which is not only a potent vasodilator but also inhibits platelet aggregation, smooth muscle cell proliferation, monocyte adhesion and adhesion molecule expression, thus protecting the vessel wall against the development of atherosclerosis and thrombosis. In human hypertension, endothelial dysfunction has been documented in peripheral and coronary macro- and microcirculation and in renal circulation. The mechanism responsible for endothelial alteration in essential hypertensive patients appears to be the activation of an alternative pathway involving cyclooxygenase, which reduces NO availability through production of oxidative stress. In the presence of impaired NO availability a hyperpolarizing factor seems to act as a compensatory pathway to sustain endothelium-dependent relaxation. This compensatory pathway can be further depressed by the simultaneous presence of essential hypertension and hyperhomocysteinaemia, another cardiovascular risk factor causing endothelial dysfunction. Finally, reduced NO availability can increase the biological activity of endothelin-1 because, while in healthy conditions the vasoconstrictor effect of endothelin-1 is partially blunted by endothelial ETB-receptor mediated NO production, in essential hypertensive patients this protective mechanism is lacking on account of impaired NO availability. This alteration in the NO pathway could be the main mechanism through which a dysfunctional endothelium could be a promoter of atherosclerosis and thrombosis and therefore lead to cardiovascular events in essential hypertensive patients.
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PMID:Endothelial dysfunction in hypertension. 1181 68

The results of the Randomized Aldactone Evaluation Study (RALES) and of several experimental studies have indicated that excess aldosterone detrimentally affects cardiovascular morbidity and mortality by acting through both classical and non-classical mineralocorticoid receptors. The effects mediated through classical mineralocorticoid receptors entail enhanced sodium and water reabsorption, potassium loss and hypokalaemia, congestion, increased vascular resistance and hypertension. Those occurring through non-classical mineralocorticoid receptors located on myofibroblasts comprise cardiac hypertrophy and fibrosis, which may be due to a direct effect of aldosterone on collagen synthesis. Data obtained in primary aldosteronism patients demonstrated left ventricular hypertrophy, as well as changes in left ventricular filling that can be accounted for by cardiac fibrosis. Available clinical data indicate that in a considerable proportion of congestive heart failure (CHF) patients treated with angiotensin converting enzyme (ACE) inhibitors, aldosterone secretion can escape from blockade of the renin-angiotensin system, thus suggesting that additional mechanisms, besides angiotensin II, can play an important role in the regulation of aldosterone secretion. Compelling evidence indicates that endothelin (ET)-1 is overtly increased in severe CHF and thus is a likely candidate for the aldosterone 'escape' phenomenon in CHF. Endothelin-1 is expressed in the adrenal cortex, together with its receptor subtypes A (ETA) and B (ETB), and directly stimulates aldosterone secretion in different species, in humans by acting via both ETA and ETB receptor subtypes. Moreover, we have recently found that the novel endothelin peptide ET-1 (1-31), by acting as an ETA agonist, can also be involved in the regulation of growth of the adrenal cortex, as well as in the pathogenesis of Conn's adenoma. In this paper, we review the findings suggesting a relationship between activation of the ET-1 system, enhanced aldosterone secretion and cardiac fibrosis and discuss the implications of endothelin antagonism for cardiovascular disease.
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PMID:The endothelin-aldosterone axis and cardiovascular diseases. 1181 78

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

Hypertension is associated with enhanced peripheral vascular resistance, which may be mediated by enhanced vasoconstriction. The impact of the recently detected G-protein beta3-subunit gene C825T polymorphism on the response to the major pressor mediators has been studied in vivo in the human microcirculation. We assessed the effects of endothelin-1 (ET-1), angiotensin II (AT), endothelin-antagonists (BQ-123 and BQ-788) and noradrenaline (NA, each 10-16-10-8 mol) on vasoconstriction in the human skin microcirculation in vivo in 25 healthy male volunteers (13 with CC genotype, 12 TC/TT genotype) using laser Doppler flowmetry. The effects of endothelium-derived vasodilation on NA-induced effects were studied using the NO-synthase inhibitor l-nitro-monomethyl-arginine (L-NMMA) and the alpha2-adrenoceptor-antagonist yohimbine (YO). ET-1, AT and NA caused a dose-dependent vasoconstriction (P < 0.001). In carriers of the 825T allele the response to ET-1, AT and NA was significantly enhanced leading to a shift to the left of the dose-response curve of up to two log units (ET-1: P < 0.001 vs. CC; AT: P < 0.01 vs. CC; NA: P < 0.05 vs. CC). After pretreatment with L-NMMA or YO, NA induced vasoconstriction was no longer different between subjects with the CC- and CT/TT genotypes. However, following combined pretreatment with both L-NMMA and YO, vasoconstriction to NA was significantly potentiated in carriers of the T-allele. Vasodilatation to an ETA-antagonist (BQ-123) was more pronounced in the CT/TT genotype, while ETB-antagonism (BQ-788) led to a more pronounced vasoconstriction in the CT/TT genotype (not significant vs. CC). Healthy, normotensive carriers of the 825T-allele have enhanced vasoconstriction to ET-1, AT and NA in the skin microcirculation. This enhanced vasoconstriction appears to be partially antagonized by an enhanced release of endothelium derived vasodilators mediated by the stimulation of endothelial alpha2-adrenoceptors. The GNB3 C825T polymorphism is potentially an attractive pharmacogenetic marker to predict hormone-mediated responses in humans.
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PMID:Enhanced vasoconstriction to endothelin-1, angiotensin II and noradrenaline in carriers of the GNB3 825T allele in the skin microcirculation. 1217 18

Endothelin-1 (ET-1) has been found to be one of the most potent vasoconstrictive peptides known, and is therefore considered to be an important factor in diseases such as hypertension, heart failure, pulmonary hypertension, renal diseases, etc. Thus, the development of ET-receptor antagonists may offer a new therapeutic strategy in these fields. In this article, we summarize the method for assessing our compound as a selective ETA-receptor antagonist. Binding assays and in vitro function assays (isolated vessels) were examined for the assessment of in vitro potency, selectivity of the ETA receptor against the ETB receptor, specificity for ET receptors, agonistic activities for ET receptors and the blocking manner of the compound on ET receptors. Chinese hamster ovary (CHO) cells expressing human ET receptors and tissue membrane preparations from both human and animals were used for the binding assays. The specificity of the compound against ET receptors was demonstrated using 116 and 9 receptor binding and enzyme assays, respectively. The agonistic activity and potency of the compound at tissue levels were examined using isolated vessels. We also demonstrated the effect of protein binding on the potency of the compound by adding a physiological concentration of serum albumin to the tissue baths. In vivo potency and features of the compound as a selective ETA-antagonist were confirmed using mice, rats and dogs exogenously treated with ET-1 or big ET-1. We also demonstrated the compound's duration of action and pharmacokinetics in animal models and intact animals, respectively. From these experiments, we found a nonpeptide, potent, orally active and long-lasting, highly selective ETA-receptor antagonist.
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PMID:Methods for assessing endothelin ETA-receptor antagonists in preclinical studies. 1222 43

Three isopeptides of endothelin (ET-1, -2, and -3) exert various actions through stimulation of two sub-types of receptor (ETA and ETB). Vascular endothelial cells produce only ET-1. In addition to its powerful vasoconstrictor action, ET-1 has direct mitogenic actions on cardiovascular tissues, as well as comitogennic actions with a wide variety of growth factors and vasoactive substances. ET-1 also promotes the synthesis and secretion of growth factors and various substances, including extracellular constituents. These effects of endogenous ET-1 would naturally be thought to be concerned with the development and/or aggravation of chronic cardiovascular diseases; e.g., hypertension, pulmonary hypertension, vascular remodeling (stenosis, atherosclerosis), renal failure, and heart failure. A large number of peptide and orally active non-peptide endothelin receptor antagonists have been developed, and utilized to analyze physiological and pathophysiological roles of endogenous ET-1. These antagonists have been shown to exert excellent therapeutic effects in animal models of various kinds of diseases by either acute or chronic treatment. Therapeutic treatment of patients suffering from the above-mentioned cardiovascular diseases with ET-receptor antagonists have also been taking place, and bosentan (ETA/ETB antagonist) was recently approved by the FDA as a formal therapeutic drug for pulmonary hypertension. In this review, perspectives for therapeutic applicability of ET-receptor antagonists will be explored.
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PMID:[New expansion of endothelin research: perspectives for clinical application of endothelin-receptor antagonists]. 1261 54

The purpose of this study was to determine if rats lacking the ETB receptor have altered renal endothelin (ET) production and NO synthase (NOS) activity in response to high salt and if female rats are better able to control blood pressure through higher NOS activity in rats heterozygous (sl/+) and homozygous (sl/sl) for ETB receptor deficiency. On normal salt (0.4% NaCl; NS), male sl/sl rats had higher systolic blood pressures compared with male sl/+ and female sl/+ and sl/sl rats. On a high salt diet (10% NaCl; HS), blood pressure in male sl/+ rats was significantly higher than female sl/+ rats. However, ETB receptor deficiency caused much larger increases in blood pressure in male and female rats. On NS, urinary ET excretion was not different between male and female of either genotype. HS significantly increased ET excretion in male and female sl/+ rats, but the increase was significantly less in sl/sl compared with sl/+. Homogenates of inner medullary collecting duct tissue were separated into particulate and cytosolic fractions and total NOS activity measured by conversion of [3H]L-arginine to [3H]L-citrulline. Female rats had significantly greater cytosolic NOS activity compared with male rats on NS. On HS, cytosolic NOS activity was lower in all groups compared with NS rats, whereas particulate NOS activity was significantly greater in male and female sl/+ rats compared with male and female sl/sl rats. These data support our hypothesis that NOS protects against rises in blood pressure in female rats and ETB receptors prevent further increases in blood pressure due to increases in renal ET production and NOS activity.
Hypertension 2003 Mar
PMID:Gender differences in ET and NOS systems in ETB receptor-deficient rats: effect of a high salt diet. 1262 75

Experiments were conducted to determine the influence of ETB receptors in the control of renal medullary function. The acute relation between renal perfusion pressure (RPP) and natriuresis was examined in anesthetized rats treated with the ETB antagonist A-192621 (10 mg/kg IV). In A-192621-treated rats, sodium excretion (UNaV) was 0.4+/-0.1, 0.6+/-0.3, and 2.7+/-0.5 micromol/min at RPP of 80+/-1, 107+/-1, and 144+/-5 mm Hg, respectively. In control rats, UNaV averaged 0.8+/-0.4, 3.4+/-1.2, and 8.1+/-1.7 micromol/min at RPP of 77+/-2, 115+/-5, and 137+/-3 mm Hg, respectively. For normal and high RPP, UNaV was significantly lower in A-192621-treated rats compared with control rats. Additional experiments determined the effects of Big ET-1 (10 pmol/kg per minute) on intrarenal blood flow. Medullary blood flow (MBF) and cortical blood flow were measured in anesthetized rats by single-fiber, laser Doppler flowmetry. Cortical blood flow significantly decreased in response to Big ET-1 in rats on a normal or high salt diet. Big ET-1 significantly increased MBF in rats on a high salt diet, whereas there was no change in MBF in rats on a normal salt diet. These results demonstrate that medullary vasodilation produced by Big ET-1 is more prominent in rats on a high salt diet and are consistent with a contribution of ETB-mediated events in the natriuretic response to high salt intake. Taken together, these findings support the hypothesis that endothelin plays an important role in regulating sodium excretion through activation of ETB receptors.
Hypertension 2003 Jun
PMID:Functional role of ETB receptors in the renal medulla. 1271 43


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