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

1. The aims of the present study were to characterize the pharmacological profile of a new endothelin (ET) receptor antagonist, TAK-044 and to consider whether it limits the extension of myocardial infarct size in rats. 2. Binding of [125I]-ET-1 to ET receptors on rabbit ventricular and cerebellar membrane fractions was inhibited by TAK-044 with IC50 values of 3.8 nM and 130 nM, respectively. 3. It inhibited ET-1, ET-2 and ET-3-induced vasoconstriction of porcine isolated coronary arteries in a competitive (ET-1, ET-2) and a non-competitive (ET-3) manner. 4. In the rat in vivo, the ET-1-induced blood pressure changes including transient hypotension followed by sustained hypertension, were inhibited by TAK-044 (0.1-10 mg kg-1, i.v.) in a dose-dependent manner. 5. Acute myocardial infarction induced by 1 h coronary occlusion followed by 24 h reperfusion in rats caused an infarct size of 60 +/- 2% (n = 12) of the area-at-risk by weight. 6. Intravenous injection of TAK-044 10 min before coronary occlusion reduced the infarct size in a dose-dependent manner: 32% and 54% reductions at 1 and 3 mg kg-1, respectively. 7. TAK-044 administered 10 min before or 1 h after reperfusion (1 mg kg-1, i.v.) showed similar inhibitory effects: 34% and 23% reductions, respectively. 8. We conclude that TAK-044 is an ETA/ETB receptor antagonist which shows strong inhibitory effects on the extension of myocardial infarct size after coronary artery occlusion-reperfusion in rats.
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PMID:Pharmacology of a non-selective ETA and ETB receptor antagonist, TAK-044 and the inhibition of myocardial infarct size in rats. 778 Jun 49

Cyclosporin A (CsA) treatment is associated with hypertension and renal dysfunction. Increased circulating endothelin (ET) has been implicated in this renal dysfunction, which is secondary to renal vasoconstriction and decreases in RBF. The effects of the selective blockade of ETA receptors or the combined blockade of ETA and ETB receptors on the acute hemodynamic response to CsA in anesthetized rats were examined. Rats were pretreated with vehicle, BQ-123 (selective ETA receptor antagonist; 0.6 micron/kg per minute), or BQ-123 and PD 142893 (combined ETA/ETB receptor antagonist; 0.6 micron/kg per minute) to achieve both ETA and ETB receptor blockade. After a 10-min pretreatment, CsA (20 mg/kg over 10 min) was administered; mean arterial blood pressure, RBF, and iliac blood flow were monitored continuously. Hemodynamic responses to exogenous endothelin-1 (ET-1, 0.3 and 1 nmol/kg) with and without antagonist pretreatment were measured in separate groups to demonstrate effective receptor blockade. CsA elevated blood pressure 17 to 20% in all three groups; renal resistance maximally increased 23, 20, and 23% in vehicle, BQ-123, and BQ-123 and PD 142893 pretreated groups, respectively. In contrast, the combination of BQ-123 and PD 142893 blocked systemic pressor responses to 0.3 and 1 nmol of ET-1 approximately 50 and 37%, respectively; changes in renal resistance were blocked 81 and 89%, respectively. In conclusion, the elevation in systemic blood pressure and the renal vasoconstrictor activity of CsA do not appear to be mediated through ETA or ETB receptors.
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PMID:Effects of selective endothelin antagonists on the hemodynamic response to cyclosporin A. 816 26

The existence of vasoconstrictive factors originating from the endothelium was confirmed by the description of endothelin, a 21-amino-acid peptide derived from a series of precursors, preproendothelin and a 38-amino-acid big endothelin. Three isoforms of endothelin, endothelin-1, -2 and -3, and 3 receptors (ETA, ETB and ETC) have been described and cloned. The cellular mode of action of endothelin seems to involve the modulation of intracellular calcium (through inositol trisphosphate, diacylglycerol and phospholipase C) and activation of calcium channels. The effects of endothelin are predominantly on the cardiovascular system. Its major effect is vasoconstriction, both systemic and pulmonary, with additional positive chronotropic and inotropic effects on the heart. It has also been implicated in homeostatic regulation of kidney microcirculation, and has powerful mitogenic effects on fibroblasts and smooth muscle cells. Many additional effects have been described on the endocrine system and on other systems. However, the clinical relevance of such effects is uncertain. Increased plasma endothelin levels have been reported in many diseases, but as yet it is not certain whether they are a cause or a consequence of the pathology. Pathologies most probably related to endothelin dysfunction are the vasospastic diseases, especially vasospasm after subarachnoid haemorrhage. Endothelin could be implicated to a lesser measure in diseases typical of the elderly population, such as hypertension or atherosclerosis. Drugs are being developed which act on endothelin metabolism, the most promising of which appear to be the inhibitors of endothelin converting enzyme and endothelin receptor antagonists. Some already existing drugs, such as calcium channel blockers or angiotensin converting enzyme inhibitors, probably act at least in part by interfering with endothelin metabolism or effects.
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PMID:Endothelins. A potential target for pharmacological intervention in diseases of the elderly. 819 96

Cultured rat vascular smooth muscle cells (VSMCs) possess receptors for potent vasoconstrictor endothelin-1 (ET-1) as well as potent vasodilator natriuretic peptides (atrial, brain, and C-type natriuretic peptides [ANP, BNP, and CNP, respectively]). However, little is known about molecular interactions between endothelin receptors and natriuretic peptides in VSMCs. To elucidate whether natriuretic peptides regulate vascular endothelin receptors, we studied the effects of three natriuretic peptides on the capacity of 125I-ET-1 binding and expression of endothelin type A (ETA) and type B (ETB) receptor mRNAs in cultured rat VSMCs. CNP (10(-6) mol/L) increased 125I-ET-1 binding capacity in a time-dependent manner (6 to 48 hours) and stimulated cyclic GMP (cGMP) generation in a dose-dependent manner (10(-8)) to 10(-6) mol/L). Pretreatment with CNP (10(-8) to 10(-6) mol/L) and 8-bromo-cGMP (10(-5) to 10(-3) mol/L) for 24 hours resulted in dose-dependent increases in 125I-ET-1 binding in VSMCs. The three natriuretic peptides at the highest concentration (10(-6) mol/L) increased 125I-ET-1 binding and stimulated cGMP generation with almost the same rank order of efficacy (CNP > BNP > ANP). Scatchard analysis of binding studies revealed that CNP (10(-6) mol/L) and 8-bromo-cGMP (10(-3) mol/L) increased vascular endothelin receptor number by 28% and 88%, respectively, without changing its affinity. Pretreatment with both CNP and 8-bromo-cGMP increased ET-1-stimulated inositol 1,4,5-trisphosphate formation.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1994 Jun
PMID:C-type natriuretic peptide upregulates vascular endothelin type B receptors. 820 31

ENDOTHELIUM-DERIVED NITRIC OXIDE: The endothelium is a source of vasoactive factors among which the most relevant are nitric oxide and endothelin. Nitric oxide is synthesized from L-arginine by a family of nitric oxide synthases and is a widespread biological mediator. It is implicated in many physiological and pathophysiological processes, including a variety of cardiovascular diseases like hypertension. NITRIC OXIDE AND HYPERTENSION: The release of nitric oxide seems to be modulated by changes in blood pressure. However, the role of nitric oxide in hypertension is still controversial and seems to vary depending on the stage of the disease and the model studied. In spontaneous hypertension, the production of nitric oxide is increased but inefficacious, probably because of increased inactivation or scavenging. In the heart the production of nitric oxide seems to be increased, probably as a compensatory mechanism against hypertension. In salt-induced hypertension, nitric oxide production may be impaired. In human hypertension, pharmacological experiments reveal an impaired nitric oxide dilator mechanism. In pulmonary hypertension, the use of nitric oxide gas inhalation has been proposed as a future therapy for this condition. ENDOTHELIN: Endothelin-1 is a potent vasoconstrictor peptide produced and released from endothelial cells. In isolated blood vessels, endothelin causes profound contraction. The hemodynamic effects of endothelin can be explained by the activation of two endothelin receptors, ETA and ETB. The relationship between endothelin and hypertension is not clear. Although plasma endothelin levels are normal in most patients with essential hypertension, the hypertensive blood vessel wall may contract more profoundly in response to the peptide; hence, endothelin antagonists may have antihypertensive effects in patients with hypertension.
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PMID:Endothelium-derived vasoactive factors in hypertension: nitric oxide and endothelin. 857 87

1. We examined preproendothelin-1, ETA and ETB receptor mRNA levels in aortic endothelial and smooth muscle cells from cyclosporine (CyA)-induced hypertensive rats using the reverse transcription polymerase chain reaction method. 2. Aortic endothelial preproendothelin-1 mRNA expression was about 1.5-fold higher, while that of ETB receptor mRNA was markedly decreased in CyA-treated rats compared with those in controls. 3. The expression of ETA receptor mRNA in smooth muscle cells from CyA-induced hypertensive rats was increased about two-fold over that in cells from control animals. 4. Thus, increased endothelial preproendothelin-1, and ETA receptor mRNA levels in smooth muscle cells, which are concomitant with the decrease in ETB receptor mRNA levels in endothelium, may contribute to CyA-induced hypertension in rats.
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PMID:Gene expression of endothelin receptors in aortic cells from cyclosporine-induced hypertensive rats. 858 89

We have established a transgenic rat model for the expression of the human endothelin-2 (ET-2). These animals exhibit overexpression of the transgene in tissues as well as in plasma. Despite these changes, blood pressure remains normal. To understand the regulatory mechanisms for normotension in the presence of increased ET-2 levels, we have investigated the ET system in more detail. We used competitive reverse transcription-polymerase chain reaction (RT-PCR) to evaluate possible overexpression or downregulation of endothelin A and B receptors at the mRNA level. PCR analyses revealed no significant differences of ETA and ETB receptor expression. In conclusion, the expression of human ET-2 in transgenic rats does not result in hypertension. Normotension in the transgenic animals is independent of ET receptor regulation. The reason for this may be counterregulation by other vasoactive systems, such as the NO system. Future studies will take this into account and will also concentrate on possible histomorphologic alterations caused by mitogenic properties of the endothelins.
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PMID:Regulation of the endothelin system in transgenic rats expressing the human endothelin-2 gene. 858 1

The renal endothelin (ET) system has been implicated in the maintenance of hypertension in spontaneously hypertensive rats (SHRs). However, little is known about the expression and cellular distribution of the ET receptor subtypes in the kidney of SHRs. We therefore analyzed the expression of ET receptor subtypes in the kidneys of 16-week-old SHRs. Wistar-Kyoto (WKY) rats served as controls. Furthermore, we investigate the effects of the ETA receptor antagonist BQ 123 and the mixed (ETA/ETB) receptor antagonist bosentan on mean arterial blood pressure (MAP), renal blood flow (RBF), and glomerular filtration rate (GFR) in conscious, chronically instrumented rats. In SHRs we found overexpression of the ETA in the glomeruli and smooth muscle cells of intrarenal arteries compared to age-matched WKY rats. Furthermore, our study revealed a pronounced upregulation of the ETB in the glomeruli of SHRs. Blockade of ETA and ETB receptors in SHR with bosentan as well as with BQ 123 led to a significant decrease in MAP and a significant increase in RBF, indicating that the ETA receptor plays a major role in the maintenance of high blood pressure and the regulation of RBF in SHRs. The blockade of both ETA and ETB receptors by bosentan has no further effect on MAP reduction or increase in RBF in SHRs compared to ETA blockade by BQ 123. In contrast, combined blockade of ETA and ETB receptors by bosentan significantly decreased GFR in SHRs, whereas no effect on GFR was observed in WKY rats, suggesting that the glomerular ETB overexpression in SHRs is of pathophysiologic relevance.
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PMID:Significance of endothelin receptor subtypes in the kidneys of spontaneously hypertensive rats: renal and hemodynamic effects of endothelin receptor antagonists. 858 49

We used Ro 46-8443, non-peptidic antagonist selective of endothelin ETB receptors, to study the role of ETB receptors in rat hypertension models. In normotensive rats, Ro 46-8443 decreased blood pressure, but in SHR and DOCA rats, it induced a pressor effect, due to blockade of ETB-mediated release of nitric oxide since L-NAME prevented it. In rats rendered hypertensive by chronic L-NAME, Ro 46-8443 did not induce a pressor but depressor effect. Thus, in DOCA rats and SHR, Ro 46-8443 reveals a predominant influence of endothelial 'vasorelaxant' ETB receptors, while in normotensive rats the prevailing role of ETB receptors seems to be in mediating a vasoconstrictor tone.
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PMID:The role of ETB receptors in normotensive and hypertensive rats as revealed by the non-peptide selective ETB receptor antagonist Ro 46-8443. 861 87

Microinjection of N-methyl-D-aspartate (NMDA) (0.068 to 6.8 nmol) into the periaqueductal gray area (PAG) of anaesthetized rats caused dose-dependent increases in blood pressure. Preinjection (10 min before) of FR 139317 (an ETA receptor selective antagonist; 5 nmol) or SB 209670 (an ETA/ETB receptor non-selective antagonist; 5 nmol) to the PAG reduced the pressor response to NMDA whereas BQ-788 (an ETB receptor selective antagonist; 5 nmol) did not affect the NMDA-induced hypertension. Pretreatment with DL-2-amino-5-phosphono valeric acid (2-APV) (an NMDA receptor selective antagonist, 5 nmol) also abolished the pressor response induced by NMDA. Dose-dependent increases in blood pressure induced by injection of angiotensin II (0.1-10 nmol) to the PAG were unaffected by FR 139317 or SB 209670. Thus, our data indicate that endogenous ET-1, via an action on ETA receptors, contributes to the pressor effects of NMDA within the brain.
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PMID:Involvement of endothelin in the pressor response following injection of NMDA to the periaqueductal gray area of rats. 868 Jul 7


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