Role of endothelin in the increased vascular tone of patients with essential hypertension.
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We investigated the possible role of endothelin in the increased vasoconstrictor tone of hypertensive patients using antagonists of endothelin receptors. Forearm blood flow (FBF) responses (strain-gauge plethysmography) to intraarterial infusion of blockers of endothelin-A (ETA) (BQ-123) and endothelin-B (ETB) (BQ-788) receptors, separately and in combination, were measured in hypertensive patients and normotensive control subjects. In healthy subjects, BQ-123 alone or in combination with BQ-788 did not significantly modify FBF (P=0.78 and P=0.63, respectively). In hypertensive patients, in contrast, BQ-123 increased FBF by 33+/-7% (P<0.001 versus baseline), and the combination of BQ-123 and BQ-788 resulted in a greater vasodilator response (63+/-12%; P=0.006 versus BQ-123 alone in the same subjects). BQ-788 produced a divergent vasoactive effect in the two groups, with a decrease of FBF (17+/-5%; P=0.004 versus baseline) in control subjects and transient vasodilation (15+/-7% after 20 minutes) in hypertensive patients (P<0.001, hypertensives versus controls). The vasoconstrictor response to endothelin-1 was slightly higher (P=0.04) in hypertensive patients (46+/-4%) than in control subjects (32+/-4%). Our data indicate that patients with essential hypertension have increased vascular endothelin activity, which may be of pathophysiological relevance to their increased vascular tone. In these patients, nonselective ETA and ETB blockade seems to produce a greater vasodilator effect than selective ETA blockade. (+info)
Different contributions of endothelin-A and endothelin-B receptors in the pathogenesis of deoxycorticosterone acetate-salt-induced hypertension in rats.
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We investigated the involvement of actions mediated by endothelin-A (ETA) and endothelin-B (ETB) receptors in the pathogenesis of deoxycorticosterone acetate (DOCA)-salt-induced hypertension in rats. Two weeks after the start of DOCA-salt treatment, rats were given ABT-627 (10 [mg/kg]/d), a selective ETA receptor antagonist; A-192621 (30 [mg/kg]/d), a selective ETB receptor antagonist; or their vehicle for 2 weeks. Uninephrectomized rats without DOCA-salt treatment served as controls. Treatment with DOCA and salt for 2 weeks led to a mild but significant hypertension; in vehicle-treated DOCA-salt rats, systolic blood pressure increased markedly after 3 to 4 weeks. Daily administration of ABT-627 for 2 weeks almost abolished any further increases in blood pressure, whereas A-192621 did not affect the development of DOCA-salt-induced hypertension. When the degree of vascular hypertrophy of the aorta was histochemically evaluated at 4 weeks, there were significant increases in wall thickness, wall area, and wall-to-lumen ratio in vehicle-treated DOCA-salt rats compared with uninephrectomized control rats. The development of vascular hypertrophy was markedly suppressed by ABT-627. In contrast, treatment with A-192621 significantly exaggerated these vascular changes. In vehicle-treated DOCA-salt rats, renal blood flow and creatinine clearance decreased, and urinary excretion of protein, blood urea nitrogen, fractional excretion of sodium, and urinary N-acetyl-beta-glucosaminidase activity increased. Such damage was overcome by treatment with ABT-627 but not with A-192621; indeed, the latter agent led to worsening of the renal dysfunction. Histopathologic examination of the kidney in vehicle-treated DOCA-salt rats revealed tubular dilatation and atrophy as well as thickening of small arteries. Such damage was reduced in animals given ABT-627, whereas more severe histopathologic changes were observed in A-192621-treated animals. These results strongly support the view that ETA receptor-mediated action plays an important role in the pathogenesis of DOCA-salt-induced hypertension. On the other hand, it seems likely that the ETB receptor-mediated action protects against vascular and renal injuries in this model of hypertension. A selective ETA receptor antagonist is likely to be useful for treatment of subjects with mineralocorticoid-dependent hypertension, whereas ETB-selective antagonism alone is detrimental to such cases. (+info)
Gene expression of vasoactive intestinal contractor/endothelin-2 in ovary, uterus and embryo: comprehensive gene expression profiles of the endothelin ligand-receptor system revealed by semi-quantitative reverse transcription-polymerase chain reaction analysis in adult mouse tissues and during late embryonic development.
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Vasoactive intestinal contractor (VIC)/endothelin-2 (ET-2) is a 21 amino acid intestinal peptide characterized as a potent vasoactive and intestinal smooth muscle-contracting compound. To investigate the physiological roles of VIC/ET-2 further, we characterized the specificity of VIC gene expression relative to that of other members of the endothelin (ET) ligand-receptor system in adult mouse tissues and during embryonic development. Gene expression of ET-1, ET-3, ETA and ETB was ubiquitous in almost all tissues we examined while gene expression of VIC was localized to certain tissues. A high level of VIC gene expression was observed in ovary and uterus. The gene expression of VIC, relative to that of glyceraldehyde-3-phosphate dehydrogenase, was approximately 2.0%, 0.4%, and 2.3% in ovary, uterus, and intestine respectively, and was approximately 1.6 and 7. 1 times higher than that of ET-1 in ovary and intestine respectively. Thus, VIC may have some physiological role in adult ovary and uterus as well as intestine. In embryonic development, VIC gene expression sharply increased between 11 and 15 days post coitus and decreased after birth, suggesting an involvement in the later stages of embryonic development. (+info)
Mechanisms of endothelin-induced venoconstriction in isolated guinea pig mesentery.
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In the present study, endothelin (ET) agonists and receptor selective antagonists were used to characterize ET receptors mediating constriction in guinea pig mesenteric veins (250-300 micrometers diameter) in vitro. The contribution of ET-evoked vasodilator release to venous tone was also explored. Computer-assisted video microscopy was used to monitor vein diameter. Endothelin-1 (ET-1), endothelin-3 (ET-3), and sarafotoxin 6c (S6c) produced sustained concentration-dependent contractions with a rank order agonist potency of ET-1 = S6c > ET-3. Indomethacin (1 microM) and Nomega-nitro-L-arginine (100 microM) enhanced ET-1 and S6c responses. The ETA selective antagonists BQ-610 (100 nM) and PD156707 (10 nM) shifted ET-1 concentration-response curves rightward and decreased maximal ET-1 responses, without changing S6c responses. The ETB selective antagonist BQ-788 (100 nM) shifted S6c responses rightward but produced no change in ET-1 responses. Combined application of BQ-788 and BQ-610 or BQ-788 and PD 156707 produced a rightward shift in ET-1 responses that was greater than shifts produced by BQ-610 or PD 156707 alone. In conclusion, smooth muscle in guinea pig mesenteric veins expresses ETA and ETB receptors coupled to contractile mechanisms. Activation of endothelial ETB receptors results in release of vasodilators, primarily nitric oxide. (+info)
Plasma endothelin levels in patients with abdominal aortic aneurysms.
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OBJECTIVES: endothelin 1,2 plays a significant role in the process of atherogenesis and vascular wall injury. The aim of this study was to assess whether plasma endothelin 1,2 levels were elevated in patients with large or symptomatic abdominal aortic aneurysms (AAAs). DESIGN: a prospective open study. MATERIALS AND METHODS: plasma endothelin 1,2 levels were measured in 65 consecutive patients with infrarenal aortic aneurysms and compared with the levels in 44 healthy volunteer controls. The data for abdominal aneurysm patients was analysed in four subgroups: (i) small aneurysms (<5 cm), (ii) large aneurysms (>/=5 cm), (iii) asymptomatic aneurysms and (iv) symptomatic aneurysms. Comparisons were made between endothelin 1,2 levels in aneurysm patients and controls and between the different aneurysm subgroups. RESULTS: a highly significant difference (p<0.0001) was found between aneurysm patients and controls. Patients with large aneurysms had significantly higher levels than patients with small aneurysms (p<0.01). There was no statistical difference in endothelin 1,2 levels between symptomatic and asymptomatic patients; however, the highest levels were found in large, symptomatic aneurysms and the lowest in small, asymptomatic aneurysms. CONCLUSIONS: plasma endothelin 1,2 is an endogenous marker of aneurysm diameter. Further studies are required to determine whether it relates to the rate of growth of aneurysms. (+info)
Purification, structural characterization, and myotropic activity of endothelin from trout, Oncorhynchus mykiss.
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Endothelin (ET) from a nontetrapod species has never been characterized, either structurally or biologically. A single molecular form of trout ET with 21-amino-acid residues was isolated in pure form from an extract of the kidney of the steelhead trout, Oncorhynchus mykiss and its primary structure established as Cys-Ser-Cys-Ala-Thr-Phe-Leu-Asp-Lys-Glu10-Cys-Val-Tyr-Phe-Cys-His- L eu-Asp-Ile-Ile20-Trp. This amino acid sequence shows only three substitutions (Ala4-->Ser, Thr5-->Ser, and Phe6-->Trp) compared with human ET-2, demonstrating that the structure of the peptide has been well conserved during evolution and that the pathway of posttranslational processing of preproendothelin in the trout is probably similar to that in mammals. Synthetic trout ET produced concentration-dependent constrictions of isolated rings of vascular tissue from trout efferent branchial artery (EBA; pD2 = 7. 90 +/- 0.06, n = 5), caeliacomesenteric artery (pD2 = 8.03 +/- 0. 04, n = 4), anterior cardinal vein (ACV; pD2 = 8.57 +/- 0.25, n = 4), and rat abdominal aorta (AO; pD2 = 8.86 +/- 0.08, n = 7). Trout and rat vessels were more sensitive to mammalian ET-1 than to trout ET (pD(2) for human ET-1 in: EBA = 9.12 +/- 0.14; ACV = 9.90 +/- 0.15; AO = 8.86 +/- 0.08), but there was no significant difference in the maximum tension produced by either peptide in these vessels. (+info)
Endothelin-mediated calcium signaling in preglomerular smooth muscle cells.
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This study was performed to test the hypothesis that endothelin peptides differentially influence intracellular calcium concentration ([Ca(2+)](i)) in preglomerular microvascular smooth muscle cells (MVSMC), in part through activation of endothelin (ET)(A) receptors. Experiments were performed in vitro with the use of single MVSMC freshly isolated from rat preglomerular microvessels. The effect of ET-1, ET-2, and ET-3 on [Ca(2+)](i) was measured with the use of the calcium-sensitive dye, fura 2, and standard fluorescence microscopy techniques. Baseline [Ca(2+)](i) averaged 84+/-3 nmol/L (n=141 cells from 23 dispersions). ET-1 concentrations of 1, 10, and 100 nmol/L evoked peak increases in [Ca(2+)](i) of 48+/-16, 930+/-125, and 810+/-130 nmol/L, respectively. The time course of the [Ca(2+)](i) response was biphasic, beginning with a rapid initial increase followed by a sustained plateau phase or a period during which [Ca(2+)](i) oscillated sharply. Similar responses were observed after ET-2 administration. In contrast, ET-3 stimulated monophasic increases in [Ca(2+)](i) of only 14+/-5, 33+/-16, and 44+/-19 nmol/L at peptide concentrations of 1, 10, and 100 nmol/L, respectively. These responses are significantly smaller than responses to ET-1 or ET-2, respectively. The relative contributions of calcium mobilization and calcium influx in the response to ET-1 were also evaluated. Removal of calcium from the bathing medium did not significantly alter the peak response to 10 nmol/L ET-1 but abolished the late phase elevation of [Ca(2+)](i). These data demonstrate that endothelin peptides increase [Ca(2+)](i) in preglomerular MVSMC. The concentration-response profiles are consistent with the response involving activation of ET(A) receptors. Furthermore, these results suggest that ET-1 increases [Ca(2+)](i) by stimulating both the release of intracellular calcium and the influx of calcium from the extracellular medium. (+info)
Contraction to big endothelin-1, big endothelin-2 and big endothelin-3, and endothelin-converting enzyme inhibition in human isolated bronchi.
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All three endothelin precursor peptides, i.e. big endothelin-1 (big ET-1), big endothelin-2 (big ET-2) and big endothelin-3 (big ET-3), produced contractile responses in human isolated bronchi, demonstrating the presence of functional endothelin-converting enzyme (ECE) in this tissue. The maximal contractile responses were equal to 108.4+/-8.0% (0.1 microM big ET-1; n=4), 85.2+/-11.8% (0.1 microM big ET-2; n=7) and 43.0+/-7.2% (0.1 microM big ET-3; n=5) of the reference response to acetylcholine (1 mM). The response to big ET-1 (0.1 microM), but not endothelin-1 (ET-1, 0.1 microM), was diminished after overnight storage of the tissue at 4 degrees C, demonstrating instability of the enzyme. The responses to all three big-endothelins were significantly inhibited, by the ECE inhibitors CGS 26393 and CGS 26303, in a concentration-related manner. The responses to the mature peptides ET-1, endothelin-2 (ET-2), and endothelin-3 (ET-3) were unaffected by CGS 26393 and CGS 26303. Phosphoramidon (10 microM) also produced an inhibition of the response to big ET-1 that was equivalent to that produced by CGS 26393 (10 microM). Combination of CGS 26393 (10 microM) and phosphoramidon (10 microM) did not produce an additive inhibition. These results demonstrate the presence of functional ECE for all three big endothelins in human bronchus and inhibition of the enzyme by newly developed orally active ECE inhibitors, as well as phosphoramidon. British Journal of Pharmacology (2000) 129, 170 - 176 (+info)