(1/3445) Role of endothelin in the increased vascular tone of patients with essential hypertension.
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)
(2/3445) Different contributions of endothelin-A and endothelin-B receptors in the pathogenesis of deoxycorticosterone acetate-salt-induced hypertension in rats.
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)
(3/3445) Modulation of basal intracellular calcium by inverse agonists and phorbol myristate acetate in rat-1 fibroblasts stably expressing alpha1d-adrenoceptors.
In rat-1 fibroblasts stably expressing alpha1d-adrenoceptors BMY 7378, phentolamine, chloroethylclonidine and 5-methyl urapidil decreased basal [Ca2+]i. WB 4101 induced a very small effect on this parameter but when added before the other antagonists it blocked their effect. All these agents inhibited the action of norepinephrine. Phorbol myristate acetate also blocked the effect of norepinephrine and decreased basal [Ca2+]i. Staurosporine inhibited these effects of the phorbol ester. Our results suggest that: (1) alpha1d-adrenoceptors exhibit spontaneous ligand-independent activity, (2) BMY 7378, phentolamine, chloroethylclonidine and 5-methyl urapidil act as inverse agonists and (3) protein kinase C activation blocks spontaneous and agonist-stimulated alpha1d-adrenoceptor activity. (+info)
(4/3445) Endogenous plasma endothelin concentrations and coronary circulation in patients with mild dilated cardiomyopathy.
OBJECTIVE: To determine whether increased plasma concentrations of endothelin-1 (ET-1) and big endothelin (BET) play a role in the regulation of coronary circulation in patients with idiopathic dilated cardiomyopathy (IDCM). SETTING: Tertiary referral centre for cardiac diseases. PATIENTS: Fourteen patients (eight male/six female; mean (SD) age 59 (9) years) with IDCM (ejection fraction 36 (9)%) and five normotensive subjects (two male/three female; age 52 (7) years) serving as controls were studied. METHODS: Functional status was classified according to New York Heart Association (NYHA) class. Endogenous ET-1 and BET plasma concentrations from the aorta and the coronary sinus were determined by radioimmunoassay. Coronary blood flow, using the inert chromatographic argon method, myocardial oxygen consumption, and coronary sinus oxygen content under basal conditions were determined. RESULTS: In the aorta, mean (SD) concentrations of ET-1 (IDCM 0.76 (0.25) v controls 0.31 (0.06) fmol/ml; p = 0.002) and BET (IDCM 3.58 (1.06) v controls 2.11 (0.58) fmol/ml; p = 0.014) were increased in patients with IDCM. Aortic ET-1 concentrations correlated positively with NYHA class (r = 0. 731; p < 0.001), myocardial oxygen consumption (r = 0.749; p < 0. 001), and coronary blood flow (r = 0.645; p = 0.003), but inversely with coronary sinus oxygen content (r = -0.633; p = 0.004), which was significantly decreased in IDCM patients (IDCM 4.68 (1.05) v controls 6.70 (1.06) vol%; p = 0.003). CONCLUSIONS: The coronary circulation in patients with IDCM is exposed to an increased endothelin load. ET-1 concentrations correlate with functional deterioration. A decrease of the coronary sinus content of oxygen suggests a mismatch between coronary blood flow and metabolic demand. Thus, ET-1 might be a marker of a disequilibrium between myocardial oxygen demand and coronary blood flow in IDCM. (+info)
(5/3445) Nitric oxide modulates endothelin 1-induced Ca2+ mobilization and cytoskeletal F-actin filaments in human cerebromicrovascular endothelial cells.
A functional interrelation between nitric oxide (NO), the endothelial-derived vasodilating factor, and endothelin 1 (ET-1), the potent vasoconstrictive peptide, was investigated in microvascular endothelium of human brain. Nor-1 dose-dependently decreased the ET-1-stimulated mobilization of Ca2+. This response was mimicked with cGMP and abrogated by inhibitors of guanylyl cyclase or cGMP-dependent protein kinase G. These findings indicate that NO and ET-1 interactions involved in modulation of intracellular Ca2+ are mediated by cGMP/protein kinase G. In addition, Nor-1-mediated effects were associated with rearrangements of cytoskeleton F-actin filaments. The results suggest mechanisms by which NO-ET-1 interactions may contribute to regulation of microvascular function. (+info)
(6/3445) Endogenous endothelin-1 depresses left ventricular systolic and diastolic performance in congestive heart failure.
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. (+info)
(7/3445) Relaxation of endothelin-1-induced pulmonary arterial constriction by niflumic acid and NPPB: mechanism(s) independent of chloride channel block.
We investigated the effects of the Cl- channel blockers niflumic acid, 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB) and 4, 4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS) on endothelin-1 (ET-1)-induced constriction of rat small pulmonary arteries (diameter 100-400 microm) in vitro, following endothelium removal. ET-1 (30 nM) induced a sustained constriction of rat pulmonary arteries in physiological salt solution. Arteries preconstricted with ET-1 were relaxed by niflumic acid (IC50: 35.8 microM) and NPPB (IC50: 21.1 microM) in a reversible and concentration-dependent manner. However, at concentrations known to block Ca++-activated Cl- channels, DIDS (=500 microM) had no effect on the ET-1-induced constriction. Similar results were obtained when pulmonary arteries were preincubated with these Cl- channel blockers. When L-type Ca++ channels were blocked by nifedipine (10 microM), the ET-1-induced (30 nM) constriction was inhibited by only 5.8%. However, niflumic acid (30 microM) and NPPB (30 microM) inhibited the ET-1-induced constriction by approximately 53% and approximately 60%, respectively, both in the continued presence of nifedipine and in Ca++-free physiological salt solution. The Ca++ ionophore A23187 (10 microM) also evoked a sustained constriction of pulmonary arteries. Surprisingly, the A23187-induced constriction was also inhibited in a reversible and concentration-dependent manner by niflumic acid (IC50: 18.0 microM) and NPPB (IC50: 8.8 microM), but not by DIDS (= 500 microM). Our data suggest that the primary mechanism by which niflumic acid and NPPB inhibit pulmonary artery constriction is independent of Cl- channel blockade. One possibility is that these compounds may block the Ca++-dependent contractile processes. (+info)
(8/3445) Endothelin up-regulation and localization following renal ischemia and reperfusion.
BACKGROUND: Endothelin (ET), a potent vasoconstrictor, is known to play a role in ischemic acute renal failure. Although preproET-1 (ppET-1) mRNA is known to be up-regulated following ischemia/reperfusion injury, it has not been determined which component of the injury (ischemia or reperfusion) leads to initial gene up-regulation. Likewise, although ET-1 peptide expression has been localized in the normal kidney, its expression pattern in the ischemic kidney has not been determined. Therefore, the purpose of this study was twofold: (a) to determine whether ischemia alone or ischemia plus reperfusion is required for the up-regulation of ppET-1 mRNA to occur, and (b) to localize ET-1 peptide expression following ischemia in the rat kidney to clarify better the role of ET in the pathophysiology of ischemia-induced acute renal failure. METHODS: Male Lewis rats underwent clamping of the right renal vascular pedicle for either 30 minutes of ischemia (group 1), 60 minutes of ischemia (group 2), 30 minutes of ischemia followed by 30 minutes of reperfusion (group 3), or 60 minutes of ischemia followed by three hours of reperfusion (group 4). The contralateral kidney acted as a control. ppET-1 mRNA up-regulation and ET-1 peptide expression were examined using the reverse transcription-polymerase chain reaction and immunohistochemistry, respectively. RESULTS: Reverse transcription-polymerase chain reaction yielded a control (nonischemic) value of 0.6 +/- 0.2 densitometric units (DU) of ppET-1 mRNA in the kidney. Group 1 levels (30 min of ischemia alone) were 1.8 +/- 0.4 DU, a threefold increase (P < 0.05). Group 2 levels (60 min of ischemia alone) increased almost six times above baseline, 3.5 +/- 0.2 DU (P < 0.01), whereas both group 3 and group 4 (ischemia plus reperfusion) did not experience any further significant increases in mRNA levels (1.9 +/- 0.4 DU and 2.8 +/- 0.6 DU, respectively) beyond levels in group 1 or 2 animals subjected to similar ischemic periods. ET-1 peptide expression in the ischemic kidneys was significantly increased over controls and was clearly localized to the endothelium of the peritubular capillary network of the kidney. CONCLUSIONS: Initial ET-1 gene up-regulation in the kidney occurs secondary to ischemia, but reperfusion most likely contributes to sustaining this up-regulation. The marked increase of ET-1 in the peritubular capillary network suggests that ET-induced vasoconstriction may have a pathophysiological role in ischemic acute tubular necrosis. (+info)