Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclosporin-induced hypertension is a major complication of immunosuppression in transplant recipients but its pathophysiology is only partly understood. Cyclosporin reduces endothelium-dependent vasodilation and increases endothelin synthesis and release, which may contribute to this hypertension. We examined the effects of: (1) nitric oxide enhancement with L-arginine administration and antagonism with N-nitro-L-arginine; and (2) chronic endothelin receptor blockade with the non-peptide endothelin receptor antagonist, bosentan, in two animal models of cyclosporin-induced hypertension. Cyclosporin, administered daily to female Wistar rats (10 mg/kg per day for 30 days, s.c.) and to marmosets (30 mg/kg per day for 20 days, p.o.) significantly elevated tail cuff systolic blood pressure (BP). L-arginine (250 mg/kg, in saline, i.p.), N-nitro-L-arginine (25 mg/kg, in saline, i.p.), bosentan (100 mg/kg, in arabic gum, p.o.) or vehicle were given daily to the rats during the last week of cyclosporin treatment. Marmosets received L-arginine (300 mg/kg, in water, p.o.), bosentan (100 mg/kg/day in arabic gum, p.o.) or vehicle for the last 7 days of cyclosporin treatment. L-arginine, but not saline alone significantly lowered BP in the cyclosporin-hypertensive rats from 129 +/- 2 mm Hg to 122 +/- 3 mm Hg (P < 0.05), and cyclosporin-hypertensive marmosets from 156 +/- 2 mm Hg to 139 +/- 4 mm Hg (P < 0.01). NOLA significantly increased systolic BP in cyclosporin-treated (from 133 +/- 2 mm Hg at week 3 to 142 +/- 3 mm Hg, P < 0.05) and control rats (from 124.0 +/- 2 mm Hg to 134 +/- 2 mm Hg, P < 0.05) indicating that nitric oxide synthesis in cyclosporin-hypertensive rats could be further antagonised. Bosentan, but not arabic gum alone, also lowered BP in the cyclosporin-hypertensive rats from 134 +/- 1 mm Hg to 122 +/- 3 mm Hg (P < 0.01), and cyclosporin-hypertensive marmosets from 156 +/- 2 mm Hg to 139 +/- 4 mm Hg (P < 0.01). These results support the roles of both increased endothelin synthesis and decreased nitric oxide activity in the pathogenesis of cyclosporin A-induced hypertension.
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PMID:Modulation of nitric oxide improves cyclosporin A-induced hypertension in rats and primates. 988 6

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

1. The effects of the endothelin antagonist bosentan on adrenocorticotrophic hormone (ACTH)-induced hypertension were examined in the conscious male Sprague-Dawley rat. 2. In order to confirm endothelin antagonism, 18 rats were randomly divided into two groups: receiving either (i) endothelin-1 (0.125, 0.25, 0.5 and 1 nmol/kg, i.v.); or (ii) endothelin-1 at these doses following bosentan (100 mg/kg gavage) and mean arterial pressure recorded (study A). Subsequently, 40 male rats (320 +/- 5 g) were randomly divided into four groups (n = 10): (i) Sham (0.9% saline, s.c.) + 5% acacia gum gavage; (ii) ACTH (500 micrograms/kg per day, s.c.) + 5% acacia gum gavage; (iii) Sham injection + bosentan (100 mg/kg per day) gavage; or (iv) ACTH + bosentan. Six control days (C1-C6) were followed by 11 treatment days (T0-T10). Systolic blood pressure, water intake, urine volume, food intake and bodyweight were measured every second day (study B). 3. Bosentan significantly attenuated the endothelin-1-induced blood pressure rise at 0.125 nmol/kg (P < 0.05), but not at higher doses. 4. Bosentan at a dose which attenuated endothelin-1-induced blood pressure increase had no effect on either blood pressure or metabolic parameters in ACTH-treated rats. 5. These results suggest that endothelin does not play a major role in ACTH-induced hypertension.
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PMID:Adrenocorticotrophic hormone-induced hypertension in the rat: effects of the endothelin antagonist bosentan. 1047 78

The relative contribution of cardiac output (CO) and total peripheral conductance (TPC) to the changes in blood pressure (BP) evoked by an intravenous injection of bosentan, a nonpeptide mixed endothelin (ET) antagonist, were investigated in conscious unrestrained deoxycorticosterone acetate (DOCA)-salt hypertensive rats and sham-control rats. Blood pressure was recorded by radiotelemetry devices and CO by ultrasonic transit-time flow probes. Bosentan significantly reduced BP (from 141 +/- 3 to 111 +/- 3 mm Hg) and increased TPC (from 1.19 +/-0.1 to 1.72 +/- 0.2 mL/min/kg/mm Hg) in DOCA-salt hypertensive rats, but not in sham rats. An increase in CO opposed the BP-lowering effect of the antagonist. The results demonstrate that the role of ET receptors in the maintenance of the hypertensive state in the DOCA-salt model of hypertension is exerted at the level of the resistance vessels and not on factors that regulate cardiac output.
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PMID:Total peripheral conductance mediates antihypertensive effect of nonpeptide mixed endothelin receptor antagonist in deoxycorticosterone acetate-salt hypertensive rats. 1048 Apr 81

1. Male DOCA-salt rats exhibit vasoconstriction upon ET(B) activation. Because hypertension is less severe in female than male DOCA rats, we hypothesized that female DOCA rats would display attenuated ET(B) vasoconstrictor responses. 2. Uninephrectomized Wistar rats received DOCA and drinking water containing NaCl/KCl. Control rats received vehicle and tap water. Systolic blood pressure was higher in male vs female DOCA rats. Responses to endothelin-1 (ET-1), IRL-1620, an ET(B) agonist, and acetylcholine were evaluated in isolated aortas and in vivo in the mesenteric microcirculation. 3. Endothelium-denuded aortas from male, but not female, DOCA rats displayed increased sensitivity to ET-1. IRL-1620 contracted aortas from male DOCA rats, but not control or female DOCA aortas. Noradrenaline-constricted and endothelium-intact aortas from male, but not female, DOCA rats displayed increased relaxation to IRL-1620 compared to control aortas. 4. In vivo, increased vasoconstriction to ET-1 was observed in male and female DOCA rats. IRL-1620 induced vasodilation in control rats, but vasoconstriction in male DOCA rats. There were minimal changes in diameter in vessels from female DOCA rats. 5. The initial fall in blood pressure induced by ET-1 and IRL-1620 was attenuated in male DOCA rats. Bosentan, a mixed ET(A)/ET(B) receptor antagonist, lowered blood pressure in male and female DOCA rats, but a greater and marked decrease occurred in the male DOCA group. 6. The gender-related differences in ET-1/ET(B)-mediated effects both in the vasculature and blood pressure suggest that sex-related functional up-regulation of ET(B) receptors may play a role in the more severe hypertension in male DOCA hypertensive rats.
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PMID:Deoxycorticosterone acetate-salt hypertensive rats display gender-related differences in ET(B) receptor-mediated vascular responses. 1088 94

Reports on the effectiveness of endothelin receptor blockers in angiotensin (Ang) II-induced end-organ damage are conflicting, and the mechanisms involved are uncertain. We tested the hypothesis that endothelin (ET)(A/B) receptor blockade with bosentan (100 mg/kg by gavage after age 4 weeks) ameliorates cardiac and renal damage by decreasing inflammation in rats harboring both human renin and angiotensinogen genes (dTGR). Furthermore, we elucidated the effect of bosentan on tissue factor (TF), which is a key regulator of the extrinsic coagulation cascade. We compared bosentan with hydralazine (80 mg/L in the drinking water for 3 weeks) as a blood pressure control. Untreated dTGR featured hypertension, focal necrosis in heart and kidney, and a 45% mortality rate (9 of 20) at age 7 weeks. Compared with Sprague-Dawley controls, both systolic blood pressure and 24-hour albuminuria were increased in untreated dTGR (203+/-8 versus 111+/-2 mm Hg and 67.1+/-8.6 versus 0.3+/-0.06 mg/d at week 7, respectively). Bosentan and hydralazine both reduced blood pressure and cardiac hypertrophy. Mortality rate was markedly reduced by bosentan (1/15) and partially by hydralazine (4/15). However, only bosentan decreased albuminuria and renal injury. Untreated and hydralazine-treated dTGR showed increased nuclear factor (NF)-kappaB and AP-1 expression in the kidney and heart; the p65 NF-kappaB subunit was increased in the endothelium, vascular smooth muscles cells, infiltrating cells, glomeruli, and tubules. In the heart and kidney, ET(A/B) receptor blockade inhibited NF-kappaB and AP-1 activation compared with hydralazine treatment. Macrophage infiltration, ICAM-1 expression, and the integrin expression on infiltrating cells were markedly reduced. Renal vasculopathy was accompanied by increased tissue factor expression on macrophages and vessels of untreated and hydralazine-treated dTGR, which was markedly reduced by bosentan. Thus, ET(A/B) receptor blockade inhibits NF-kappaB and AP-1 activation and the NF-kappaB- and/or AP-1-regulated genes ICAM-1, VCAM-1, and TF, independent of blood pressure-related effects. We conclude that Ang II-induced NF-kappaB and AP-1 activation and subsequent inflammation and coagulation involve at least in part the ET(A/B) receptors.
Hypertension 2000 Aug
PMID:Effect of bosentan on NF-kappaB, inflammation, and tissue factor in angiotensin II-induced end-organ damage. 1094 91

In experimental models of hypertension, blood pressure reaches a higher level in male than in female rats. Because endothelin-1 (ET-1) seems to play a role in blood pressure elevation in deoxycorticosterone acetate (DOCA)-salt hypertension, we hypothesized that male DOCA-salt rats would display a greater vascular responsiveness to ET-1 than female DOCA-salt rats. Male and female Wistar rats were uninephrectomized, received DOCA injections (50 mg/kg/week) and water plus 1.0% NaCl/0.2% KCl. Control rats received vehicle and tap water. Responses to ET-1, norepinephrine (NE), serotonin (5-HT), IRL-1620, a selective endothelin-B- (ET(B)) receptor agonist, and acetylcholine (ACh) were evaluated in isolated aortic rings and also in vivo in the mesenteric microcirculation. Endothelium-intact aortas from male and female DOCA rats displayed increased sensitivity (p < 0.05) to NE and 5-HT, but decreased relaxation to ACh in comparison to aortas from respective control male and female rats. Endothelium-denuded, but not endothelium-intact, arteries from male DOCA rats displayed increased sensitivity (-log EC20) to ET-1, but no changes in ET-1 sensitivity were observed in female DOCA aortas. IRL-1620 induced contraction in male DOCA aortas, but not in female DOCA or control endothelium-denuded aortas. In the microcirculation, IRL-1620 induced vasodilation in male and female control rats, but marked vasoconstriction in male DOCA and minimal changes in vessels diameter in female DOCA rats. Bosentan, an ET(A)/ET(B)-receptor antagonist, induced a greater decrease in mean arterial blood pressure in male than in female DOCA-salt hypertensive rats. These data support the hypothesis that DOCA-salt rats exhibit gender differences in ET-1 vascular reactivity, which probably result from functional changes in ET(B)-receptors. The increased ET(B) responses in male DOCA-salt hypertensive rats may play a role in their higher blood pressure levels.
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PMID:Gender differences in vascular reactivity to endothelin-1 in deoxycorticosterone-salt hypertensive rats. 1107 48

In previous studies, we have observed that endothelin participates in the progression of renal vascular and glomerular fibrosis during hypertension by activating collagen I gene synthesis. The present study investigated whether administration of endothelin receptor antagonists leads to the regression of renal sclerotic lesions. Experiments were performed in transgenic mice harboring the luciferase gene under the control of the collagen I-alpha2 chain promoter. Hypertension was induced by long-term inhibition of nitric oxide synthesis by N(G)-nitro-L-arginine methyl ester (L-NAME); systolic pressure gradually increased, reaching a plateau of 165 mm Hg after 10 weeks of hypertensive treatment. At the same time, collagen I gene expression was increased 2- and 5-fold compared with control animals in afferent arterioles and glomeruli, respectively (P<0.01). This increase was accompanied by the appearance of sclerotic lesions within the renal vasculature. When renal vascular lesions had been established (20 weeks of L-NAME), animals were divided into 2 subgroups: the one continued to receive L-NAME, whereas in the other, bosentan, a dual endothelin antagonist, was coadministered with L-NAME for an additional period of 10 weeks. Bosentan coadministration did not alter the increased systolic pressure at 30 weeks; in contrast, collagen I gene activity returned almost to control levels in renal vessels and glomeruli. In this subgroup of animals, renal vascular lesions (collagen and/or extracellular matrix deposition) and mortality rates were substantially reduced compared with untreated mice. These data indicate that endothelin participates in the mechanism(s) of renal vascular fibrosis by activating collagen I gene. Treatment with an endothelin antagonist normalizes expression of collagen I gene and leads to the regression of renal vascular fibrosis and to the improvement of survival, thus providing a complementary curative approach against renal fibrotic complications associated with hypertension.
Hypertension 2001 Feb
PMID:Regression of renal vascular fibrosis by endothelin receptor antagonism. 1123 Mar 24

We tested the hypothesis that angiotensin II (Ang II)-induced stimulations of endothelin (ET) and isoprostanes are implicated in the slow pressor responses to Ang II. We infused either vehicle (group 1) or Ang II (groups 2 to 4) intravenously at 5 ng/kg per minute via osmotic pumps for 15 days into Sprague-Dawley rats. Groups 3 and 4 received 30 mg/kg per day of either losartan (Ang II type 1 receptor blocker) or bosentan (ET(A) and ET(B) receptor blocker) in their drinking water. We measured systolic blood pressure (SBP) every 3 days during the infusion. Plasma levels of Ang II, ET, isoprostanes, and urinary nitrites were determined at 15 days. Vehicle infusion did not change SBP (from 138+/-13 to 136+/-2 mm Hg at day 15). Circulating Ang II, ET, and isoprostane levels were 35+/-9, 39+/-3, and 111+/-10 pg/mL, respectively, whereas urinary nitrites were 2.3+/-0.4 microgram/d. Ang II increased SBP (from 133+/-10 to 158+/-8 mm Hg), plasma Ang II (179+/-77 pg/mL), and isoprostanes (156+/-19 pg/mL) without altering ET levels (38+/-5 pg/mL) or urinary nitrites (1.8+/-0.5 microgram/d). Losartan prevented Ang II-induced increases in SBP and isoprostanes (SBP went from 137+/-5 to 120+/-4 mm Hg; isoprostanes were 115+/-15 pg/mL) while increasing urinary nitrite levels (5.2+/-1.1 microgram/d). Losartan did not alter Ang II (141+/-57 pg/mL) or ET (40+/-4 pg/mL) levels. Bosentan also blocked Ang II-induced hypertension (from 135+/-4 to 139+/-3 mm Hg) but did not decrease isoprostanes (146+/-14 pg/mL). Ang II (63+/-11 pg/mL), ET levels (46+/-2 pg/mL), and urinary nitrites (2.8+/-0.4 microgram/d) were not altered. In conclusion, our results suggest that low-dose Ang II increases isoprostanes via its Ang II type 1 receptor and causes an ET-dependent hypertension, without altering circulating ET levels.
Hypertension 2001 Feb
PMID:Role of endothelin and isoprostanes in slow pressor responses to angiotensin II. 1123 Mar 26

Since its discovery in 1988, there has been increasing evidence that endothelin-1 (ET-1) plays an important role in the pathophysiology of hypertension and its related end-organ damages. First studies, using ET-1 administration in animals or in humans suspected this role by demonstrating the hypertensive properties of ET-1. The latter, due to stimulation of ET(A) receptors inducing sustained vasoconstriction have been reported to follow transient vasodilation linked with activation of an endothelial ET(B) receptor releasing nitric oxide (NO). In certain instances, ET(B) smooth-muscle receptors might also induce contraction. Cloning of these receptors helped to develop ET-1 receptor antagonists. As soon as one of them became available, bosentan, a dual (ET(A) and ET(B)) ET-1 receptor antagonist, we tested its effects in the canine model of perinephritic hypertension. Bosentan was found to exert striking hypotensive effects, due to peripheral vasodilation but without affecting cardiac function. In further experiments, we observed that effects of bosentan were additional to those of ACE inhibitors or angiotensin II antagonists. This opened new therapeutic perspectives and also suggested a proper role of ET-1 in hypertension, independent of the renin-angiotensin system. To explain this role, we demonstrated a real imbalance characterized by an impairment of the NO system in favor of the ET-1 pathway. Recent studies suggest that such an imbalance may also occur in human hypertension. Furthermore, the contribution of ET-1 to human hypertension appears more convincing since bosentan was shown to decrease blood pressure in hypertensive subjects. Finally, ET-1 receptor antagonists might be of therapeutic interest to prevent hypertension induced end-organ damages. Whether or not these compounds are able to prevent or to reverse target organ injuries in man remains to be investigated.
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PMID:Therapeutic role of bosentan in hypertension: lessons from the model of perinephritic hypertension. 1144


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