Role of endothelin in stress-induced hypertension

In this study we investigated the role of endogenous endothelin in the cardiovascular response to acute stress, ie mild footshocks in conscious rats. Footshock-stress significantly increased mean arterial pressure and heart rate (P < 0.05). Peripheral or intracerebroventricular (IVT) administration of BQ 788, a selective antagonist of ET(B) receptor, did not alter pressor response to footshocks. Intraperitoneal injections of BQ 123 (1 mg/kg), a selective antagonist of the ET(A)-receptor, had a tendency to decrease, while BQ 123 (203 ng/5 microl) IVT administration significantly reduced the pressor response to footshocks (-12 mm Hg, P < 0.001). Neither ET(A) nor ET(B) antagonists, when injected centrally or peripherally, altered basal blood pressure or heart rate. Our results may indicate a role of brain endothelin in the sympathetic mediated cardiovascular response to stress, via stimulation of ET(A) receptor.     

Role of endothelin in noradrenaline-induced hypertension in rats

OBJECTIVE: To investigate the role of endothelin in noradrenaline-induced hypertension in rats. DESIGN: The dose-response relationship of chronic noradrenaline infusion on arterial pressure was characterized to identify a dose that would produce sustained hypertension, and the effect of combined endothelin ETA and ETB receptor blockade (TAK-044) on the response to this dose was then examined. METHODS AND RESULTS: Noradrenaline (or vehicle) was infused intravenously at 1 (subpressor acutely), 24 or 48 microg/kg per h (acute pressor response of 9 +/- 1 and 11 +/- 1 mmHg, respectively) for a 14-day infusion, and blood pressure was measured by radiotelemetry. Noradrenaline infusion at 1 microg/kg per h did not produce a 'slow pressor' rise in blood pressure. During noradrenaline infusions at 24 and 48 microg/kg per h, mean arterial pressure peaked initially on days 2-3 (+10 +/- 1 and 14 +/- 2 mmHg, respectively; P < 0.01), fell towards basal levels after day 3, and then began to rise again at days 5-6 only with 48 microg/kg per h, being 10 +/- 1 mmHg above control levels at days 13-14 (P < 0.05). TAK-044 treatment did not alter the magnitude of the initial (13 +/- 1 mmHg) or eventual (12 +/- 2 mmHg) rise in blood pressure achieved in response to 14 days' infusion of noradrenaline at 48 microg/kg per h, but abolished the transient fall. CONCLUSION: Chronic noradrenaline infusion at acutely pressor doses leads either to a transient blood pressure elevation at a moderate dose, or to a triphasic but sustained hypertension at a higher dose, with a temporary escape from the hypertension apparently mediated by endothelin.     

Role of endothelium in the abnormal response of mesenteric vessels in rats with portal hypertension and liver cirrhosis

BACKGROUND & AIMS: Previous studies have shown that nitric oxide synthesis inhibition corrects the hyporesponsiveness to vasoconstrictors present in the mesenteric vascular bed of portal- hypertensive rats. The origin of this elevated NO production, whether endothelial or muscular, is unknown. The aim of this study was to evaluate the role of vascular endothelium in the hyporesponsiveness to methoxamine (MTX) in the mesenteric vascular bed of portal vein-ligated (PVL) and cirrhotic rats. METHODS: Endothelial denudation was achieved using a combined treatment of cholic acid and distilled water. RESULTS: Compared with the respective control groups, PVL rats showed a reduced vascular response to MTX. Similar results were obtained in cirrhotic animals. The presence of ascites was associated with a more severe reduction in the response to MTX. Removal of the endothelium completely corrected the vascular hyporesponsiveness of PVL, cirrhotic nonascitic, and ascitic animals. In these experiments, acetylcholine-mediated vasodilation was practically absent whereas that of sodium nitroprusside was potentiated, which indicates a successful elimination of the endothelium and the preservation of smooth muscle function. Immunostaining for NO synthase isoforms revealed the presence of endothelial NO synthase protein in healthy and PVL rats exclusively in the endothelium. CONCLUSIONS: The mesenteric vascular hyporesponsiveness to MTX present in these models of liver diseases and portal hypertension is solely due to endothelium-dependent factors. (Gastroenterology 1996 Dec;111(6):1627-32)     

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.     

Role of endothelin in mediating tumor necrosis factor-induced hypertension in pregnant rats

Hypertension during preeclampsia is associated with an increase in plasma levels of tumor necrosis factor (TNF)-alpha, a cytokine known to contribute to endothelial dysfunction. Recently, our laboratory reported that a 2-fold increase in plasma TNF-alpha produces hypertension in pregnant rats. Endothelin is also elevated in preeclampsia and endothelin synthesis is enhanced by TNF-alpha. The purpose of this study was to determine the role of endothlelin in mediating TNF-alpha-induced hypertension in pregnant rats. To achieve this goal, TNF-alpha (50 ng/d for 5 days) was infused into control pregnant rats and pregnant rats treated with an endothelin receptor A antagonist, ABT 627 (5 mg/kg per day for 5 days). At day 19 of gestation, arterial pressure was measured and aorta, kidneys, and placentas were harvested. Infusion of TNF-alpha into pregnant rats increased plasma concentration of TNF-alpha (13.5+/-0.8 to 28.0+/-3.7 pg/mL) and arterial pressure (101+/-2 to 122+/-1 mm Hg). The increase in arterial pressure was associated with an increase in preproendothelin mRNA expression in placenta, aorta, and kidneys measured by real-time polymerase chain reaction (PCR). Pretreatment with the endothelin receptor A antagonist completely abolished the blood pressure response to TNF-alpha in pregnant rats (105+/-1 versus 97+/-2 mm Hg). In sharp contrast, the ETA receptor antagonist had no effect on arterial pressure in normal pregnant rats (97+/-2 versus 101+/-2 mm Hg). Moreover, chronic infusion of TNF-alpha had no significant effect on arterial pressure or renal preproendothelin levels in virgin rats. These results suggest an important role for endothelin in mediating TNF-alpha-induced hypertension in pregnant rats.     

Role of blood pressure response to provocative tests in the prediction of hypertension inadolescents

To assess the value of exercise stress testing and of mentalstress as predictors of hypertension, we studied 130 normotensivemales 14–18 years of age. Sixty-five had at least onehypertensive parent (SHT), while 65 had normotensive parents(SNT). Systolic (SBP) and diastolic (DBP) blood pressure, rate-pressureproduct (RPP) and 12-lead ECG were recorded at rest, throughoutthe tests and during the recovery phase.The two groups werenot significantly different at rest for the examined variables.However, the SHT group showed a greater average SBP than theSNT group (198.4±18.7 vs 189.5±14.9 mmHg; P<0.05)at the peak of exercise. A significantly higher proportion ofSHT subjects (40.0% vs 18.5%: P<0.01) had SBP >200 mmHg.No difference in the ECG pattern between the two groups wasobserved.During mental stress, no significant differences inthe examined variables between the two groups were noted, althoughSBP, DBP, HR and RPP were slightly higher in SHT than in SNTsubjects.These data suggest that the SBP response to dynamicexercise may be a good predictor of hypertension in subjectsat risk.     

Cardiac endothelin and big endothelin in right-heart hypertrophy due to monocrotaline-induced pulmonary hypertension in rat

OBJECTIVE: Recent observations suggest the existence of a myocardial endothelin (ET) system and its possible involvement in left-ventricular myocardial hypertrophy and failure. However, nothing is known about the role of myocardial ET in right-ventricular hypertrophy. METHODS: Rats (80-100 g) were given an intraperitoneal injection of saline (controls) or monocrotaline (50 mg/kg) resulting in pulmonary hypertension-induced myocardial hypertrophy (n = 11 in both groups). After 10 weeks, the animals were sacrificed and hearts perfused in vitro to determine levels of big ET-1 and ET-1 in coronary effluent, interstitial fluid and ventricular tissue homogenates; plasma levels were also determined. RESULTS: In monocrotaline-treated animals, weights of right ventricles were 1.5 and of right atria 1.8-fold higher than in controls (p < 0.05), indicating substantial right-ventricular hypertrophy as also evident from greatly increased myocardial production of atrial natriuretic peptide. Left-ventricular weights were not different. Release of big ET-1 in coronary effluent, and of ET-1 in coronary effluent and interstitial transudate were similar in control and hypertrophic hearts (p > 0.05). Disruption of endothelium with collagenase reduced release of both peptides close to zero, indicating endothelial (not myocardial) origin of the peptides. Levels of big ET-1 and ET-1 were similar in left ventricles of both experimental groups, but lower in right ventricles of hypertrophic than control hearts (p < 0.05), reflecting increased tissue mass rather than reduced peptide production. On the other hand, plasma levels of both peptides and of ANP were twofold and levels of angiotensin II 1.3-fold higher in rats with right-heart hypertrophy than in controls (p < 0.05 in each case). CONCLUSION: These data do not support a role for local cardiac ET-1 and/or big ET-1 in right-ventricular hypertrophy, but point to blood-borne endothelins as possible mediators.     

Role of bile acids in splanchnic hemodynamic response to chronic portal hypertension

Previous studies from our laboratory suggest that humoral factors, namely glucagon, can account for approximately 30% of the splanchnic vasodilation in rats with prehepatic portal hypertension. A reduced vascular sensitivity to norepinephrine, vasopressin, and angiotensin II may contribute to the splanchnic vasodilation. However, neither glucagon nor an altered vasoconstrictor sensitivity can fully account for the splanchnic vasodilation observed in portal hypertensive subjects. Therefore, the present study was designed to examine the role of bile acids in the splanchnic hyperemia of portal hypertension since (1) serum bile acids are elevated in portal hypertensive subjects and (2) bile acids are potent intestinal vasodilators. Prehepatic portal hypertension was induced in Sprague-Dawley rats by surgical constriction of the portal vein. Ten to 14 days after the induction of portal hypertension, the enterohepatic circulation of control and portal hypertensive rats was surgically interrupted. The animals were placed in Bollman restraint cages and allowed to recover. Eighteen to 24 hr later, the rats were anesthetized with sodium pentobarbital and regional blood flow measured with radiolabeled microspheres. Normal and portal hypertensive animals without bile fistula served as controls. Plasma bile acid levels measured by radioimmunoassay were approximately 3.8 times higher in portal hypertensive animals than in control. Bile duct cannulation effectively depleted both normal and portal hypertensive animals of their circulating bile acid pool and significantly reduced portal venous inflow in portal hypertensive but not in control rats. A role for bile acids as partial mediators of the splanchnic hyperemia of portal hypertension is suggested since bile acid depletion did not completely abolish the gastrointestinal hyperemia.     

一氧化氮和内皮素在高血压左室肥厚形成中的作用

目的 探讨一氧化氮（NO）和内皮素（ET）在高血压左室肥厚（LVH）形成中的作用。方法 采用放射免疫分析法（RIA）和硝酸还原酶法检测30例单纯原发性高血压（EH,观察Ⅰ组）、30名健康体检者（对照组）及20例EH伴LVH（观察Ⅱ组）患者降压治疗前后血清ET、NO水平。并对结果进行相关分析。结果 观察Ⅰ组血清ET明显高于对照组、NO明显低于对照组（P均〈0．01）;观察Ⅱ组血清ET明显高于观察Ⅰ组、NO明显低于观察Ⅰ组（P均〈0．01）,且ET与NO水平呈负相关（r=0．586,P〈0．01）;左心室重量指数（LVMI）与ET呈正相关（r=0．427,P〈0．05）、与NO呈负相关（r=0．653,P〈0．01）。观察Ⅱ组治疗后,血清ET水平明显低于治疗前、NO水平明显高于治疗前（p均〈0．01）。结论 ET和NO两者失衡可能参与了EH及LVH形成的病理生理过程。     

Role of the endothelium in modulation of the acetylcholine vasoconstrictor response in porcine coronary microvessels.

STUDY OBJECTIVE--The aim was to investigate the role of the endothelium in modulating the acetylcholine response in porcine coronary microvessels and compare the results with simultaneously studied large coronary arteries. DESIGN--Coronary microvessels [104 (SEM 3.3) microns; range 38-150] were removed from fresh porcine hearts and studied in vitro during no flow constant pressure conditions. Endothelium derived relaxing factor (EDRF) activity and the role of the endothelium in modulating the acetylcholine response in microvessels was assessed by measuring changes in intraluminal diameter using a video tracking device. Large coronary arteries were simultaneously studied using conventional isometric ring techniques. EXPERIMENTAL MATERIAL--Fresh porcine hearts were obtained from a local slaughterhouse. MEASUREMENTS AND MAIN RESULTS--Acetylcholine was a potent vasoconstrictor (EC50 = 0.17 microM) of passively distended microvessels. The effects of EDRF were studied by either inactivation with haemoglobin or inhibition of EDRF synthesis with N-omega-nitro-L-arginine. Preconstricted microvessels exposed to either N-omega-nitro-L-arginine or haemoglobin constricted further, consistent with basal release of EDRF. Neither drug affected passively distended microvessels. The acetylcholine vasoconstrictor response was potentiated after exposure of microvessels to either drug. Atropine, but not indomethacin, blocked the acetylcholine response in microvessels. As with microvessels, acetylcholine was a vasoconstrictor (EC50 = 0.3 microM) of large coronary arteries. In contrast to microvessels, indomethacin antagonised acetylcholine vasoconstriction in vessels with intact endothelium. Bioassay experiments using indomethacin-treated large epicardial donor artery segments showed basal release of EDRF but no EDRF release in response to acetylcholine. CONCLUSIONS--The results show the microvessels and large coronary arteries are similar in their vasoconstrictor response to acetylcholine, that both release EDRF basally, and that vasoconstriction to acetylcholine is importantly modulated by the endothelium. In large arteries, acetylcholine does not stimulate EDRF release and, in contrast to microvessels, a cyclo-oxygenase product influences the vasoconstrictor action of acetylcholine.     

Plasma immunoreactive endothelin in essential hypertension

PURPOSE: Endothelin plays a role in the regulation of vascular tonus. Therefore, it has been hypothesized that increased production or release of endothelin or both may contribute to the pathogenesis of hypertension. To assess any changes in the plasma endothelin concentration in essential hypertension, plasma immunoreactive endothelin concentrations were measured in patients with essential hypertension. PATIENTS AND METHODS: We measured plasma immunoreactive endothelin concentrations in 42 subjects with essential hypertension, 12 subjects with borderline hypertension, and 25 normotensive control subjects. RESULTS: The concentrations were higher in hypertensive patients than in borderline hypertensive patients and normotensive subjects (both p less than 0.05), although values in normotensives and hypertensives overlapped. Reverse-phase high-performance liquid chromatography (HPLC) and radioimmuno-assay showed two components of plasma endothelin, one corresponding to synthetic endothelin-1 (1-21) and the other corresponding to synthetic big endothelin (human, 1-38). The HPLC profile of plasma endothelin of hypertensive patients was the same as that of normotensive subjects. Hypertensives with reduced glomerular filtration rates or increased serum creatinine levels had higher plasma endothelin concentrations than hypertensive patients as a whole (p less than 0.05). Mean blood pressure and serum creatinine levels were correlated to plasma endothelin in the hypertensives. Correlation was negative between glomerular filtration rate and the endothelin level in the hypertensives. CONCLUSION: Plasma endothelin was elevated in many hypertensive patients with severe hypertension or renal involvement. Its major components were endothelin-1 and big endothelin.     

Role of the endothelium in inflammatory bowel diseases

Inflammatory bowel diseases(IBD) are a complex group of diseases involving alterations in mucosal immunity and gastrointestinal physiology during both initiation and progressive phases of the disease.At the core of these alterations are endothelial cells,whose continual adjustments in structure and function coordinate vascular supply,immune cell emigration,and regulation of the tissue environment.Expansion of the endothelium in IBD(angiogenesis),mediated by inflammatory growth factors,cytokines and chemokin...     

Myocardial ultrasonic backscatter in hypertension: relation to aldosterone and endothelin

A disproportionate accumulation of fibrillar collagen is a characteristic feature of hypertensive heart disease, but the extent of myocardial fibrosis may differ in different models of hypertension. In experimental studies, aldosterone and endothelins emerge as important determinants of myocardial fibrosis. Changes in myocardial extracellular matrix and collagen deposition can be estimated noninvasively by analysis of the ultrasonic backscatter signal, which arises from tissue heterogeneity within the myocardium and describes myocardial texture. This study was designed to investigate the relations between myocardial integrated backscatter and circulating aldosterone and immunoreactive endothelin in human hypertension. The study population consisted of 56 subjects: 14 healthy normotensive volunteers and 42 hypertensive patients (14 with primary aldosteronism, 7 with renovascular hypertension, and 21 with essential hypertension). The patients with essential and secondary hypertension were matched for age, gender, body mass index, and blood pressure. Myocardial integrated backscatter at diastole was 19.8+/-2.0 and 20.8+/-2.9 decibels in normotensive control subjects and patients with essential hypertension and significantly higher in patients with primary aldosteronism (27.4+/-3.8 decibels, P<0.01) and renovascular hypertension (26.8+/-4.8 decibels, P<0.01). In the population as a whole, as well as in the hypertensive subpopulation, myocardial integrated backscatter was directly related to plasma aldosterone (r=0.73 and 0.71, P<0.01 for both) and immunoreactive endothelin (r=0.60 and 0.56, P<0.01 for both). The data of this study suggest that in human hypertension, circulating aldosterone and immunoreactive endothelin may induce alterations in left ventricular myocardial texture, possibly related to increased myocardial collagen content.     

The endothelin system in pulmonary arterial hypertension

Endothelin-1 (ET-1), a peptide produced primarily by vascular endothelial cells, was discovered in 1980 and it was characterized as a powerful vasoconstrictor and mitogen for smooth muscle. ET-1 binds to two types of receptors, ETA and ETB: ETA-receptors are found in smooth muscle cells, whereas ETB-receptors are localized on both endothelial cells and in smooth muscle cells. Activation of ETA- and ETB-receptors on smooth muscle cells mediates the vasoconstrictive and mitogenic effects of ET-1. Stimulation of endothelial ETB-receptors promotes ET-1 clearance and activation of NO and prostacyclin release. Pulmonary arterial hypertension (PAH) is a severe condition characterized by a progressive increase in pulmonary vascular resistance leading to right ventricular failure and death. An activation of the ET-1 system has been demonstrated in both plasma and lung tissues of PAH patients as well as in animal models of PAH. The most efficient way to antagonize the ET-1 system is the use of ET-1 receptor antagonists that can block either ETA- or ETA- and ETB-receptors. These drugs are effective in animal models of PAH and have been tested in multiple clinical trials in patients with PAH. Bosentan, an orally active, dual ET-1 receptor antagonist has been shown to improve symptoms, exercise capacity, hemodynamics, echocardiographic parameters and the outcome of patients with severe PAH, and it has been approved for clinical use in many countries. The selective ETA-receptor antagonist sitaxentan has improved exercise capacity and hemodynamics of PAH patients in two preliminary studies. The main side effect of ET-1 antagonists is the increase of liver enzymes likely due to an accumulation of bile salts cytotoxic to hepatocytes. Additional trials with these drugs are currently ongoing. In conclusion, the hypothesis that the ET-1 system over-activation can be successfully antagonised in patients with PAH has been clearly demonstrated.     

Augmented endothelin vasoconstriction in intermittent hypoxia-induced hypertension

We reported previously that simulating sleep apnea in rats by exposing them 7 hours per day to intermittent hypoxia/hypercapnia (IH) elevates plasma endothelin-1 and causes hypertension, which is reversed by an endothelin-1 antagonist. We hypothesized that in this model of sleep apnea-induced hypertension, vascular sensitivity to endothelin-1 is increased in combination with the elevated plasma endothelin-1 to cause the endothelin-1-dependent hypertension. In small mesenteric arteries with endothelial function disabled by passing air through the lumen, diameter and vessel wall [Ca2+] were recorded simultaneously. IH arteries demonstrated increased constrictor sensitivity to endothelin-1 (percentage max constriction 100+/-0% IH versus 80+/-10% Sham; P<0.05). This was accompanied by increased calcium sensitivity of IH arteries. In contrast, constrictor sensitivity and increases in vessel wall [Ca2+] to KCl and phenylephrine were not different between IH and Sham arteries. We have shown previously that endothelin-1 constriction in mesenteric arteries is mediated by endothelin A receptors. In the current study, the selective increase in endothelin-1 constriction in IH resistance arteries was accompanied by increased expression of endothelin A receptor expression (densitometry units 271+/-23 IH versus 158+/-25 Sham; P<0.05). Thus, IH hypertension appears to cause alterations in signaling components unique to endothelin-1 at the receptor level and in postreceptor signaling that increases calcium sensitivity during endothelin A activation. Future studies will determine the specific changes in vascular smooth muscle signaling in IH hypertension causing this augmented contractile phenotype.     

天麻钩藤饮改善高血压患者内皮功能的机理研究

目的　探讨天麻钩藤饮改善高血压患者内皮功能的机理。方法　选择肝阳上亢型高血压患者 6 0例 ,随机分为两组 ,治疗组服用天麻钩藤饮 ,对照组服用非洛地平 ,分别检测两组治疗前后血清谷胱甘肽过氧化物酶(GSH- PX)和过氧化氢酶 (CAT)含量。结果　治疗后 ,两组 GSH- PX和 CAT含量均增加 (P<0 .0 1) ,但治疗组较对照组增加明显 (P<0 .0 1)。结论　天麻钩藤饮改善高血压患者内皮功能的机理可能是通过增加 GSH- PX和CAT含量 ,清除过多的氧自由基 ,防止血管内皮细胞脂质过氧化 ,从而改善患者的血管内皮功能。