Endothelin-1 In Hypertension Research Articles

Role of endothelin in hypertension of experimental chronic renal failure.

Surgical ablation of renal mass leads to a reduction in kidney function and commonly to the development of hypertension and chronic renal failure (CRF) in rats. The objective of this study was to determine whether endothelin (ET)-1 is involved in the maintenance of the hypertension that accompanies loss of renal mass. First, we demonstrated the antihypertensive efficacy of PD 155080, a selective, orally active ET(A) receptor antagonist, in a group of rats made hypertensive by continuous intravenous infusion of ET-1 (2.5 pmol x kg(-1) x min[-1]) for 7 days. ET-1 produced a sustained hypertension and PD 155080 (56.4 micromol/kg [25mg/kg] BID PO) normalized blood pressure (BP) during the 5 days of drug administration. In a second experiment, Sprague-Dawley rats underwent a 5/6 reduction in renal mass (RRM); 4 weeks later, PD 155080 administered for 7 days resulted in a sustained reduction in BP. Sham-operated rats also showed a slight hypotensive response to PD 155080 administration. Plasma urea nitrogen, plasma creatinine, urinary protein excretion, and creatinine clearance were not altered by PD 155080 administration in RRM or sham rats. In a third experiment, we investigated the contribution of the renin-angiotensin system to BP control in RRM rats given PD 155080. In these rats, PD 155080 reduced BP during 5 treatment days, and this antihypertensive effect was not altered by coadministration of the angiotensin-converting enzyme inhibitor enalapril in the drinking water (508 micromol/L [250 mg/L]). These results demonstrate that (1) ET-1 plays a role in established RRM hypertension through activation of the ET(A) receptor subtype, (2) lowering blood pressure with PD 155080 in RRM rats does not adversely affect renal function, and 3) the antihypertensive effect of ET(A) receptor antagonism is not opposed by the renin-angiotensin system.

Role of endothelin in hypertension

Role of endothelin in hypertension

Endothelin in hypertension

The endothelins, 21-amino-acid peptides produced by the endothelium of blood vessels and many other tissues such as the kidney, brain, endocrine organs, etc., are potent vasoconstrictors, and are also endowed with mitogenic and cell hypertrophic properties. Endothelin may be involved in the pathogenesis of hypertension through vascular, renal, endocrine, and neural effects. Although many studies have been performed to test the hypothesis that these peptides have a pathophysiologic role in hypertension, it is only recently that evidence has been found of enhanced production of endothelin-1 in some models of hypertension, particularly in blood vessels in deoxycorticosterone acetate-salt hypertensive rats. Vascular responses to endothelin-1 have been shown to be normal or depressed in many models of experimental hypertension, and also in humans with essential hypertension. Elevation of blood pressure and development of vascular hypertrophy is blunted in deoxycorticosterone acetate-salt hypertensive rats treated chronically with endothelin receptor antagonists. Spontaneously hypertensive rats do not overexpress vascular endothelin, and do not exhibit a hypotensive response to chronic endothelin receptor antagonism. Malignant spontaneously hypertensive rats treated with deoxycorticosterone acetate and salt exhibit vascular overexpression of endothelin-1 and respond to endothelin antagonists with lowering of blood pressure. A genetic role of components of the endothelin system has been suggested in Dahl salt-sensitive rats. In human essential hypertension, there is as yet little evidence of activation of the endothelin system. A role of endothelins in hypertension is thus becoming increasingly apparent in severe forms of experimental hypertension, but further studies are required to establish whether these peptides are involved in the human disease.

Role of endothelin-1 in hypertension induced by long-term inhibition of nitric oxide synthase

We examined the effect of long-term nitric oxide (NO) synthase inhibition on vascular and renal endothelin-1 levels and evaluated the antihypertensive effect of endothelin ET A receptor antagonist FR139317 (( R)2-[( R)-2-[( S)-2-[[1-(hexahydro-1 H-azepinyl)]-carbonyl]amino-4-methyl-pentanoyl]amino-3-[3-(1-methyl-1 H-indolyl)]propionyl]amino rats in which NO synthase was blocked. Chronic NO blockade was produced by oral administration of the NO synthase inhibitor N G-nitro- l-arginine for 4 weeks, which produced sustained hypertension. At the end of this time, there were no significant changes in aortic and renal immunoreactive-endothelin levels between N G-nitro- l-arginine-treated hypertensive rats and normotensive control rats. Intravenous injection of FR139317 (10 mg/kg), which had a sufficient hypotensive effect on deoxycorticosterone acetate-salt hypertensive rats, to N G-nitro- l-arginine-treated hypertensive rats produced only a moderate hypotensive effect, to the same degree as seen in normotensive rats. The results indicate that long-term NO synthase inhibition did not affect vascular and renal endothelin-1 levels in these rats. It seems likely that endothelin-1 and ET A receptors do not contribute to the sustained hypertension induced by NO synthesis blockade.

Latest clues to role of endothelin in hypertension

The puzzle of endothelin’s role in hypertension has not yet been solved but further clues were presented at the 15th Scientific Meeting of the International Society of Hypertension [Melbourne, Australia; March 1994]. It is becoming clear that this field of research holds potential as a base for new drug development.

The endothelin ET A receptor antagonist, BQ-123, normalizes the response of SHR aorta to Ca 2+ channel activator

Hypertension is associated with a hypersensitive response to the Ca 2+ channel activator, Bay K 8644. We investigated the effect of the endothelin ET A receptor antagonist, BQ-123, on the contractions induced by Bay K 8644 in aorta from spontaneously hypertensive (SHR) and normotensive Wistar Kyoto (WKY) rats. BQ-123 (1 μM) decreased the sensitivity to Bay K 8644 of aorta of SHR down to that of WKY. This observation is consistent with a role for endothelin in hypertension.

Role of endothelin in hypertension

Role of endothelin in hypertension

Potential role of endothelin in hypertension. Controversy on endothelin in hypertension.

Potential role of endothelin in hypertension. Controversy on endothelin in hypertension.

Heterogeneity of endothelial dysfunction in hypertension

The endothelium may play a role as a target and mediator of hypertension. Due to its anatomical position, it is very exposed to mechanical forces; as a source of vasoactive material it may participate in increasing peripheral vascular resistance and in promoting local ischaemia in the heart and brain. Morphological and functional changes in the endothelium occur in experimental and human hypertension. However, the severity of the defect and the mechanisms involved among vascular beds and models of hypertension are heterogeneous. Endothelium-dependent relaxations are impaired in the aorta, carotid artery and in cerebral and mesenteric arterioles in hypertension. In the coronary circulation the defect is less pronounced. The mechanisms involve a reduced formation of nitric oxide, an enhanced production of prostaglandin H2 and an impaired responsiveness of vascular smooth muscle to nitric oxide. The role of endothelin in hypertension is controversial; circulating levels appear unaltered except in the presence of renal failure or atherosclerosis. The local vascular production of endothelin, however, may still be increased. The potentiating effects of threshold concentrations of endothelin on the vasoconstrictor response to noradrenaline are enhanced in hypertension. Thus, subtle and distinct endothelial function defects occur in hypertension, but not all vascular beds are similarly affected and different mechanisms contribute. Endothelial dysfunction may contribute to increased peripheral resistance, tissue ischaemia and cardiovascular complications.

Endothelium-Derived Relaxing Factor and Endothelin in Hypertension

In resistance arteries, endothelium-derived nitric oxide inhibits vasoconstrictors;this and endothelium-dependent relaxations to acetylcholine are blunted in hypertension. The sensitivity of hypertensive resistance arteries with endothelium to intraluminal endothelin-1 is normal but is reduced without endothelium. Thus hypertension impairs endothelial regulation of the resistance circulation.

Role of endothelium in the response to endothelin in hypertension.

The relation between endothelin and acetylcholine (ACh) was examined and compared in aortas from Wistar-Kyoto (WKY) rats and from stroke-prone spontaneously hypertensive rats (SHRSP). The relaxation produced by ACh in an endothelin-induced contraction was less in aortas from WKY rats than in those from SHRSP. In aortas from WKY rats but not in those from SHRSP, the contraction produced by endothelin was augmented when the intact aortic rings were treated with methylene blue (10(-5) M). This augmentation was also found in preparations of the WKY rat aortic rings in which the endothelium had been removed. The augmentation was not present in SHRSP aortic rings that had been similarly denuded. Treatment with indomethacin (5 x 10(-6) M) had no effect on endothelin-induced contraction in either WKY rat or SHRSP aortic rings. Our findings indicate that endothelin and ACh have in common the ability to release endothelium-derived relaxing factor (EDRF) in WKY rat aortic rings. The reduced endothelium-dependent relaxation in response to ACh in the WKY rat probably reflects the fact that endothelin had already released the EDRF in rings from this strain of rats. The release of EDRF by endothelin is less in SHRSP than it is in WKY rats. Because of this failure of endothelin to release EDRF in SHRSP, endothelin may contribute to the increase in total peripheral resistance in this form of hypertension.

Is there a role for endothelin in hypertension?

Is there a role for endothelin in hypertension?

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 <0.05), although values in normotensives and hypertensives overlapped. Reverse-phase high-performance liquid chromatography (HPLC) and radioimmunoassay 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 <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.