Endothelin A Receptor Antagonist, Atrasentan, Attenuates Renal and Cardiac Dysfunction in Dahl Salt-Hypertensive Rats in a Blood Pressure Independent Manner

We determined the role of an endothelium-derived contracting factor in the impaired relaxation response to ACh of conduit pulmonary arteries (PAs) isolated from rats with hypoxic pulmonary hypertension (PH). A PGH2/thromboxane A2(TxA2)-receptor antagonist (ONO-3708) partially restored the impairment of ACh-induced relaxation, whereas TxA2 synthase inhibitors (OKY-046 and CV-4151) did not affect the impaired relaxation in phenylephrine-precontracted hypertensive PAs. Endothelium-denuded hypertensive PA rings showed no difference in the response to ACh between preparations with and without ONO-3708. In both endothelium-denuded control and hypertensive PAs, exogenous PGH2 induced contractions, and the magnitude of the contractions was greater in the control than in hypoxic PH preparations. An endothelin A-receptor antagonist (BQ-485), an endothelin B-receptor antagonist (BQ-788), and a superoxide anion scavenger (superoxide dismutase) did not restore the impaired response to ACh in hypertensive PAs. These findings suggest that PGH2 produced from the conduit PAs of rats with chronic hypoxic PH may be the endothelium-derived contracting factor responsible for the impairment of ACh-mediated vasorelaxation.

Download Full-text

Blood Pressure–Independent Reduction in Proteinuria and Arterial Stiffness After Acute Endothelin-A Receptor Antagonism in Chronic Kidney Disease

Hypertension ◽

10.1161/hypertensionaha.109.132670 ◽

2009 ◽

Vol 54 (1) ◽

pp. 113-119 ◽

Cited By ~ 76

Author(s):

Neeraj Dhaun ◽

Iain M. MacIntyre ◽

Vanessa Melville ◽

Pajaree Lilitkarntakul ◽

Neil R. Johnston ◽

...

Keyword(s):

Blood Pressure ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Arterial Stiffness ◽

Receptor Antagonism ◽

Endothelin A Receptor ◽

Endothelin A ◽

Pressure Independent

Download Full-text

Endothelin receptor A blockade reduces proteinuria and vascular hypertrophy in spontaneously hypertensive rats on high-salt diet in a blood-pressure-independent manner

Clinical Science ◽

10.1042/cs103s385s ◽

2002 ◽

Vol 103 (s2002) ◽

pp. 385S-388S ◽

Cited By ~ 6

Author(s):

Jörg TRENKNER ◽

Friedrich PRIEM ◽

Christian BAUER ◽

Hans-Hellmut NEUMAYER ◽

Manfred RASCHAK ◽

...

Keyword(s):

Blood Pressure ◽

Urinary Protein Excretion ◽

Urinary Protein ◽

Hypertensive Rats ◽

Independent Manner ◽

High Salt Diet ◽

Salt Diet ◽

Spontaneously Hypertensive ◽

Protein Excretion ◽

Pressure Independent

The renal endothelin (ET) system is involved in the pathogenesis of kidney fibrosis as well as blood pressure control by regulating tubular sodium excretion. Long-term effects of ETA receptor blockade on blood pressure and kidney function in spontaneously hypertensive rats (SHRs) on a high-salt diet are unknown. We treated SHRs on a 6% (w/v) NaCl sodium diet (SHR-S) for 48 weeks with the ETA antagonist LU 135252 (whose selectivity for ETA is 150 times greater than for ETB) with 10, 30 and 100mg·kg-1·day-1 or placebo. The ETA antagonist had at no time-point any effect on blood pressure. Glomerular filtration rate was normal in SHR-S and not altered by LU 135252. However, urinary albumin excretion was markedly reduced by the ETA antagonist (SHR-S, 145±50mg/day; SHR-S+10mg·kg-1·day-1 LU 135252, 33±11mg/day, P<0.05 versus SHR-S; SHR-S+30mg·kg-1·day-1 LU 135252, 55±16mg/day and SHR-S+100mg·kg-1·day-1 LU 135252, 32±11mg/day, P<0.05 versus SHR-S at both concentrations). Total urinary protein excretion was likewise significantly reduced by treatment with 10mg·kg-1·day-1 LU 135252 (SHR-S, 0.25±0.06g/day; SHR-S+10mg·kg-1·day-1 LU 135252, 0.089±0.01g/day, P<0.05 versus SHR-S). The higher dosages of LU 135252 showed only a trend towards reduction of total urinary protein excretion. Computer-aided image analysis after haematoxylin/eosin and periodic acid-Schiff staining revealed that treatment with 10mg·kg-1·day-1 LU 135252 significantly reduces the media/lumen ratio of intrarenal arteries. Higher dosages of LU 135252 were less effective. Renal matrix protein synthesis in SHR-S was not altered by LU 135252. In conclusion, the renal ET system contributes in a blood-pressure-independent manner to the regulation of urinary protein excretion and renal vascular hypertrophy in SHR-S. Lower doses of the ETA antagonist were more effective, indicating that a potential additional blockade of the ETB receptor using higher doses of LU 135252 seems to oppose the beneficial effects of a sole ETA blockade. Urinary protein excretion is an independent risk factor of chronic renal failure, thus ETA antagonists might be a therapeutic tool to prevent proteinuria-induced chronic renal failure.

Download Full-text