Renal vascular effects of the selective endothelin receptor antagonists in anaesthetized rats

Matsuura, Takeshi; Miura, Katsuyuki; Ebara, Tsuneyuki; Yukimura, Tokihito; Yamanaka, Shinya; Kim, Shokei; Itoh, Hiroshi

doi:10.1038/sj.bjp.0701349

Cited by 43 publications

(47 citation statements)

References 39 publications

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“…So far, few studies have investigated the effects of systemic inhibition of each step in the cascade of big ET/ET-1 cellular action on its renal function. 12,43,44 These studies do not allow for an unequivocal conclusion that ET B receptors coupled to NO synthesis are responsible for the diuretic and natriuretic actions of big ET-1 or locally produced ET-1. Therefore, the present study was carried out to test the involvement of the ET B receptor/NO axis in the renal and systemic actions of big ET-1.…”

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confidence: 96%

Mechanisms of Big Endothelin-1–Induced Diuresis and Natriuresis

et al. 2000

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Endothelin-1 (ET-1) at high concentrations has marked antidiuretic and antinatriuretic activities, whereas its precursor, big endothelin-1 (big ET-1), has surprisingly potent diuretic and natriuretic actions. The mechanisms underlying the excretory effects of big ET-1 have not been fully elucidated. To explore these mechanisms, we examined the effects of a highly selective ET(B) antagonist (A-192621.1), a calcium channel blocker (verapamil), a nitric oxide synthase inhibitor (N-nitro-L-arginine methyl ester [L-NAME]), and a cyclooxygenase inhibitor (indomethacin) on the systemic and renal actions of big ET-1 in anesthetized rats. An intravenous bolus injection of incremental doses of big ET-1 (0.3, 1. 0, and 3.0 nmol/kg) produced a significant hypertensive effect that was dose dependent and prolonged (from 113+/-7 mm Hg to a maximum of 148+/-6 mm Hg). The administration of big ET-1 induced marked diuretic and natriuretic responses (urinary flow rate increased from 8.5+/-1 to 110+/-14 microL/min, and fractional excretion of sodium increased from 0.38+/-0.13% to 7.51+/-1.24%). Glomerular filtration rate and renal plasma flow significantly decreased only at the highest dose of big ET-1. Pretreatment with A-192621.1 (3 mg/kg plus 3 mg. kg(-1). h(-1)) significantly abolished the diuretic (17+/-5 microL/min to a maximum of 19+/-3 microL/min) and natriuretic (0. 29+/-0.1% to a maximum of 1.93+/-0.37%) responses induced by big ET-1. Moreover, A-192621.1 potentiated the decline in glomerular filtration rate and renal plasma flow and the increase in mean arterial blood pressure produced by the low doses of big ET-1. Similar to A-192621.1, pretreatment with a nitric oxide synthase inhibitor (L-NAME, 10 mg/kg plus 5 mg. kg(-1). h(-1)) significantly and comparably reduced the diuretic and natriuretic actions of big ET-1 and augmented the hypoperfusion/hypofiltration and systemic vasoconstriction induced by high doses of the peptide. Pretreatment with verapamil (2 mg. kg(-1). h(-1)) slightly inhibited the diuretic/natriuretic effects of the high-dose big ET-1 and completely prevented the increase in mean arterial blood pressure provoked by the peptide. Unlike verapamil and L-NAME, only indomethacin administration was associated with significant natriuretic/diuretic responses and did not influence the pressor effect and renal actions of big ET-1. Taken together, these results suggest that big ET-1-induced diuretic and natriuretic responses are mediated mainly by stimulation of nitric oxide production coupled to ET(B) receptor subtype activation.

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confidence: 96%

Mechanisms of Big Endothelin-1–Induced Diuresis and Natriuresis

et al. 2000

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“…40 Acute administration of ET A receptor antagonists have little effect on renal and cardiovascular function in healthy normotensive animals, suggesting that ET does not exert a tonic influence on vascular resistance via the ET A receptor. 47,48 Information regarding the role of ET B receptors in regulating fluid volume balance has been obtained from studies using ET B receptor antagonists or rats and mice deficient in the ET B receptor gene. Gariepy et al have reported that rats deficient in a functional ET B receptor become hypertensive when given a high-salt diet.…”

Section: Et B Receptors In Hypertensionmentioning

confidence: 99%

Endothelin, Angiotensin, and Oxidative Stress in Hypertension

Pollock

2005

Hypertension

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E ndothelin (ET)-1 is a potent vasoconstrictor and mitogen, and because of these properties, it is thought to play a role in the development of hypertension. 1,2 The vascular endothelium is a major source of ET-1 production, although a variety of other cell types also have been shown to synthesize and release ET-1. ET-1 is believed to act in a paracrine manner on ET A and ET B receptors on smooth muscle, which mediate contraction, cell proliferation, and hypertrophy. Activation of ET B receptors on endothelial cells stimulates the production of prostacyclin and nitric oxide to induce vasorelaxation and inhibition of sodium transport in renal tubules. Given these properties, considerable attention has been paid to the mechanisms of ET-1 action as it relates to the renal control of blood pressure and the pathogenesis of salt-dependent hypertension. Renal ET synthesis is increased in experimental animals maintained on a high-salt diet and ET A receptor antagonists lower arterial pressure primarily in salt-dependent models of hypertension. 1,2 For the past 30 to 40 years, the actions of angiotensin (Ang) II has been arguably the most widely investigated factor in hypertension research. Although physiology textbooks agree on the major actions of Ang II, eg, vasoconstriction and release of aldosterone, recent attention has focused on its ability to stimulate the synthesis of ET-1, 3-5 as well as reactive oxygen species. 6 There are many reactive oxygen species such as superoxide, hydroxyl radical, and hydrogen peroxide that are produced by all cell types and can have profound effects on the vascular system to impact blood pressure regulation. Most recent attention has been paid to the role of superoxide. There are many enzymatic sources of superoxide including NADPH oxidase, xanthine oxidase, nitric oxide synthase, and cytochrome P450. The focus of the current review, however, is be on the interaction between the 2 peptide systems, ET-1 and Ang II, as they relate to oxidative stress. ET-1 in Ang II Hypertension ET-1 and Oxidative StressThe clinical significance of oxidative stress and its role in hypertension was recently reviewed by Touyz, 18 and so the current discussion is limited to the interaction between ET-1, Ang II, and superoxide.Studies from Ortiz et al have shown that the slow pressor response to Ang II is associated with increases in ET, as well as isoprostanes, a marker of lipid oxidation and an index of oxidative stress. 9 These effects could be prevented with bosentan, suggesting a role for ET in mediating the increase in oxidative stress in this model. They went on to demonstrate that antioxidant treatment with the superoxide dismutase mimetic, tempol, or the combination of vitamins C and E reduced Ang II-induced changes in ET expression. 14 Acute administration of tempol also has antihypertensive effects in rats chronically infused with Ang II. 15 Long-term treatment with tempol will lower arterial pressure in several models of hypertension associated with increases in ET production, including chroni...

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“…Initial experimental evidence suggested that the constriction of the renal vasculature under physiological conditions was mediated by the ET B receptor given that (i) administration of the ET B receptor agonist sarafotoxin 6c induced a sustained renal vasoconstriction [9,35] and (ii) the constrictor activity of exogenously administered ET-1 could not be attenuated by ET A receptor blockade [9,36]. As pointed out by Matsuura et al [37], inhibition of endogenously produced ET is probably more physiologically relevant given their paracrine/autocrine mode of action. The administration of specific ET A antagonists under basal conditions has no effect on renal vascular tone [9,37,38] while ET B receptor blockade causes renal vasoconstriction [37,38] indicating that under physiological conditions in the rat ET reduces renal vascular tone via stimulation of the ET B receptor.…”

Section: Discussionmentioning

confidence: 83%

“…As pointed out by Matsuura et al [37], inhibition of endogenously produced ET is probably more physiologically relevant given their paracrine/autocrine mode of action. The administration of specific ET A antagonists under basal conditions has no effect on renal vascular tone [9,37,38] while ET B receptor blockade causes renal vasoconstriction [37,38] indicating that under physiological conditions in the rat ET reduces renal vascular tone via stimulation of the ET B receptor. Under pathophysiological conditions, changes in the expression of ET receptors in the kidney have been reported.…”

Section: Discussionmentioning

confidence: 99%

The Role of Endothelin inEarly Renal Cortical Reperfusionin Renal Transplantation

Hammad¹,

Davis²,

Zhang³

et al. 2000

Eur Surg Res

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The role of specific endothelin receptors in the early renal reperfusion and long-term survival in renal transplantation was investigated in Lewis rats. Left renal transplantation was performed following 2 h cold ischaemia without and with ET_A receptor antagonism and following 16 h cold ischaemia with no treatment, with ET_A receptor antagonism and with ET_B receptor antagonism. The ET_A and ET_B receptor antagonists, BQ-610 and A-192621 respectively, were added to the preservation solution. Renal cortical perfusion (RCP) was measured postoperatively using laser Doppler flowmetry. All rats in the 2-hour groups survived for 15 days. Animals in the untreated 16-hour group or in the A-192621-treated group died between days 3 and 6 after surgery. Fifty percent of the rats in the 16-hour and BQ-610-treated group died between days 4 and 7 after surgery while the other 50% survived for 15 days. Survival rates correlated well with both the postoperative serum creatinine and the recovery of RCP. We conclude that addition of an ET_A receptor antagonist to the preservation solution improves renal reperfusion and long-term survival following prolonged ischaemia, whereas ET_B receptor antagonism does neither.

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Renal vascular effects of the selective endothelin receptor antagonists in anaesthetized rats

Cited by 43 publications

References 39 publications

Mechanisms of Big Endothelin-1–Induced Diuresis and Natriuresis

Mechanisms of Big Endothelin-1–Induced Diuresis and Natriuresis

Endothelin, Angiotensin, and Oxidative Stress in Hypertension

The Role of Endothelin inEarly Renal Cortical Reperfusionin Renal Transplantation

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