Selective ETA receptor antagonism with BQ-123 is insufficient to inhibit angioplasty induced neointima formation in the rat

Douglas, Stephen A.; Vickery-Clark, Lynne M.; Louden, Calvert; Ohlstein, Eliot H.

doi:10.1016/s0008-6363(96)88634-2

Cited by 43 publications

(7 citation statements)

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“…We speculate that ET B receptors in the detrusor might, under normal circumstances, mediate the mitogenic activity of ET-1 (as reported previously in vascular tissue [14,15]) or ET-1-mediated nitric oxide\prostacyclin release [16,17]. The autoradiographic studies showed that Naf prevented both ET A -and ET B -selective radioligand binding in a dose-dependent manner (0.01-1.0 µM), indicating that this drug is a mixed ET A \ET B antagonist.…”

Section: Discussionsupporting

confidence: 71%

Reduction of endothelin-1 binding and inhibition of endothelin-1-mediated detrusor contraction by naftidrofuryl

et al. 2002

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Endothelin-1 (ET-1) causes urinary bladder smooth muscle contraction and the endothelin receptors A and B (ET(A) and ET(B)) are both known to be present in the rabbit urinary bladder. Alterations in ET-1 signalling have been implicated in the pathophysiology of urinary tract disorders secondary to bladder outlet obstruction and also in diabetic cystopathy. Naftidrofuryl (Naf) (marketed under the trade name Praxilene) improves walking distance in patients with peripheral vascular disease, an effect which may be partially attributed to ET-1 antagonism. The purpose of this study is to assess whether Naf will reduce ET-1 binding in the rabbit detrusor muscle and to assess whether there is inhibition of ET-1-mediated detrusor contraction. Detrusor smooth muscle strips were mounted in organ baths and cumulative response curves were measured for ET-1-mediated contractions in the presence and absence of 10(-6) M Naf (therapeutic concentration). In addition, ET-1 was added to the detrusor strips in the presence of the ET(A) antagonist, BQ123, and the ET(B) antagonist, BQ788, to identify the receptor subtype functionally involved. Overall inhibition of [(125)I]ET-1 binding by Naf was assessed using autoradiography. Identification of receptor-subtype binding reduction was assessed using the radioligands [(125)I]PD151242 and [(125)I]BQ3020. Naf inhibited ET-1-mediated detrusor contractions significantly (P<0.04), e.g. at 10(-10) M ET-1, contraction was completely abolished by Naf. Autoradiography indicated that Naf competitively inhibited [(125)I]ET-1 binding in a dose-dependent manner (IC(50)=3x10(-7) M). All radioligand binding was reduced indicating binding of Naf to both ET(A) and ET(B) receptors. Naf reduces binding of ET-1 to rabbit detrusor ET(A) and ET(B) receptors and inhibits ET-1-induced detrusor contractions mediated by ET(A) receptors. Naf may have therapeutic potential in the treatment of bladder disorders secondary to bladder outlet obstruction and diabetes mellitus.

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Section: Discussionsupporting

confidence: 71%

Reduction of endothelin-1 binding and inhibition of endothelin-1-mediated detrusor contraction by naftidrofuryl

et al. 2002

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“…We previously demonstrated that the switching of ET receptor subtypes from ET A to ET B occurs in human vascular SMCs during atherogenesis [10]. Consistent with this, the density of ET B receptors is increased in the neointima of balloon-injured rabbit arteries [34], and administration of the selective ET A receptor antagonist BQ-123 fails to reduce angioplasty-induced neointima formation [34,35], whereas nonselective ET A /ET B antagonists are effective [36,37]. Furthermore, intimal hyperplasia in an organ culture of human saphenous vein is mainly mediated through the ET B receptor [38].…”

Section: Discussionmentioning

confidence: 63%

Blockade of Endothelin Receptors Reduces Diet-Induced Hypercholesterolemia and Atherosclerosis in Apolipoprotein E-Deficient Mice

Iwasa¹,

Fan²,

Miyauchi³

et al. 2001

Pathobiology

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Objective: Endothelin (ET)-1 has proatherogenic properties, since ET receptor antagonists reduce atherosclerotic lesions in animals. However, we recently demonstrated that ET-1 and ET_B receptors are increased in atherosclerotic lesions. To further examine the effects of ET_B receptor antagonism on atherogenesis, we investigated the chronic effects of the nonselective ET_A/ET_B receptor antagonist SB209670 on the development of atherosclerosis in apolipoprotein E (ApoE)-deficient mice. Methods: Ninety-four male mice (10 weeks of age) were randomly divided into four groups: mice fed a Western-type diet or a chow diet with SB209670 treatment (10 mg/kg/day) or placebo for 12 weeks. Results: In mice fed the Western-type diet, but not in mice fed the chow diet, treatment with SB209670 significantly attenuated the increase in plasma total cholesterol, predominantly in the very-low-density lipoprotein and intermediate-density lipoprotein fractions, without altering the plasma triglyceride level. Furthermore, treatment with SB209670 significantly reduced the extent of aortic atherosclerosis, by 53% in mice fed the Western-type diet and by 38% in mice fed the chow diet. Histological analysis revealed that SB209670 prevented the formation of atheromatous plaque lesions by inhibiting the fibroproliferative process. Conclusion: We found that chronic administration of SB209670 reduced diet-induced hypercholesterolemia and atherosclerosis in ApoE-deficient mice. Thus, nonselective ET receptor antagonists may have a therapeutic potential in the treatment of human atherosclerotic disease.

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“…A pathophysiologic role of ETB stimulation has also been suggested in patients with essential hypertension and atherosclerosis who could have endothelial dysfunction (37,38). In patients with essential hypertension, nonselective ETA/ETB blockade was reported to induce a greater vasodilatory effect than selective ETA blockade (38), suggesting a vasoconstrictive role of ETB stimulation under the existence of endothelial dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Endothelin A Receptor Blockade and Endothelin B Receptor Blockade Improve Hypokalemic Nephropathy by Different Mechanisms

Suga¹,

Yasui²,

Yoshihara

et al. 2003

Journal of the American Society of Nephrology

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Abstract. Hypokalemia causes renal tubulointerstitial injury with an elevation in renal endothelin-1 (ET-1). It was hypothesized that hypokalemic tubulointerstitial injury is ameliorated by the blockade of ET-A receptors (ETA), whereas ET-B receptor (ETB) antagonism may exacerbate the injury, because ETB is thought to mediate vasodilation. Rats were fed a K ϩ -deficient diet alone (LC) or with an ETA-selective antagonist ABT-627 (LA) or an ETB-selective antagonist A-192621 (LB) for 8 wk. Control rats were on a normal K ϩ diet alone or with the ETA-selective or ETB-selective antagonists. The severity of hypokalemia was not significantly different among LA, LB, and LC. LC developed tubulointerstitial injury with an elevation of renal preproET-1 mRNA level. There was an increase in tubular osteopontin expression, macrophage infiltration, collagen accumulation, and tubular cell hyperplasia.ETA blockade significantly ameliorated all parameters for renal injury in the cortex without suppressing local ET-1 and ETA expression. By contrast, ETB blockade significantly reduced local ET-1 and ETA expression and improved the injury to a similar extent in the cortex. In the medulla, ETA or ETB blockade only partially blocked renal injury. ETA blockade did not affect BP in normokalemic or hypokalemic rats. ETB blockade induced a BP elevation with a decrease in urinary Na ϩ excretion in normokalemic but not in hypokalemic rats. These results indicate that ET-1 can mediate hypokalemic renal injury in two different ways: by directly stimulating ETA and by locally promoting endogenous ET-1 production via ETB. Thus, ETA as well as ETB blockade may be renoprotective in hypokalemic nephropathy.Endothelin-1 (ET-1) is a potent vasoconstrictive peptide originally isolated from endothelial cells, but it has since been shown to also be produced by non-endothelial cells, including renal epithelial cells and mesangial cells. ET-1 exerts its biologic actions through the activation of two different receptor isoforms. Whereas ET-A receptors (ETA) mediate vasoconstriction, mononuclear cell infiltration, and production of matrix proteins (1), ET-B receptors (ETB) on endothelial cells mediate endothelium-dependent vasorelaxation via nitric oxide (NO) and prostacyclin formation (2). Several other functions are also attributed to ETB, including regulation of renal sodium (Na ϩ ) and water excretion (3) and stimulation of ET-1 gene expression (4). Taking these biologic actions into consideration, it is not surprising to regard ET-1 as one of the important mediators for the progression of chronic renal injury (5,6). Urinary excretion of ET-1 as well as preproET-1 mRNA expression in mononuclear cells increases in patients with glomerulonephritis (7,8). Renal ET-1 levels and/or preproET-1 mRNA levels are upregulated in several experimental renal disease models of immune and nonimmune origins (5). The significance of ET-1 has been strengthened by the observation that glomerular and tubulointerstitial injury develop in preproET-1 transgenic mice despite ...

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Selective ETA receptor antagonism with BQ-123 is insufficient to inhibit angioplasty induced neointima formation in the rat

Cited by 43 publications

References 0 publications

Reduction of endothelin-1 binding and inhibition of endothelin-1-mediated detrusor contraction by naftidrofuryl

Reduction of endothelin-1 binding and inhibition of endothelin-1-mediated detrusor contraction by naftidrofuryl

Blockade of Endothelin Receptors Reduces Diet-Induced Hypercholesterolemia and Atherosclerosis in Apolipoprotein E-Deficient Mice

Endothelin A Receptor Blockade and Endothelin B Receptor Blockade Improve Hypokalemic Nephropathy by Different Mechanisms

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