Antihypertensive Effects of a Novel Endothelin-A Receptor Antagonist in Rats

Bird, J. E.; Moreland, Suzanne; Waldron, Thomas L.; Powell, J.R.

doi:10.1161/01.hyp.25.6.1191

Cited by 49 publications

(33 citation statements)

References 17 publications

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“…Consistent with the actions of AT 1 receptor Sprague-Dawley rats treated with DOCA and drinking 0.9% NaCl (DOCA-salt rats) develop hypertension that is associated with a suppression of the renin-angiotensin system and increased tissue levels of ET-1 (Fujita et al, 1995;Schiffrin et al, 1996). Consequently, ET A receptor antagonists (Bird et al, 1995;Schiffrin et al, 1997) but not AT 1 receptor antagonists (Wada et al, 1995;Pollock et al, 2000) have shown antihypertensive activity in this model. Compounds A and C reduced blood pressure in hypertensive DOCA-salt rats, consistent with the actions of an ET A receptor antagonist.…”

Section: Discussionmentioning

confidence: 89%

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Novel Dual Action AT₁ and ET_A Receptor Antagonists Reduce Blood Pressure in Experimental Hypertension

Kowala¹,

Murugesan²,

Tellew³

et al. 2004

J Pharmacol Exp Ther

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Angiotensin II and endothelin-1 activate their respective AT 1 and ET A receptors on vascular smooth muscle cells, producing vasoconstriction, and both peptides are implicated in the pathogenesis of essential hypertension. Angiotensin II potentiates the production of endothelin, and conversely endothelin augments the synthesis of angiotensin II. Both AT 1 and ET A receptor antagonists lower blood pressure in hypertensive patients; thus, a combination AT 1 /ET A receptor antagonist may have greater efficacy and broader utility compared with each drug alone. By rational drug design a biphenyl ET A receptor blocker was modified to acquire AT 1 receptor antagonism. These compounds (C and D) decreased Sar-Ile-Angiotensin II binding to AT 1 receptors and endothelin-1 binding to ET A receptors, and compound C inhibited angiotensin II-and endothelin-1-mediated Ca 2ϩ transients. In rats compounds C and D reduced blood pressure elevations caused by intravenous infusion of angiotensin II or big endothelin-1. Compound C decreased blood pressure in Na ϩ -depleted spontaneously hypertensive rats and in rats with mineralocorticoid hypertension. Compound D was more efficacious than AT 1 receptor antagonists at reducing blood pressure in spontaneously hypertensive rats, and its superiority was likely due to its partial blockade of ET A receptors. Therefore compounds C and D are novel agents for treating a broad spectrum of patients with essential hypertension and other cardiovascular diseases.

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Section: Discussionmentioning

confidence: 89%

“…This study was performed as described previously (Bird et al, 1995). Sprague-Dawley rats were prepared as described above.…”

Section: Radioligand Binding Studiesmentioning

confidence: 99%

Novel Dual Action AT₁ and ET_A Receptor Antagonists Reduce Blood Pressure in Experimental Hypertension

Kowala¹,

Murugesan²,

Tellew³

et al. 2004

J Pharmacol Exp Ther

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“…Selective ET A antagonists such as BQ 123, BMS 182874 and FR 139317 block the rise of BP in certain rat models, which shows that hypertension is to some extent dependent on endothelin-related mechanisms. 7,26,27 Selective ET A receptor antagonists significantly reduce BP in hypertensive subjects. 28,29 ET A receptor antagonists cause a greater degree of vasodilatation in forearm vessels of essential hypertensive patients than in normotensive controls, suggesting a predominant role of ET A receptors in the regulation of vascular tone by endogenous ET-1 in hypertension.…”

Section: Discussionmentioning

confidence: 99%

Common genetic variation in the type A endothelin-1 receptor is associated with ambulatory blood pressure: a family study

et al. 2008

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The endothelins are among the most potent vasoconstrictors known. Pharmacological inhibition of endothelin receptors lowers blood pressure (BP). It is unknown whether naturally occurring genetic variation in the endothelin receptors influences BP. We have evaluated the type A endothelin receptor (EDNRA) as a candidate gene for hypertension in a large family study. A total of 1425 members of 248 families selected via a proband with hypertension were studied. Ambulatory BP monitoring was conducted using the A&D TM2421 device. Four haplotype-tagging single nucleotide polymorphisms (SNPs) spanning the EDNRA gene were typed. There was evidence of association between genotype at the rs5335 (C þ 70G) SNP and night systolic blood pressure ( þ 1.24% (s.e. 0.64) per G allele; P ¼ 0.05); night diastolic blood pressure ( þ 1.64% (s.e. 0.71) per G allele; P ¼ 0.021) and night mean BP ( þ 1.51% (s.e. 0.64) per G allele; P ¼ 0.017). Borderline significant trends in the same direction were seen for daytime BPs. Proportions of hypertensives in each of the three genotype groups were C/C 34.7%, C/G 37.9%, G/G 42.4% yielding an odds ratio for hypertension per G allele of 1.19 (95% confidence interval 1.00-1.41; P ¼ 0.05). In conclusion, the rs5335 (C þ 70G) polymorphism of the EDNRA gene has small effects on the risk of hypertension. Natural variation in other genes in the endothelin-signalling pathway should be explored to identify additional influences on BP regulation.

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“…As an example, the combined ET A /ET B receptor antagonist bosentan produced minor changes on elevated MABP and vascular hypertrophy in deoxycorticosterone acetate-salt hypertensive rats (Li et al, 1994), whereas it did not modify MABP in spontaneously hypertensive rats (Li and Schiffrin, 1995). Administration of another orally active ET A receptor antagonist showed a similar discrepancy of effect between the two models (Bird et al, 1995). Thus, ET A receptor antagonism was active in abrogating the marked cardiovascular alterations produced by prednisolone.…”

Section: Nitro-prednisolone Does Not Cause Hypertension 1137mentioning

confidence: 94%

The Distinct Alterations Produced in Cardiovascular Functions by Prednisolone and Nitro-prednisolone (NCX-1015) in the Rat Highlight a Causal Role for Endothelin-1

Filippo

Rossi²,

Ongini³

et al. 2004

J Pharmacol Exp Ther

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Daily administration of prednisolone, but not the derivative NCX-1015 (or prednisolone 21-[4Ј-nitrooxymethyl]benzoate), to rats resulted in a time-and dose-dependent increase in mean arterial blood pressure (MABP), significant after 1 week for the dose of 6.9 mol/kg i.p. (n ϭ 10; P Ͻ 0.05), and 3 weeks for the lower dose of 1.38 mol/kg. A similar dichotomy of behavior was observed with respect to myocardial contractility and renal vascular resistance, in either case augmented by 3-week treatment with prednisolone but not NCX-1015. In contrast, both NCX-1015 and prednisolone reduced plasma levels of corticosterone in a dose-(dose range of 0.69 -6.9 mol/kg i.p.) and time-dependent (1-3 weeks) manner. Similar profiles were obtained for plasma nitrate values, although they were increased selectively after NCX-1015 administration. In contrast, prednisolone, but not NCX-1015, augmented plasma endothelin 1 (ET-1) with a profile that mirrored the changes observed in MABP and renal blood flow. Supply in the drinking water of the ET-1 receptor typeantagonists prevented the changes produced by a 21-day treatment with prednisolone. In conclusion, this study indicates 1) a lack of occurrence of cardiovascular alterations by nitro-releasing derivative of prednisolone (NCX-1015), and 2) a functional link between prednisolone effects and the endogenous endothelin-1 system. Glucocorticoids (GCs) have wide clinical applications for the management of a variety of disorders, including autoimmune, allergic, and lymphoproliferative diseases. In most of these pathologies, GC must be administered for long term, and this increases the likelihood of the appearance of major side effects, thus limiting further use (Whitworth, 1994;Saruta, 1996). Marked side effects include obesity with the classical "moon face"; hirsutism; cataracts; osteoporosis; diabetes mellitus; immune suppression; and cardiovascular disorders, including hypertension and atherosclerosis (Ross and Linch, 1982;Schä cke et al., 2002). Among these multiple effects, cardiovascular complications are an important factor for predicting the morbidity and mortality of patients overtreated with GCs (Ross and Linch, 1982). Plasma volume expansion due to sodium retention gives a minor contribution to GC cardiovascular effects (Whitworth et al., 1989;Whitworth, 1994;Saruta, 1996). In contrast, increase in peripheral vascular resistance, demonstrated by an augmented pressor response to catecholamines and angiotensin II, is a major contributor to the pathogenesis of hypertension after excess use of GCs (Pirpiris et al., 1992;Whitworth, 1994;Saruta, 1996). The molecular mechanism whereby GC excess causes the increase in vascular resistance and hypertension has not been fully elucidated, although a recent study has provided a functional link between dexamethasone administration and down-regulation of endothelial nitric-oxide (NO) synthase (Wallerath et al., 2004

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Antihypertensive Effects of a Novel Endothelin-A Receptor Antagonist in Rats

Cited by 49 publications

References 17 publications

Novel Dual Action AT₁ and ET_A Receptor Antagonists Reduce Blood Pressure in Experimental Hypertension

Novel Dual Action AT₁ and ET_A Receptor Antagonists Reduce Blood Pressure in Experimental Hypertension

Common genetic variation in the type A endothelin-1 receptor is associated with ambulatory blood pressure: a family study

The Distinct Alterations Produced in Cardiovascular Functions by Prednisolone and Nitro-prednisolone (NCX-1015) in the Rat Highlight a Causal Role for Endothelin-1

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Antihypertensive Effects of a Novel Endothelin-A Receptor Antagonist in Rats

Cited by 49 publications

References 17 publications

Novel Dual Action AT1 and ETA Receptor Antagonists Reduce Blood Pressure in Experimental Hypertension

Novel Dual Action AT1 and ETA Receptor Antagonists Reduce Blood Pressure in Experimental Hypertension

Common genetic variation in the type A endothelin-1 receptor is associated with ambulatory blood pressure: a family study

The Distinct Alterations Produced in Cardiovascular Functions by Prednisolone and Nitro-prednisolone (NCX-1015) in the Rat Highlight a Causal Role for Endothelin-1

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Novel Dual Action AT₁ and ET_A Receptor Antagonists Reduce Blood Pressure in Experimental Hypertension

Novel Dual Action AT₁ and ET_A Receptor Antagonists Reduce Blood Pressure in Experimental Hypertension