(Hypertension. 1995;25:818-822.)
© 1995 American Heart Association, Inc.
Articles |
Antihypertensive Actions of the Novel Nonpeptide Endothelin Receptor Antagonist SB 209670
From the Departments of Cardiovascular (S.A.D., M.E., G.Z.F., E.H.O.) and Renal (M.G.) Pharmacology and Medicinal Chemistry (J.D.E.), SmithKline Beecham Pharmaceuticals, King of Prussia, Pa.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract Indirect evidence has implicated endothelin-1 in the pathogenesis of hypertension. In the present study we examined such a role directly with SB 209670, a novel nonpeptide endothelin receptor antagonist. The antihypertensive and hemodynamic effects of SB 209670 were examined in conscious, unrestrained spontaneously hypertensive (SHR), normotensive Wistar-Kyoto (WKY), and renin-hypertensive rats. Sustained intravenous infusion of SB 209670 (10 µg · kg-1 · min-1 for 6 hours) produced a significant, reversible reduction in mean arterial pressure in SHR but not in WKY rats. The antihypertensive response to 10 µg · kg-1 · min-1 SB 209670 (~25 mm Hg reduction in blood pressure) was associated with bradycardia (16% decrease in heart rate) but only a minimal reduction (3%) in cardiac output, because stroke volume was elevated (by 15%). Therefore, the antihypertensive effect of SB 209670 resulted from a decrease (13%) in total peripheral resistance. A sustained antihypertensive effect could also be observed after intraduodenal administration of SB 209670 (3 mg/kg) in conscious SHR (reduction of ~35 mm Hg 5 hours after administration). SB 209670 (3 mg/kg intravenous bolus) did not alter the pressor response or tachycardia observed in pithed SHR after stimulation of thoracolumbar sympathetic outflow. SB 209670 was also antihypertensive in renin-hypertensive rats, lowering blood pressure to an extent similar to that observed in SHR. Thus, the data presented provide evidence to support a role for endothelin-1 in the pathophysiology of two animal models of hypertension.
Key Words: endothelins • hypertension, experimental • rats, inbred SHR • rats, inbred WKY • antihypertensive agents
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Endothelin-1 (ET-1), a 21–amino acid peptide synthesized by the endothelium, is the most potent mammalian vasoconstrictor identified to date.1 Numerous studies have indirectly implicated ET-1 in the development and/or maintenance of essential hypertension, gestational proteinuric hypertension (pre-eclampsia), and primary pulmonary hypertension. For example, such disorders are associated with elevated plasma endothelin immunoreactivity, changes in receptor kinetics, and alterations in vascular reactivity to ET-1.2 3 However, because these changes may be a consequence of an unrelated primary hypertensive mechanism, they have not, on their own, led to conclusions about a direct cause-effect relationship. Indeed, it has been suggested that ET-1 promotes hypertension indirectly: for example, by means of activation or synergism with the renin-angiotensin system.3 4 5 6
The direct vasoconstrictor actions of ET-1 are mediated by both endothelin-A (ETA) and endothelin-B (ETB) receptors.3 7 In addition, ET-1 stimulates the release of numerous vasoactive factors that influence smooth muscle tone, platelet function, and hemostasis both directly and indirectly, effects that have been attributed to both ETA and ETB receptor activation.2 3 ET-1 has also been implicated in the structural remodeling of the vasculature under numerous pathological conditions: both ETA and ETB receptor subtypes have been implicated in ET-1–induced cellular hypertrophy and hyperplasia and matrix deposition.2 3 In addition, ET-1 increases chemotactic and adhesion molecule release and expression and, therefore, may also promote cellular migration by means of an indirect mechanism.3
Thus, there is a growing body of evidence implicating activation of both ETA and ETB in the pathogenesis of hypertensive disorders. With the recent development and availability of potent and selective endothelin receptor antagonists, the role of endothelin in pathophysiological states, including hypertension, is being elucidated. SB 209670 is highly potent at both cloned human ETA (Ki=0.4 nmol/L) and ETB (Ki=7.0 nmol/L) receptors.8 9 10 SB 209670 [(±)-(1S, 2R, 3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxy-phenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid] is also a potent and competitive ETA/ETB receptor antagonist, as seen in functional studies in isolated vascular smooth muscle.9 11 Furthermore, SB 209670 has been used to demonstrate a pathogenic role of endothelin in neointimal formation and acute renal failure.7 12 The aim of the current study was to assess the antihypertensive efficacy of this novel nonpeptide endothelin receptor antagonist in experimental animal models of hypertension.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
After induction of anesthesia (sodium pentobarbital, 65 mg/kg IP), 14-week-old male spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) (350 to 400 g; Charles River) were chronically instrumented with systemic arterial and venous catheters implanted under aseptic conditions in the abdominal aorta and vena cava via the left femoral artery and vein, respectively.13 Once secured, cannulas were tunneled out under the skin, exited at the base of the tail, and passed through a custom-designed tail swivel. The arterial cannula was linked to a Grass model 79D polygraph via a miniature Gould P23ID pressure transducer, allowing for the continuous recording of systemic arterial blood pressure (BP) in freely moving, conscious rats. The venous cannula was connected to a Harvard model 22 microinfusion pump providing a systemic line for intravenous administration of antagonist or vehicle. When not in use, all cannulas were filled with a 1:1 mixture of dextrose (50%, vol/wt) and heparin (1000 U/mL) to avoid obstructive thrombus formation. Prior to any experimentation, animals were allowed 3 days to recover from instrumentation so basal mean arterial pressure could stabilize. On the day of the experiment, either vehicle (0.9% NaCl, wt/vol) or SB 209670 (10 µg · kg-1 · min-1) was administered to SHR continuously over a 6-hour period (50 µL/min IV). Antagonist was also administered to WKY. Cardiovascular parameters were recorded during this infusion period, and monitoring was continued for a period of up to 48 hours after the cessation of the infusion.
A similar group of animals was prepared as described above, with the exception that these animals were instrumented with intraduodenal (ID) catheters so the antihypertensive effects of bolus SB 209670 (0.1 to 3 mg/kg ID) or an equal volume of vehicle (1 mL/kg 0.9% NaCl, IV bolus) could be examined in SHR after enteric administration.
In a separate group of chronically instrumented rats, the acute systemic hemodynamic actions of 10 µg · kg-1 · min-1 SB 209670 were investigated in greater detail. SHR were prepared as described above with the exception that they were also chronically instrumented with a pulsed Doppler flow probe placed around the ascending aorta. Thus, variations in heart rate (derived from the BP recording) and cardiac output (pulsed Doppler shift), and therefore variations in total peripheral resistance (mean arterial pressure/Doppler shift) and stroke volume (Doppler shift/heart rate), could be continuously monitored during an intravenous infusion of SB 209670 or vehicle.
In a fourth set of experiments, SHR were anesthetized with sodium thiamylol (10 mg/kg IV), tracheostomies were performed, and rats were pithed with a steel rod.13 Immediately after being pithed, rats were ventilated artificially with room air (60 cycles/min; 20 mL/kg). The pithing rod was insulated except for a 6-cm thoracolumbar section. After treatment with tubocurarine and atropine sulfate (1 mg/kg IV bolus doses administered through the left jugular vein), animals were placed on a thermostatic heating pad to maintain body temperature at 37±1°C. Diastolic arterial BP was monitored by means of a cannula placed in the left carotid artery. Stimulation of thoracolumbar sympathetic outflow (50 V, 0.3 millisecond pulse duration, 0.3 to 5 Hz over a 15-second train duration) produced frequency-dependent increases in diastolic BP and heart rate. Three control frequency-response curves were performed and averaged at each frequency, a process that was repeated 10 minutes after administration of bolus intravenous vehicle or 3 mg/kg SB 209670 (a dose known to abolish the vasopressor actions of exogenously administered ET-1).9
In a final series of experiments, male Sprague-Dawley rats (350 to 400 g) were anesthetized with ketamine (60 mg/kg IM) and pentobarbital (20 mg/kg IV) so they could be instrumented with intravascular catheters as described. After 3 to 4 days of recovery, animals were reanesthetized and renin-dependent hypertension was established by partial unilateral renal ablation (ligation of two of the three branches of the left renal artery through an incision made in the flank of the rat).13 Animals were allowed 1 week to recover from this surgery, after which the antihypertensive effect of SB 209670 was examined: following a 1-hour intravenous vehicle infusion, antagonist was infused (10 and 100 µg · kg-1 · min-1) for 2 hours. In the same group of animals, the antihypertensive effect of SB 209670 was compared with that obtained with a maximal dose of the angiotensin-converting enzyme inhibitor captopril (3 mg/kg IV bolus; Sigma Chemical Co). The administration of either captopril or SB 209670 was randomized, and there were at least 2 days between the two separate procedures.
SB 209670 was synthesized in the Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals. All experiments described were performed specifically in accordance with the guidelines of the Animal Care and Use Committee, SmithKline Beecham Pharmaceuticals, and the American Association of Laboratory Animal Care. All values are expressed as mean±SEM, and n represents the number of individual rats studied in a particular group. Statistical comparisons were made using paired or unpaired Student's t test, with P<.05 considered significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The antihypertensive effect of SB 209670, administered as a continuous intravenous infusion or a single bolus intraduodenal dose, was examined in SHR and WKY.
Compared with vehicle, the continuous 6-hour intravenous infusion of 10 µg · kg-1 · min-1 SB 209670 produced a significant, reversible reduction in mean arterial pressure (~25 mm Hg) in conscious, freely moving SHR (Fig 1). The response to SB 209670 in SHR was an antihypertensive rather than a nonspecific, hypotensive one, because 10 µg · kg-1 · min-1 SB 209670 failed to produce a significant decrease in BP in normotensive WKY controls (basal mean arterial pressures and heart rates in SHR and WKY were 160±6 and 103±4 mm Hg and 313±9 and 323±10 beats per minute, respectively). SB 209670 did not produce a significant effect on heart rate in these studies.
|
The bolus intraduodenal administration of SB 209670 (0.1 to 3 mg/kg) produced a dose-dependent, sustained reduction in mean arterial pressure in conscious, freely moving SHR (Fig 2), an effect that was not observed after vehicle administration (basal mean arterial pressures and heart rates in vehicle- and SB 209670–treated rats were 145±13 and 156±15 mm Hg and 357±15 and 322±15 beats per minute, respectively). Once again, the reduction in BP (~35 mm Hg with 3 mg/kg SB 209670 ID) was fully reversible.
|
The hemodynamic effects of a 2-hour continuous intravenous infusion of vehicle or 10 µg · kg-1 · min-1 SB 209670 were evaluated in further detail in conscious, unrestrained SHR chronically implanted with pulsed Doppler aortic flow probes (basal mean arterial pressure and heart rate were 159±3 mm Hg and 369±12 beats per minute, respectively). As reported above, SB 209670 was antihypertensive in SHR compared with vehicle-treated rats: sustained infusion of SB 209670 reduced mean arterial pressure by ~16% (Fig 3), an effect accompanied by a decrease in heart rate (16±2%). However, as is shown in Fig 3, because this bradycardia was also associated with a 15% increase in stroke volume, cardiac output was not significantly altered (the decrease was 3% and therefore could not account for the drop in BP observed). Because BP was reduced yet cardiac output remained unaffected, the antihypertensive effect was the result of a decrease in total peripheral resistance (which decreased by 13% after a 2-hour infusion of SB 209670).
|
Stimulation of thoracolumbar sympathetic outflow produced frequency-dependent increases in diastolic BP and heart rate in SHR (basal diastolic BP and heart rate were 38±5 mm Hg and 318±15 beats per minute, respectively). Compared with values obtained under control conditions, the pressor responses and tachycardia observed in response to stimulation of thoracolumbar sympathetic outflow were unaffected by administration of either vehicle or SB 209670 (Fig 4).
|
Fig 5 shows that infusion of 10 and 100 µg · kg-1 · min-1 SB 209670 resulted in a significant reduction in BP (decreases of 19% and 20%, respectively) in renin-hypertensive rats 2 hours later (basal mean arterial pressure and heart rate in renin-hypertensive rats were 155±6 mm Hg and 376±9 beats per minute, respectively). The maximal response seemed to be produced by infusion of 10 µg · kg-1 · min-1 SB 209670. Infusion of 10 and 100 µg · kg-1 · min-1 SB 209670 had no significant effect on heart rate (producing increases of 4% and 1%, respectively). SB 209670 lowered BP to a degree similar to that observed after bolus intravenous injection of captopril (3 mg/kg) in this model.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
ET-1 has the potential to act as both an acute and a chronic pressor stimulus, possessing pronounced vasoconstrictor actions and an ability to modify vascular smooth muscle hypertrophy and hyperplasia, migration, adhesion, and matrix deposition.2 3 In addition to modulating peripheral vascular and neuroendocrine functions directly, ET-1 may also control systemic hemodynamics by means of central mechanisms, modulating neuronal function within the specific cardiovascular centers of the brain.3 14 15 16 17 For example, centrally administered ET-1 causes profound changes in systemic hemodynamic function, responses that are dependent on the site of administration; and both central and peripheral administration of ET-1 modulate baroreceptor reflexes and peripheral neurotransmission.3 18 19 20 21 22
Indirect evidence has accumulated to support a pathogenic role for ET-1 in the development and maintenance of essential hypertension, preeclampsia, and pulmonary hypertension (disorders associated with altered plasma endothelin immunoreactivity, contractile reactivity, and receptor kinetics). Nevertheless, such evidence remains largely indirect and does not establish an unequivocal cause-effect relationship. SB 209670 inhibits the proliferative effects of endothelin in both in vitro and in vivo studies.2 3 12 Because both the proliferative and the contractile actions of ET-1 are mediated by the ETA and ETB receptor subtypes, it follows that, if ET-1 is involved in the pathogenesis of hypertension, an antagonist of these receptors may be an efficacious antihypertensive agent. Indeed, the present study, in which such an antagonist is used, supports this hypothesis.
The acute antihypertensive mechanism of SB 209670 is related primarily to a reduction in total peripheral resistance resulting from systemic vasodilation (and is not, for example, due to a reduction in cardiac output). These findings support previous reports that the administration of specific neutralizing antibodies to ET-1 or of endothelin receptor antagonists, such as BQ-123, Ro 46-2005, Ro 47-0203, and BMS-182874 (but not FR 139317), is antihypertensive or vasculoprotective in several rat models of essential hypertension and of monocrotaline/hypobaric pulmonary hypertension.3 23 24 25 26 27 28 29 30
Interestingly, hemodynamic studies indicate that the antihypertensive action of SB 209670 is associated with bradycardia in SHR (but not in renin-hypertensive rats). This has been reported previously with the ETA-selective antagonist BQ-123.13 Normally, one would expect to see a reflex tachycardia in response to an acute drop in BP. It is unclear why reflex tachycardia is not observed in SHR treated with SB 209670, and it remains to be seen whether this is the result of an interaction with the normal baroreceptor-mediated reflexes in this strain of rat. However, as has been observed with BQ-123, SB 209670 does not alter the degree of sympathetic drive to the vasculature in pithed SHR, because the systemic pressor responses observed after stimulation of thoracolumbar sympathetic outflow were unaltered by SB 209670.13 It is noteworthy that infusions of SB 209670 produced a gradual reduction in BP in conscious SHR. This response has also been reported for BQ-123.13 The explanation for this may be related to the extremely slow off-rate of ET-1 from its receptor, the existence of a large receptor reserve, or slow peripheral/central distribution kinetics (and may explain why BQ-123 is ineffective as an antihypertensive agent when administered as an intravenous bolus).30
In addition to any beneficial actions that result from the acute administration of an endothelin receptor antagonist in models of experimental hypertension, cardiovascular protection may also be obtained from chronic administration. Although the present study describes only the acute effects of SB 209670 administration, this antagonist has been shown to exhibit vasculoprotective actions both in vitro and in vivo (for example, inhibiting vascular smooth muscle cell proliferation and angioplasty-induced neointima formation).3 7 9 12 Similarly, the antihypertensive effects of endothelin receptor antagonist administration have also been reported to be associated with a reduction in left ventricular hypertrophy in the hearts of deoxycorticosterone acetate–salt–sensitive rats.7
Thus, in summary, direct evidence now exists that ET-1 is involved in the sustained elevation of BP in established animal models of hypertension (at least during the maintenance phase). Therefore, the development of novel, orally active nonpeptide endothelin receptor antagonists designed to inhibit both the vasoconstrictor and growth-promoting actions of ET-1 may prove beneficial for the chronic treatment of hypertension.
|
Acknowledgments |
|---|
The authors would like to thank Jack Leber, Aming Gao, Russell Cousins, and Amparo Lago, Department of Medicinal Chemistry, SmithKline Beecham, for the synthesis of the SB 209670 used in this study.
|
Footnotes |
|---|
Reprint requests to Dr Eliot H. Ohlstein, Department of Cardiovascular Pharmacology (UW 2510), SmithKline Beecham Pharmaceuticals, 709 Swedeland Rd, PO Box 1539, King of Prussia, PA 19406-0939.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsue Y, Yazaki Y, Goto K, Masaki T. Endothelin: a novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332:411-415. [Medline] [Order article via Infotrieve]
2. Ohlstein EH, Douglas SA. Endothelin-1 modulates vascular smooth muscle structure and vasomotion: implications in cardiovascular pathology. Drug Dev Res. 1993;29:108-128.
3. Ohlstein EH, Douglas SA, Brooks DP, Hay DWP, Feuerstein GZ, Ruffolo RR Jr. Functions mediated by peripheral endothelin receptors. In: Ruffolo RR Jr, ed. Endothelin Receptors: From the Gene to the Human. Boca Raton, Fla: CRC Press. In press.
4.
Dohi Y, Hahn AWA, Boulanger C, Bühler FR, Lüscher
TF. Endothelin stimulated by angiotensin II augments contractility of
SHR resistance arteries. Hypertension. 1992;19:131-137.
5.
Mortensen LH, Fink GD. Captopril prevents chronic
hypertension produced by infusions of endothelin-1 in rats.
Hypertension. 1992;19:676-680.
6.
Lüscher TF, Seo B-G, Bühler FR. Potential role of
endothelin in hypertension: controversy on endothelin in hypertension.
Hypertension. 1993;21:752-757.
7. Douglas SA, Meek TD, Ohlstein EH. Novel receptor antagonists welcome a new era in endothelin biology. Trends Pharmacol Sci. 1994;181:313-316.
8. Elliott JD, Lago A, Cousins RD, Gao A, Leber JD, Erhard K, Eggleston D, Nambi P, Lee JA, Brooks DP, Feuerstein G, Ruffolo RR Jr, Weinstock J, Gleason JG, Peishoff CE, Ohlstein EH. (1S, 2R, 3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxy phenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid, a potent and selective non-peptide endothelin receptor antagonist. J Med Chem. 1994;37:1553-1557. [Medline] [Order article via Infotrieve]
9.
Ohlstein EH, Nambi P, Douglas SA, Edwards RM, Gellai M, Lago
A, Leber JD, Cousins RD, Gao A, Frazee JS, Peishoff CE, Bean JW,
Eggleston DS, Elshourbagy NA, Kumar C, Lee JA, Brooks DP, Ruffolo RR
Jr, Feuerstein GZ, Weinstock J, Gleason JG, Elliott JD. SB 209670,
rationally designed potent nonpeptide endothelin receptor antagonist.
Proc Natl Acad Sci U S A. 1994;91:8052-8056.
10.
Nambi J, Wu HL, Pullen M, Elshourbagy N, Ohlstein EH, Brooks
DP, Elliott JD, Gleason J, Ruffolo RR Jr. Non-peptide endothelin
receptor antagonists, I: effects on binding and signal transduction in
human ETA and ETB receptors. J Pharmacol
Exp Ther. 1994;271:755-761.
11.
Ohlstein EH, Beck G, Douglas SA, Nambi P, Gleason JG, Ruffolo
RR Jr, Feuerstein GZ, Elliott JD. Non-peptide endothelin receptor
antagonists, II: pharmacological characterization of SB 209670.
J Pharmacol Exp Ther. 1994;271:762-768.
12.
Douglas SA, Louden C, Vickery-Clark LV, Storer BS, Hart T,
Feuerstein GZ, Elliott JD, Ohlstein EH. A role for endogenous
endothelin-1 in neointima formation following rat carotid
artery balloon angioplasty: protective effects of the novel nonpeptide
endothelin receptor antagonist SB 209670. Circ
Res. 1994;75:190-197.
13. Douglas SA, Gellai M, Ezekiel M, Ohlstein EH. BQ-123, a selective endothelin subtype A-receptor antagonist, lowers blood pressure in different models of hypertension. J Hypertens. 1994;12:561-567. [Medline] [Order article via Infotrieve]
14.
Koseki C, Imai M, Hirata Y, Yanagisawa M, Masaki T.
Autoradiographic distribution in rat tissues of binding sites for
endothelin: a neuropeptide? Am J Physiol. 1989;256:R858-R866.
15.
MacCumber MW, Ross CA, Glaser BM, Snyder SM. Endothelin:
visualization of mRNAs by in situ hybridization provides evidence for
local action. Proc Natl Acad Sci U S A. 1989;86:7285-7289.
16. Lee ME, De la Monte SM, Ng SC, Bloch KD, Quertermous T. Expression of the potent vasoconstrictor endothelin in the human central nervous system. J Clin Invest. 1990;86:141-147.
17.
Masaki T. Endothelins: homeostatic and compensatory actions in
the circulatory and endocrine systems. Endocr Rev. 1993;14:256-268.
18.
Ouchi Y, Kim S, Souza AC, Iijima S, Hattori A, Orimo H,
Yoshizumi M, Kurihara H, Yazaki Y. Central effect of endothelin on
blood pressure in conscious rats. Am J Physiol. 1989;256:H1747-H1751.
19.
Mosqueda-Garcia R, Inagami T, Appalsamy M, Sugiura M,
Robertson RM. Endothelin as a neuropeptide: cardiovascular effects in
the brainstem of normotensive rats. Circ Res. 1992;72:20-35.
20. Roy S, Robello S, Marwah BS, Saxena PR, Gulati A. Systemic hemodynamics and regional circulatory effects of centrally administered endothelin (ET). FASEB J. 1994;8:A333. Abstract.
21. Van den Busse M, Itoh S. Central effects of endothelin on baroreflex of spontaneously hypertensive rats. J Hypertens. 1993;11:379-387. [Medline] [Order article via Infotrieve]
22.
Chapleau MW, Hajduczok G, Abboud FM. Suppression of
baroreceptor discharge by endothelin at high carotid sinus pressure.
Am J Physiol. 1992;263:R103-R108.
23. Ohno A, Naruse M, Kato S, Hosaka M, Karuse K, Demura H. Endothelin-specific antibodies decrease blood pressure and increase glomerular filtration rate and renal plasma flow in spontaneously hypertensive rats. J Hypertens. 1992;10:781-785. [Medline] [Order article via Infotrieve]
24.
Sogabe K, Nirei H, Shoubo M, Nomoto A, Ao S, Notsu Y, Ono T.
Pharmacological profile of FR 139317, a novel, potent endothelin ETA
receptor antagonist. J Pharmacol Exp Ther. 1992;264:1040-1044.
25. Nishikibe M, Tsuchida S, Okada M, Fukuroda T, Shimamoto K, Yano M. Antihypertensive effect of a newly synthesized endothelin antagonist, BQ-123, in a genetic hypertensive model. Life Sci. 1993;52:717-724. [Medline] [Order article via Infotrieve]
26. Stein PD, Hunt JT, Floyd DM, Moreland S, Dickinson KEJ, Mitchell C, Liu ECK, Webb ML, Murugesan N, Dickey J, McMullen D, Zhang R, Lee VG, Serafino R, Delaney C, Schaeffer TR, Kozlowski M. The discovery of sulfonamide endothelin antagonists and the development of the orally active ETA antagonist 5-(dimethylamino)-N-(3,4,-dimethyl-5-isoxazolyl)-1-naphthalene-sulfonamide. J Med Chem. 1994;37:329-331. [Medline] [Order article via Infotrieve]
27. Clozel M, Breu V, Burri K, Cassal JM, Fischli W, Gray GA, Hirth G, Löffler BM, Müller M, Neidhart W, Ramutz H. Pathophysiological role of endothelin revealed by the first orally active endothelin receptor antagonist. Nature. 1993;365:759-761. [Medline] [Order article via Infotrieve]
28.
Miyauchi T, Yorikane R, Sakai S, Sakurai T, Okada M, Nishikibe
M, Yano M, Yamaguchi I, Sugishita Y, Goto K. Contribution of endogenous
endothelin-1 to the progression of cardiopulmonary alterations in rats
with monocrotaline-induced pulmonary hypertension. Circ
Res. 1993;73:887-897.
29.
Bonvallet ST, Zamora MR, Hasunuma K, Sato K, Hanasato N,
Anderson D, Sato K, Stelzner TJ. BQ-123, an ETA-receptor
antagonist, attenuates hypoxic pulmonary hypertension in rats. Am
J Physiol. 1994;266:H1327-H1331.
30. Bazil MK, Lappe RW, Webb RL. Pharmacologic characterization of an endothelinA (ETA) receptor antagonist in conscious rats. J Cardiovasc Pharmacol. 1992;20:940-948.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  P. Martin, D. Ninio, and H. Krum Effect of Endothelin Blockade on Basal and Stimulated Forearm Blood Flow in Patients With Essential Hypertension Hypertension, March 1, 2002; 39(3): 821 - 824. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. A. Reinhart, L. C. Preusser, T. J. Opgenorth, C. D. Wegner, and B. F. Cox Endothelin and ETA receptors in long-term arterial pressure homeostasis in conscious nonhuman primates Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2000; 279(5): R1701 - R1706. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Haapaniemi, T. Tatlisumak, K. Hamel, L. Soinne, C. Lanni, T. J. Opgenorth, and M. Kaste Plasma Endothelin-1 Levels Neither Increase nor Correlate With Neurological Scores, Stroke Risk Factors, or Outcome in Patients With Ischemic Stroke Stroke, March 1, 2000; 31(3): 720 - 725. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Munter, H. Ehmke, and M. Kirchengast Maintenance of blood pressure in normotensive dogs by endothelin Am J Physiol Heart Circ Physiol, March 1, 1999; 276(3): H1022 - H1027. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Balakrishnan, H. D. Wang, V. Gopalakrishnan, T. W. Wilson, and J. R. McNeill Effect of an Endothelin Antagonist on Hemodynamic Responses to Angiotensin II Hypertension, November 1, 1996; 28(5): 806 - 809. [Abstract] [Full Text]
|
|
|
|
|
|
B. Bartholomeusz, K. J. Hardy, A. S. Nelson, and P. A. Phillips Bosentan Ameliorates Cyclosporin A–Induced Hypertension in Rats and Primates Hypertension, June 1, 1996; 27(6): 1341 - 1345. [Abstract] [Full Text]
|
|
|
|
 |
|
 W. G. Haynes, C. J. Ferro, K. P. J. O'Kane, D. Somerville, C. C. Lomax, and D. J. Webb Systemic Endothelin Receptor Blockade Decreases Peripheral Vascular Resistance and Blood Pressure in Humans Circulation, May 15, 1996; 93(10): 1860 - 1870. [Abstract] [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||