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(Hypertension. 1995;25:1191-1195.)
© 1995 American Heart Association, Inc.

Articles

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

J. Eileen Bird; Suzanne Moreland; Thomas L. Waldron; James R. Powell

From the Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ.

Correspondence to Eileen Bird, DVM, PhD, Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543-4000. E-mail bird@ bms.com.

	Abstract

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Abstract Endothelin is a potent pressor agent mediated primarily through activation of endothelin-A receptors on vascular smooth muscle. Surprisingly, there is no consensus in the literature regarding the role of endothelin itself or endothelin-A receptors in hypertension. The goal of this study was to compare the effects of the novel, selective endothelin-A receptor antagonist BMS-182874 in various models of hypertension. BMS-182874 specifically inhibited the pressor response to endothelin-1 (0.3 nmol/kg IV) in Sprague-Dawley rats in a dose-dependent manner (ED₂₅=8 µmol/kg IV) but had no effect on changes in mean arterial pressure brought about by other vasoactive agents. The antihypertensive effects of BMS-182874 were evaluated in conscious deoxycorticosterone acetate (DOCA)–salt hypertensive rats, spontaneously hypertensive rats (SHR), and sodium-deplete SHR. BMS-182874 reduced blood pressure in DOCA-salt hypertensive rats when administered at a dose of 30, 100, or 300 µmol/kg IV. A maximal decrease of approximately 45 mm Hg was observed after treatment with 100 µmol/kg IV. Three days of oral or intravenous treatment with BMS-182874 (100 µmol/kg) elicited a sustained decrease in blood pressure in the DOCA-salt hypertensive rats. In SHR, BMS-182874 decreased blood pressure by approximately 30 mm Hg, but the antihypertensive effects were similar at doses of 75, 150, and 450 µmol/kg PO. In sodium-deplete SHR, BMS-182874 did not significantly reduce blood pressure. In summary, BMS-182874 is a specific, orally active endothelin-A receptor antagonist that is efficacious in mineralocorticoid hypertension in rats but has less effect in sodium-replete and sodium-deplete SHR. Thus, endothelin-A receptor activation may play a role in volume-dependent or low-renin hypertension but is unlikely to be important in all hypertensive states.

Key Words: hypertension, experimental • hypertension, mineralocorticoid • receptors, endothelin • endothelins

	Introduction

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The potent vasoconstrictor actions of endothelin-1 (ET-1)^{1 2} have led investigators to propose a role for endothelin in the maintenance or regulation of blood pressure (BP).^{3 4} Evidence suggests that ET-1 contributes to the pathogenesis of deoxycorticosterone acetate (DOCA)–salt hypertension, a low-renin model of hypertension. For example, immunoreactive ET-1 content in aortas and mesenteric arteries from DOCA-salt hypertensive rats was increased compared with that in uninephrectomized controls,⁵ and preproET-1 gene expression was increased in blood vessels from DOCA-salt hypertensive rats.⁶ Li et al⁷ reported a significantly smaller increase in systolic BP in DOCA-salt hypertensive rats treated for 3 weeks with the nonselective endothelin receptor antagonist bosentan than in vehicle-treated rats. We described acute antihypertensive effects of the selective ET_A receptor antagonist BMS-182874 in DOCA-salt hypertensive rats.⁸ ET-1 may also be involved in the maintenance of hypertension under conditions of normal renin levels. In spontaneously hypertensive rats (SHR), antihypertensive effects of the peptide ET_A receptor antagonist BQ-123 have been reported.⁹ In addition, SHR were more sensitive to ET-1 than normotensive rats when pressor responses¹⁰ or aortic strip contractions¹¹ were evaluated.

BMS-182874 [5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalene sulfonamide] is a recently disclosed, low molecular weight, nonpeptide, selective ET_A receptor antagonist.^{8 12} We previously reported inhibition of an ET-1–induced pressor response after BMS-182874 administration in normotensive rats.¹² In the current study, we characterized the effects of BMS-182874 in normotensive and hypertensive rats. We measured the specificity of BMS-182874 for ET_A receptors in vivo by determining its effects on the pressor or depressor responses to ET-1 and other vasoactive agents in normotensive rats. Subsequently, we evaluated the effects of this novel ET_A receptor antagonist on BP in three commonly used models of hypertension in rats: the low-renin model of DOCA-salt hypertensive rats, the normal-renin model of SHR, and the high-renin model of sodium-deplete SHR.

	Methods

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Conscious Normotensive Rat Studies
Procedures followed were in accordance with the animal use guidelines of Bristol-Myers Squibb. Male Sprague-Dawley rats (9 weeks of age) were prepared surgically for direct measurement of BP according to the method of Weeks and Jones.¹³ Rats were anesthetized with sodium pentobarbital (50 mg/kg IP). Catheters (PE-10) were placed in the descending aorta for mean arterial pressure (MAP) measurement and in the vena cava for drug administration; both catheters were extruded through the skin at the back of the neck. Two weeks later, the pressor response to ET-1 was measured before and after BMS-182874 administration. For these experiments, conscious rats (n=4-13 per dose) were allowed 30 minutes to adapt to the testing environment, and then a bolus of ET-1 (0.3 nmol/kg IV) was administered as a control challenge for each rat group. When BP returned to baseline, three consecutive intravenous injections of BMS-182874 (1, 3, 10, 30, 100, or 300 µmol/kg) were made 5 minutes before subsequent ET-1 challenges. The peak in MAP occurred within 20 minutes after dosing of ET-1. Ninety minutes were allowed between ET-1 injections. The effect of oral administration of BMS-182874 on the ET-1–induced pressor response was also evaluated in fasted rats (n=6). In this experiment, vehicle (agar) was administered before the control challenge with ET-1, and then a single oral dose of BMS-182874 (100 µmol/kg) was administered 15 minutes before the second challenge with ET-1.

In a separate study that evaluated the specificity of BMS-182874 as an ET_A receptor antagonist in vivo, rats were challenged with an intravenous bolus of bradykinin (20 µg/kg), angiotensin II (100 ng/kg), acetylcholine (10 µg/kg), isoproterenol (1 µg/kg), glyceryl trinitrate (30 µg/kg), the thromboxane receptor agonist U46619 (1 µg/kg), norepinephrine (1 µg/kg), arginine vasopressin (AVP, 300 ng/kg), and histamine (30 µg/kg). Vehicle (5% NaHCO₃) or BMS-182874 (100 µmol/kg IV) was injected into rats (n=4 per group), and the agonist challenges were repeated.

Conscious Hypertensive Rat Studies
DOCA-salt hypertensive rats were prepared by the following protocol. Male Sprague-Dawley rats (200 to 220 g) were anesthetized with sodium pentobarbital (50 mg/kg IP). A midline abdominal incision was made, the left kidney was removed, and catheters (PE-10) were placed in the descending aorta for MAP measurement and in the vena cava for drug administration. Catheters were extruded through the skin at the back of the neck. A 100-mg DOCA pellet was placed subcutaneously. Rats drank water containing 0.9% NaCl and 0.2% KCl and ate standard rat chow.

At least 2 weeks after surgery, each rat was placed in a harness. The catheter was passed through a tightly wound steel spring and connected to a feed-through miniature swivel. The swivel was connected to a transducer (Cobe Laboratories) through a rotary fluid switch and to a pressurized (13 lb/in²) reservoir that provided a slow flow (0.03 to 0.06 mL/min) of saline into the arterial catheter. MAP of each rat was recorded every 5 minutes, digitized, and stored on an IBM AT computer. Six 5-minute readings were averaged to give a mean value representing a 30-minute sample that was stored for further analysis.

A dose-response study of intravenous doses of BMS-182874 in DOCA-salt hypertensive rats was performed. A bolus injection of BMS-182874 (30, 100, or 300 µmol/kg IV) or 5% NaHCO₃ was administered to DOCA-salt hypertensive rats (n=5-7 per group), and MAP was evaluated for 24 hours. For determination of the effect of repeated dosing with BMS-182874, the effects of 3 days of intravenous or oral BMS-182874 administration were measured. DOCA-salt hypertensive rats received 100 µmol/kg IV of BMS-182874 or vehicle (5% NaHCO₃) daily for 3 days (n=6-7 per group), and MAP was evaluated for 72 hours. For testing of the oral antihypertensive effects of BMS-182874, noncatheterized DOCA-salt hypertensive rats (n=8-9 per group) received daily doses of vehicle (agar) or BMS-182874 (100 µmol/kg PO) for 3 days, with daily monitoring of systolic BP 2 hours after dosing. Systolic BP was measured with the tail-cuff method after rats were warmed and under slight restraint.

The effects of BMS-182874 on BP were tested in SHR. Male SHR (12 to 14 weeks of age) were prepared surgically for direct measurement of BP as described above. Two weeks later, rats (n=6-8 per group) were prepared for continuous measurement of MAP, and BMS-182874 was administered (75, 150, 450 µmol/kg PO). MAP was measured for 24 hours after dosing. For determination of the effect of repeated dosing with BMS-182874, a group of noncatheterized SHR received daily oral doses of vehicle (agar), BMS-182874 (150 µmol/kg), or the angiotensin-converting enzyme (ACE) inhibitor fosinopril (85 µmol/kg) for 3 days (n=10 per group), with daily monitoring of systolic BP 2 hours after dosing. Systolic BP was measured with the tail-cuff method after rats were warmed and under slight restraint.

The effect of BMS-182874 administration was also evaluated in sodium-deplete SHR. In order to deplete rats of sodium, we placed chronically catheterized SHR on a low sodium diet (45 ppm sodium) for 5 days and treated them with furosemide (Hoechst-Roussel) at a dose of 2.5 mg/kg IM daily for 3 days. Rats (n=6-7 per group) were treated orally with vehicle (agar), BMS-182874 (150 µmol/kg), or the ACE inhibitor captopril (150 µmol/kg), and MAP was monitored for 24 hours.

Materials
ET-1 was obtained from Peninsula Laboratories. BMS-182874 was synthesized by the Department of Chemistry, Bristol-Myers Squibb.

Statistical Analysis
Results are presented as mean±SEM. Effects of drugs on MAP in hypertensive rats were analyzed by ANOVA followed by Dunnett's one-sided test or ANOVA for repeated measures and contrasts. The null hypothesis was rejected at a value of P<.05.

	Results

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Conscious Normotensive Rats
The ET_A receptor antagonist BMS-182874 inhibited the pressor response to ET-1 in Sprague-Dawley rats (n4) in a dose-dependent manner after intravenous administration (Fig 1). Maximal percent inhibition of the ET-1 pressor response ranged from 4±4.7% after 1.0 µmol/kg IV BMS-182874 to 59±2.7% inhibition after 300 µmol/kg IV BMS-182874. Oral administration of 100 µmol/kg BMS-182874 inhibited the pressor response to ET-1 by 48±6.7%, which was similar to the maximal inhibition observed after 100 µmol/kg IV BMS-182874 (55±4.2% inhibition).

View larger version (13K): [in this window] [in a new window]   Figure 1. Line graph shows inhibition of the pressor response to endothelin-1 (ET-1, 0.3 nmol/kg IV) after intravenous injection of BMS-182874 in conscious, normotensive rats. Mean±SEM is given; n=4-13 per dose.

To evaluate the specificity of BMS-182874 for ET_A receptor–mediated effects, the responses to five depressor agents (bradykinin, acetylcholine, isoproterenol, nitroglycerin, and histamine) and four pressor agents (angiotensin II, norepinephrine, AVP, and the thromboxane mimetic U46619) were measured before and after administration of vehicle or BMS-182874 (100 µmol/kg IV). Repeated injections of the agonists produced consistent changes in MAP in conscious, normotensive rats (n=4 per group). Responses to these vasodilator and vasoconstrictor agents were not changed by BMS-182874 administration (Table).

View this table: [in this window] [in a new window]   Table 1. Mean Arterial Pressure Changes Elicited by Intravenous Injection of Vasoactive Agents Before and After Administration of 100 µmol/kg BMS-182874 in Conscious, Normotensive Rats

Conscious Hypertensive Rats
The antihypertensive effects of BMS-182874 were evaluated in three rat models of hypertension (n5 per group). The first series of experiments was conducted in DOCA-salt hypertensive rats, a low-renin model of hypertension. A dose-response study of intravenous doses of BMS-182874 in DOCA-salt hypertensive rats was performed. MAP was reduced by 25±14, 44±3, and 45±10 mm Hg after administration of 30, 100, and 300 µmol/kg IV BMS-182874, respectively. Baseline MAP was 185±7.2, 179±7.7, and 157±6.2 mm Hg before administration of these three doses of BMS-182874, respectively. Vehicle administration had no significant effect on MAP. For determination of the effect of repeated dosing with BMS-182874, a daily dose of 100 µmol/kg IV BMS-182874 was administered for 3 consecutive days. This dosing regimen caused significant reductions in MAP at all time points evaluated, while MAP remained stable in vehicle-treated rats (Fig 2). There was an overall reduction in MAP of 65 mm Hg from a baseline of 186±4 to 121±6 mm Hg on day 3. BMS-182874 was also orally active in this model. Daily oral administration of 100 µmol/kg BMS-182874 to DOCA-salt hypertensive rats for 3 days significantly lowered systolic BP on each day of treatment compared with vehicle-treated rats (Fig 3).

View larger version (28K): [in this window] [in a new window]   Figure 2. Line graph shows effects of daily intravenous administration of vehicle () or BMS-182874 (, 100 µmol/kg) for 3 days on mean arterial pressure (MAP) in conscious, deoxycorticosterone acetate–salt hypertensive rats. Starting MAP was 179±9 mm Hg in the vehicle (5% NaHCO3) group and 186±4 mm Hg in the BMS-182874–treated group. Daily treatment with BMS-182874 significantly reduced MAP at all time points evaluated compared with vehicle. Mean±SEM is given; n=6-7 per group.

View larger version (15K): [in this window] [in a new window]   Figure 3. Line graph shows effects of daily oral administration of vehicle () or BMS-182874 (, 100 µmol/kg) for 3 days on systolic pressure in conscious, deoxycorticosterone acetate–salt hypertensive rats. Daily treatment with BMS-182874 significantly reduced systolic pressure on days 1, 2, and 3 compared with vehicle. Mean±SEM is given; n=8-9 per group. *P<.05.

The second series of experiments was conducted in SHR, a normal-renin model of hypertension. In conscious SHR, MAP decreased by 32±4 mm Hg at 24 hours after oral administration of BMS-182874 (150 µmol/kg). The maximal reduction in MAP during the 24-hour period after oral dosing with vehicle, 75, 150, and 450 µmol/kg BMS-182874 was 17±2, 32±5, 32±4, and 29±4 mm Hg, respectively, from control pressures of 168±6, 162±2, 170±4, and 167±3 mm Hg, respectively. Daily oral administration of BMS-182874 (150 µmol/kg) for 3 days in SHR did not produce consistent or sustained reductions in systolic BP (Fig 4). BMS-182874 had no significant antihypertensive effect on systolic BP on days 1 or 3 of dosing compared with vehicle, although systolic BP was significantly lowered on day 2 of treatment. Oral administration of the ACE inhibitor fosinopril produced significant lowering of systolic BP on each day of treatment in this model.

View larger version (17K): [in this window] [in a new window]   Figure 4. Line graph shows effects of daily oral administration of vehicle (), fosinopril (, 85 µmol/kg), or BMS-182874 (, 150 µmol/kg) on systolic pressure in conscious, spontaneously hypertensive rats. Daily treatment with fosinopril significantly reduced systolic pressure on days 1, 2, and 3 compared with vehicle. Daily treatment with BMS-182874 significantly reduced systolic pressure on day 2 compared with vehicle. Mean±SEM is given; n=10 per group. *P<.05.

Treatment with BMS-182874 had little effect on MAP in the high-renin model of sodium-deplete SHR. BMS-182874 (150 µmol/kg PO) did not significantly reduce MAP during the 24-hour period after dosing; MAP decreased by 17±3 mm Hg (from a control level of 148±3.8 mm Hg) in BMS-182874–treated rats versus 8±5.1 mm Hg (from 155±5.9 mm Hg) in vehicle-treated controls. In contrast, MAP was significantly reduced by 43±3.9 mm Hg (from 149±3.3 mm Hg) in rats treated with 150 µmol/kg PO of the ACE inhibitor captopril.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Yanagisawa et al¹⁴ were the first to postulate a role for endothelin in the long-term regulation of vascular tone. Endothelin has been implicated in the pathogenesis of mineralocorticoid or DOCA-salt hypertension because of the decreased vascular responsiveness to ET-1 in blood vessels of hypertensive rats and increased ET-1 content in the vasculature of DOCA-salt hypertensive rats.^{5 15} Li et al⁷ described a significantly smaller increase in systolic BP in DOCA-salt hypertensive rats treated for 3 weeks with the nonselective endothelin receptor antagonist bosentan than in vehicle-treated rats, suggesting that endothelin may play a role in BP elevation in this model. In the current study, we have extended our previous findings in acute studies in DOCA-salt hypertensive rats⁸ and shown that selective blockade of ET_A receptors by repeated treatment with a novel naphthalene sulfonamide, BMS-182874, decreased BP in this model of hypertension. The progressive reduction in BP occurring in DOCA-salt hypertensive rats after administration of the selective ET_A receptor antagonist BMS-182874 for 3 days is consistent with the hypothesis initially advanced by Li et al that ET-1 is involved in the maintenance of hypertension in this model. Our results suggest that these ET-1 effects are mediated primarily through the ET_A receptor, and the antihypertensive effects of the nonselective endothelin receptor antagonist bosentan⁷ in DOCA-salt hypertensive rats are likely due to its activity at ET_A receptors.

The antihypertensive effects of BMS-182874 in DOCA-salt hypertensive rats might involve antagonism of AVP receptor–mediated actions, as AVP is an important contributory factor in this model of mineralocorticoid hypertension.¹⁶ Bakris et al¹⁷ described stimulation of endothelin production by AVP in cultured human mesangial cells. Moreover, administration of AVP antiserum decreased BP in DOCA-salt hypertensive rats.¹⁸ Thus, AVP may contribute to the increased ET-1 content in the vasculature of DOCA-salt hypertensive rats.⁵ However, at a dose of BMS-182874 that markedly inhibited an ET-1–induced pressor response, we found no effect of BMS-182874 on the cardiovascular effects induced by AVP or other vasoactive agents. We have previously reported that BMS-182874 is highly selective for the ET_A receptor subtype.^{8 12} It is also unlikely that BMS-182874 lowered BP in this model by inhibition of ACE or neutral endopeptidase, as BMS-182874 concentrations as high as 10 µmol/L had little inhibitory effect on these proteases in vitro (unpublished data, 1994). These data support the hypothesis that the antihypertensive effects of BMS-182874 are due to interaction with ET_A receptors rather than blockade of AVP receptors or nonspecific vasodilation.

We observed an acute antihypertensive effect (approximately 30 mm Hg) of BMS-182874 in conscious SHR, but BP depression was similar at doses of 75 to 450 µmol/kg. Repeated administration of BMS-182874 in SHR did not produce sustained or consistent antihypertensive effects. By contrast, antihypertensive effects of BMS-182874 in DOCA-salt hypertensive rats were maintained with repeated treatment, and 3 days of dosing with the ACE inhibitor fosinopril in SHR significantly reduced BP on each of the 3 days. Ohlstein et al¹⁹ reported antihypertensive effects (approximately 30 mm Hg) in conscious SHR during a 6-hour infusion of the peptide ET_A receptor antagonist BQ-123. McMahon et al⁹ described a decrease in MAP of 25 mm Hg in conscious SHR infused with BQ-123 (50 mg/kg per hour) for 5 hours, but lower doses of BQ-123 (10 and 30 mg/kg per hour), which inhibited an ET-1–induced pressor response, failed to reduce BP. Taken together, the results of these studies suggest that the role of endothelin in this genetic, normal-renin model of hypertension is a minor one.

Treatment with BMS-182874 had minimal effects on BP in sodium-deplete SHR, a high-renin model of hypertension. BMS-182874 also did not lower BP in normotensive rats. Clozel et al²⁰ reported that administration of a nonselective endothelin receptor antagonist to sodium-deplete squirrel monkeys (a normotensive animal model) produced a decrease in MAP of 25 to 35 mm Hg. We cannot rule out the possible contribution of ET_B receptors to BP maintenance in sodium-deplete SHR. Additional testing of nonselective endothelin receptor antagonists will be necessary to further define the role of endothelin in high-renin forms of hypertension.

In summary, the selective ET_A receptor antagonist BMS-182874 is an orally active, specific, and efficacious antihypertensive agent in mineralocorticoid hypertension in rats, a low-renin model of hypertension. Effects in normal- and high-renin models of hypertension were less marked. Similar results were reported by McMahon et al⁹ and Bazil et al²¹ using BQ-123 and by Li et al⁷ using bosentan. It is likely that ET_A receptor activation plays a role in the maintenance of volume-dependent hypertension in which renin levels are low.

	Acknowledgments

 
We thank Dr Phillip D. Stein for the synthesis of BMS-182874, Dr William A. Schumacher for assistance with the statistical analyses, Thomas R. Schaeffer and Mary R. Giancarli for technical assistance, and Dr Nick C. Trippodo for helpful discussions.

Received November 25, 1994; first decision January 3, 1995; accepted February 16, 1995.

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