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J D Elliott

Publications and source records attributed to J D Elliott.

At least 37 records · Page 2Linked to original sources
PubMed1995

In vivo pharmacological characterization of the non-peptide endothelin receptor antagonist SB 209670.

1. The aim of the present study was to assess the ability of SB 209670, a high affinity non-peptide endothelin receptor antagonist (0.4 and 18 nM Kis at human cloned ETA and ETB receptors, respectively), to inhibit the haemodynamic actions of endothelin-1 in vivo. 2. Systemic administration of (+/-)-SB 209670, given either as a bolus i.v. injection or as a continuous i.v. infusion, did not alter basal haemodynamic parameters in the anaesthetized rat. 3. Infusion of (+/-)-SB 209670 (10 micrograms kg-1 min-1) selectively inhibited the depressor and carotid vasodilator response to exogenous endothelin-1: 100 micrograms kg-1 min-1 was required to inhibit significantly the biphasic haemodynamic actions of endothelin-1. The haemodynamic actions of angiotensin II and calcitonin gene-related peptide were unaltered by 100 micrograms kg-1 min-1 (+/-)-SB 209670. 4. Bolus i.v. administration of (+/-)-SB 209670 (1 mg kg-1) selectively inhibited the depressor and carotid vasodilator actions of endothelin-1: 10 mg kg-1 (+/-)-SB 209670 was required to inhibit the secondary vasoconstrictor actions of endothelin-1. 5. (+/-)-SB 209670 (10 mg kg-1) was also effective at antagonizing the pressor actions of endothelin-1 in the conscious rat for up to 3 h after intraduodenal administration thereby demonstrating that the antagonist was bioavailable upon enteric administration. This dose of (+/-)-SB 209670 did not alter basal haemodynamic parameters in the conscious rat. 6. Thus, ( +/- )-SB 209670 is an effective endothelin receptor antagonist in vivo. Using the doses defined in this study, SB 209670 may, therefore, serve as a useful tool for understanding the role of endogenous endothelin-I in the control of cardiovascular function under both physiological and pathophysiological conditions.

Angiotensin II↗
PubMed1995

Pharmacological evidence for the presence of three distinct functional endothelin receptor subtypes in the rabbit lateral saphenous vein.

1. Contraction of the rabbit isolated saphenous vein is mediated by a heterogeneous endothelin (ET) receptor population. This study has characterized these receptor subtypes by use of several pharmacologically distinct ET receptor agonists and antagonists. 2. ET-1, ET-3, sarafotoxin S6c (STXc) and [Ala3,11]ET-1 produced biphasic, concentration-dependent contractions of the saphenous vein, responses which were best fitted by a two-site model comprised of a high (pM) and a low (nM) affinity site. In contrast, IRL 1620 only recognized one of these sites. ET(16-21) was devoid of contractile activity. ET-1, ET-3 and STXc were equipotent at the high affinity site (pD2s of 12.0 +/- 0.2, 12.2 +/- 0.2 and 12.3 +/- 0.3) indicating that this site had the characteristics of an ETB receptor. In contrast, the low affinity site had the functional characteristics of an ETc receptor since the pD2s for ET-3 (10.2 +/- 0.3) and STXc (10.6 +/- 0.3) were significantly greater than that for ET-1 (9.1 +/- 0.1). These contractile responses were insensitive to BQ-123, confirming that ETA receptors were not involved in mediating this effect. 3. SB 209670 differentially antagonized the high affinity phases of the isopeptide concentration-response curves in a fashion dependent on the competing agonist: relative to the KB obtained against STXc (0.15 nM). SB 209670 was 10 fold less potent when ET-1 was used as the competing agonist. This differential effect was not evident at the low affinity site (KB = 38 nM). SB 209670 produced parallel, concentration-dependent rightward shifts in the concentration-response curve to STXc Ro 47-0203 was approximately 1 to 2 orders of magnitude less potent than SB 209670 at inhibiting the high affinity component of the concentration-response curve to STXc, whereas BQ-788 and Ro 46-2005 were approximately 3 orders of magnitude less potent than SB 209670. In addition to RES-701 and BQ-123, the high affinity site was insensitive to PD 142893 suggesting that it may represent an ETB2 receptor. Ro 47-0203 and SB 209670 were equipotent at inhibiting the low affinity component of the STXc concentration-response curve. Although Ro 46-2005, BQ-788, PD 142893 and RES-701 produced significant antagonism at the low affinity site, they were at least ten fold less potent than SB 209670. 4. ET-1, ET-3 and STXc produced endothelium-dependent vasorelaxation in the precontracted saphenous vein. Antagonist IC50s were approximated as being: SB 209670, 3 nM; BQ-788 and RES 701,300 nM; Ro 46-2005 and PD 142893, 3 microM; BQ-123, > 10 .M, consistent with vasorelaxation being mediated by an ETB1 receptor.5. In summary, three pharmacologically distinct ET receptor subtypes have been identified in the rabbits aphenous vein. Two contractile receptors are present on the vascular smooth muscle, a high affinity site with the characteristics of an ETB2 receptor and a distinct lower affinity site with the characteristics of an ETc receptor. In addition, an ETBI receptor is present on the endothelium which mediates the vasodilator actions of this peptide family.

Animals↗
PubMed1995

Antihypertensive actions of the novel nonpeptide endothelin receptor antagonist SB 209670.

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 micrograms.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 micrograms.kg-1.min-1 SB 209670 (approximately 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 evaluated (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 approximately 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.

Animals↗
PubMed1995

Nonpeptide endothelin receptor antagonists. V: Prevention and reversal of acute renal failure in the rat by SB 209670.

The ability of the mixed endothelin (ETA/ETB) receptor antagonist (+/-)-SB 209670 to prevent and reverse ischemia-induced acute renal failure (ARF) was studied in rats with moderate and severe ARF. Uninephrectomized, chronically instrumented Sprague-Dawley rats were used. Moderate and severe ARF was induced by occlusion of the renal artery for 30 and 45 min, respectively. During the 24 hr after 30-min ischemia (moderate ARF), glomerular filtration rate (GFR) decreased by 95%, and fractional excretion of sodium increased from 0.6% to 10%. Infusion of (+/-)-SB 209670 at 10, 30 and 100 micrograms/kg.min for 30 min before, during and 60 min after renal ischemia had a moderate effect on renal function. Thus, with the highest dose, the ischemia-induced reduction in GFR was 70%. This dose, however, had no effect in rats when given before, during and after 45 min of renal ischemia (severe ARF). In contrast, when infused at 30 micrograms/kg.min for 3 hr on the day after ischemia, (+/-)-SB 209670 markedly increased survival rate (75%) in rats with severe ARF by significantly increasing tubular reabsorption of Na+, followed by a slow and gradual increase in GFR and reversal of the increase in plasma K+ concentration. Data from acute renal clearance studies in rats with moderate ARF showed that when infused 24 hr after ischemia, (+/-)-SB 209670 acutely reversed the impairment in sodium reabsorption without increasing GFR or renal blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗
PubMed1995

Pharmacologic evidence for the presence of three functional endothelin receptor subtypes in rabbit saphenous vein.

The contractile responses to endothelin-1 (ET-1), endothelin-3 (ET-3), and sarafotoxin S6c (STXc) were best-fitted by a two-site model in the rabbit isolated saphenous vein. Agonists were equipotent at the high-affinity site (pD2s 12.0 +/- 0.2, 12.2 +/- 0.2, and 12.3 +/- 0.3, respectively), characteristic of an ETB receptor, whereas ET-3 and STXc were significantly more potent than ET-1 as vasoconstrictors at the low-affinity site (pD2s 10.2 +/- 0.3, 10.6 +/- 0.3, and 9.1 +/- 0.1, respectively), characteristic of an ETC-like receptor. The high affinity, ETB-mediated response was inhibited by SB 209670, Ro 47-0203, BQ-788, and Ro 46-2005 (Kbs of 0.15, 14, 110, and 280 nM against STXc, respectively) but was insensitive to PD 142893, RES-701 and BQ-123 (Kbs > or = 10 microM), consistent with this response being mediated by the ETB2-like receptor subtype. The low-affinity ETC-like-mediated component was inhibited by SB 209670, Ro 47-0203, BQ-788, Ro 46-2005, PD 142893, and RES-701 (Kbs 38 nM, 62 nM, 670 nM, 580 nM, 1.7 microM, and 2.0 microM, respectively), but was insensitive to BQ-123 (Kb > or = 10 microM). ET-3 produced endothelium-dependent vasorelaxation in the presence of active tone. Antagonist IC50s were approximated as being: SB 209670 3 nM; BQ-788 and RES 701,300 nM; Ro 46-2005 and PD 142893 3 microM; BQ-123 > or = 10 microM. These values were consistent with vasorelaxation being mediated by an ETB1-like receptor. Therefore, three pharmacologically distinct ET receptor subtypes have been identified in rabbit saphenous vein. Two contractile receptors, ETB2-like and ETC-like, are present on the vascular smooth-muscle receptor, whereas an ETB1-like receptor, which mediates the vasodilator actions of this peptide family, is present on the endothelium.

Animals↗
PubMed1995

Endothelin receptor subtypes in the pathogenesis of angioplasty-induced neointima formation in the rat: a comparison of selective ETA receptor antagonism and dual ETA/ETB receptor antagonism using BQ-123 and SB 209670.

The present study compared the vasculoprotective efficacy of acute and chronic endothelin (ET) ETA or dual ETA/B receptor antagonism in the rat common carotid artery (RCCA) model using BQ-123 and SB 209670. Acute intra-arterial infusion (0.1 mg/kg/min) for 2 h at the time of angioplasty of either BQ-123 or SB 209670 did not attenuate the neointima lesion formation observed 2 weeks after angioplasty (neointima:media ratios of 137% and 116% of control, respectively). In contrast, chronic administration of SB 209670 (bolus i.p. injection, 2.5 mg/kg b.i.d.) attenuated lesion formation (neointima:media ratio inhibited by 52% relative to vehicle control; p < 0.05). An identical dosage regimen of BQ-123 did not exhibit significant vasculoprotection (neointima:media ratio of 128% vehicle control). However, this dosage regimen of BQ-123 was associated with significant and selective ETA receptor antagonism. The systemic pressor response to exogenous ET-1 administration was inhibited by 91% (p < 0.05), whereas the associated depressor response was not different from that observed in vehicle-treated rats. Therefore, since chronic administration of pharmacologic doses of the ETA-selective antagonist BQ-123 does not prevent lesion formation in the RCCA model, whereas the ETA/B receptor antagonist SB 209670 is vasculoprotective, the data implicate a significant role for the ETB receptor subtype, either exclusively or in concert with ETA receptor activation, in the pathogenesis of neointima formation in the rat.

Angioplasty, Balloon↗
PubMed1995

Agonist-dependent inhibition by peptide and nonpeptide endothelin receptor antagonists in the rabbit isolated pulmonary artery.

This study examined the effect of peptide and nonpeptide endothelin (ET) receptor antagonists on the contractile actions of ET-1 and sarafotoxin S6c (STXc) in the rabbit isolated pulmonary artery (RbPA). The peptide antagonists BQ-123, BQ-788, and RES-701 (10 microM) did not inhibit ET-1-induced RbPA contractions. The nonpeptide antagonists PD 156123, Ro 47-0203, and SB 217242 (10 microM) also had no effect on ET-1--induced contractions. In contrast, the nonpeptide antagonists SB 209670 and L-749,239 (10 microM) both caused a shift to the right of the ET-1 concentration-response curve (Kbs of 231 nM and 1.42 microM, respectively) and a two- to three-fold increase in nH (Hill slope), without altering the Rmax (maximal agonist-induced contraction). Contractile responses to STXc were unaffected by BQ-123, RES-701, and PD 156123 (10 microM). SB 209670, SB 217242, L-749,239, Ro 47-0203, and BQ-788 (10 microM) caused a shift to the right of the STXc response curve (Kbs of 16, 353, 202, 1,303 and 1,499 nM, respectively) and an increase in nH and Rmax. SB 209670 and L-749,239 were both approximately 10-fold more potent in antagonizing STXc than ET-1. Assuming, at best, Kbs of 10 microM for SB 217242, Ro 47-0203, and BQ-788 against ET-1, these antagonists were also at least 10-fold more potent in blocking STXc. The effects of various incubation and washout times on the antagonistic properties of SB 209670 (1 microM) against STXc were studied. Washing the antagonist from the tissue bath caused a 100-fold decrease in affinity (Kbs of 23-2,373 nM at 0 and 30 min, respectively) and a return to near control levels of nH (within 30 min). In contrast, the augmented Rmax response did not return to control levels until 6 hr later. As the incubation time was increased, the augmented Rmax was sustained (6 h), but affinity decreased (Kbs of 21 and 793 nM after 5 min and 6 h of incubation), and nH returned to near control values. In conclusion, agonist-dependent inhibition by ETB receptor antagonists is observed in the RbPA. Heterogenous populations of ET receptors, differential binding domains, and/or functionally uncoupled receptors may account for this phenomenon.

Animals↗
PubMed1995

The endothelin receptor antagonist SB 217242 reduces cerebral focal ischemic brain injury.

Previously, we demonstrated that cerebral focal ischemic tissue exhibits a significant increase in immunoreactive endothelin (ET). Because increased ET might exacerbate the consequences of cerebral ischemia, we evaluated the effects of the orally active ETA/B receptor antagonist SB 217242 on middle cerebral artery occlusion (MCAO) in the spontaneously hypertensive rat (SHR). SHRs were treated b.i.d. with vehicle or with 3 or 15 mg/kg SB 217242 p.o. for 7 days. Permanent MCAO was performed on day 7 and animals were sacrificed on day 8. Forebrains were stained and the extent of cerebral (i.e., cortical) infarction was determined using image analysis. Hemispheric swelling (%), hemispheric infarct (%), and infarct volume (mm3) were quantitated for each animal. SB 217242 treatment produced a significant decrease in ischemic brain injury. Hemispheric infarction and infarct volume were reduced after the 15 mg/kg treatment (12.0 +/- 1.1% and 69 +/- 6 mm3) compared to vehicle (17.3 +/- 1.5% and 99 +/- 8 mm3) (p < 0.05). No significant effects on hemispheric swelling were observed. This is the first demonstration of an ET receptor antagonist exhibiting efficacy in cerebral focal ischemia. The fact that a 30% reduction in ischemic brain injury can be demonstrated after oral administration of SB 217242 suggests that ET antagonists may be of therapeutic utility in focal stroke.

Animals↗
PubMed1994

Tyr-129 is important to the peptide ligand affinity and selectivity of human endothelin type A receptor.

Molecular modeling and protein engineering techniques have been used to study residues within G-protein-coupled receptors that are potentially important to ligand binding and selectivity. In this study, Tyr-129 located in transmembrane domain 2 of the human endothelin (ET) type A receptor A (hETA) was targeted on the basis of differences between the hETA and type B receptor (hETB) sequences and the position of the residue on ET receptor models built using the coordinates of bacteriorhodopsin. Replacement of Tyr-129 of hETA by alanine, glutamine, asparagine, histidine, lysine, serine, or phenylalanine results in receptor variants with enhanced ET-3 and sarafotoxin 6C affinities but with unchanged ET-1 and ET-2 affinities. Except for Tyr-129-->Phe hETA, these hETA variants have two to three orders of magnitude lower binding affinity for the ETA-selective antagonist BQ123. Replacement of His-150, the residue in hETB that is analogous in sequence to Tyr-129 of hETA, by either tyrosine or alanine does not affect the affinity of peptide ligands. These results indicate that although transmembrane domain 2 is important in ligand selectivity for hETA, it does not play a significant role in the lack of ligand selectivity shown by hETB. Chimeric receptors have been constructed that further support these conclusions and indicate that at least two hETA regions contribute to ligand selectivity. Additionally, the data support an overlap in the binding site in hETA of agonists ET-3 and sarafotoxin 6C with that of the antagonist BQ123.

Animals↗
PubMed1994

Conformationally constrained peptides and semipeptides derived from RGD as potent inhibitors of the platelet fibrinogen receptor and platelet aggregation.

Structure-activity studies have been pursued on cyclo-S,S-[Ac-Cys-(N alpha-Me)Arg-Gly-Asp-Pen]-NH2, 2 (SK&F 106760), a potent inhibitor of platelet aggregation, in an effort to improve potency and affinity for the GPIIb/IIIa receptor. Modifications on the N- and C-termini of 2 produced a series of peptides which indicate that the C-terminal carboxylate group may be a secondary receptor-binding element. Further modification by replacing the disulfide tether N alpha-acetylcysteine/penicillamineamide with the novel, inexpensive, achiral, constrained, and more lipophilic tether 2-mercaptobenzoyl/2-mercaptoaniline (Mba/Man) afforded the semipeptide cyclo-S,S-[Mba-(N alpha-Me)Arg-Gly-Asp-Man], 18 (SK&F 107260), which exhibited significant enhancement in both affinity and potency. To further investigate the effect of the phenyl ring at the C-terminus, peptides bearing the novel (2R,3S)- and (2R,3R)-beta-phenylcysteines were synthesized, which culminated in the cyclo-S,S-[Ac-Cys-(N alpha-Me)Arg-Gly-Asp-(2R,3S)-beta-phenylCys]-OH peptide, 22, which displayed substantial affinity and potency. We describe, herein, the development of both 18 and 22 and the additional structural modifications within the constrained cyclic disulfide ring to probe the stereochemical and steric requirements for receptor interaction.

Amino Acid Sequence↗
PubMed1994

A role for endogenous endothelin-1 in neointimal formation after rat carotid artery balloon angioplasty. Protective effects of the novel nonpeptide endothelin receptor antagonist SB 209670.

The observation that levels of the mitogenic peptide endothelin-1 are elevated in the human coronary sinus after percutaneous transluminal coronary angioplasty (PTCA) has implicated endothelin-1 in the etiology of vascular restenosis. The present study examined this hypothesis in both an in vitro and an in vivo rat model of neointimal formation by using the novel nonpeptide endothelin receptor antagonist SB 209670. In vitro, endothelin-1 (1 nmol/L) induced a ninefold increase in rat aortic vascular smooth muscle [3H]thymidine incorporation. This endothelin A receptor-mediated effect was completely inhibited by SB 209670 (IC50, 6.2 +/- 2.2 nmol/L). In vivo, acute intra-arterial administration of exogenous endothelin-1 (5 to 500 pmol/kg over a 30-minute period immediately after angioplasty) dose-dependently augmented the degree of neointimal formation (by up to 150% when assessed 14 days after surgery). This response was evident as early as 7 days after angioplasty. Hemodynamic studies indicated that this action was unrelated to a systemic pressor action of the peptide. Administration of SB 209670 (2.5 mg/kg IP, twice a day for 3 days before and for 2 weeks after surgery) reduced neointimal formation by approximately 50% relative to control animals. Thus, the data indicate for the first time that (1) endothelin-1 promotes neointimal formation in vivo and (2) endogenous endothelin-1 is involved in the pathogenesis of angioplasty-induced lesion formation in the rat. Endothelin receptor antagonists such as SB 209670 may therefore serve as useful adjuncts to PTCA, attenuating the degree of vascular restenosis observed after vascular wall injury.

Angioplasty, Balloon↗
PubMed1994

Nonpeptide endothelin receptor antagonists. I. Effects on binding and signal transduction on human endothelinA and endothelinB receptors.

The effect of a series of endothelin (ET) receptor antagonists, including the novel nonpeptide receptor antagonist, SB 209670, on [125I]ET-1 binding to human ET receptors (ETA and ETB) cloned and stably expressed in Chinese hamster ovary cells was studied. SB 209670 was found to compete for [125I]ET-1 binding with apparent Ki values of 0.43 +/- 0.09 and 14.7 +/- 3.0 nM for ETA and ETB receptors, respectively. This inhibition was competitive because addition of SB 209670 in saturation binding experiments resulted in decreased affinity, with no change in maximum binding. In addition, SB 209670 inhibited ET-1-mediated accumulation of inositol phosphates and intracellular calcium release in a concentration-dependent manner. The racemic mixtures, (+/-)-SB 209670 and (-)-SB 209670, were approximately 1.5 and at least 200-fold less potent than SB 209670. The binding affinity of (+/-)-SB 209670 therefore resides in (+)-antipode. The peptide antagonists, BQ123 (ETA-selective) and RES 701 (ETB-selective), were 40- and 6-fold less potent than SB 209670 in inhibition of [125I] ET-1 binding to ETA and ETB receptors, respectively. The nonselective peptide antagonist, PD 142893, was 75- and 10-fold less potent than SB 209670, whereas the nonpeptide antagonist, bosentan, was approximately 80- and approximately 30-fold less potent than SB 209670 in inhibition of [125I]ET-1 binding to ETA and ETB receptors, respectively. Thus, the present studies indicate clearly that SB 209670 is the most potent nonpeptide ET receptor antagonist yet described.

Animals↗
PubMed1994

Nonpeptide endothelin receptor antagonists. II. Pharmacological characterization of SB 209670.

The pharmacological characterization of SB 209670, a highly potent nonpeptide endothelin ETA/ETB receptor antagonist was performed. SB 209670 produced concentration-dependent, parallel rightward shifts in the ET-1 concentration-response curves in the isolated rat aorta (ETA receptor-mediated vascular contraction). The Kb for inhibition of ETA receptor-mediated contraction by SB 209670 was 0.4 +/- 0.04 nM. Inhibition by SB 209670 was stereoselective as the (+)-antipode of SB 209670 was approximately 575-fold more potent than the (-)-antipode. Relative to other ET receptor antagonists, the potency of SB 209670 for inhibiting ETA receptor-mediated vascular contraction was 45-, 180- and 775-fold more potent than the ETA selective antagonist BQ-123, or the mixed ETA/ETB receptor antagonists bosentan or PD142893, respectively. The pharmacological antagonism produced by SB 209670 was specific for ET-1. SB 209670 inhibited ETB receptors in the isolated rabbit pulmonary artery as demonstrated by concentration-dependent, parallel rightward shifts in either the ET-1 or sarafotoxin S6c (S6c) concentration-response curves. The Kb values for inhibition were 200 +/- 9 and 52 +/- 14 nM for ET-1 and S6c, respectively. In contrast, neither the ETB selective antagonist RES-701 (10 microM) nor BQ-123 (10 microM) inhibited S6c-mediated vasoconstriction. However, PD 142893 (10 microM) and bosentan (10 microM) produced a small rightward shift in the S6c concentration-response curve, each with Kb values of 1.5 to 3.7 microM. In isolated human circumflex coronary arteries, (+/-)-SB 209670 inhibited ET-1 mediated contraction with a Kb value of 7 +/- 3 nM.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Nonpeptide endothelin receptor antagonists. III. Effect of SB 209670 and BQ123 on acute renal failure in anesthetized dogs.

Endothelin (ET) is a potent vasoconstrictor that has been implicated in the pathogenesis of acute renal failure (ARF). In order to investigate the potential role of ET in ARF in the dog, the effect of a mixed ETA and ETB receptor antagonist, (+/-)-SB 209670, [(1RS-2SR,3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-5- (prop-1-yloxy) indane-2-carboxylic acid], and a selective ETA antagonist, BQ123, were evaluated in anesthetized uninephrectomized dogs undergoing 60 min of renal occlusion. (+/-)-SB 209670 (1 microgram/kg/min) and BQ123 (10 micrograms/kg/min) were infused directly into the renal artery (intrarenal) for 30 min before renal occlusion, during occlusion and for 60 min after reperfusion at doses that inhibited the renal vasoconstrictor effects of intrarenal renal artery infusions of ET-1. Renal occlusion resulted in a significant reduction in inulin clearance (from 26.2 +/- 1.8 to 3.2 +/- 1.1 ml/min). This response was significantly (P < .05) attenuated by (+/-)-SB 209670 (from 23.5 +/- 2.2 to 7.6 +/- 2.0 ml/min) but not by BQ123 (from 23.5 +/- 1.7 to 4.9 +/- 1.2 ml/min). Endogenous creatinine clearance showed the same pattern. After renal artery occlusion, fractional sodium and fractional potassium excretions were increased significantly. (+/-)-SB 209670, but not BQ123, resulted in a significant reduction in fractional sodium; however, neither compound altered fractional potassium excretion. The data suggest that ET receptor antagonists, possibly by altering tubular sodium reabsorption, may be beneficial in ischemia-induced ARF.

Acute Kidney Injury↗
PubMed1993

Positive selection of T lymphocytes on fibroblasts.

Thymocytes are selected for expression of alpha beta T-cell antigen receptors (TCR) which recognize antigen in conjunction with self-major histocompatibility complex (MHC) molecules. In the thymus the restriction element is imprinted on radioresistant stromal elements and on cells of haematopoietic origin. In mice negative for beta 2-microglobulin that are devoid of mature cytotoxic T lymphocytes, we find that intrathymic injection of different fibroblasts causes the maturation of CD4-CD8+TCRhigh thymocytes with distinct patterns of TCR V beta distribution. Here we show that in TCR-transgenic mice, intrathymic injection of L cells expressing the selecting H-2Kb molecule (L-Kb cells) reconstitutes the maturation of thymocytes bearing the transgenic TCR, and that in normal B10.BR (H-2k) mice, H-2Kb molecules expressed on L-Kb cells lead to the development of T lymphocytes with recognition restricted to H-2Kb. A class I MHC restriction element can thus be selected by interaction with fibroblasts, that is, cells of other than epithelial or haematopoietic origin.

Animals↗
PubMed1992

Regional vasodilation to endothelin-1 is mediated by a non-ETA receptor subtype in the anaesthetized rat: effect of BQ-123 on systemic haemodynamic responses.

The sustained infusion of 75 nmol/kg per min BQ-123 selectively attenuates the systemic pressor responses to i.v. bolus endothelin-1 in the anaesthetized rat; the initial systemic vasodepression is only attenuated when a 10-fold higher dose of this ETA-selective antagonist is infused. These doses of BQ-123 do not antagonize the haemodynamic actions of angiotensin II or calcitonin gene-related peptide nor do they alter basal systemic haemodynamics. The secondary increase in carotid vascular resistance associated with the systemic pressor actions of endothelin-1 is selectively attenuated by the bolus i.v. administration of BQ-123 (1.6 mumol/kg); the maximum degree of the vasorelaxation that precedes this more sustained constriction is unaltered. Thus, the initial carotid vasodilation observed to endothelin-1, and the associated systemic vasodepression, is mediated by a non-ETA receptor subtype. Furthermore, subtle differences might exist between the receptors mediating mesenteric and carotid vasoconstriction since only the latter is sensitive to BQ-123.

Anesthesia↗
PubMed1992

The selective endothelin ETA receptor antagonist BQ123 antagonizes endothelin-1-mediated mitogenesis.

The mitogenic effects of endothelin isopeptides and the selective ETA receptor antagonist BQ123 were evaluated in rat aortic vascular smooth muscle cells. Endothelin-1 (ET-1) and endothelin-3 (ET-3) produced concentration-dependent increases in [3H]thymidine incorporation (EC50 = 0.1 and 25 nM, respectively). The ETB-selective agonist sarafotoxin 6c did not produce significant effects on [3H]thymidine incorporation. BQ123 produced selective and concentration-dependent inhibition of ET-1-mediated [3H]thymidine incorporation. These data demonstrate that ET-1-mediated mitogenesis in vascular smooth muscle is mediated by ETA receptors.

Animals↗