a-192621 and Disease-Models--Animal

Endothelin (ET) receptor antagonism reduces neointimal lesion formation in animal models. This investigation addressed the hypothesis that the selective ETA receptor antagonist sitaxentan would be more effective than mixed ETA / B receptor antagonism at inhibiting neointimal proliferation in a mouse model of intraluminal injury.. Antagonism of ETA receptors by sitaxentan (1-100 nM) was assessed in femoral arteries isolated from adult, male C57Bl6 mice using isometric wire myography. Neointimal lesion development was induced by intraluminal injury in mice receiving sitaxentan (ETA antagonist; 15 mg·kg(-1) ·day(-1) ), A192621 (ETB antagonist; 30 mg·kg(-1) ·day(-1) ), the combination of both antagonists or vehicle. Treatment began 1 week before, and continued for 28 days after, surgery. Femoral arteries were then harvested for analysis of lesion size and composition.. Sitaxentan produced a selective, concentration-dependent parallel rightward shift of ET-1-mediated contraction in isolated femoral arteries. Sitaxentan reduced neointimal lesion size, whereas ETB and combined ETA / B receptor antagonism did not. Macrophage and α-smooth muscle actin content were unaltered by ET receptor antagonism but sitaxentan reduced the amount of collagen in lesions.. These results suggest that ETA receptor antagonism would be more effective than combined ETA /ETB receptor antagonism at reducing neointimal lesion formation.

Topics: Animals; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Femoral Artery; Isoxazoles; Male; Mice; Mice, Inbred C57BL; Muscle Contraction; Muscle, Smooth, Vascular; Myography; Neointima; Pyrrolidines; Thiophenes

Diabetes increases the risk of stroke and contributes to poor clinical outcomes in this patient population. Myogenic tone of the cerebral vasculature, including basilar arteries, plays a key role in controlling cerebral blood flow. Increased myogenic tone is ameliorated with ET receptor antagonism in Type 1 diabetes. However, the role of endothelin-1 (ET-1) and its receptors in cerebrovascular dysfunction in Type 2 diabetes, a common comorbidity in stroke patients, remains poorly elucidated. Therefore, we hypothesized that 1) cerebrovascular dysfunction occurs in the Goto-Kakizaki (GK) model of Type 2 diabetes, and 2) pharmacological antagonism of ETA receptors ameliorates, while ETB receptor blockade augments vascular dysfunction. GK or control rats were treated with antagonists to either ETA (atrasentan, 5 mg.kg(-1).day(-1)) or ETB (A-192621, 15 or 30 mg.kg(-1).day(-1)) receptors for 4 wk and vascular function of basilar arteries was assessed using a wire myograph. GK rats exhibited increased sensitivity to ET-1. ET(A) receptor antagonism caused a rightward shift, indicating decreased sensitivity in diabetes, while it increased sensitivity to ET-1 in control rats. Endothelium-dependent relaxation was impaired in diabetes. ETA receptor blockade restored relaxation to control values in the GK animals with no significant effect in Wistar rats and ETB blockade with 30 mg.kg(-1).day(-1) A-192621 caused paradoxical constriction in diabetes. These studies demonstrate that cerebrovascular dysfunction occurs and may contribute to altered regulation of myogenic tone and cerebral blood flow in diabetes. While ETA receptors mediate vascular dysfunction, ETB receptors display differential effects. These results underscore the importance of ETA/ETB receptor balance and interactions in cerebrovascular dysfunction in diabetes.

Topics: Acetylcholine; Animals; Atrasentan; Basilar Artery; Diabetes Mellitus, Type 2; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Male; Pyrrolidines; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents; Viper Venoms

Vascular dysfunction, which presents either as an increased response to vasoconstrictors or an impaired relaxation to dilator agents, results in worsened cardiovascular outcomes in diabetes. We have established that the mesenteric circulation in Type 2 diabetes is hyperreactive to the potent vasoconstrictor endothelin-1 (ET-1) and displays increased nitric oxide-dependent vasodilation. The current study examined the individual and/or the relative roles of the ET receptors governing vascular function in the Goto-Kakizaki rat, a mildly hyperglycemic, normotensive, and nonobese model of Type 2 diabetes. Diabetic and control rats received an antagonist to either the ET type A (ETA; atrasentan; 5 mg x kg(-1) x day(-1)) or type B (ET(B); A-192621; 15 or 30 mg x kg(-1) x day(-1)) receptors for 4 wk. Third-order mesenteric arteries were isolated, and vascular function was assessed with a wire myograph. Maximum response to ET-1 was increased in diabetes and attenuated by ETA antagonism. ETB blockade with 15 mg/kg A-192621 augmented vasoconstriction in controls, whereas it had no further effect on ET-1 hyperreactivity in diabetes. The higher dose of A-192621 showed an ETA-like effect and decreased vasoconstriction in diabetes. Maximum relaxation to acetylcholine (ACh) was similar across groups and treatments. ETB antagonism at either dose had no effect on vasorelaxation in control rats, whereas in diabetes the dose-response curve to ACh was shifted to the right, indicating a decreased relaxation at 15 mg/kg A-192621. These results suggest that ETA receptor blockade attenuates vascular dysfunction and that ETB receptor antagonism exhibits differential effects depending on the dose of the antagonists and the disease state.

Topics: Acetylcholine; Animals; Atrasentan; Cardiovascular Agents; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Male; Mesenteric Arteries; Microcirculation; Myography; Peptides, Cyclic; Pyrrolidines; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Up-Regulation; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents; Viper Venoms

The susceptibility of changes in responsiveness to noxious cold stimulation of rats submitted to chronic constriction of the infraorbital nerve (CION) or carrageenan to drug inhibition was compared. Nocifensive responses were measured as total time rats engaged in bilateral facial grooming with both forepaws over the first 2 min following tetrafluoroethane spray application to the snout. Carrageenan (50 microg, s.c. into upper lip) caused short-lived ipsilateral cold hyperalgesia (peak at 3 h: vehicle 8.4+/-1.3, carrageenan 21.2+/-3.0 s) which was markedly suppressed by i.p. indomethacin (4 mg/kg), celecoxib (10mg/kg) or s.c. dexamethasone (0.5 mg/kg), endothelin ET(A) or ET(B) receptor antagonists (BQ-123 and BQ-788, respectively; 10 nmol/lip). CION caused ipsilateral cold hyperalgesia between Days 2 and 12, which peaked on Days 4 (sham 15.3+/-1.8, CION 32.4+/-5.3s) to 6. Established peak CION-induced cold hyperalgesia was unaffected by indomethacin and celecoxib, whereas dexamethasone, BQ-123, BQ-788, and i.v. injections of selective antagonists of ET(A) (atrasentan, 3-10 mg/kg) or ET(B) (A-192621, 5-20 mg/kg) receptors caused significant inhibitions lasting 1-2.5h (peaks approximately 65-90%). Bosentan (dual ET(A)/ET(B) receptor antagonist, 10 mg/kg, i.v.) abolished CION-induced cold hyperalgesia for up to 6h. Thus, once established, CION-induced orofacial hyperalgesia to cold stimuli appears to lack an inflammatory component, but is alleviated by endothelin ET(A) and/or ET(B) receptor antagonists. If this CION injury model bears predictive value to trigeminal neuralgia (i.e., paroxysmal orofacial pain triggered by various stimuli), endothelin receptors might constitute new targets for treatment of this disorder.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Atrasentan; Bosentan; Carrageenan; Celecoxib; Cold Temperature; Dexamethasone; Disease Models, Animal; Drug Evaluation, Preclinical; Endothelin-1; Endothelins; Grooming; Hyperalgesia; Indomethacin; Male; Maxillary Nerve; Nerve Compression Syndromes; Oligopeptides; Peptide Fragments; Peptides, Cyclic; Piperidines; Pyrazoles; Pyrrolidines; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Sulfonamides; Trigeminal Neuralgia

Endothelin-1 (ET-1) receptor antagonist is expected to improve the prognosis of patients with heart failure, but the role of the ET(B) receptor in cardiac function and structure is complicated. In the present study the NADPH diaphorase activity and ET-1 content in the failing heart treated with ET(A) or ET(B) receptor antagonist were evaluated in a model of dilated cardiomyopathy.. Selective ET(A) receptor antagonist, ABT-627 (10 mg/kg per day), or selective ET(B) antagonist, A-192621 (30 mg/kg per day), was given to 22-week-old J2N-k cardiomyopathic hamsters for 8 weeks. The effects of ABT-627 and A-192621 on cardiac function, left ventricular (LV) histology, ET-1 content and NADPH diaphorase activity in the LV were evaluated. Treatment with ABT-627, but not A-192621, significantly decreased ET-1 content and NADPH diaphorase activity. Although the improvement of LV function was modest, ABT-627 prevented tissue damage in J2N-k hamsters. In contrast, A-192621 worsened the degeneration of cardiomyocytes despite improving hemodynamic parameters.. Selective ET(A) antagonist, but not ET(B) antagonist, reduced the ET-1 content as well as the NADPH diaphorase activity, and preserved the fine structure of LV myocardium in cardiomyopathic hamsters. Long-term blockade of ET(B) receptor might worsen the degeneration of cardiomyocytes through the ET-1/ET(A) system even if LV function could be improved.

Topics: Animals; Atrasentan; Cardiomyopathy, Dilated; Cricetinae; Disease Models, Animal; Endothelin B Receptor Antagonists; Heart; Heart Function Tests; Male; Muscle Cells; Myocardium; Pyrrolidines; Ventricular Function, Left

Tumors including sarcomas and breast, prostate, and lung carcinomas frequently grow in or metastasize to the skeleton where they can induce significant bone remodeling and cancer pain. To define products that are released from tumors that are involved in the generation and maintenance of bone cancer pain, we focus here on endothelin-1 (ET-1) and endothelin receptors as several tumors including human prostate and breast have been shown to express high levels of ETs and the application of ETs to peripheral nerves can induce pain. Here we show that in a murine osteolytic 2472 sarcoma model of bone cancer pain, the 2472 sarcoma cells express high levels of ET-1, but express low or undetectable levels of endothelin A (ETAR) or B (ETBR) receptors whereas a subpopulation of sensory neurons express the ETAR and non-myelinating Schwann cells express the ETBR. Acute (10 mg/kg, i.p.) or chronic (10 mg/kg/day, p.o.) administration of the ETAR selective antagonist ABT-627 significantly attenuated ongoing and movement-evoked bone cancer pain and chronic administration of ABT-627 reduced several neurochemical indices of peripheral and central sensitization without influencing tumor growth or bone destruction. In contrast, acute treatment (30 mg/kg, i.p.) with the ETBR selective antagonist, A-192621 increased several measures of ongoing and movement evoked pain. As tumor expression and release of ET-1 has been shown to be regulated by the local environment, location specific expression and release of ET-1 by tumor cells may provide insight into the mechanisms that underlie the heterogeneity of bone cancer pain that is frequently observed in humans with multiple skeletal metastases.

Topics: Analysis of Variance; Animals; Atrasentan; Behavior, Animal; Bone Neoplasms; Calcitonin Gene-Related Peptide; Disease Models, Animal; Dynorphins; Endothelin Receptor Antagonists; Endothelin-1; Ganglia, Spinal; Gene Expression Regulation, Neoplastic; Glial Fibrillary Acidic Protein; Immunohistochemistry; Male; Mice; Mice, Inbred Strains; Pain; Pain Measurement; Pyrrolidines; Receptors, Endothelin; Sarcoma; Sciatic Nerve; Time Factors

A rat model of acute pulmonary air embolism (APAE) was developed. These animals had a higher right ventricular systolic pressure (RVSP) (+ 69% at 15-minute peak, and 21-34% at 30-180 minutes), as well as a reduced mean arterial blood pressure (10-20% at 60-180 minutes), heart rate (20-26% at 60-180 minutes) and PaO2 (9-11% at 30-180 minutes) compared with control rats. The role of the endothelin (ET) system, known to be involved in pulmonary hypertension of various etiologies, was investigated by evaluating the effect of the four classes of ET blockers: ET-converting enzyme inhibitor (ECEi) (CGS 35066), selective endothelin-A receptor antagonist (ETA-Ra) (Atrasentan, ABT-627), endothelin-B receptor antagonist (ETB-Ra) (A-192621) or mixed endothelin-A/endothelin-B receptor antagonist (ETA/B-Ra) (A-182086) in this animal model. All four were effective, to various degrees, at reducing the APAE-induced rise in RVSP. The relative efficacy of those compounds in reducing the acute elevation (15 minutes) of RVSP was ECEi >or= ETA/B-Ra >> ETA-Ra = ETB-Ra. The sustained elevation (30-180 minutes) of RVSP was totally abolished by ECEi and attenuated by other ET blockers with a relative efficacy of ETA-Ra > ETA/B-Ra >or= ETB-Ra. ET receptor antagonists did not affect right ventricular basal tone (control rats) whereas ECEi reduced it by up to 12% after 2 hours. The APAE reduction in mean arterial blood pressure was unaffected by ETARa, was completely normalized by ETB-Ra, but was further reduced by either ETA/B-Ra or ECEi. The basal mean arterial blood pressure in control rats was unaffected by ETA-Ra, was elevated by ETB-Ra, but was depressed by ETA/B-Ra and ECEi. All ET blockers maintained normal oxygen saturation in APAE. These results support a role for ETs in rat APAE, since ET blockers can attenuate the cardiopulmonary deterioration and blood gas exchange. However, modulation of the central hemodynamic profile is more complex and may limit the usefulness of some ET blockers.

Topics: Acute Disease; Animals; Aspartic Acid Endopeptidases; Atrasentan; Benzofurans; Cardiovascular Agents; Disease Models, Animal; Embolism, Air; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-Converting Enzymes; Endothelins; Hemodynamics; Hypertension, Pulmonary; Male; Metalloendopeptidases; Organophosphonates; Protease Inhibitors; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Sulfonamides; Time Factors; Ventricular Dysfunction, Right

Endothelin-1 (ET-1) is involved in the pathogenesis of cardiac and renal hemodynamic changes and impaired excretory function in congestive heart failure. It has previously been demonstrated that acute administration of ABT-627 (endothelin-A blocker) abolished systemic and renal vasoconstriction in controls and rats with congestive heart failure induced by a surgically created aortocaval fistula (Abassi et al. Clin Sci (Lond) 2002;103:S245-S248). In contrast, acute endothelin-B blockade by A-192621 exaggerated the ET-1 induced systemic and renal vasoconstriction. The present study examined the renal and systemic effects of chronically administered ABT-627 (24 mg/kg per day) or A-192621 (72 mg/kg per day) for 7 days via osmotic minipumps inserted intraperitoneally on the day of operation of sham controls and rats with congestive heart failure. Tailcuff measurements revealed that ABT- 627 significantly decreased mean arterial pressure from 108 +/- 2 mmHg to 87 +/- 2 mmHg (P < 0.05), whereas A-192621 significantly increased mean arterial pressure from 110 +/- 3 mmHg to 122 +/- 3 mmHg (P < 0.05) in controls. Despite the hypotensive effect of ABT-627, daily sodium excretion dramatically increased, but to a lesser extent in A-192621-treated controls. Furthermore, chronic administration of ABT-627 to controls attenuated the systemic and renal vasoconstriction induced by ET-1 (1 nmol/kg intravenous), whereas A-192621 augmented these effects. Similarly, chronic treatment with ABT-627 totally abolished the systemic and renal vasoconstriction caused by injected ET-1 in rats with congestive heart failure, whereas A192621 potentiated these effects. Chronic treatment of animals with congestive heart failure with ABT-627 did not influence daily sodium excretion, whereas treatment with A192621 significantly improved daily sodium excretion. Interestingly, treatment with either ABT-627 or A192621 significantly decreased cardiac hypertrophy in rats with congestive heart failure. In conclusion, in sham controls endothelin-B receptor mediated vasodilation and natriuresis, probably as a result of tubular action, whereas in congestive heart failure the excretory contribution of endothelin-B receptor was attenuated, resulting in Na+ retention.

Topics: Animals; Atrasentan; Blood Pressure; Cardiomegaly; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Heart Failure; Hemodynamics; Infusion Pumps, Implantable; Kidney; Male; Natriuresis; Pyrrolidines; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Time Factors; Vasoconstriction; Vasodilation

The receptors underlying the endothelin-dependent component of lung plasma extravasation and leucocyte infiltration induced by oleic acid were assessed in mice. Oleic acid (1 mg.kg(-1) intravenously), but not endothelin-1 (up to 1 nmol.kg(-1) intravenously), increased accumulation of Evans blue in the lungs (excluding the trachea and main bronchi) from 11.8+/-3.9 to 98.6+/-10.7 microg 1 h after injection. Bosentan, the antagonist of endothelin receptors (ET(A) and ET(B)) or the selective ET(B) receptor antagonists Ro 46-8443 or A-192621 (administered 1 h before oleic acid at doses of 30, 10 and 30 mg x kg(-1) respectively) reduced the effect of oleic acid by 71%, 58% and 79% respectively. However, the selective ET(A) receptor antagonist A-127722.5 (10 mg x kg(-1)) was inactive. Oleic acid (2 mg xkg(-1), intravenously) raised the number of total leucocytes, mononuclear cells and neutrophils in broncho-alveolar lavage fluid 4 h after injection. Bosentan and Ro 46-8443 (at doses of 30 and 10 mg x kg(-1) respectively) inhibited the neutrophil infiltration induced by oleic acid by approx. 80%. None of the antagonists modified control (basal) pulmonary microvascular permeability or total and differential cell counts. Thus, endogenous endothelins, acting via ET(B) receptor-dependent mechanisms, play a major role in oleic acid-induced lung injury in the mouse by promoting infiltration of circulating neutrophils and enhancement of pulmonary microvascular plasma extravasation. These findings suggest that either ET(B) or mixed ET(A)/ET(B) receptor antagonists might be beneficial in the treatment of the adult respiratory distress syndrome.

Topics: Acute Disease; Analysis of Variance; Animals; Atrasentan; Bosentan; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Evans Blue; Lung; Male; Mice; Mice, Inbred Strains; Neutrophil Infiltration; Oleic Acid; Pyrimidines; Pyrrolidines; Receptor, Endothelin A; Receptor, Endothelin B; Respiratory Distress Syndrome; Sulfonamides