RESUMO
The therapeutic utility of KATP channel opening agents (KCOs) in the treatment of overactive bladder may be limited by hypotension as a result of insufficient selectivity in vivo for bladder versus vasculature smooth muscle. Recently, we demonstrated that the putative uroselective KCOs, A-278637, ZD-6169, and WAY-133537 suppress unstable bladder contraction in an in vivo pre-clinical pig model of detrusor instability secondary to partial outlet obstruction. In the present study in the anesthetized dog we targeted plasma concentrations 3-, 10-, and 30-fold above a common index of in vivo efficacy (EC35) for suppression of unstable bladder contraction in pigs, to provide a comprehensive cardiovascular profile of these compounds. When compared at similar multiples of efficacy, dose-dependent reductions in SVR were greater in ZD-6169 and WAY-133537-treated animals versus A-278637. A-278637, unlike ZD-6169 or WAY-133537, produced no effect on MAP at concentrations 10-fold above the EC35. At concentrations 30-fold above the EC35, MAP in A-278637-treated animals was reduced -11% from baseline versus -24% and -42% for ZD-6169 and WAY-133537. Accordingly, at plasma concentrations approximately 30-fold above the EC35 reflex-mediated increases in HR were modest for A-278637-treated animals (15% above baseline) versus ZD-6169 (22%) or WAY-133537 (35%). Increases in both dP/dt and cardiac output occurred at lower therapeutic multiples and were greater in magnitude for animals treated with WAY-133537 (66% and 64% above baseline, respectively, 60 minutes into compound infusion) and ZD-6169 (10% and 13%) versus A-278637 (-2% and 6%). Thus, A-278637 exerted lesser effects on cardiovascular function at equivalent multiples of the EC35 than either ZD-6169 or WAY-133537. These data suggest that A-278637 possesses a greater functional selectivity for urinary bladder versus vascular smooth muscle in vivo and that A-278637 may exhibit a more favorable therapeutic index than either ZD-6169 or WAY-133537.
Assuntos
Amidas/farmacologia , Benzofenonas/farmacologia , Óxidos S-Cíclicos/farmacologia , Ciclobutanos/farmacologia , Nifedipino/farmacologia , Nitrilas/farmacologia , Canais de Potássio/fisiologia , Quinolonas/farmacologia , Trifosfato de Adenosina/química , Amidas/sangue , Animais , Benzofenonas/sangue , Pressão Sanguínea/efeitos dos fármacos , Óxidos S-Cíclicos/sangue , Ciclobutanos/sangue , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Eletrocardiografia/métodos , Frequência Cardíaca/efeitos dos fármacos , Hipotensão/induzido quimicamente , Infusões Intravenosas , Ativação do Canal Iônico/efeitos dos fármacos , Ativação do Canal Iônico/fisiologia , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Nifedipino/sangue , Nitrilas/sangue , Veículos Farmacêuticos/administração & dosagem , Veículos Farmacêuticos/química , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Canais de Potássio/efeitos dos fármacos , Quinolonas/sangue , Taquicardia/induzido quimicamente , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/fisiologia , Incontinência Urinária/tratamento farmacológico , Incontinência Urinária/fisiopatologia , Resistência Vascular/efeitos dos fármacosRESUMO
Endothelins (ETs), 21-amino-acid peptides involved in the pathogenesis of various diseases, bind to ET(A) and ET(B) receptors to initiate their effects. Based on the same core structure, we have developed four small-molecule ET receptor antagonists, ABT-627 (atrasentan), ABT-546, A-182086 and A-192621, which exhibit differences in selectivity for ET(A) and ET(B) receptors. In this report, we compare the efficacy, potency and pharmacokinetic properties of these four antagonists, including potency in inhibiting ET-1- or Sarafotoxin 6c-induced vessel constriction in isolated arteries and efficacy in antagonizing ET-1-, big ET-1- or Sarafotoxin 6c-induced pressor responses in rats.