(-)-(9S)-9-(3-Bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide (A-278637), a novel ATP-sensitive potassium channel opener: hemodynamic comparison to ZD-6169, WAY-133537, and nifedipine in the anesthetized canine
| Autor: | Glenn A. Reinhart, Bryan F. Cox, C. Thomas Lin, Samuel V. Calzadilla, Ryan M. Fryer, Hongyu Xu, Lee C. Preusser, Murali Gopalakrishnan, Yanhui Hu, Kennan C. Marsh |
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| Rok vydání: | 2004 |
| Předmět: |
Male
Vascular smooth muscle Contraction (grammar) Potassium Channels ATP-sensitive potassium channel Nifedipine Urinary Bladder Drug Evaluation Preclinical Blood Pressure Pharmacology Quinolones Polyethylene Glycols Benzophenones Electrocardiography Therapeutic index Adenosine Triphosphate Dogs In vivo Heart Rate Tachycardia Nitriles medicine Animals Infusions Intravenous Urinary bladder Dose-Response Relationship Drug Chemistry Muscle Smooth medicine.disease Amides Cyclic S-Oxides Disease Models Animal medicine.anatomical_structure Urinary Incontinence Overactive bladder Anesthesia Vascular Resistance Hypotension Pharmaceutical Vehicles Cardiology and Cardiovascular Medicine Ion Channel Gating Cyclobutanes medicine.drug Muscle Contraction |
| Zdroj: | Journal of cardiovascular pharmacology. 44(2) |
| ISSN: | 0160-2446 |
| Popis: | The therapeutic utility of K A T P 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 preclinical 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 (EC 3 5 ) 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 EC 3 5 . At concentrations 30-fold above the EC 3 5 , 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 EC 3 5 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 EC 3 5 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. |
| Databáze: | OpenAIRE |
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