Effects of dofetilide on cardiovascular tissues from normo- and hypertensive rats.
The aim was to test whether dofetilide has some potential for use in the treatment of heart failure. Dofetilide at < or = 3 x 10(-5) M had no effect on the quiescent Wistar Kyoto (WKY) rat aorta, mesenteric and intralobar arteries, or the spontaneous contractions of the WKY rat portal vein. Dofetilide at 10(-6) to 3 x 10(-5) M relaxed the KCl-contracted aorta. Dofetilide at 10(-9)-10(-7) M augmented the force of contraction of leftventricle strips from 12- and 18-month-old WKY rats at 2 Hz. Spontaneously hypertensive rats (SHRs) at 12 and 17-21 months of age are models of cardiac hypertrophy and failure, respectively. The augmentation of force at 2 Hz with dofetilide was similar on 12- and 18-month-old WKY rats and 12-month-old SHRs but reduced on the 18-month-old SHR left ventricle. At a higher more physiological frequency, 4 Hz, the threshold concentration of dofetilide required to augment the force responses of 21-month-old SHR left ventricles was markedly increased and the maximum augmenting effect was decreased. Dofetilide at 10(-7)-10(-5) M reduced the rate of the 17-month-old WKY rat right atrium, and had a similar effect on age-matched SHR right atrium. In summary, dofetilide is a positive inotrope and negative chronotrope in the rat. However, as the positive inotropic effect is not observed with clinically relevant concentrations at a physiological rate in heart failure, dofetilide is unlikely to be useful as a positive inotrope in the treatment of heart failure.
Doggrell
Sheila A
SA
Cardiovascular Pharmacology Group, Faculty of Medicine and Health Science, The University of Auckland, New Zealand. s.doggrell@mailbox.uq.edu.au
Nand
Vinita
V
D000818:Animals; D001011:Aorta / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001808:Blood Vessels / Q000187:drug effects*; D002303:Cardiac Output, Low / Q000188:drug therapy / Q000503:physiopathology; D006332:Cardiomegaly / Q000188:drug therapy / Q000503:physiopathology; D004195:Disease Models, Animal; D004558:Electric Stimulation; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects; D006973:Hypertension / Q000503:physiopathology*; D066298:In Vitro Techniques; D008638:Mesenteric Arteries / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects*; D010627:Phenethylamines / Q000494:pharmacology* / Q000627:therapeutic use; D011169:Portal Vein / Q000187:drug effects; D026902:Potassium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D011651:Pulmonary Artery / Q000187:drug effects; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use
D010627:Phenethylamines; D026902:Potassium Channel Blockers; D013449:Sulfonamides; C063533:dofetilide