Effects of dofetilide on cardiovascular tissues from normo- and hypertensive rats.

Abstract

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.

• Authors: Sheila A Doggrell, Vinita Nand
• Journal: The Journal of pharmacy and pharmacology (J Pharm Pharmacol) Vol. 54 Issue 5 Pg. 707-15 (May 2002) ISSN: 0022-3573 [Print] England
• PMID: 12005366 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Phenethylamines
• Potassium Channel Blockers
• Sulfonamides
• dofetilide

Topics

• Animals
• Aorta (drug effects)
• Blood Pressure (drug effects)
• Blood Vessels (drug effects)
• Cardiac Output, Low (drug therapy, physiopathology)
• Cardiomegaly (drug therapy, physiopathology)
• Disease Models, Animal
• Electric Stimulation
• Heart Rate (drug effects)
• Heart Ventricles (drug effects)
• Hypertension (physiopathology)
• In Vitro Techniques
• Mesenteric Arteries (drug effects)
• Myocardial Contraction (drug effects)
• Phenethylamines (pharmacology, therapeutic use)
• Portal Vein (drug effects)
• Potassium Channel Blockers (pharmacology, therapeutic use)
• Pulmonary Artery (drug effects)
• Rats
• Rats, Inbred SHR
• Rats, Inbred WKY
• Sulfonamides (pharmacology, therapeutic use)