Cromakalim does not protect against skeletal muscle fatigue in an anaesthetized rat model of acute hindlimb ischaemia.
The effects of the potassium (K+) channel opener, cromakalim, on skeletal muscle performance were studied in a model of acute hindlimb ischaemia in the anaesthetized rat. Twitch contractions to direct electrical stimulation of the extensor digitorum and tibialis anterior skeletal muscles were recorded following administration of cromakalim (10-100 micrograms kg-1 i.v.) under normal and reduced whole limb blood flow. With normal blood flow, twitch responses (0.5 and 1 Hz) of the hindlimb skeletal muscles were sustained for > 30 min. Controlled adjustment of the perfusion pressure in the contralateral hindlimb to 45, 30 or 0 mm Hg by partial or total occlusion of the abdominal aorta produced a pressure-related fall in flow to the working hindlimb, and a corresponding increase in the rate of muscle fatigue. Cromakalim (10-100 micrograms kg-1 i.v.) produced a dose-dependent reduction in mean carotid arterial blood pressure, femoral arterial pressure and hindlimb vascular resistance together with an increase in iliac artery blood flow and heart rate, but did not attenuate skeletal muscle fatigue under the different conditions of muscle work and ischaemia employed. A similar profile was observed with levcromakalim (15 micrograms kg-1 i.v.), the active enantiomer of cromakalim. These results demonstrate that in the direct muscle-stimulated hindlimb of the anaesthetized rat, the K+ channel opener cromakalim does not prevent acute ischaemia-induced skeletal muscle fatigue. The previous observation that K+ channel openers improve nutritive blood flow in a chronic model of rat hindlimb ischaemia is not reflected by an improvement in muscle function in the present study.
Trezise
D J
DJ
Department of Cardiovascular and Respiratory Pharmacology, Glaxo Group Research Ltd., Ware, Hertfordshire, UK.
Drew
G M
GM
Roach
A G
AG
Watts
I S
IS
Weston
A H
AH
D000818:Animals; D001578:Benzopyrans / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D019806:Cromakalim; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D006339:Heart Rate / Q000187:drug effects; D006614:Hindlimb / Q000098:blood supply; D007511:Ischemia / Q000188:drug therapy / Q000503:physiopathology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009132:Muscles / Q000187:drug effects* / Q000503:physiopathology; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology* / Q000627:therapeutic use
D001578:Benzopyrans; D011758:Pyrroles; D014665:Vasodilator Agents; D019806:Cromakalim