Effect of cromakalim on skeletal muscle function and blood flow in the ferret ischemic hindlimb.
Cromakalim, an agent that opens ATP-modulated potassium channels, has recently been reported to reduce skeletal muscle contractile force during anoxia in vitro. To determine whether this activity occurs in vivo, cromakalim was tested for its ability to influence muscle function and blood flow in a model of skeletal muscle ischemia. In anesthetized ferrets the muscles of the hindlimb were stimulated electrically via the sciatic nerve and isometric force of contraction was measured. Under normal perfusion conditions, contractile force peaked (324 +/- 33 g) within 1 or 2 min and gradually declined to about 85% of the peak over 20 min. Following this initial period, the abdominal aorta was partially occluded to reduce femoral blood pressure to 35-40 mm Hg, and infusion of cromakalim or vehicle was started. After 60 min of treatment, a second exercise challenge was performed. In the vehicle-treated group, peak force was reduced by 33% (p < 0.05), and over the 20-min stimulation period, the area under the force-time curve (AUC) was 22.8 +/- 2.6% of that seen during the normal flow period. Compared to vehicle, cromakalim infusions of 1.33 or 3.0 micrograms/kg/min reduced mean arterial blood pressure by 7 and 45%, but had no significant effect on either peak force or AUC. Although the higher dose of cromakalim significantly reduced vascular resistance in resting, normally perfused skeletal muscle of the forelimbs, neither dose affected blood flow in the ischemic skeletal muscles of the hindlimb during exercise. These results suggest that cromakalim does not influence skeletal muscle blood flow or function during an acute ischemic insult.
Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543.
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EO
Weselcouch
A J
AJ
Baird
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D019806:Cromakalim; D004558:Electric Stimulation; D005289:Ferrets; D006614:Hindlimb / Q000098:blood supply*; D007261:Infusions, Intra-Arterial; D007511:Ischemia / Q000150:complications / Q000503:physiopathology*; D007537:Isometric Contraction / Q000502:physiology; D008297:Male; D018482:Muscle, Skeletal / Q000098:blood supply / Q000187:drug effects / Q000502:physiology*; D010276:Parasympatholytics / Q000494:pharmacology*; D015221:Potassium Channels / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology
D001578:Benzopyrans; D010276:Parasympatholytics; D015221:Potassium Channels; D011758:Pyrroles; D019806:Cromakalim