Combined administration of an IK(ATP) activator and Ito blocker increases coronary flow independently of effects on heart rate, QT interval, and ischaemia-induced ventricular fibrillation in rats.
The effects of combined administration of the ATP-dependent K+ channel opener cromakalim and the transient outward K+ current (Ito) blocker tedisamil on ventricular tachyarrhythmias, QT interval, and coronary flow were investigated in isolated rat heart (n = 12/group) subjected to 30-min regional ischaemia. When administered alone, beginning 5 min before onset of ischaemia and continuously thereafter, neither cromakalim (10 microM) nor tedisamil (3 microM) had any significant influence on the incidence of VF, although tedisamil abolished sustained VF (SVF, defined as VF lasting > 2 min). Cromakalim did not affect tedisamil's ability to abolish SVF when administered concurrently with tedisamil and had no effect on SVF when administered alone; incidences of SVF were 64, 0 (p < 0.05), 66, and 0% (p < 0.05) in control, tedisamil, cromakalim, and combined treatment groups, respectively. Occurrence of SVF was related to the width of the ventricular complex at 50% of repolarisation (QT50). Pretreatment with tedisamil widened QT50 (p < 0.05), and this effect was not attenuated by combined treatment with cromakalim. Cromakalim increased coronary flow (14 +/- 0.4 in controls versus 21 +/- 0.6 ml/min/g in cromakalim-treated hearts, p < 0.05). This effect was not reduced by coadministration of tedisamil (20 +/- 0.9 ml/min/g in hearts cotreated with both drugs). Tedisamil alone had no significant effect on coronary flow.(ABSTRACT TRUNCATED AT 250 WORDS)
Rees
S A
SA
Department of Pharmacology, King's College, University of London, England.
Tsuchihashi
K
K
Hearse
D J
DJ
Curtis
M J
MJ
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000494:pharmacology; D001578:Benzopyrans / Q000008:administration & dosage / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003326:Coronary Circulation / Q000187:drug effects*; D019806:Cromakalim; D003521:Cyclopropanes / Q000008:administration & dosage / Q000494:pharmacology*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004562:Electrocardiography / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008297:Male; D017202:Myocardial Ischemia / Q000503:physiopathology*; D015221:Potassium Channels / Q000187:drug effects; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology; D014693:Ventricular Fibrillation / Q000188:drug therapy* / Q000209:etiology
D000889:Anti-Arrhythmia Agents; D001578:Benzopyrans; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003521:Cyclopropanes; D015221:Potassium Channels; D011758:Pyrroles; D014665:Vasodilator Agents; D019806:Cromakalim; C059921:tedisamil