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Potassium channel activators cromakalim and celikalim (WAY-120,491) fail to decrease myocardial infarct size in the
J M Kitzen1, J D McCallum, C Harvey
1Department of Cardiovascular-Metabolic, Wyeth-Ayerst Research Laboratories, Princeton, N.J.
Insights
K channel activator drugs like cromakalim and celikalim worsened myocardial infarction injury when given directly into the coronary artery. Intravenous administration did not show these harmful effects, suggesting they are not suitable for acute heart attack treatment.
Area of Science:
- Cardiovascular Pharmacology
- Ischemic Heart Disease Research
Background:
- Potassium (K) channel activators are investigated for potential cardioprotective effects.
- Myocardial infarction (MI) involves ischemia and reperfusion injury, necessitating effective acute treatments.
Purpose of the Study:
- To evaluate the cardioprotective efficacy of K channel activators, cromakalim and celikalim, in a canine model of myocardial infarction.
- To determine the impact of drug administration route (intracoronary vs. intravenous) on infarct size.
Main Methods:
- A canine model of myocardial infarction was induced (90 min ischemia, 5 h reperfusion).
- Cromakalim and celikalim were administered via intracoronary or intravenous routes.
- Infarct size, area at risk, and rate-pressure product were assessed.
Main Results:
- Intracoronary administration of cromakalim and celikalim significantly increased infarct size compared to vehicle control.
- Intravenous administration of these drugs did not alter infarct size.
- Diltiazem administered intravenously showed a trend towards reducing infarct size, though not statistically significant.
Conclusions:
- K channel activators, cromakalim and celikalim, may exacerbate ischemic injury when administered intracoronarily.
- These drugs are unlikely to be effective for acute therapeutic management of myocardial ischemic injury.
- The route of administration is critical when considering K channel activators for cardiovascular conditions.
Abstract:
The cardioprotective effects of the K channel activator drugs celikalim (WAY-120,491) and cromakalim were studied in a canine model of myocardial infarction consisting of 90 min of ischemia and 5 h of reperfusion. Intracoronary infusion of cromakalim and celikalim at 0.2 microgram/kg/min beginning 10 min before occlusion of the left circumflex coronary artery and continuing throughout the duration of the reperfusion period appeared to exacerbate ischemic injury. Infarct size (percent of risk area) was 27.7 +/- 5.6% in vehicle control animals (n = 5), 40.3 +/- 6.2% for cromakalim (n = 5) and 55.7 +/- 6.4% (p less than 0.05 vs. vehicle) for celikalim-treated animals (n = 5). When these compounds were administered intravenously, using doses shown to increase total coronary flow in nonoccluded control animals, no exacerbation of ischemic injury was observed. Anatomic infarct size was 32.8 +/- 7.1% for vehicle animals (n = 5) and 32.6 +/- 13.3 and 30.9 +/- 9.8% for cromakalim- (n = 6) and celikalim-treated (n = 5) animals, respectively. Intravenous diltiazem decreased myocardial infarct size to 16.3 +/- 7.3% (n = 5) of area at risk (p = NS vs. vehicle). The anatomic area at risk was similar in all three treatment groups, and no significant differences in rate-pressure product were observed. Results of this study suggest that K-channel-activating drugs such as cromakalim and celikalim may not be effective agents in the acute therapeutic management of myocardial ischemic injury.