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Effect of cromakalim (BRL 34915) on hemodynamic and electrocardiographic changes induced by endothelin in dogs
T Tsunetoshi1, A Otsuka, H Mikami
1Department of Geriatric Medicine, Osaka University Medical School, Japan.
Insights
Cromakalim, a potassium channel activator, effectively inhibited the blood pressure and electrocardiogram changes caused by endothelin in dogs. This suggests cromakalim can counteract endothelin
Area of Science:
- Cardiovascular Pharmacology
- Endocrinology
Background:
- Endothelin is a potent vasoconstrictive peptide.
- Cromakalim is a vasorelaxant agent that opens potassium channels.
Purpose of the Study:
- To investigate the effects of cromakalim on the systemic actions of endothelin.
- To determine if potassium channel activation can mitigate endothelin-induced cardiovascular changes.
Main Methods:
- Anesthetized dogs were administered endothelin intravenously.
- Hemodynamic (blood pressure, cardiac output, total peripheral resistance) and electrocardiographic parameters were monitored.
- Dogs were pretreated with cromakalim before endothelin administration in a separate group.
Main Results:
- Endothelin alone caused significant increases in blood pressure, early cardiac output, and late total peripheral resistance.
- Endothelin induced distinct electrocardiographic changes (ST-elevation/depression).
- Cromakalim pretreatment completely abolished endothelin-induced hemodynamic and electrocardiographic alterations.
Conclusions:
- Cromakalim, a potassium channel activator, effectively inhibited the pressor and electrocardiographic effects of endothelin.
- This suggests that hyperpolarization via potassium channel activation counteracts endothelin's action, likely by inhibiting voltage-dependent calcium channels.
Abstract:
We evaluated whether cromakalim (BRL 34915), a vasorelaxant agent which acts by opening potassium channels, could affect the systemic effects of endothelin, a newly discovered vasoconstrictive peptide. Intravenous administration of endothelin alone (400 pmol/kg) to anesthetized dogs produced blood pressure elevation, which was associated with an increase in cardiac output in the early phase, and was associated with an increase in total peripheral resistance in the late phase. Electrocardiogram showed significant ST-elevation in II, III, and aVF, and ST-depression in aVR and aVL. The same dose of endothelin given to dogs pretreated with cromakalim did not induce these hemodynamic and electrocardiographic changes. Thus, cromakalim, a potassium activator, inhibited the hemodynamic and electrocardiographic actions of endothelin, suggesting that hyperpolarization due to potassium channel activation inhibited the voltage-dependent calcium channel, which is thought to be a major mechanism for the pressor action of endothelin.