Abstract
The heart generates and propagates action potentials through synchronized activation of ion channels allowing inward Na+ and Ca2+ and outward K+ currents. There are a number of K+ channel types expressed in the heart that play key roles in regulating the cardiac cycle. Large conductance calcium-activated potassium (BK) ion channels are not thought to be directly involved in heart function. Here we present evidence that heart rate can be significantly reduced by inhibiting the activity of BK channels. Agents that specifically inhibit BK channel activity, including paxilline and lolitrem B, slowed heart rate in conscious wild-type mice by 30% and 42%, respectively. Heart rate of BK channel knock-out mice (Kcnma1−/−) was not affected by these BK channel inhibitors, suggesting that the changes to heart rate were specifically mediated through BK channels. The possibility that these effects were mediated through BK channels peripheral to the heart was ruled out with experiments using isolated, perfused rat hearts, which showed a significant reduction in heart rate when treated with the BK channel inhibitors paxilline (1 µM), lolitrem B (1 µM), and iberiotoxin (0.23 µM), of 34%, 60%, and 42%, respectively. Furthermore, paxilline was shown to decrease heart rate in a dose-dependent manner. These results implicate BK channels located in the heart to be directly involved in the regulation of heart rate.
Highlights
Large conductance calcium-activated potassium (BK) ion channels are expressed in many tissues that exhibit diverse physiological characteristics
Both lolitrem B and paxilline were found to have no effect on mean blood pressure in wild-type mice (Fig. 1A & B), but both inhibitors induced a significant decrease in heart rate (Fig. 1C & D)
These results show that BK channel inhibitors significantly decrease heart rate under conditions of normal autonomic tone
Summary
Large conductance calcium-activated potassium (BK) ion channels are expressed in many tissues that exhibit diverse physiological characteristics. BK channels are highly expressed in smooth muscle where they have been shown to affect myogenic tone [1] and regulate blood pressure [2], cerebrovascular circulation [3], erectile function [4], and urinary bladder function [5,6]. They are prevalent in the brain where they have important roles in the regulation of neuronal circuits in the hippocampus [7], in motor function and cerebellum [5,8,9], and in circadian rhythm and the hypothalamus [10]. BK-type channels are thought to be present in the inner mitochondrial membrane of cardiac myocytes and protect against cardiac ischemia [17]
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