Date Published: January 14, 2010
Publisher: Public Library of Science
Author(s): Wendy L. Imlach, Sarah C. Finch, John H. Miller, Andrea L. Meredith, Julie E. Dalziel, Arnold Schwartz. http://doi.org/10.1371/journal.pone.0008698
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.
Partial Text: Large conductance calcium-activated potassium (BK) ion channels are expressed in many tissues that exhibit diverse physiological characteristics. BK channels are activated by intracellular calcium and depolarizing membrane voltages. BK channels are highly expressed in smooth muscle where they have been shown to affect myogenic tone  and therefore regulate blood pressure , cerebrovascular circulation , erectile function , and urinary bladder function , . They are also prevalent in the brain where they have important roles in the regulation of neuronal circuits in the hippocampus , in motor function and cerebellum , , , and in circadian rhythm and the hypothalamus . BK channels have also been found to have roles in hearing , , kidney filtration , colonic K+ secretion , , and immune function . BK-type channels are thought to be present in the inner mitochondrial membrane of cardiac myocytes and protect against cardiac ischemia .
The decrease in heart rate produced by BK channel inhibitors, paxilline and lolitrem B, in wild-type mice was unexpected since BK channels are not thought to be present in the heart. The observation that these compounds had no effect on heart rate in Kcnma1−/− mice further implicates BK channels in this effect. The lack of effect of the BK channel inhibitors on blood pressure, using a non-invasive blood pressure analysis system, was supported by preliminary results obtained using telemetry equipment in which paxilline given to telemetrized, freely moving, wild-type mice (n = 4, data not shown) also resulted in a decrease in heart rate. These results indicate that the decrease in heart rate is unlikely to be due to a secondary reflex compensatory effect related to a change in blood pressure since no immediate change in blood pressure was detected. It is unclear why no change in blood pressure was detected, given the contractile responses reported for BK channel inhibitors in smooth muscle in vitro, . It is possible that this is due to redundancy among K+ ion channels in control of blood pressure. The normal blood pressure in Kcnma1−/− mice is consistent with that previously reported for this phenotype at rest .