Abstract 11600: Heterogeneous Role of Kv7 Channels in the Cerebral and Coronary Circulation
Recent studies have implicated Kv7 channels as important in the regulation of smooth muscle contractility in the vasculature including in aorta, renal and cerebral arteries. The present studies examined the hypotheses that 1. Kv7 channels are present in cerebral and coronary arteries and regulate vascular reactivity, and that 2. differences in local requirements result in a heterogeneous role for these channels. Qualitative PCR was performed on male WT mouse brain, basilar, Circle of Willis arteries, cardiac tissue and left anterior descending (LAD) artery. Vascular function of the basilar and LAD arteries from WT male mice was assessed by myography. Brain and Circle of Willis expressed all subtypes of Kv7 (1-5) and basilar artery expressed Kv7.1, 7.3 and 7.4 while heart and LAD expressed predominantly Kv7.1 and 7.4. Maximal responses of acetylcholine (ACh) and sodium nitroprusside (SNP)-induced vasorelaxation was comparable between basilar and LAD arteries, while relaxation induced by the Kv7 channel activator, retigabine (1-50 μM) was significantly reduced in the LAD compared to basilar artery (P<0.05). In addition, application of the Kv7 channel blocker, linopirdine (10 μM) resulted in greater contractile response in basilar artery compared to LAD (19.5 ± 2.1% vs. 5.2 ± 0.9%, P<0.05, percentage of contraction to 100 mM KCl). An additional Kv7 channel blocker, XE991 (10 μM) also increased contractility in the basilar arteries (15.3 ± 1.6 vs. 5.2 ± 0.9%, P<0.05). Furthermore, pre-incubation with linopirdine (10 μM) reduced forskolin (cAMP activator)-induced vasorelaxation (1 nM-1 μM) in the basilar but did not alter forskolin-induced vasorelaxation in the LAD arteries, suggesting that Kv7 channels may play a more prominent role in the cerebral than coronary circulation. Consistent with the pharmacological data, at the single cerebral VSMC level whole cell Kv7 currents were demonstrated and were inhibited by linopirdine while being potentiated by retigabine. This study provides evidence that Kv7 channels may play different roles in the regulation of cerebral and coronary blood flow. The finding of such heterogeneity has important implications in the development of novel therapeutics for cardiovascular diseases including stroke and cardiac arrest.
- Potassium channel
- Cerebrovascular circulation
- Coronary microcirculation
- © 2013 by American Heart Association, Inc.