Pharmacological activation of KCa3.1/KCa2.3 channels produces endothelial hyperpolarization and lowers blood pressure in conscious dogs

Abstract

BACKGROUND AND PURPOSE In rodents, the endothelial KCa channels, KCa3.1 and KCa2.3, have been shown to play a crucial role in initiating endothelium‐derived hyperpolarizing factor (EDHF) vasodilator responses. However, it is not known to what extent these channels are involved in blood pressure regulation in large mammals, which would also allow us to address safety issues. We therefore characterized canine endothelial KCa3.1 and KCa2.3 functions and evaluated the effect of the KCa3.1/KCa2.3 activator SKA‐31 on blood pressure and heart rate in dogs. EXPERIMENTAL APPROACH Canine endothelial KCa3.1/KCa2.3 functions were studied by patch‐clamp electrophysiology and wire myography in mesenteric arteries. Systemic cardiovascular actions of acute SKA‐31 administration were monitored in conscious, unstressed beagle dogs. KEY RESULTS Mesenteric endothelial cells expressed functional KCa3.1 and KCa2.3 channels that were strongly activated by SKA‐31. SKA‐31 hyperpolarized the endothelial membrane and doubled endothelial hyperpolarization‐dependent vasodilator responses in mesenteric arteries. SKA‐31 (2 mg·kg−1, i.v.) rapidly decreased the MAP by 28 ± 6 mmHg; this response was transient (8 ± 1 s), and the initial drop was followed by a fast and pronounced increase in HR (+109 ± 7 beats min−1) reflecting baroreceptor activation. SKA‐31 significantly augmented similar transient depressor responses elicited by ACh (20 ng·kg−1) and doubled the magnitude of the response over time. CONCLUSIONS AND IMPLICATIONS Activation of endothelial KCa3.1 and KCa2.3 lowers arterial blood pressure in dogs by an immediate electrical vasodilator mechanism. The results support the concept that pharmacological activation of these channels may represent a potential unique endothelium‐specific antihypertensive therapy.

Regulation of Cellular Communication by Signaling Microdomains in the Blood Vessel Wall

“…In a mouse model in which the expression level of SK Ca can be manipulated with dietary doxycycline, the amount of SK Ca expression in the EC was inversely correlated with the blood pressure . It is noteworthy that several studies in small and large animals demonstrated that activation of IK Ca and SK Ca channels using the drug SKA-31 could decrease blood pressure, making these channels a potential therapeutic target for treatment of hypertension (Sankaranarayanan et al, 2009;Hasenau et al, 2011;Damkjaer et al, 2012).…”

New Positive Ca2+-Activated K+ Channel Gating Modulators with Selectivity for KCa3.1

“…In dogs, i.v. injection of 2 mg/kg SKA-31 produced an immediate and strong (230 mmHg) but short-lived reduction in blood pressure (Damkjaer et al, 2012). In mice, SKA-31 doses of 10-30 mg/kg have been reported to lower blood pressure more prolonged (∼30 mmHg) for 60-90 minutes) (Sankaranarayanan et al, 2009;Köhler, 2012).…”

“…Since both K Ca 3.1 and K Ca 2.3 are expressed in vascular endothelium and have been shown to be involved in the so-called endothelium-derived hyperpolarization (EDH) response Dalsgaard et al, 2010;Edwards et al, 2010;Köhler et al, 2010), SKA-31 was used as a pharmacologic tool to explore the role of K Ca channels in blood pressure regulation. While mice deficient in K Ca 3.1 and/or K Ca 2.3 exhibit impaired EDH responses and an increased mean arterial blood pressure (MAP) (Brahler et al, 2009), pharmacologic K Ca channel activation with SKA-31 lowered blood pressure in both mice and dogs (Sankaranarayanan et al, 2009;Damkjaer et al, 2012;Radtke et al, 2013). In dogs, i.v.…”

Opening of Small and Intermediate Calcium-Activated Potassium Channels Induces Relaxation Mainly Mediated by Nitric-Oxide Release in Large Arteries and Endothelium-Derived Hyperpolarizing Factor in Small Arteries from Rat

“…In addition, opening SK Ca and IK Ca channels decreases myogenic tone, increases acetylcholine (ACh)-induced relaxation in rat cremaster arterioles (Sheng et al, 2009), and restores attenuated EDHF-type relaxation in mesenteric small arteries from Zucker diabetic fatty rats (Brøndum et al, 2010). Moreover, opening IK Ca channels decreases mean arterial blood pressure in angiotensin IIinduced hypertensive mice (Sankaranarayanan et al, 2009) and conscious dogs (Damkjaer et al, 2011). These results support findings that SK Ca and IK Ca channels are involved in controlling blood pressure and organ blood flow, and this often is attributed to EDHF-type relaxation.…”