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

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 hyperpolarising factor(EDHF) vasodilator responses. However, it is not known to which extent these channels are involved in blood pressure regulation in large mammals which also allow addressing safety issues. We therefore characterized canine endothelial KCa3.1 and KCa2.3 functions and evaluated the effect on blood pressure and heart rate of the KCa3.1/KCa2.3-activator SKA-31 in dogs. Experimental approach.  Canine endothelial KCa3.1/KCa2.3 functions were studied by patch-clamp electrophysiology and wire-myography in mesenteric arteries. The 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 produced solid endothelial membrane hyperpolarisation and doubled endothelial hyperpolarisation-dependent vasodilator responses in mesenteric arteries. Administration of SKA-31 (2mg/kg, i.v.) produced a fast depressor response of -28 ± 6 mmHg in MAP. The response was transient (8 ± 1 sec) and the initial drop was followed by a fast and pronounced increase in HR (+ 109 ± 7 bpm) reflecting baroreceptor activation. SKA-31 significantly augmented the likewise transient depressor responses elicited by acetylcholine (20ng/kg) from -33 ± 3 to -46 ± 6 mmHg and doubled the magnitude of the response over time. Conclusions and implications.  The present study demonstrates that 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 anti-hypertensive therapy.