Pharmacological Targeting of KCa Channels to Improve Endothelial Function in the Spontaneously Hypertensive Rat

Abstract

Systemic hypertension is a major risk factor for the development of cardiovascular disease and is often associated with endothelial dysfunction. KCa2.3 and KCa3.1 channels are expressed in the vascular endothelium and contribute to stimulus-evoked vasodilation. We hypothesized that acute treatment with SKA-31, a selective activator of KCa2.x and KCa3.1 channels, would improve endothelium-dependent vasodilation and transiently lower mean arterial pressure (MAP) in male, spontaneously hypertensive rats (SHRs). Isolated vascular preparations exhibited impaired vasodilation in response to bradykinin (i.e., endothelial dysfunction) compared with Wistar controls, which was associated with decreased bradykinin receptor expression in mesenteric arteries. In contrast, similar levels of endothelial KCa channel expression were observed, and SKA-31 evoked vasodilation was comparable in vascular preparations from both strains. Addition of a low concentration of SKA-31 (i.e., 0.2–0.3 μM) failed to augment bradykinin-induced vasodilation in arteries from SHRs. However, responses to acetylcholine were enhanced. Surprisingly, acute bolus administration of SKA-31 in vivo (30 mg/kg, i.p. injection) modestly elevated MAP compared with vehicle injection. In summary, pharmacological targeting of endothelial KCa channels in SHRs did not readily reverse endothelial dysfunction in situ, or lower MAP in vivo. SHRs thus appear to be less responsive to endothelial KCa channel activators, which may be related to their vascular pathology.

Modulation of Cardiovascular Function in Primary Hypertension in Rat by SKA-31, an Activator of KCa2.x and KCa3.1 Channels

“…Pre-incubation with SKA-31 (0.1 µM) enhanced the effect of Ach-mediated vasodilation only in sMAs from SHR. In related studies, SKA-31 has been reported to have potentiating effects on Ach-induced EDH-type vasodilation in pressurized sMAs of WKY and SHR [17], murine carotid arteries, dog first-order mesenteric and rat middle cerebral arteries [13,14,19], and in carotid artery hypertensive K Ca 3.1 −/− mice [37]. We hypothesized, that in the presence of a Ca 2+ mobilizing receptor agonists, such as ACh, K Ca channel activator can certainly augment such actions by boosting or “priming” K Ca channel activities, which was previously shown in isolated endothelial cells and intact vascular tissue [38,52].…”

“…Moreover, it effectively reduces blood pressure in normotensive mice, dogs, and pigs [13,14,15] and in mice with hypertension induced by angiotensin II [13], connexin40 deficiency [16]. SKA-31 is also shown to produce a transient decrease in mean arterial BP that was accompanied by either a reflex tachycardia [14], bradycardia [16] or unchanged heart rate [13,15,17]. Using arterial pressure myography, it has been shown that SKA-31 increased coronary flow in a K Ca 3.1 -dependent manner in diabetic rats [18], evoked concentration-dependent inhibition of myogenic tone in the rat cremaster and middle cerebral arteries [19] and in small mesenteric arteries (sMAs) in a K Ca 2.3 / K Ca 3.1 -dependent manner [20].…”