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

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.

The vascular endothelium: A regulator of arterial tone and interface for the immune system.

As the primary interface between the blood and various tissues of the body, the vascular endothelium exhibits a diverse range of roles and activities, all of which contribute to the overall health and function of the cardiovascular system. In this focused review, we discuss several key aspects of endothelial function, how this may be compromised and subsequent consequences. Specifically, we examine the dynamic regulation of arterial contractility and distribution of blood flow through the generation of chemical and electrical signaling events that impinge upon vascular smooth muscle. The endothelium can generate a diverse range of vasoactive compounds and signals, most of which act locally to adjust blood flow in a dynamic fashion to match tissue metabolism. Disruption of these vascular signaling processes (e.g. reduced nitric oxide bioavailability) is typically referred to as endothelial dysfunction, which is a recognized risk factor for cardiovascular disease in patients and occurs early in the development and progression of hypertension, atherosclerosis and tissue ischemia. Endothelial dysfunction is also associated with type-2 Diabetes and aging and increased mechanistic knowledge of the cellular changes contributing to these effects may provide important clues for interventional strategies. The endothelium also serves as the initial site of interaction for immune cells entering tissues in response to damage and acts to facilitate the actions of both the innate and acquired immune systems to interact with the vascular wall. In addition to representing the main cell type responsible for the formation of new blood vessels (i.e. angiogenesis) within the vasculature, the endothelium is also emerging as a source of extracellular vesicle or microparticles for the transport of signaling molecules and other cellular materials to nearby, or remote, sites in the body. The characteristics of released microparticles appear to change with the functional status of the endothelium; thus, these microparticles may represent novel biomarkers of endothelial health and more serious cardiovascular disease.

SKA-31, an activator of endothelial Ca2+-activated K+ channels evokes robust vasodilation in rat mesenteric arteries.

It is now well recognized that endothelial KCa2.3 and KCa3.1 channel activities contribute to dilation of resistance arteries via endothelium-mediated hyperpolarization and vascular smooth muscle relaxation. In this study, we have investigated the functional effect of the KCa channel activator SKA-31 in third order rat mesenteric arteries using arterial pressure myography. Isolated arteries were cannulated, pressurized intraluminally to 70 mmHg at 36 °C and then constricted with 1 µM phenylephrine. Acute bath exposure to SKA-31 evoked a robust and reversible inhibition of developed tone (IC50 = 0.22 µM). The vasodilatory effects of SKA-31 and acetylcholine were blunted in the presence of KCa2.3 and KCa3.1 channel antagonists, and were largely prevented following endothelial denudation. Western blot and q-PCR analyses of isolated mesenteric arteries revealed KCa2.3 and KCa3.1 channel expression at the protein and mRNA levels, respectively. Penitrem-A, an inhibitor of KCa1.1 channels, decreased vasodilatory responses to acetylcholine, sodium nitroprusside and NS-1619, but had little effect on SKA-31. Similarly, bath exposure to the eNOS inhibitor L-NAME did not alter SKA-31 and acetylcholine-mediated vasodilation. Collectively, these data highlight the major cellular mechanisms by which the endothelial KCa channel activator SKA-31 inhibits agonist-evoked vasoconstriction in rat small mesenteric arteries.

Pharmacologic targeting of endothelial Ca2+-activated K+ channels: A strategy to improve cardiovascular function.

Endothelial small and intermediate-conductance, Ca2+-activated K+ channels (KCa2.3 and KCa3.1, respectively) play an important role in the regulation of vascular function and systemic blood pressure. Growing evidence indicates that they are intimately involved in agonist-evoked vasodilation of small resistance arteries throughout the circulation. Small molecule activators of KCa2.x and 3.1 channels, such as SKA-31, can acutely inhibit myogenic tone in isolated resistance arteries, induce effective vasodilation in intact vascular beds, such as the coronary circulation, and acutely decrease systemic blood pressure in vivo. The blood pressure-lowering effect of SKA-31, and early indications of improvement in endothelial dysfunction suggest that endothelial KCa channel activators could eventually be developed into a new class of endothelial targeted agents to combat hypertension or atherosclerosis. This review summarises recent insights into the activation of endothelial Ca2+ activated K+ channels in various vascular beds, and how tools, such as SKA-31, may be beneficial in disease-related conditions.