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

Rayan Khaddaj Mallat,Ramesh C Mishra,Dylan J Kendrick,Cini Mathew John,Andrew P Braun

doi:10.3390/ijms20143481

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.

Highlights

Hypertension contributes significantly to worldwide cardiovascular morbidity and mortality [1,2,3], and appears to have a complex association with endothelial dysfunction, a phenotypic alteration of the vascular endothelium that precedes and predicts the development of adverse cardiovascular events [4,5,6]
We have examined the effect of the KCa channel activator SKA-31 [21] on endothelium-dependent vasodilation in small resistance arteries and mean arterial blood pressure in spontaneously hypertensive rats (SHRs), a model of genetic hypertension exhibiting endothelial dysfunction [24,25,26]
We performed arterial pressure myography with third order mesenteric arteries pre-constricted with phenylephrine (PE, 1 μM), and myogenically active cremaster skeletal muscle resistance arteries isolated from male SHRs (16–18 weeks of age) and aged-matched male Wistar rats

Summary

Introduction

Hypertension contributes significantly to worldwide cardiovascular morbidity and mortality [1,2,3], and appears to have a complex association with endothelial dysfunction, a phenotypic alteration of the vascular endothelium that precedes and predicts the development of adverse cardiovascular events [4,5,6]. Genetic inactivation of endothelial KCa2.3 and/or KCa3.1 channels in mice significantly decreases endothelium-dependent vasodilation and produces a hypertensive phenotype [18,19], whereas pharmacological activators of KCa channels evoke robust vasodilation in situ and acute hypotension in vivo [20,21,22,23]. Such observations demonstrate that manipulation of endothelial KCa channel activity can have major effects on the vasculature that could be exploited to mitigate endothelial dysfunction and hypertension-associated cardiovascular disease. We suggest that the SHR model exhibits altered responsiveness to the known vasodilatory actions of SKA-31

Methods

Results

Conclusion