ET-CORM Mediated Vasorelaxation of Small Mesenteric Arteries: Involvement of Kv7 Potassium Channels

Abstract

Although the vasoactive properties of carbon monoxide (CO) have been extensively studied, the mechanism by which CO mediates vasodilation is not completely understood. Through-out published studies on CO mediated vasodilation there is inconsistency on the type of K+-channels that are activated by CO releasing molecules (CORMs). Since the vasorelaxation properties of enzyme triggered CORMs (ET-CORMs) have not been studied thus far, we first assessed if ET-CORMs can mediate vasodilation of small mesenteric arteries and subsequently addressed the role of soluble guanylate cyclase (sGC) and that of K-channels herein. To this end, 3 different types of ET-CORMs that either contain acetate (rac-1 and rac-4) or pivalate (rac-8) as ester functionality, were tested ex vivo on methoxamine pre-contracted small rat mesenteric arteries in a myograph setting. Pre-contracted mesenteric arteries strongly dilated upon treatment with both types of acetate containing ET-CORMs (rac-1 and rac-4), while treatment with the pivalate containing ET-CORM (rac-8) resulted in no vasodilation. Pre-treatment of mesenteric arteries with the sGC inhibitor ODQ abolished rac-4 mediated vasodilation, similar as for the known sGC activator SNP. Likewise, rac-4 mediated vasodilation did not occur in KCL pretreated mesenteric arteries. Although mesenteric arteries abundantly expressed a variety of K+-channels only Kv7 channels were found to be of functional relevance for rac-4 mediated vasodilation. In conclusion the current results identified Kv7 channels as the main channel by which rac-4 mediates vasodilation. In keeping with the central role of Kv7 in the control of vascular tone and peripheral resistance these promising ex-vivo data warrant further in vivo studies, particularly in models of primary hypertension or cardiac diseases, to assess the potential use of ET-CORMs in these diseases.

Carbon monoxide therapy: a promising strategy for cancer

“…55 Not coincidentally, Zhang et al suggested that enzyme-triggered CORMs could mediate vasodilation of small mesenteric arteries in a soluble guanylate cyclase and Kv7 channel-dependent manner, and the effect could be blocked by soluble guanylate cyclase inhibitors. 56 Another study on aortic endothelial cells isolated from chronically hypoxic rat sources confirmed the ability of HO-derived CO to activate large-conductance Ca 2+ -activated K + channels in endothelial cells, while the activation decreased vasoconstriction responsiveness. 57 The diastolic effect of CO in humans has also been demonstrated.…”

The Vasodilator Effect and Mechanism of 18β-glycyrrhetinic Acid on Isolated Pulmonary Artery Rings in Rats

“…Changes in the activity of potassium channels can lead to changes in cell membrane potential, thereby inhibiting extracellular calcium influx and causing vasodilation. There are four kinds of potassium channels in vascular smooth muscle, namely ATP-sensitive potassium channel (K ATP ), inward rectifier potassium channel (Kir), Ca 2+ activated potassium channel (KCa), and voltage-sensitive potassium channel (Kv) (Zhang et al, 2021; Zingman et al, 2007). TEA and BaCl 2 are KCa and Kir blockers, respectively.…”

Metal-based carbon monoxide releasing molecules with promising cytotoxic properties

“…According to these findings, the primary K + -channel by which 46 mediates vasodilation is Kv7. 202 Motterlini and co-workers proposed four iron(II)-allyl CORMs, 58, 59, 60 and 61 (Figure 11) that spontaneously release CO. Complexes 5860 were soluble in DMSO, while 61 was soluble in water due to its ionic nature. In the concentration range of 10-40 µM, about one mole of CO/ mole of each complex was released.…”