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.
Highlights
Carbon monoxide (CO), endogenously produced by heme oxygenases (HO), is considered to be an important signaling molecule participating in a variety of cellular functions (Romanski et al, 2012a; Olas, 2014; Naito et al, 2016)
The tested concentrations were chosen on the basis of preliminary experiments assessing the toxicity of these ET-CO releasing molecules (CORMs)
Pre-contracted mesenteric arteries strongly dilated upon treatment with both types of acetate containing ET-CORMs, while treatment with the pivalate containing ETCORM resulted in no vasodilation (Figures 2E,F)
Summary
Carbon monoxide (CO), endogenously produced by heme oxygenases (HO), is considered to be an important signaling molecule participating in a variety of cellular functions (Romanski et al, 2012a; Olas, 2014; Naito et al, 2016). While in phase I clinical studies CO was applied in its gaseous form, in recent years a number of different CO releasing molecules (CORMs) have been synthesized and successfully tested in in vitro and in vivo inflammation models. CO release can be influenced by the type and position of the ester substituent of the ET-CORM as well as by the mother compound from which it is derived (Romanski et al, 2013). This concept allows the design of protease specific CO release, paving avenues for the implementation of cell specific CO delivery (Sitnikov et al, 2015)
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