Transient Receptor Potential Channel Opening Releases Endogenous Acetylcholine, which Contributes to Endothelium-Dependent Relaxation Induced by Mild Hypothermia in Spontaneously Hypertensive Rat but Not Wistar-Kyoto Rat Arteries

Abstract

Mild hypothermia causes endothelium-dependent relaxations, which are reduced by the muscarinic receptor antagonist atropine. The present study investigated whether endothelial endogenous acetylcholine contributes to these relaxations. Aortic rings of spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto (WKY) rats were contracted with prostaglandin F 2a and exposed to progressive mild hypothermia (from 37 to 31°C). Hypothermia induced endotheliumdependent, Nv-nitro-L-arginine methyl ester-sensitive relaxations, which were reduced by atropine, but not by mecamylamine, in SHR but not in WKY rat aortae. The responses in SHR aortae were also reduced by acetylcholinesterase (the enzyme responsible for acetylcholine degradation), bromoacetylcholine (inhibitor of acetylcholine synthesis), hemicholinium-3 (inhibitor of choline uptake), and vesamicol (inhibitor of acetylcholine release). The mild hypothermia-induced relaxations in both SHR and WKY rat aortae were inhibited by AMTB [N-(3-aminopropyl)-2-[(3-methylphenyl)methoxy]-N-(2-thienylmethyl)-benzamide; the transient receptor potential (TRP) M8 inhibitor]; only those in SHR aortae were inhibited by HC-067047 [2-methyl-1-[3-(4-morpholinyl)propyl]-5-phenyl-N-[3-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide; TRPV4 antagonist] while those in WKY rat aortae were reduced by HC-030031 [2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl) acetamide; TRPA1 antagonist]. The endothelial uptake of extracellular choline and release of cyclic guanosine monophosphate was enhanced by mild hypothermia and inhibited by HC-067047 in SHR but not in WKY rat aortae. Compared with WKY rats, the SHR preparations expressed similar levels of acetylcholinesterase and choline acetyltransferase, but a lesser amount of vesicular acetylcholine transporter, located mainly in the endothelium. Thus, mild hypothermia causes nitric oxide-dependent relaxations by opening TRPA1 channels in WKY rat aortae. By contrast, in SHR aortae, TRPV4 channels are opened, resulting in endothelial production of acetylcholine, which, in an autocrine manner, activates muscarinic receptors on neighboring cells to elicit endothelium-dependent relaxations in response to mild hypothermia.

Downregulation of Endothelial Transient Receptor Potential Vanilloid Type 4 Channel and Small-Conductance of Ca 2+ -Activated K + Channels Underpins Impaired Endothelium-Dependent Hyperpolarization in Hypertension

“…37 The reason for the difference between our present study and the study by Zou et al 37 is not known, but it might relate to the differential expression of TRPA1 channels in the aorta versus superior mesenteric arteries. In the aorta of WKY, TRPA1 but not TRPV4 plays a role in the hypothermia-induced relaxation, whereas the function of TRPA1 is lost and the upregulation of TRPV4 activity compensates for the loss of TRPA1 in the aorta of SHR.…”

“…In the aorta of WKY, TRPA1 but not TRPV4 plays a role in the hypothermia-induced relaxation, whereas the function of TRPA1 is lost and the upregulation of TRPV4 activity compensates for the loss of TRPA1 in the aorta of SHR. 37 Because a previous experiment failed to detect TRPA1 expression in the endothelium of rat mesenteric arteries, 38 such complementary interplay between TRPA1 and TRPV4 observed in the aorta of SHR might not function in the superior mesenteric arteries of SHRSP.…”

Acetylcholine released by endothelial cells facilitates flow‐mediated dilatation

“…) and isolated artery preparations (Zou et al . ). Importantly, in the latter study, endogenous production of ACh by the endothelium was proposed to contribute to the vasorelaxation induced by hypothermia in the spontaneously hypertensive rat (Zou et al .…”

“…Importantly, in the latter study, endogenous production of ACh by the endothelium was proposed to contribute to the vasorelaxation induced by hypothermia in the spontaneously hypertensive rat (Zou et al . ). Fluid flow also induces a nitric oxide‐dependent dilatation of canine coronary arteries that is sensitive to AChE (Martin et al .…”

Thirty Years of Saying NO

“…15 Moderate decreases in temperature stimulate cold-sensitive TRP-channels (TRP ankyrin type 1 and TRPV4 subtypes) leading to increased endothelial synthesis of acetylcholine and autocrine initiation of endothelium-dependent, eNOS-dependent relaxations. 87 The physiological role, if any, played by this phenomenon in thermoregulatory vascular adaptations is unknown.…”