Possible Role for K ⁺ in Endothelium-Derived Hyperpolarizing Factor–Linked Dilatation in Rat Middle Cerebral Artery

Abstract

Background and Purpose-Endothelium-derived hyperpolarizing factor (EDHF) and K ϩ are vasodilators in the cerebral circulation. Recently, K ϩ has been suggested to contribute to EDHF-mediated responses in peripheral vessels. The EDHF response to the protease-activated receptor 2 ligand SLIGRL was characterized in cerebral arteries and used to assess whether K ϩ contributes as an EDHF. Methods-Rat middle cerebral arteries were mounted in either a wire or pressure myograph. Concentration-response curves to SLIGRL and K ϩ were constructed in the presence and absence of a variety of blocking agents. In some experiments, changes in tension and smooth muscle cell membrane potential were recorded simultaneously. Results-SLIGRL (0.02 to 20 mol/L) stimulated concentration and endothelium-dependent relaxation. In the presence of N G -nitro-L-arginine methyl ester, relaxation to SLIGRL was associated with hyperpolarization and sensitivity to a specific inhibitor of IK Ca , 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (1mol/L), reflecting activation of EDHF. Combined inhibition of K IR with Ba 2ϩ (30mol/L) and Na ϩ /K ϩ -ATPase with ouabain (1 mol/L) markedly attenuated the relaxation to EDHF. Raising extracellular [K ϩ ] to 15 mmol/L also stimulated smooth muscle relaxation and hyperpolarization, which was also attenuated by combined application of Ba 2ϩ and ouabain. Conclusions-SLIGRL evokes EDHF-mediated relaxation in the rat middle cerebral artery, underpinned by hyperpolarization of the smooth muscle.

Evidence for Involvement of Both IK Ca and SK Ca Channels in Hyperpolarizing Responses of the Rat Middle Cerebral Artery

“…For example, blockade of endothelial cell IK Ca channels alone is sufficient to block endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation and hyperpolarization in rat middle cerebral arteries. 1,2 This is a dramatic contrast to other peripheral vessels, where in general EDHF-mediated responses are abolished by combined inhibition of both SK Ca and IK Ca in the endothelium. 3 In arteries where blockade of EDHF-mediated responses require the simultaneous block of SK Ca and IK Ca, such as porcine coronary and rat mesenteric arteries, functional, electrophysiological and immunohistochemical data demonstrate that these channels are clearly expressed only within the endothelium.…”

“…The additional inhibition of cyclo-oxygenase has no effect in this artery. 2 Papaverine (150 mol/L) was added at the end of each experiment to assess overall tone. All drugs were allowed to equilibrate for at least 20 minutes before vasodilator responses were stimulated.…”

“…2 Alone, L-NAME (100 mol/L) evoked smooth-muscle depolarization (12.8Ϯ0.7 mV, nϭ4) and associated constriction (2. 8Ϯ0.4 mN, nϭ4).…”

ACh-induced relaxations of rabbit small mesenteric arteries: role of arachidonic acid metabolites and K+

“…Previous studies have suggested that IK Ca channels are restricted to the endothelium, and K ϩ efflux via these channels may serve as an EDHF in some arteries (2,7,17,27). In contrast, K ϩ does not appear to significantly contribute to the EDHF response in arteries such as porcine coronary, guinea pig carotid, and mouse mesenteric artery (6,25).…”

Unstructured to structured transition of an intrinsically disordered protein peptide in coupling Ca 2+ -sensing and SK channel activation

“…By dampening the firing of action potentials, activation of SK/IK channels contributes to the regulation of neuronal excitability, dendritic integration, synaptic transmission, and plasticity in the central nervous system (9,11,13,15,16). In the cardiovascular system, vascular endothelial cells express both IK and SK3 channels, which are implicated in the endothelium-derived hyperpolarizing factor-mediated vasodilation (17)(18)(19)(20). The importance of SK/IK channels is demonstrated further by their potential roles in clinical abnormalities (21)(22)(23)(24).…”