Novel Roles for K(v)7 Channels in Shaping Histamine-Induced Contractions and Bradykinin-Dependent Relaxations in Pig Coronary Arteries

Voltage-gated K(v)7 channels are inhibited by agonists of G(q)-protein-coupled receptors, such as histamine. Recent works have provided evidence that inhibition of vascular K(v)7 channels may trigger vessel contractions. In this study, we investigated how K(v)7 activity modulates the histamine-induced contractions in “healthy” and metabolic syndrome (MetS) pig right coronary arteries (CAs). We performed isometric tension and immunohistochemical studies with domestic, lean Ossabaw, and MetS Ossabaw pig CAs. We found that neither the K(v)7.2/K(v)7.4/K(v)7.5 activator ML213 nor the general K(v)7 inhibitor XE991 altered the tension of CA rings under preload, indicating that vascular K(v)7 channels are likely inactive in the preloaded rings. Conversely, ML213 potently dilated histamine-pre-contracted CAs, suggesting that K(v)7 channels are activated during histamine applications and yet partially inhibited by histamine. Immunohistochemistry analysis revealed strong K(v)7.4 immunostaining in the medial and intimal layers of the CA wall, whereas K(v)7.5 immunostaining intensity was strong in the intimal but weak in the medial layers. The medial K(v)7 immunostaining was significantly weaker in MetS Ossabaw CAs as compared to lean Ossabaw or domestic CAs. Consistently, histamine-pre-contracted MetS Ossabaw CAs exhibited attenuated ML213-dependent dilations. In domestic pig CAs, where medial K(v)7 immunostaining intensity was stronger, histamine-induced contractions spontaneously decayed to ~31% of the peak amplitude within 4 minutes. Oppositely, in Ossabaw CAs, where K(v)7 immunostaining intensity was weaker, the histamine-induced contractions were more sustained. XE991 pretreatment significantly slowed the decay rate of histamine-induced contractions in domestic CAs, supporting the hypothesis that increased K(v)7 activity correlates with a faster rate of histamine-induced contraction decay. Alternatively, XE991 significantly decreased the amplitude of bradykinin-dependent dilations in pre-contracted CAs. We propose that in CAs, a decreased expression or a loss of function of K(v)7 channels may lead to sustained histamine-induced contractions and reduced endothelium-dependent relaxation, both risk factors for coronary spasm.