Daniel Morales-Cano1, Laura Moreno1, Bianca Barreira1, Rachele Pandolfi1, Virginia Chamorro1, Rosario Jimenez2, Eduardo Villamor3, Juan Duarte2, Francisco Perez-Vizcaino1, Angel Cogolludo4. 1. Department of Pharmacology, School of Medicine, University Complutense of Madrid, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Ciudad Universitaria S/N, Madrid 28040, Spain Ciber Enfermedades Respiratorias (CIBERES), Madrid, Spain. 2. Department of Pharmacology, School of Pharmacy, University of Granada, Granada 18071, Spain. 3. Department of Pediatrics, Maastricht University Medical Center (MUMC+), Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands. 4. Department of Pharmacology, School of Medicine, University Complutense of Madrid, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Ciudad Universitaria S/N, Madrid 28040, Spain Ciber Enfermedades Respiratorias (CIBERES), Madrid, Spain acogolludo@med.ucm.es.
Abstract
AIMS: Voltage-gated potassium channels encoded by KCNQ genes (Kv7 channels) are emerging as important regulators of vascular tone. In this study, we analysed the contribution of Kv7 channels to the vasodilation induced by hypoxia and the cyclic AMP pathway in the coronary circulation. We also assessed their regional distribution and possible impairment by diabetes. METHODS AND RESULTS: We examined the effects of Kv7 channel modulators on K+ currents and vascular reactivity in rat left and right coronary arteries (LCAs and RCAs, respectively). Currents from LCA were more sensitive to Kv7 channel inhibitors (XE991, linopirdine) and activators (flupirtine, retigabine) than those from RCA. Accordingly, LCAs were more sensitive than RCAs to the relaxation induced by Kv7 channel enhancers. Likewise, relaxation induced by the adenylyl cyclase activator forskolin and hypoxia, which were mediated through Kv7 channel activation, were greater in LCA than in RCA. KCNQ1 and KCNQ5 expression was markedly higher in LCA than in RCA. After incubation with high glucose (HG, 30 mmol/L), myocytes from LCA, but not from RCA, were more depolarized and showed reduced Kv7 currents. In HG-incubated LCA, the effects of Kv7 channel modulators and forskolin were diminished, and the expression of KCNQ1 and KCNQ5 was reduced. Finally, vascular responses induced by Kv7 channel modulators were impaired in LCA, but not in RCA, from type 1 diabetic rats. CONCLUSION: Our results reveal that the high expression and function of Kv7 channels in the LCA and their down-regulation by diabetes critically determine the sensitivity to key regulators of coronary tone. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Voltage-gated potassium channels encoded by KCNQ genes (Kv7 channels) are emerging as important regulators of vascular tone. In this study, we analysed the contribution of Kv7 channels to the vasodilation induced by hypoxia and the cyclic AMP pathway in the coronary circulation. We also assessed their regional distribution and possible impairment by diabetes. METHODS AND RESULTS: We examined the effects of Kv7 channel modulators on K+ currents and vascular reactivity in rat left and right coronary arteries (LCAs and RCAs, respectively). Currents from LCA were more sensitive to Kv7 channel inhibitors (XE991, linopirdine) and activators (flupirtine, retigabine) than those from RCA. Accordingly, LCAs were more sensitive than RCAs to the relaxation induced by Kv7 channel enhancers. Likewise, relaxation induced by the adenylyl cyclase activator forskolin and hypoxia, which were mediated through Kv7 channel activation, were greater in LCA than in RCA. KCNQ1 and KCNQ5 expression was markedly higher in LCA than in RCA. After incubation with high glucose (HG, 30 mmol/L), myocytes from LCA, but not from RCA, were more depolarized and showed reduced Kv7 currents. In HG-incubated LCA, the effects of Kv7 channel modulators and forskolin were diminished, and the expression of KCNQ1 and KCNQ5 was reduced. Finally, vascular responses induced by Kv7 channel modulators were impaired in LCA, but not in RCA, from type 1 diabeticrats. CONCLUSION: Our results reveal that the high expression and function of Kv7 channels in the LCA and their down-regulation by diabetes critically determine the sensitivity to key regulators of coronary tone. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Gema Mondéjar-Parreño; Javier Moral-Sanz; Bianca Barreira; Alicia De la Cruz; Teresa Gonzalez; Maria Callejo; Sergio Esquivel-Ruiz; Daniel Morales-Cano; Laura Moreno; Carmen Valenzuela; Francisco Perez-Vizcaino; Angel Cogolludo Journal: Br J Pharmacol Date: 2019-05-11 Impact factor: 8.739
Authors: Riazuddin Mohammed; Carlos E Salinas; Dino A Giussani; Carlos E Blanco; Angel L Cogolludo; Eduardo Villamor Journal: Physiol Rep Date: 2017-11
Authors: Maria Consiglia Trotta; Monica Salerno; Anna Lisa Brigida; Vincenzo Monda; Antonietta Messina; Carmela Fiore; Roberto Avola; Renato Bernardini; Francesco Sessa; Gabriella Marsala; Guido N Zanghì; Giovanni Messina; Michele D'Amico; Clara Di Filippo Journal: Oncotarget Date: 2017-12-14