BACKGROUND: Research on the physiological role of endothelium-derived hyperpolarizing factor (EDHF) is hampered by the persistent controversy on its nature and mechanisms of action, as well as by the lack of specific inhibitors that are suitable for in vivo use. Recent in vitro studies support a role for gap junctions in EDHF-mediated signal transmission. The present study examines the contribution of gap junctional communication to the EDHF-mediated responses in the rat renal microcirculation in vivo and addresses the physiological role of EDHF. METHODS: The effects of intrarenal administration of connexin-mimetic peptides on the L-NAME- and indomethacin-resistant renal blood flow (RBF) response to acetylcholine, on basal RBF and on systemic blood pressure were examined. RESULTS: 43Gap 27, a peptide homologous to the second extracellular loop of connexin 43, partially inhibited the L-NAME- and indomethacin-resistant RBF response to acetylcholine, whereas 40Gap 27, homologous to the second extracellular loop of connexin 40, abolished the response. A control peptide, with a replacement of two amino acids in the motif SRPTEK present in the second extracellular loop of connexins 40 and 43, was without effect. None of the peptides affected the response to DETA-NONOate, pinacidil or papaverine. Intrarenal infusion of 43Gap 27 or 40Gap 27 decreased basal RBF and increased mean arterial blood pressure, both in the presence and absence of systemic infusion of L-NAME and indomethacin. CONCLUSIONS: Inhibition of gap junctional communication with connexin-mimetic peptides blocks EDHF-mediated signal transmission in vivo, as suggested by the abolishment of L-NAME- and indomethacin-resistant renal vasodilation. The peptides also decrease basal RBF and increase blood pressure, supporting a role for tonic EDHF release in the control of tissue perfusion and vascular resistance.
BACKGROUND: Research on the physiological role of endothelium-derived hyperpolarizing factor (EDHF) is hampered by the persistent controversy on its nature and mechanisms of action, as well as by the lack of specific inhibitors that are suitable for in vivo use. Recent in vitro studies support a role for gap junctions in EDHF-mediated signal transmission. The present study examines the contribution of gap junctional communication to the EDHF-mediated responses in the rat renal microcirculation in vivo and addresses the physiological role of EDHF. METHODS: The effects of intrarenal administration of connexin-mimetic peptides on the L-NAME- and indomethacin-resistant renal blood flow (RBF) response to acetylcholine, on basal RBF and on systemic blood pressure were examined. RESULTS: 43Gap 27, a peptide homologous to the second extracellular loop of connexin 43, partially inhibited the L-NAME- and indomethacin-resistant RBF response to acetylcholine, whereas 40Gap 27, homologous to the second extracellular loop of connexin 40, abolished the response. A control peptide, with a replacement of two amino acids in the motif SRPTEK present in the second extracellular loop of connexins 40 and 43, was without effect. None of the peptides affected the response to DETA-NONOate, pinacidil or papaverine. Intrarenal infusion of 43Gap 27 or 40Gap 27 decreased basal RBF and increased mean arterial blood pressure, both in the presence and absence of systemic infusion of L-NAME and indomethacin. CONCLUSIONS: Inhibition of gap junctional communication with connexin-mimetic peptides blocks EDHF-mediated signal transmission in vivo, as suggested by the abolishment of L-NAME- and indomethacin-resistant renal vasodilation. The peptides also decrease basal RBF and increase blood pressure, supporting a role for tonic EDHF release in the control of tissue perfusion and vascular resistance.
Authors: T Takenaka; T Inoue; H Okada; Y Ohno; T Miyazaki; D J Chaston; C E Hill; H Suzuki Journal: Diabetologia Date: 2011-05-15 Impact factor: 10.122
Authors: Kasper Moller Boje Rasmussen; Thomas Hartig Braunstein; Max Salomonsson; Jens Christian Brasen; Charlotte Mehlin Sorensen Journal: Pflugers Arch Date: 2016-03-11 Impact factor: 3.657
Authors: Armin Just; Lisa Kurtz; Cor de Wit; Charlotte Wagner; Armin Kurtz; William J Arendshorst Journal: J Am Soc Nephrol Date: 2009-05-14 Impact factor: 10.121