ABSTRACT
Research on the physiological role of EDHF is hampered by the lack of specific inhibitors that are suitable for in vivo use. In vitro studies support a role for gap junctions in EDHF-mediated signal transmission. This study examines the contribution of gap junctional communication to the EDHF-mediated responses in the renal microcirculation of the rat in vivo and addresses the physiological role of EDHF. The effects of intrarenal administration of connexin-mimetic peptides on the L-NAME-and indomethacin-resistant renal blood flow response to acetylcholine on basal renal blood flow and on systemic blood pressure were examined. 43Gap 27, a peptide homologous to the second extracellular loop of connexin 43, partially inhibited the L-NAME-and indomethacin-resistant renal blood flow 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 detaNONOate, pinacidil or papaverine. Intrarenal infusion of 43Gap 27 or 40Gap 27 decreased basal renal blood flow and increased mean arterial blood pressure, both in the presence and absence of systemic infusion of L-NAME and indomethacin. It is concluded that inhibition of gap junctional communication with connexinmimetic peptides blocks EDHF-mediated signal transmission in vivo. The peptides also decrease basal renal blood flow and increase blood pressure, supporting a role for tonic EDHF release in the control of tissue perfusion and vascular resistance.
