Abstract 1305: Connexin 43 Mediates Endothelium-Dependent Hyperpolarising Factor Induced Vasodilatation in Human Resistance Arteries
Introduction: The nature of endothelium-derived hyperpolarising factor (EDHF) is controversial but gap junctions appear to have a central role. Connexin mimetic peptides (CMPs), designated as 37,43Gap27, 40Gap27 and 43Gap26 according to homology with the three major vascular connexins (Cx37, 40 and 43), were used to assess the role of gap junctions in EDHF-mediated relaxation of human arteries.
Methods and Results: Resistance arteries were obtained from subcutaneous fat of healthy women undergoing elective cesarean section. Using wire myography, responses to the endothelium-dependent vasodilator bradykinin (BK) were assessed after preconstriction. L-NAME and indomethacin (nitric oxide synthase and cyclooxygenase inhibitors respectively) attenuated maximal relaxation to BK (Rmax) by +50% (n=27). Co-incubation of vessels with L-NAME, indomethacin and the combined CMPs (37,43Gap27, 40Gap27 and 43Gap26, 300 μmol/L each) almost abolished relaxation to BK (Rmax 12.2 ± 3.7% [n=6]). After incubation with L-NAME and indomethacin, the addition of either 37,43Gap27 or 40Gap27 (900 βmol/L) had no effect on Rmax whilst 43Gap26 (900 βmol/L) caused marked inhibition (Rmax 21 ± 6.4%, p=0.005 vs. L-NAME plus indomethacin alone; n=5 for each; Fig⇓.). Endothelium-independent vasorelaxation to sodium nitroprusside was unaffected. Immunohis-tochemistry revealed Cx37, 40 and 43 in the endothelium and vascular smooth muscle.
Conclusions: In pregnant women, EDHF-mediated vasorelaxation of subcutaneous resistance arteries is dependent on Cx43 and gap junctions. This is the first study to demonstrate the central role of connexins in human EDHF-mediated vasorelaxation.