Osama F Harraz1, Suzanne E Brett1, Anil Zechariah1, Monica Romero1, Jose L Puglisi1, Sean M Wilson1, Donald G Welsh2. 1. From the Department of Physiology and Pharmacology, Hotchkiss Brain and Libin Cardiovascular Institutes, University of Calgary, Calgary, Alberta, Canada (O.F.H., S.E.B., A.Z., D.G.W.); Department of Pharmacology and Toxicology, Alexandria University, Alexandria, Egypt (O.F.H.); Department of Basic Sciences, Division of Pharmacology, Loma Linda University, CA (M.R., S.M.W.); Department of Pharmacology, University of California, Davis (J.L.P.); and Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada (D.G.W.). 2. From the Department of Physiology and Pharmacology, Hotchkiss Brain and Libin Cardiovascular Institutes, University of Calgary, Calgary, Alberta, Canada (O.F.H., S.E.B., A.Z., D.G.W.); Department of Pharmacology and Toxicology, Alexandria University, Alexandria, Egypt (O.F.H.); Department of Basic Sciences, Division of Pharmacology, Loma Linda University, CA (M.R., S.M.W.); Department of Pharmacology, University of California, Davis (J.L.P.); and Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada (D.G.W.). dwelsh@ucalgary.ca.
Abstract
OBJECTIVE: In resistance arteries, there is an emerging view that smooth muscle CaV3.2 channels restrain arterial constriction through a feedback response involving the large-conductance Ca(2+)-activated K(+) channel (BKCa). Here, we used wild-type and CaV3.2 knockout (CaV3.2(-/-)) mice to definitively test whether CaV3.2 moderates myogenic tone in mesenteric arteries via the CaV3.2-ryanodine receptor-BKCa axis and whether this regulatory mechanism influences blood pressure regulation. APPROACH AND RESULTS: Using pressurized vessel myography, CaV3.2(-/-) mesenteric arteries displayed enhanced myogenic constriction to pressure but similar K(+)-induced vasoconstriction compared with wild-type C57BL/6 arteries. Electrophysiological and myography experiments subsequently confirmed the inability of micromolar Ni(2+), a CaV3.2 blocker, to either constrict arteries or suppress T-type currents in CaV3.2(-/-) smooth muscle cells. The frequency of BKCa-induced spontaneous transient outward K(+) currents dropped in wild-type but not in knockout arterial smooth muscle cells upon the pharmacological suppression of CaV3.2 channel. Line scan analysis performed on en face arteries loaded with Fluo-4 revealed the presence of Ca(2+) sparks in all arteries, with the subsequent application of Ni(2+) only affecting wild-type arteries. Although CaV3.2 channel moderated myogenic constriction of resistance arteries, the blood pressure measurements of CaV3.2(-/-) and wild-type animals were similar. CONCLUSIONS: Overall, our findings establish a negative feedback mechanism of the myogenic response in which CaV3.2 channel modulates downstream ryanodine receptor-BKCa to hyperpolarize and relax arteries.
OBJECTIVE: In resistance arteries, there is an emerging view that smooth muscle CaV3.2 channels restrain arterial constriction through a feedback response involving the large-conductance Ca(2+)-activated K(+) channel (BKCa). Here, we used wild-type and CaV3.2 knockout (CaV3.2(-/-)) mice to definitively test whether CaV3.2 moderates myogenic tone in mesenteric arteries via the CaV3.2-ryanodine receptor-BKCa axis and whether this regulatory mechanism influences blood pressure regulation. APPROACH AND RESULTS: Using pressurized vessel myography, CaV3.2(-/-) mesenteric arteries displayed enhanced myogenic constriction to pressure but similar K(+)-induced vasoconstriction compared with wild-type C57BL/6 arteries. Electrophysiological and myography experiments subsequently confirmed the inability of micromolar Ni(2+), a CaV3.2 blocker, to either constrict arteries or suppress T-type currents in CaV3.2(-/-) smooth muscle cells. The frequency of BKCa-induced spontaneous transient outward K(+) currents dropped in wild-type but not in knockout arterial smooth muscle cells upon the pharmacological suppression of CaV3.2 channel. Line scan analysis performed on en face arteries loaded with Fluo-4 revealed the presence of Ca(2+) sparks in all arteries, with the subsequent application of Ni(2+) only affecting wild-type arteries. Although CaV3.2 channel moderated myogenic constriction of resistance arteries, the blood pressure measurements of CaV3.2(-/-) and wild-type animals were similar. CONCLUSIONS: Overall, our findings establish a negative feedback mechanism of the myogenic response in which CaV3.2 channel modulates downstream ryanodine receptor-BKCa to hyperpolarize and relax arteries.
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