Pituitary adenylate-cyclase-activating peptides relax human coronary arteries by activating K(ATP) and K(Ca) channels in smooth muscle cells.
Pituitary adenylate-cyclase-activating peptides (PACAPs) are potent dilators of arteries, including human coronary arteries. We tested the importance of specific K+ channel regulatory mechanisms in human arterial smooth muscle relaxation induced by PACAPs, using contraction and patch clamp measurements on human coronary artery vascular smooth muscle cells. PACAP27 and PACAP38 produced dose-dependent relaxations of 5 microM PGF2alpha-preconstricted rings, with half-maximal relaxations at 1.0 nM and 2.0 nM, respectively. Both peptides induced complete relaxation at 100 nM. Pretreatment of the vessels with the ATP-dependent K+ (K(ATP)) channel blocker glibenclamide (1 microM) or with the Ca2+-activated K+ (K(Ca)) channel blocker iberiotoxin (100 nM) inhibited PACAP27-induced relaxation in an additive manner. Moreover, in the patch clamp experiments on freshly isolated cells from human coronary arteries, PACAP27 (100 nM) induced a large, nonrectifying, outward (I(K)(ATP)) K+ current in a proportion of cells and a voltage-dependent outward (I(K)(Ca)) K+ current in other cells. The PACAP27-induced I(K)(ATP) was blocked by glibenclamide (3 microM), while the PACAP27-stimulated I(K)(Ca) was blocked by iberiotoxin (100 nM). These findings provide the first evidence that relaxation of arterial smooth muscle cells by PACAPs is mediated by opening of K(ATP) and K(Ca) channels. The data indicate that both K(ATP) and K(Ca) channels in vascular smooth muscle cells may serve as final common pathway to induce vasorelaxation by endogenous vasoactive signals in man.
Bruch
L
L
First Medical Clinic, Charité University Hospital, Berlin, Germany.
Bychkov
R
R
Kästner
A
A
Bülow
T
T
Ried
C
C
Gollasch
M
M
Baumann
G
G
Luft
F C
FC
Haller
H
H
D003331:Coronary Vessels / Q000502:physiology*; D046508:Culture Techniques; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D009479:Neuropeptides / Q000494:pharmacology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D015221:Potassium Channels / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology*
C495401:ADCYAP1 protein, human; D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D015221:Potassium Channels; D014665:Vasodilator Agents