Cyclic AMP enhances agonist-induced Ca2+ entry into endothelial cells by activation of potassium channels and membrane hyperpolarization.
The mechanism underlying cyclic AMP (cAMP)-mediated amplification of agonist-induced Ca2+ responses in endothelial cells was investigated in pig endothelial cells. Forskolin, adenosine and isoprenaline, as well as the membrane-permeant cAMP analogue dibutyryl cAMP, enhanced bradykinin-induced rises in intracellular free Ca2+ as well as bradykinin-induced Mn2+ entry. These agents were also found to hyperpolarize endothelial cells without increasing intracellular Ca2+ by itself, i.e. in the absence of bradykinin. Both amplification of bradykinin effects and the hyperpolarizing action was blocked by the protein kinase inhibitor H-8. The involvement of K+ channels in the hyperpolarizing effects of forskolin was consequently studied in perforated outside-out vesicles. Two different types of K+ channels were recorded, one of which had a large conductance (170 pS) and was activated by forskolin. We suggest that stimulation of endothelial adenylate cyclase results in activation of large-conductance K+ channels and consequently in membrane hyperpolarization, which in turn enhances bradykinin-induced entry of Ca2+ by increasing its electrochemical gradient.
Institut für Pharmakologie und Toxikologie, Universität Graz, Austria.
W F
WF
Graier
W R
WR
Kukovetz
K
K
Groschner
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001011:Aorta; D001920:Bradykinin / Q000494:pharmacology; D003994:Bucladesine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism / Q000494:pharmacology*; D004563:Electrochemistry; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D004988:Ethers, Cyclic / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D008345:Manganese / Q000378:metabolism; D019319:Okadaic Acid; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D047428:Protein Kinase Inhibitors; D013552:Swine
D004988:Ethers, Cyclic; D007546:Isoquinolines; D015221:Potassium Channels; D047428:Protein Kinase Inhibitors; D005576:Colforsin; D019319:Okadaic Acid; D008345:Manganese; D003994:Bucladesine; C053177:N-(2-(methylamino)ethyl)-5-isoquinolinesulfonamide; D000242:Cyclic AMP; D001920:Bradykinin; D002118:Calcium