Relationship between alpha(1)-adrenergic receptor-induced contraction and extracellular signal-regulated kinase activation in the bovine inferior alveolar artery.
The endogenous adrenergic agonists norepinephrine (NE) and epinephrine regulate vascular tone by stimulating alpha(1)-adrenergic receptors (ARs) on smooth muscle cells to cause contraction. In addition, alpha(1)-ARs also couple to growth factor pathways, through stimulation of mitogen-activated protein kinases (MAPKs). MAPKs are a family of serine-threonine kinases that include extracellular signal-regulated kinase (ERK) and a variety of other kinases that are able to activate transcription factors when stimulated. We examined alpha(1)-AR stimulation of contraction and ERK activation in the bovine inferior alveolar artery (BIAA), using in vitro contraction studies and Western blotting. Using antagonists selective for individual adrenergic receptor types, we found that only alpha(1)-ARs were coupled to ERK activation and contraction. NE stimulated contraction (EC(50) = 11 microM) and ERK activation (EC(50) = 21 microM) with similar potency. Using alpha(1)-AR subtype-selective antagonists, we identified the alpha(1)-AR subtypes coupled to each response. Affinity values for alpha(1)-AR subtype-selective antagonists were consistent with alpha(1A)-AR-mediated contraction. In contrast, simultaneous treatment with concentrations of these antagonists selective for each alpha(1)-AR subtype (alpha(1A)-, alpha(1B)-, and alpha(1D)-AR) was required to inhibit ERK activation, suggesting that all three alpha(1)-ARs activate ERK in BIAA. Transmural electrical stimulation of BIAA segments resulted in activation of ERK, which was inhibited by the alpha(1)-AR-selective antagonist BE 2254 (2-[[beta-(4-hydroxyphenyl)ethyl]aminomethyl]-1-tetralone). These data suggest that in an intact artery, NE released from sympathetic nerves stimulates alpha(1)-ARs to cause contraction and ERK activation, and that redundancy among subtypes exists for alpha(1)-AR activation of ERK.
Hague
Chris
C
Department of Pharmacology, Creighton University School of Medicine, Omaha, Nebraska 68178, USA. chague@creighton.edu
Gonzalez-Cabrera
Pedro J
PJ
Jeffries
William B
WB
Abel
Peter W
PW
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D002417:Cattle; D003891:Desipramine / Q000494:pharmacology; D004789:Enzyme Activation; D006854:Hydrocortisone / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D009638:Norepinephrine / Q000494:pharmacology; D011650:Pulmonary Alveoli / Q000098:blood supply*; D011651:Pulmonary Artery / Q000502:physiology*; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects / Q000502:physiology*
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D018340:Receptors, Adrenergic, alpha-1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D003891:Desipramine; D006854:Hydrocortisone; D009638:Norepinephrine