Vol. 303, Issue 1, 403-411, October 2002

Relationship between ₁-Adrenergic Receptor-Induced Contraction and Extracellular Signal-Regulated Kinase Activation in the Bovine Inferior Alveolar Artery

Chris Hague, Pedro J. Gonzalez-Cabrera, William B. Jeffries and Peter W. Abel

Department of Pharmacology, Creighton University School of Medicine, Omaha, Nebraska

The endogenous adrenergic agonists norepinephrine (NE) and epinephrine regulate vascular tone by stimulating ₁-adrenergic receptors (ARs) on smooth muscle cells to cause contraction. In addition, 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 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 ₁-ARs were coupled to ERK activation and contraction. NE stimulated contraction (EC₅₀ = 11 µM) and ERK activation (EC₅₀ = 21 µM) with similar potency. Using ₁-AR subtype-selective antagonists, we identified the ₁-AR subtypes coupled to each response. Affinity values for ₁-AR subtype-selective antagonists were consistent with _1A-AR-mediated contraction. In contrast, simultaneous treatment with concentrations of these antagonists selective for each ₁-AR subtype (_1A-, _1B-, and _1D-AR) was required to inhibit ERK activation, suggesting that all three ₁-ARs activate ERK in BIAA. Transmural electrical stimulation of BIAA segments resulted in activation of ERK, which was inhibited by the ₁-AR-selective antagonist BE 2254 (2-[[-(4-hydroxyphenyl)ethyl]aminomethyl]-1-tetralone). These data suggest that in an intact artery, NE released from sympathetic nerves stimulates ₁-ARs to cause contraction and ERK activation, and that redundancy among subtypes exists for ₁-AR activation of ERK.