Aktuel Urol 1996; 27: 100-103
DOI: 10.1055/s-2008-1055668
© Georg Thieme Verlag, Stuttgart · New York

Molecular Mechanism of the Alpha-1 Adrenoceptor Induced Cavernous Smooth Muscle Contraction

R. E. Eckert, H. Derouet, J. Utz, W. Trautwein, M. Ziegler
  • Urologische Klinik und Poliklinik, Universität des Saarlandes (Direktor: Prof. Dr. Dr. M. Ziegler), Homburg/Saar, Germany
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Publication History

Publication Date:
19 March 2008 (online)

Summary:

The relaxation of cavernous smooth muscle tissue is the essential step in the initiation of penile erection which is the therapeutical goal in the treatment of erectile dysfunction (ED) [10]. Cellular contractility is determined by changes of the free intracellular Ca2+-concentration [Ca2+]i which is modulated by interactions of Ca2+-influx through voltage-dependent Ca2+-channels (ICa), Ca2+-release from intracellular, non-mitochondrial Ca2+-stores and Ca2+-extrusion systems [9, 17]. Hormones, neurotransmitter and other mediators may affect cavernous smooth muscle contractility by modulating these cellular compartments via second messengers [8, 9, 17]. The present study focuses on the intracellular mechanism of the α1-adrenoceptor induced cavernous smooth muscle contraction by applying the patch-clamp technique combined with the Ca2+-sensitive fluorescence dye FURA II to enzymatically dispersed human cavernous smooth muscle myocytes. The α1-adrenoceptor agonist norepinephrine (NE) selectively stimulated ICa in a dose-dependent and fully reversible fashion simultaneously elevating [Ca2+]i up to 1.4 μM. The threshold concentration was 10 nM (n = 7), EC50 was 100 nM, maximal effects were observed in the micromolar range. Intracellular application of inositol 1,4,5-trisphosphate (IP3) which releases Ca2+ from the IP3-sensitive Ca2+-pool [1, 13], imitated the NE evoked responses. Moreover the NE induced contraction was abolished when the myocytes were pretreated with the intracellular Ca2+-release blockers ryanodine (200 μM, n = 11), thapsigargin (0.1 μM, n = 12) or low-molecular weight heparin (50 mg/ml, n = 9) [2, 8, 11, 15, 17]. These experimental results indicate a coupling of α1-adrenoceptors to the phospholipase C (PLC) converting phosphoinositol 4,5-bisphosphate into diacylglycerol (DAG), an endogenous activator of the protein kinase C (PKC), and IP3 which increases [Ca2+]i by releasing Ca2+ from IP3-sensitive Ca2+-stores [1]. The elevated [Ca2+]i seems to be responsible for the stimulation of ICa most likely due to phosphorylation of voltage-dependent Ca2+-channels by the Ca2+-calmodulin dependent protein kinase (CCPK). The blockade of this pathway results in cavernous smooth muscle relaxation which could be of benefit for therapeutical applications in ED.