Basic and Translational Science Expression of cAMP-dependent Protein Kinase Isoforms in the Human Prostate: Functional Significance and Relation to PDE4 Eginhard Waldkirch, Stefan U ¨ ckert, Katja Sigl, Kristina Langnaese, Karin Richter, Christian G. Stief, Markus A. Kuczyk, and Petter Hedlund OBJECTIVES To investigate the expression of isoforms of the cyclic AMP (cAMP)– dependent protein kinase (cAK) in the transition zone of the human prostate and the functional significance of the enzyme in the control of prostate smooth muscle. METHODS Using Western blot analysis and immunohistochemistry, the expression and distribution in the prostate of cAKI, cAKI, cAKII, and cAKII in relation to -actin and the phosphodiesterase PDE4 (types A and B) were investigated. The effects of the cAK inhibitor Rp-8-CPT-cAMPS on the reversion of the adrenergic tension of isolated prostate tissue induced by forskolin, rolipram, sodium nitroprusside (SNP), and tadalafil were examined by means of the organ bath technique. RESULTS Immunosignals specific for cAKI, cAKII, and cAKII were observed in the smooth muscu- lature and glandular structures of the prostate. Double stainings revealed the colocalization of -actin and PDE4 with the cAK isoforms. The expression of the cAK isoforms was confirmed by Western blot analysis. The relaxation of the tension induced by norepinephrine brought about by forskolin, rolipram, SNP, and tadalafil was significantly attenuated by Rp-8-CPT-cAMPS. CONCLUSIONS The colocalization of smooth muscle -actin and PDE4 with cAK, as well as the results from the organ bath experiments, provide further evidence for a pivotal role of the cAMP-dependent signaling in the regulation of prostate smooth muscle contractility. Compounds interacting with the cAMP/cAK pathway might represent a new therapeutic avenue to treat symptoms of benign prostatic hyperplasia and lower urinary tract symptomatology. UROLOGY 76: 515.e8 –515.e14, 2010. © 2010 Elsevier Inc. B enign diseases of the male prostate represent a major health care problem in westernized coun- tries. Such diseases comprise irritative symptoms (lower urinary tract symptomatology [LUTS]), as well as benign prostatic hyperplasia (BPH)/benign prostatic en- largement (BPE) with variable degrees of bladder outlet obstruction (BOO). The pathophysiology of LUTS is considered a multifactorial event. In fact, the association of LUTS with bladder storage symptoms may indicate that mechanisms related to the smooth musculature of the detrusor are also involved. 1,2 The current pharmaco- logic management of LUTS and BPH/BPE involves  1 - adrenergic blockers, such as alfusozin, doxazosin, and tamsulosin, to diminish urethral resistance by reducing the tension mediated by  1 -adrenoceptors of smooth muscle located in the transitional zone. Intervention into the hormonal control of prostate growth by using inhib- itors of 5--reductase activity is another approach used to ease symptoms. 3 Specifically, the nitric oxide (NO) and cyclic GMP (cGMP) pathway has been identified as a pharmacologic target to treat male LUTS. In the transition zone of the human prostate, a dense nitrinergic innervation has been shown of the fibromuscular stroma, glandular epithelium, and blood vessels. The expression of key proteins of the NO pathway, such as the endothelial and neuronal nitric oxide synthase (eNOS, nNOS), cGMP-degrading phos- phodiesterase type 5 (PDE5), and cGMP-binding protein kinase (cGK), has also been demonstrated. 4-7 Results from clinical studies have shown that the PDE5 inhibi- tors sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis) can significantly improve symptom scores and quality of life and also increase Q max (maximum flow) in men with LUTS secondary to BPE. 8-12 From the Hannover Medical School, Department of Urology and Uro-Oncology, Hannover, Germany; MorphoSys AG, Martinsried, Germany; Otto-von-Guericke- University, Faculty of Medicine, Institute for Biochemistry and Cell Biology, Magde- burg, Germany; Ludwig-Maximilians-University, Academic Hospital Grosshadern, Department of Urology, Munich, Germany; and University Vita San Raffaele, Faculty of Medicine, Department of Urology, Urological Research Institute, Milan, Italy Reprint requests: Stefan U ¨ ckert, Ph.D., Hannover Medical School, Department of Urology and Uro-Oncology, 30623 Hannover, Germany. E-mail: sue_de_99@yahoo.de Submitted: August 5, 2009, accepted (with revisions): April 16, 2010 515.e8 © 2010 Elsevier Inc. 0090-4295/10/$34.00 All Rights Reserved doi:10.1016/j.urology.2010.04.035