RT Journal Article
SR Electronic
T1 Enhanced Thromboxane Receptor-Mediated Responses and Impaired Endothelium-Dependent Relaxation in Human Corpus Cavernosum from Diabetic Impotent Men: Role of Protein Kinase C Activity
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 783
OP 789
DO 10.1124/jpet.106.108597
VO 319
IS 2
A1 Javier Angulo
A1 Pedro Cuevas
A1 Argentina Fernández
A1 Antonio Allona
A1 Ignacio Moncada
A1 Antonio Martín-Morales
A1 José María La Fuente
A1 Iñigo Sáenz de Tejada
YR 2006
UL http://jpet.aspetjournals.org/content/319/2/783.abstract
AB We have evaluated the influence of protein kinase C (PKC) activity on penile smooth muscle tone in tissues from diabetic and nondiabetic men with erectile dysfunction. Human corpus cavernosum (HCC) strips were obtained from impotent diabetic and nondiabetic men at the time of penile prosthesis implantation and studied in organ chambers. Contractility responses to a prostanoid precursor, to prostanoids, and to the endothelium-dependent vasodilator acetylcholine were studied. Arachidonic acid (AA; 100 μM) caused cyclooxygenase-dependent relaxation of HCC. This relaxation was impaired in diabetic tissues and normalized by blocking thromboxane (TP) receptors with 20 nM [1S-[1α,2α(Z),3α,4α]]-7-[3-[[2-[(phenylamino)carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (SQ29548). Diabetes did not affect prostaglandin (PG)E1-induced relaxation, but it reduced relaxation induced by the PGE1 metabolite PGE0. This effect was related to an interaction of PGE0 with TP receptors. Diabetic tissues had reduced endothelium-dependent relaxation, which was partially improved by SQ29548 and completely normalized by the PKC inhibitor 3-[1-[3-(dimethylaminopropyl]-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione monohydrochloride (GF109203X; 1 μM). In HCC from nondiabetic patients, treatment with the PKC activator phorbol-12,13-dibutyrate (0.3 μM) significantly attenuated endothelium-dependent relaxation, an effect prevented by coadministration of GF109203X. Tissues from diabetic patients had enhanced sensitivity to the contractile effects of the TP receptor agonist 9,11-dideoxy-9α,11α-epoxymethano PGF2α (U46619) (EC50 = 0.65 ± 0.42 and 6.01 ± 2.28 nM in diabetic and nondiabetic patients, respectively). Inhibition of PKC with 1 μM GF109203X, prevented diabetes-induced hypersensitivity to U46619-induced contractions (EC50 = 8.55 ± 3.12 μM). Overactivity of PKC in diabetes is responsible for enhanced contraction and reduced endothelium-dependent relaxation of HCC smooth muscle. Such alterations can result in erectile dysfunction. The American Society for Pharmacology and Experimental Therapeutics