Enhanced thromboxane receptor-mediated responses and impaired endothelium-dependent relaxation in human corpus cavernosum from diabetic impotent men: role of protein kinase C activity.
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 microM) caused cyclooxygenase-dependent relaxation of HCC. This relaxation was impaired in diabetic tissues and normalized by blocking thromboxane (TP) receptors with 20 nM [1S-[1alpha,2alpha(Z),3alpha,4alpha]]-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)E(1)-induced relaxation, but it reduced relaxation induced by the PGE(1) metabolite PGE(0). This effect was related to an interaction of PGE(0) 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 microM). In HCC from nondiabetic patients, treatment with the PKC activator phorbol-12,13-dibutyrate (0.3 microM) 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-9alpha,11alpha-epoxymethano PGF(2alpha) (U46619) (EC(50) = 0.65 +/- 0.42 and 6.01 +/- 2.28 nM in diabetic and nondiabetic patients, respectively). Inhibition of PKC with 1 microM GF109203X, prevented diabetes-induced hypersensitivity to U46619-induced contractions (EC(50) = 8.55 +/- 3.12 microM). 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.
Angulo
Javier
J
Servicio de Histologia, Departamento de Investigación, Hospital Ramon y Cajal, Ctra. Colmenar Viejo, km 9.100, 28034 Madrid, Spain. jangulo@ibercom.com
Cuevas
Pedro
P
Fernández
Argentina
A
Allona
Antonio
A
Moncada
Ignacio
I
Martín-Morales
Antonio
A
La Fuente
José María
JM
de Tejada
Iñigo Sáenz
IS
D000527:Alprostadil / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003920:Diabetes Mellitus / Q000503:physiopathology*; D004727:Endothelium / Q000502:physiology*; D007172:Erectile Dysfunction / Q000503:physiopathology*; D005231:Fatty Acids, Unsaturated; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D008875:Middle Aged; D009126:Muscle Relaxation / Q000187:drug effects; D010413:Penis / Q000503:physiopathology*; D011493:Protein Kinase C / Q000502:physiology*; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors / Q000502:physiology*
D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D007211:Indoles; D008301:Maleimides; D017482:Receptors, Thromboxane; C045749:SQ 29548; D011493:Protein Kinase C; D000527:Alprostadil; C070515:bisindolylmaleimide I