Pharmacological characterization of kinin-induced relaxation of human corpus cavernosum.
OBJECTIVE
To characterize the kinin receptor subtype involved in the relaxation of human isolated corpus cavernosum (HCC) induced by bradykinin (BK), Lys-bradykinin (Lys-BK), Met-Lys-bradykinin (Met-Lys-BK) and des-Arg9-bradykinin, and to investigate whether the kinin-induced relaxation of HCC results from the stimulation of nonadrenergic, noncholinergic (NANC) neurons supplying the cavernosal tissue.


METHODS
Excised HCC tissues were immediately placed in Krebs solution and kept at 4 degrees C until use (never > 24 h after removal). HCC was cut in strips of approximately 2 cm, suspended in a cascade system and superfused with oxygenated and warmed Krebs solution at 5 mL/min. After equilibration for approximately 90 min, noradrenaline (3 micromol/L) was infused to induce a submaximal contraction of the HCC strips. The release of cyclo-oxygenase products was prevented by infusing indomethacin (6 micromol/L). HCC strips were calibrated by injecting a single bolus of the nitrovasodilator glyceryl trinitrate (GTN) and the sensitivity of the tissues adjusted electronically to be similar. The agonists (kinins, histamine and acetylcholine) were injected as a single bolus (up to 100 microL) and the relaxation of HCC expressed as a percentage of the submaximal relaxation induced by GTN.


RESULTS
Bradykinin, Lys-BK and Met-Lys-BK significantly relaxed the HCC tissues; on a molar basis, there was no statistical difference among the degrees of relaxation induced by these peptides. The B1 kinin receptor agonist des-Arg9-bradykinin had no effect on the HCC. The infusion of the B2 kinin receptor antagonist Hoe 140 (50 nmol/L) virtually abolished the relaxation induced by BK, Lys-BK and Met-Lys-BK without affecting those induced by acetylcholine and histamine. The infusion of the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester increased the tone of the HCC tissues and significantly reduced (P < 0.01) the relaxation induced by BK (74%), Lys-BK (90%), Met-Lys-BK (87%) and acetylcholine (89%) without affecting those induced by GTN. The subsequent infusion of L-arginine (300 micromol/L) partially reversed the increased tone and significantly (P < 0.01) restored the relaxation induced by BK, Lys-BK and Met-Lys-BK. The results were similar with the novel guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo[4,3,-alquinoxalin-1-one] which reduced by > 95% (P < 0.01) the relaxation induced by BK, Lys-BK, Met-Lys-BK, acetylcholine and GTN. The infusion of the sodium-channel blocker tetrodotoxin had no significant effect on the BK-, GTN- and acetylcholine-induced relaxation of HCC.


CONCLUSIONS
This study clearly showed the existence of functional B2 kinin receptors in human erectile tissues that when activated lead to the release of NO and hence relaxation of the HCC tissues. As tetrodotoxin failed to affect the kinin-induced relaxation of HCC strips, it is likely that these peptides release NO from the endothelium of sinusoidal capillaries rather than from neuronal sources supplying the cavernosal tissue. Although tissue kallikreins and their components have been found in the male reproductive system, the physiopathological importance of these findings has yet to be elucidated.
Teixeira
C E
CE
Department of Pharmacology, Faculty of Medical Sciences, UNICAMP, Campinas (SP), Brazil.
Moreno
R A
RA
Ferreira
U
U
Rodrigues Netto
N
N
Fregonesi
A
A
Antunes
E
E
De Nucci
G
G
D000293:Adolescent; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000328:Adult; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D065168:Bradykinin Receptor Antagonists; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007609:Kallidin / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000494:pharmacology; D010410:Penile Erection / Q000187:drug effects; D010413:Penis / Q000187:drug effects* / Q000502:physiology; D018002:Receptors, Bradykinin / Q000737:chemistry* / Q000187:drug effects
D000319:Adrenergic beta-Antagonists; D065168:Bradykinin Receptor Antagonists; D004791:Enzyme Inhibitors; D018002:Receptors, Bradykinin; C024626:bradykinin, des-Arg(9)-; D009569:Nitric Oxide; D007609:Kallidin; C018103:bradykinin, Met-Lys-; C065679:icatibant; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester