Relaxant effect of a metal-based drug in human corpora cavernosa and its mechanism of action.
We studied the mechanisms involved in the human corpora cavernosa (HCC) relaxation induced by a new metal-based nitric oxide (NO) donor, the ruthenium complex cis-[Ru(bpy)2Imn(NO)](+3) (FOR0811). FOR0811 produced relaxation in phenylephrine (PE)-precontracted HCC with a maximal response that achieved 112.9 ± 10.6%. There was no difference between the maximal relaxation induced by FOR0811 when compared with sodium nitroprusside (SNP) (106.8 ± 7.3%), BAY41-2272 (107.6 ± 4.1%) or vardenafil (103.4 ± 3.8%), however, FOR0811 was less potent than SNP and vardenafil. L-N(G)-nitroarginine methyl ester (L-NAME), a NO synthase inhibitor, had no effect in the concentration-response curve elicited by FOR0811. 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a heme-site inhibitor of soluble guanylyl cyclase (sGC) was able to either block or reverse the relaxation induced by FOR0811. On the other hand, the relaxation induced by FOR0811 was not affected by glibenclamide, a blocker of ATP-sensitive potassium channels. FOR0811 (10 μM) was able to increase cyclic guanosine monophosphate (cGMP) levels in corpora cavernosa strips. FOR0811 completely relaxes HCC by a sGC-cGMP-dependent mechanism and can be a lead compound in the development of new stable NO donors.
Departamento de Cirurgia, Divisão de Urologia, Universidade Federal do Ceará, Fortaleza, Brazil.
A S
AS
Leitão Junior
Physiology and Pharmacology, Instituto Superior de Ciências Biomédicas, Universidade Estadual do Ceará, Fortaleza, Brazil.
R M
RM
Campos
Departamento de Cirurgia, Divisão de Urologia, Universidade Federal do Ceará, Fortaleza, Brazil.
J B G
JB
Cerqueira
Departamento de Fisiologia e Farmacologia, Universidade Federal do Ceará, Fortaleza, Brazil.
M C
MC
Fonteles
Physiology and Pharmacology, Instituto Superior de Ciências Biomédicas, Universidade Estadual do Ceará, Fortaleza, Brazil.
C F
CF
Santos
Faculdade de Ciências Médicas, Departamento de Farmacologia, Universidade Estadual de Campinas, Campinas, São Paulo, Brazil.
G
G
de Nucci
Departamento de Química Orgânica e Inorgânica, Universidade Federal do Ceará, Fortaleza, Brazil.
E H S
EH
Sousa
Departamento de Química Orgânica e Inorgânica, Universidade Federal do Ceará, Fortaleza, Brazil.
L G F
LG
Lopes
Departamento de Cirurgia, Divisão de Urologia, Universidade Federal do Ceará, Fortaleza, Brazil.
L F
LF
Gonzaga-Silva
Physiology and Pharmacology, Instituto Superior de Ciências Biomédicas, Universidade Estadual do Ceará, Fortaleza, Brazil.
N R F
NR
Nascimento
D006152:Cyclic GMP / Q000502:physiology; D006162:Guanylate Cyclase / Q000502:physiology*; D006801:Humans; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009599:Nitroprusside / Q000494:pharmacology; D010410:Penile Erection / Q000187:drug effects / Q000502:physiology; D010413:Penis / Q000473:pathology / Q000502:physiology / Q000503:physiopathology; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D012107:Research Design; D017975:Ruthenium Compounds / Q000494:pharmacology*; D000071756:Soluble Guanylyl Cyclase
D020030:Nitric Oxide Donors; D018160:Receptors, Cytoplasmic and Nuclear; D017975:Ruthenium Compounds; D009599:Nitroprusside; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP