Activation of central melanocortin receptors by MT-II increases cavernosal pressure in rabbits by the neuronal release of NO.
1. Melanotan-II had been reported to cause penile erections in men with erectile dysfunction. In the present study, we investigated the mechanisms by which systemic administration of MT-II increases intracavernosal pressure in anaesthetized rabbits. 2. MT-II (10 microM) had no effect on electrical field stimulation-evoked relaxations of rabbit corpus cavernosal strips in vitro. 3. Intravenous injection of MT-II (66 and 133 microg kg(-1) elicited dose-related increases in cavernosal pressure. SHU 9119 (3 microg kg(-1), i.v.), a non-selective antagonist of MC(3) and MC(4) receptors did not significantly affect either cavernosal pressure or systemic blood pressure but abolished the MT-II-induced increases in cavernosal pressure. SHU 9119 also inhibited the depressor response produced by MT-II. 4. Intracavernosal injection 100 microl of the cocktail containing phentolamine mesylate (1 mg ml(-1)), papaverine (20 mg ml(-1)) and PGE1 (20 microg ml(-1)) increased the cavernosal pressure by about 4 fold. 5. The role of NO-cyclic GMP dependent pathway to MT-II-induced increases in cavernosal pressure was investigated by bilateral transection of the pudendal nerves and by inhibition of NO synthase with L-NAME (20 mg kg(-1), i.v. over 30 min). Ablation of the pudendal nerves or pretreatment with L-NAME abolished the MT-II-induced increases in intracavernosal pressure in anaesthetized rabbits. 6. The data suggest that activation of central melanocortin receptors by MT-II increases cavernosal pressure by the neuronal release of NO.
Vemulapalli
R
R
CNS/CV Biological Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey, NJ 07033, USA. subbarao.Vemulapalli@spcorp.com
Kurowski
S
S
Salisbury
B
B
Parker
E
E
Davis
H
H
D000527:Alprostadil / Q000494:pharmacology; D000758:Anesthesia; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D046508:Culture Techniques; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007275:Injections, Intravenous; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010208:Papaverine / Q000494:pharmacology; D010413:Penis / Q000098:blood supply* / Q000187:drug effects* / Q000294:innervation / Q000502:physiology; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000494:pharmacology*; D010646:Phentolamine / Q000494:pharmacology; D011817:Rabbits; D018043:Receptors, Corticotropin / Q000378:metabolism*; D044101:Receptors, Melanocortin; D000521:alpha-MSH / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D010456:Peptides, Cyclic; D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; C079282:melanotan-II; C103272:SHU 9119; D009569:Nitric Oxide; D000521:alpha-MSH; D009074:Melanocyte-Stimulating Hormones; D010208:Papaverine; D019001:Nitric Oxide Synthase; D000527:Alprostadil; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester; D010646:Phentolamine