Effects of sildenafil on erectile activity in mice lacking neuronal or endothelial nitric oxide synthase.
1. Using an in vivo model of erectile activity, the effects of sildenafil were studied in mice lacking neuronal or endothelial nitric oxide synthase (nNOS and eNOS, respectively). 2. Under pentobarbitone anaesthesia, intracavernous pressure (ICP) and mean arterial pressure (MAP) were monitored continuously in wild-type, nNOS-/- and eNOS-/- mice. The magnitude of erectile activity was quantified as the ratio of ICP to MAP. 3. No differences in basal ICP or MAP were observed amongst wild-type, eNOS-/- and nNOS-/- mice. Electrical stimulation of the cavernous nerve (ESCN; 4.0 V, 16 Hz, 1 ms, 30 s) evoked increases in ICP and ICP/MAP as well as penile tumescence. Responses to ESCN were reduced in nNOS-/-, but not in eNOS-/- mice. 4. L-NAME (50 mg kg(-1), i.v.) significantly increased MAP and attenuated erectile responses in both wild-type and eNOS-/- mice. 5. Sildenafil (1 mg kg(-1), i.v.) augmented electrically-evoked erectile activity in a voltage-dependent manner in wild-type mice and facilitated erectile responses in eNOS-/- mice. By contrast, sildenafil failed to augment the diminished erectile responses in mice lacking the nNOS isoform. 5. These data reveal the relative importance of nNOS, compared to eNOS, as the critical NOS isoform in the control of erectile function and illustrate that the nNOS isoform is required for sildenafil-induced facilitation of erectile responses in vivo in mice.
Cashen
Doreen E
DE
Department of Pharmacology, Merck Research Laboratories, PO Box 2000, Rahway, New Jersey, NJ 07065, USA.
MacIntyre
D Euan
DE
Martin
William J
WJ
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004558:Electric Stimulation / Q000379:methods; D007172:Erectile Dysfunction / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D010410:Penile Erection / Q000187:drug effects* / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000068677:Sildenafil Citrate; D013450:Sulfones
D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496321:Nos1 protein, mouse; C496315:Nos3 protein, mouse