Inhibition of phosphodiesterase 4 enhances clitoral and vaginal blood flow responses to dorsal clitoral nerve stimulation or PGE1 in anesthetized female rats.
INTRODUCTION.: Cyclic adenosine 3'5' monophosphate (cAMP) is produced by adenylate cyclase after activation by, e.g., vasoactive intestinal polypeptide or prostaglandin E1 (PGE1). The cAMP-degrading phosphodiesterase 4 (PDE4) is expressed in the vagina and clitoris, but no information is available on the functional role for PDE4-related signals in the female neurovascular genital response. AIM.: The aim of this study is to study the effect of inhibition of PDE4 with rolipram on nerve- and PGE1-induced vaginal and clitoral blood flow responses of rat. METHODS.: Measure of clitoral and vaginal blood flow and blood pressure in anesthetized rats during activation of the dorsal clitoral nerve (DCN) before and after intraperitoneal administration of rolipram or sildenafil (phosphodiesterase type 5 inhibitors [PDE5]) and nitro-L-arginine (L-NNA) (nitric oxide synthase inhibitor). Effect by topical administration of PGE1 on genital blood flow was also evaluated. MAIN OUTCOME MEASURE.: Blood flow was recorded as tissue perfusion units (TPU) by a Laser Doppler Flowmeter. Mean arterial blood pressure (MAP) was recorded (cmH2 O) in the carotid artery. Blood flow responses are expressed as TPU/MAP. Unpaired t-test and an analysis of variance were used. RESULTS.: Compared with control stimulations, rolipram (0.3 mg/kg) caused a twofold increase in peak blood flow (P < 0.05) and fourfold increase of the rate of clitoral blood flow during activation of the DCN (P < 0.05). Simultaneously, a twofold increase in peak blood flow and threefold increase in rate of blood flow were noted in the vagina (P < 0.05). Similar effects were noted for sildenafil (0.2 mg/kg) (P < 0.05). Inhibitory effects by L-NNA (60 mg/kg) on blood flow responses to DCN activation were significantly lower for rats treated with rolipram than with sildenafil (P < 0.05). PGE1-induced (10 μg) blood flow responses were significantly higher (P < 0.05) in rats treated with rolipram than with sildenafil. CONCLUSIONS.: These findings suggest that the cAMP/PDE4 system may be of similar functional importance as the nitric oxide/cyclic guanosine monophosphate/PDE5 pathway for neurovascular genital responses of the female rat.
Urological Research Institute, Department of Urology, San Raffaele Hospital, Via Olgettina 58, Milan, Italy. fox.castiglione@gmail.com
Fabio
F
Castiglione
Alice
A
Bergamini
Andrea
A
Russo
Giovanni
G
La Croce
Giulia
G
Castagna
Giorgia
G
Colciago
Andrea
A
Salonia
Patrizio
P
Rigatti
Francesco
F
Montorsi
Petter
P
Hedlund
D000527:Alprostadil / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects; D002987:Clitoris / Q000098:blood supply* / Q000294:innervation; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D004558:Electric Stimulation; D005260:Female; D005455:Fluorescent Antibody Technique; D017078:Laser-Doppler Flowmetry; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology*; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D020889:Rolipram / Q000494:pharmacology*; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology; D014621:Vagina / Q000098:blood supply*; D014665:Vasodilator Agents / Q000494:pharmacology
D058988:Phosphodiesterase 4 Inhibitors; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D000068677:Sildenafil Citrate; D019001:Nitric Oxide Synthase; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D000527:Alprostadil; D020889:Rolipram