Paul C. Doherty

POTENTIATION OF ERECTILE RESPONSE AND cAMP ACCUMULATION BY COMBINATION OF PROSTAGLANDIN E1 AND ROLIPRAM, A SELECTIVE INHIBITOR OF THE TYPE 4 PHOSPHODIESTERASE (PDE 4)

PURPOSE Phosphodiesterases (PDEs) are an important component of the signal transduction pathway during the erectile response. To determine the PDE isoforms in the corpora cavernosa in the cat and to establish the functional presence of PDE 4 in human cavernosal tissue, the erectile response to intracavernosal phosphodiesterase (PDE) inhibitors alone and the combination of PDE inhibitors and prostaglandin E1 (PGE1) was evaluated in the anesthetized cat. The in vitro formation of cAMP and cGMP in human cavernosal smooth muscle cells (HCSMCs) treated with PGE1 and rolipram in primary culture was also measured. MATERIALS AND METHODS In pentobarbital-anesthetized cats, increases in intracavernosal pressure, penile length, and duration of erectile response were determined after intracavernosal injections of (i) the type 3 cAMP-specific, cGMP-inhibitable PDE inhibitor, milrinone, (ii) the type 4 cAMP-specific PDE inhibitor, rolipram, (iii) the type 5 cGMP-specific PDE inhibitor, zaprinast, and (iv) the combination of rolipram and PGE1. Systemic arterial pressure was concurrently assessed in these experiments. All responses to PDE inhibitors were compared with a control triple-drug combination comprised of papaverine (1.65 mg.), PGE1 (0.5 microg.), and phentolamine (25 microg.). HCSMCs were incubated with PGE1 (3 microM) and rolipram (10 microM) individually or in combination up to 2 hours at 37C. The intracellular cAMP and cGMP was extracted by cold absolute ethanol and measured (pmol./10(6) cells) by a commercially available EIA kit. RESULTS Milrinone (3 to 100 microg.), rolipram (3 to 100 microg.), and zaprinast (3 to 100 microg.) induced dose-dependent increases in intracavernosal pressure and penile length (p <0.05) when administered intracavernosally. The maximum increase in cavernosal pressure in response to zaprinast was associated with no significant change in systemic arterial pressure. When rolipram was combined with PGE1 (0.1 microg.), the increases in intracavernosal pressure and the duration of erectile response were significantly higher (p <0.05) and longer (p <0.05) than those observed when rolipram alone was injected intracavernosally. PGE1 (3 microM) and rolipram (10 microM) produced significant increases (p <0.05) in the accumulation of intracellular cAMP levels in HCSMCs in primary culture above those of the baseline values while intracellular levels of cGMP did not change. CONCLUSIONS PDE inhibitors administered intracavernosally caused dose-dependent increases in cavernosal pressure in the cat. When a specific cAMP PDE inhibitor was combined with PGE1, the erectile response was enhanced and intracellular levels of cAMP were increased in HCSMCs in primary culture. These data suggest further exploration of the combination of various PDE inhibitors and PGE1 in the pharmacologic treatment of erectile dysfunction and provide functional evidence for the presence of PDE 4 isoenzyme in human penile cavernosal cells.

INDUCTION OF PENILE ERECTION BY INTRACAVERNOSAL AND TRANSURETHRAL ADMINISTRATION OF NOVEL NITRIC OXIDE DONORS IN THE CAT

PURPOSE The effects of novel nitric oxide (NO) donors administered intracavernosally and transurethrally on erectile function in the anesthetized cat were evaluated. MATERIALS AND METHODS In pentobarbital-anesthetized cats, increases in intracavernosal pressure, penile length, and duration of erectile response were determined after intracavernosal and transurethral injections of novel NO donors (MAHMA/NO, PAPA/NO, DEA/NO, PIPERAZI/NO and PROLI/NO). All parameters were measured after administration of NO donors intracavernosally via a 30-gauge needle and urethrally via a Jelco i.v. catheter in a volume of 200 microliters. Systemic arterial pressure was also assessed in these experiments. All NO donors were compared with a triple-drug control combination comprised of papaverine (1.65 mg.), prostaglandin E1 (0.5 microgram.), and phentolamine (25 micrograms.). RESULTS MAHMA/NO, PAPA/NO, DEA/NO, PIPERAZI/NO and PROLI/NO induced dose dependent increases in intracavernosal pressure and penile length (p < 0.05) when administered intracavernosally. The increases in cavernosal pressure and penile length were comparable to those observed with the triple-drug control combination. The maximum increase in cavernosal pressure in response to PROLI/NO and PAPA/NO was associated with no significant change in systemic arterial pressure. Transurethral administration of PROLI/NO and PIPERAZI/NO induced dose-dependent increases in cavernosal pressure and penile length (p < 0.05). The response was similar to that of the triple-drug control combination, except that transurethral PROLI/NO and PIPERAZI/NO had no significant effect on systemic blood pressure. CONCLUSIONS NO donors caused dose-dependent increases in cavernosal pressure when administered intracavernosally and transurethrally. These data suggest further exploration of the use of NO donors for the treatment of erectile dysfunction.

Feline penile erection induced by transurethral administration of sodium nitroprusside.

Abstract Nitric oxide (NO) is an important mediator in the relaxation of cavernosal smooth muscle. The aim of this study was to investigate the in vivo feline erectile response after transurethral administration of sodium nitroprusside (SNP), a NO donor drug. Erectile responses after administration of transurethral SNP were compared with those elicited by an intracavernosal control triple-drug combination (1.65 mg papaverine, 25 μg phentolamine, and 0.5 μg prostaglandin E1). SNP was administered via a 20-gauge Jelco intravenous catheter in a volume of 200 μl and changes in intracavernosal pressure, penile length, and systemic blood pressure were monitored. The control triple-drug combination was administered via a 30-gauge needle at the end of each experiment to serve as a control reference. Transurethral administration of SNP (1–4 mg) induced penile erection in a dose-dependent manner with minimal changes in systemic blood pressure. The maximum increase in intracavernosal pressure and penile length after transurethral administration of SNP (4 mg) was significantly less than after the intracavernosal injection of the control triple-drug combination (P < 0.01). These data suggest that transurethral administration of SNP can induce an erectile response in cats with minimal side effects.