Lysophosphatidic acid stimulates proliferation of cultured smooth muscle cells from human BPH tissue: sildenafil and papaverin generate inhibition.

Adolfsson PI, Ahlstrand C, Varenhorst E, Svensson SP.

Department of Medicine and Care, Division of Pharmacology, Faculty of Health Science, Linkoping University, Linkoping, Sweden. per.adolfsson far.liu.se

BACKGROUND: The endogenous substance lysophosphatidic acid (LPA) has been found to generate proliferation of cultured smooth muscle cells (SMC). Therefore, the effect of LPA on human benign prostate hyperplasia (BPH) could be of interest. METHODS: The proliferative effect of LPA on cultured human prostatic SMC from specimens obtained at trans-urethral resection of the prostate (TURP) because of BPH, was analyzed by [3H]-thymidine and [35S]-methionine incorporation. In addition, LPA stimulated BPH SMC were treated with papaverin, forskolin, sildenafil or zaprinast, well known to increase the intracellular level of cAMP or cGMP. RESULTS: LPA produced a dose-dependent increase in BPH SMC, both regarding DNA- and protein-synthesis with EC50 values of 3 and 10 microM, respectively. Furthermore, both papaverin, a general phosphodiesterase inhibitor regarding cAMP hydrolyzes, and forskolin, an adenylyl cyclase stimulating agent, inhibited the LPA-stimulated DNA replication in a dose dependent manner with IC50 = 2.5, and 0.35 microM, respectively. cGMP increasing agents, such as the NO-donors SIN-1 and SNAP, produced a weak anti-proliferative response. However, both phosphodiesterase 5 inhibitors sildenafil (Viagra) and zaprinast efficiently blocked DNA replication. In addition, when the protein synthesis was examined, we found that the LPA response was significantly inhibited by forskolin and papaverin. CONCLUSIONS: The major conclusion of this investigation is that the endogenous serum component LPA, is able to promote human BPH SMC growth. In addition, our study indicates that cyclic nucleotides can inhibit this effect. Future clinical studies will be needed to determine if different specific phosphodiesterase inhibitors per se or in combination could represent a new therapeutic possibility for the treatment of BPH. Copyright 2002 Wiley-Liss, Inc.

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Sildenafil increases ocular perfusion.

Paris G, Sponsel WE, Sandoval SS, Elliott WR, Trigo Y, Sanford DK, Harison JM.

South Texas Ocular Imaging Center, Ophthalmology Department, University of Texas Health Science Center at San Antonio, USA.

PURPOSE: Our goal was to determine whether visual system responses to sildenafil accompany shifts in ocular perfusion. The human choroid, which supports the metabolic function of the outer retina, is an erectile tissue, analogous in many respects to the corpus cavenosum. METHODS: Right eyes of 12 normal adults were evaluated before and 2 h after 50 mg oral dose of sildenafil. Pulsatile ocular blood flow (POBF), intraocular pressure (IOP), Heidelberg retinal flowmetry (HRT), 4.26 cpd, 7.5 Hz temporally-modulated contrast sensitivity (CS), full-threshold C-20 frequency doubling technology (FDT) perimetry, and blood pressure (BP) were measured. RESULTS: POBF (+29.4%; p > 0.016) and CS (+33.6%; p > 0.014%) increased within 110 (+/-7.7) minutes after sildenafil administration. No subject demonstrated decreases in either variable. HRF flow values increase among 7 of the 9 eyes producing stable scans (+8.2%; p > 0.1). FDT values did not change significantly, nor did systemic pulse amplitude or mean IOP. CONCLUSIONS: Since IOP and systemic pulse amplitude both remained stable after sildenafil administration, while POBF values increased to a level nearly one third greater than baseline. It appears sildenafil can induce intrinsic change in the choroidal vasculature, with an apparently positive impact on pericentral contrast sensitivity. This effect may be of clinical utility.

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Molecular mechanisms of cardiostimulatory effects of sildenafil.

Sugiyama A, Takeuchi N, Saegusa Y, Sugita M, Hashimoto K.

Department of Pharmacology, Yamanashi Medical University, Nakakoma-gun, Japan. atsushis res.yamanashi-med.ac.jp

To better understand the molecular mechanisms of the previously described cardiostimulatory action of the phosphodiesterase type-5 (PDE5) inhibitor sildenafil, we first evaluated its effects on cyclic AMP level in the canine ventricular membrane preparation. Sildenafil (10 micromol/L) significantly increased the net cyclic AMP production rate, the potency of which was similar to that of 3-isobutyl-1-methylxanthine (IBMX). Next, we assessed the inhibitory effect of sildenafil on PDE of bovine heart. Sildenafil (> or = 1 micromol/L) as well as IBMX significantly decreased the cyclic AMP hydrolyzing speed of PDE. These results suggest that a supra-therapeutic concentration of sildenafil may directly inhibit cyclic AMP hydrolyzing PDEs in the heart, although indirect inhibition of PDE3 via the "cross-talk" pathway cannot be totally excluded.

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Influence of sildenafil on copulatory behaviour in sluggish or normal ejaculator male rats: a central dopamine mediated effect?

Giuliani D, Ottani A, Ferrari F.

Department of Biomedical Sciences, Division of Pharmacology, University of Modena and Reggio Emilia, via G. Campi 287, 41100, Modena, Italy.

The present study investigates the effects induced by sildenafil (1 mg/kg, p.o.) and the dopamine agonist, SND 919 (0.1 mg/kg, i.p.) on copulatory behaviour of male rats, categorized, on the basis of seven consecutive mating pre-tests, as sluggish and normal ejaculators (SE and NE, respectively). The data obtained show that sildenafil modifies both sexual arousal and ejaculatory mechanisms of copulation. It appears that, although it induced a facilitatory effect on ejaculation of all rats, similarly to SND 919, the lowering of ejaculatory threshold was achieved by means of a reduction of mount frequency and intromission frequency in SE and NE groups, respectively. Differently from SND 919, sildenafil increased sexual arousal, diminishing post ejaculatory interval in SE animals and inter-intromission interval in both SE and NE rats. As the dopamine antagonist, (-)eticlopride (0.02 mg/kg, s.c.), significantly inhibited sildenafil-induced enhancement of sexual arousal in SE rats, it is suggested that the drug acts both peripherally and centrally.

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Intravenous sildenafil lowers pulmonary vascular resistance in a model of neonatal pulmonary hypertension.

Shekerdemian LS, Ravn HB, Penny DJ.

Department of Cardiac Intensive Care, Great Ormond Street Hospital, London, United Kingdom. shekel cryptic.rch.unimelb.edu.au

Persistent pulmonary hypertension secondary to meconium aspiration syndrome is an important cause of morbidity and mortality in the neonatal population. We investigated the use of the phosphodiesterase-5 inhibitor sildenafil, in its intravenous form, as a pulmonary vasodilator in a model of meconium aspiration syndrome. Pulmonary hypertension was induced in 18 piglets, by endotracheal instillation of human meconium, 6 piglets subsequently received an infusion of intravenous sildenafil for 2 hours, 6 received inhaled nitric oxide for 2 hours, and 6 control animals received no additional intervention. Meconium aspiration increased pulmonary vascular resistance by 70%, and increased oxygenation index by over 100%. Pulmonary vascular resistance remained elevated for the remainder of the study period in control animals. Inhaled nitric oxide reduced the pulmonary vascular resistance by 40% after 2 hours of treatment; intravenous sildenafil completely reversed the increase in pulmonary vascular resistance within 1 hour of commencing the infusion. Neither agent had an effect on systemic hemodynamics. Sildenafil also increased cardiac output by 30%, but while doing so did not adversely influence oxygenation. Intravenous sildenafil is a selective and highly effective pulmonary vasodilator, which is at least as effective as inhaled nitric oxide, in this model of neonatal persistent pulmonary hypertension.

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Erectile function after permanent prostate brachytherapy.

Merrick GS, Butler WM, Galbreath RW, Stipetich RL, Abel LJ, Lief JH.

Schiffler Cancer Center, Wheeling Hospital, Wheeling, WV 26003-6300, USA. schifonc wheelinghosp.com

PURPOSE: To determine the incidence of potency preservation after permanent prostate brachytherapy using a validated patient-administered questionnaire and to evaluate the effect of multiple clinical and treatment parameters on penile erectile function. MATERIALS AND METHODS: Four hundred twenty-five patients underwent permanent prostate brachytherapy from April 1995 to October 1999. Two hundred nine patients who were potent before brachytherapy and who at the time of the survey were not receiving hormonal therapy were mailed the specific erectile questions of the International Index of Erectile Function (IIEF) questionnaire with a self-addressed stamped envelope. The questionnaire consisted of 5 questions, with a maximal score of 25. Of the 209 patients, 181 (87%) completed and returned the questionnaire. The mean and median follow-up was 40.4 +/- 14.9 and 40.6 months, respectively (range 19-75). Preimplant erectile function was assigned using a three-tiered scoring system (2 = erections always or nearly always sufficient for vaginal penetration; 1 = erections sufficient for vaginal penetration but considered suboptimal; 0 = the inability to obtain erections and/or erections inadequate for vaginal penetration). Postimplant potency was defined as an IIEF score >/=11. The clinical parameters evaluated for erectile function included patient age, preimplant potency, clinical T-stage, pretreatment prostate-specific antigen level, Gleason score, elapsed time after implantation, hypertension, diabetes mellitus, and tobacco consumption. Treatment parameters included radiation dose to the prostate gland, use of hormonal manipulation, use of supplemental external beam radiotherapy (EBRT), choice of isotope, prostate volume, and planning volume. The efficacy of sildenafil citrate in brachytherapy-induced erectile dysfunction (ED) was also evaluated. RESULTS: Pretreatment erectile function scores of 2 and 1 were assigned to 125 and 56 patients, respectively. With a 6-year follow-up, 39% of patients maintained potency after prostate brachytherapy, with a plateau on the potency preservation curve. Postimplant preservation of potency (IIEF >/=11) correlated with preimplant erectile function (50.4% vs. 13.2% for preimplant scores of 2 and 1, respectively, p <0.001), patient age (57.4%, 38.2%, and 21.9% for patients <60, 60-69, and >/=70 years old, respectively, p <0.004), use of supplemental EBRT (52.0% vs. 26.4% for patients without and with EBRT, p <0.001), and a history of diabetes mellitus (41.4% vs. 0% for patients without and with diabetes, respectively, p = 0.017). In multivariate analysis, clinical stage, radiation dose to the prostate gland, hormonal manipulation, choice of isotope, history of hypertension, and tobacco consumption had no effect on the ultimate preservation of potency. Only the preimplant potency score, use of supplemental EBRT, and diabetes maintained statistical significance. Sixty-two patients used sildenafil, with 53 (85%) reporting a favorable response. When potent patients were grouped with the ED patients who used sildenafil, the 6-year actuarial rate of potency preservation was 92%. Including the 70 impotent patients who never used sildenafil, the actuarial 6-year rate of potency preservation with and without pharmacologic support was 54% and 39%, respectively. CONCLUSION: Our results suggest that brachytherapy-induced ED is more common than previously reported and may be the result of obtaining patient information by means of a validated quality-of-life instrument by mail and not by personal interview. In multivariate analysis, only pretreatment potency, supplemental EBRT, and diabetes maintained statistical significance. Most patients with brachytherapy-induced ED responded favorably to sildenafil. Although the 6-year actuarial incidence of potency preservation was 39%, 52% of patients not receiving supplemental EBRT maintained potency. In addition, with pharmacologic support, 92% of patients maintained potency.

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Sildenafil and T-1032, phosphodiesterase type 5 inhibitors, showed a different vasorelaxant property in the isolated rat aorta.

Mochida H, Inoue H, Takagi M, Noto T, Yano K, Kikkawa K.

Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., 2-2-50, Kawagishi, Toda, Saitama 335-8505, Japan. mochida tanabe.co.jp

The vasorelaxant effects of sildenafil and T-1032 [methyl-2-(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4,5-trimethoxyphenyl)-3-isoquinoline carboxylate sulfate], two phosphodiesterase type 5 inhibitors, were examined in the isolated rat aorta. Sildenafil and T-1032, both of which have almost the same potency and selectivity regarding phosphodiesterase type 5 inhibitory activity, produced a similar, moderate, relaxation at 10(-10) to 10(-7) M (sildenafil: 66.8 +/- 13.7%; T-1032: 77.9 +/- 10.8% at 10(-7) M). However, sildenafil, but not T-1032, produced further relaxation at the higher concentrations (sildenafil: 102.0 +/- 0.6%; T-1032: 81.0 +/- 7.2% at 10(-4) M, P < 0.05). Sildenafil also produced a more potent relaxation than did T-1032 at the high concentrations (10(-5) and 10(-4) M) in endothelium-denuded aortic rings and in the presence of N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor (3 x 10(-4) M). Moreover, the high concentrations of sildenafil, but not of T-1032, caused a rightward shift of the concentration-response curve for calcium chloride in K(+)-depolarized endothelium-denuded preparations. In the ligand binding assay for the L-type Ca(2+) channels, the affinities of sildenafil at 10(-5) M for binding sites of nitrendipine and (--)-desmethoxyverapamil [(--)- D888] (35.2 +/- 3.3% and 35.8 +/- 1.9%, respectively) were higher than those of T-1032 (11.8 +/- 4.0% and -13.1 +/- 1.3%, respectively, P < 0.05). Regarding cyclic nucleotide levels, both phosphodiesterase type 5 inhibitors increased cGMP levels at 10(-6) M. However, sildenafil, but not T-1032, further increased cGMP levels at the higher concentrations (sildenafil: 15.7 +/- 2.7 pmol/mg protein; T-1032: 5.6 +/- 0.6 pmol/mg protein at 10(-4) M, P < 0.05). These results suggested that high concentrations of sildenafil had additional vasorelaxant properties through mechanisms other than phosphodiesterase type 5 inhibition. Sildenafil-induced relaxation appears to be due to inhibition of the external Ca(2+)-dependent cascade for contraction and/or to an increase in cGMP levels. In contrast, T-1032 only showed a vasorelaxant property due to phosphodiesterase type 5 inhibition. In conclusion, T-1032 appears to be a specific phosphodiesterase type 5 inhibitor compared with sildenafil and a useful compound to examine the physiological function of phosphodiesterase type 5.

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Sildenafil-nitric oxide donor combination promotes ventricular tachyarrhythmias in the swine right ventricle.

Swissa M, Ohara T, Lee MH, Kaul S, Shah PK, Hayashi H, Chen PS, Karagueuzian HS.

Division of Cardiology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles 90048, USA.

We tested the hypothesis that sildenafil, singly or in combination with nitric oxide (NO) donors, promotes ventricular tachycardia (VT) and ventricular fibrillation (VF). Vulnerability to VT/VF was tested by rapid pacing in eight isolated normal swine right ventricles (RV). The endocardial activation was optically mapped, and the dynamic action potential duration (APD) restitution curves were constructed with metal microelectrodes. At baseline, no VT/VF could be induced. Sildenafil (0.2 microg/ml) or NO donor singly or in combination did not alter VT/VF vulnerability. However, when 2 microg/ml sildenafil was combined with NO donors, the incidence of VT and VF rose significantly (P < 0.01). VT with a single periodic wavefront was induced in five of eight RVs, and VF with multiple wavefronts was induced in all eight RVs. The sildenafil-NO donor pro-VT/VF combination significantly increased the maximum slope of the APD restitution curve and the amplitude of the APD alternans. The pro-VT/VF effects of sildenafil were reversible after drug-free Tyrode solution perfusion. We conclude that a sildenafil (2 microg/ml) and NO donor combination increases VT/VF vulnerability in the normal RV by a mechanism compatible with the restitution hypothesis.

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