Sildenafil: emerging cardiovascular indications.

The discovery in 1989 of sildenafil, a highly selective inhibitor of phosphodiesterase-5 (PDE-5), was the result of extensive research on chemical agents targeting PDE-5 that might potentially be useful in the treatment of coronary heart disease. Initial clinical studies onSildenafil Citrate (Viagra) in the early 1990s were not promising with respect to its antianginal potential. However, the incidental discovery of its antiimpotence effect led to its approval of for the treatment of Erectile Dysfunction. Thereafter, several reports of adverse cardiac events in patients onSildenafil Citrate (Viagra) raised concerns about its safety in cardiovascular disorders. Novel therapeutic indications are emerging forSildenafil Citrate (Viagra) with the recent discovery that PDE-5 is expressed in various other tissues such as the arterial vasculature, including pulmonary and coronary arteries, venous vasculature, skeletal muscles, platelets, and visceral and tracheobronchial muscles. In this review we briefly summarize the pharmacology ofSildenafil Citrate (Viagra) and the current available evidence on its potential therapeutic applications in cardiovascular disorders

Determination of a new phosphodiesterase V inhibitor, DA-8159, in plasma and urine by high-performance liquid chromatography.

A high-performance liquid chromatographic (HPLC) method using liquid-liquid extraction for sample preparation was developed for the determination of a new phosphodiesterase V inhibitor, DA-8159, in rat plasma and urine using Sildenafil Citrate (Viagra) as an internal standard. A 100 microl aliquot of 0.1 M Na(2)CO(3) (containing Sildenafil Citrate (Viagra), 3 microg/ml as free sildenafil) and a 1 ml aliquot of ether were added to a 100 microl aliquot of biological samples (urine samples were diluted 20 times with distilled water). After vortex centrifugation at 9000 x g for 3 min, the ether layer was collected and dried under nitrogen gas. The residue was reconstituted with a 150 microl aliquot of the mobile phase, centrifuged, and a 100 microl aliquot of the supernatant was injected onto a reversed-phase column. The mobile phases, 20 mM KH(2)PO(4) (pH 4.7):acetonitrile (70:30, v/v for plasma and tissue samples, and 75:25, v/v for urine samples), were run at a flow rate of 1.0 ml/min. The column effluent was monitored by an ultraviolet detector set at 292 nm. The retention times for DA-8159 and the internal standard were approximately 10.7 and 9.1 min, respectively, in plasma and tissue samples and the corresponding values in urine samples were 47 and 33 min. The detection limits for DA-8159 in rat plasma and urine were 20 and 100 ng/ml, respectively. The coefficients of variation of the assay were generally low: below 10% for plasma and 9.9% for urine. No interferences from endogenous substances were found.

OralSildenafil Citrate (Viagra) reduces pulmonary hypertension after cardiac surgery.

BACKGROUND: Treatment of postoperative pulmonary hypertension with intravenous (IV) pulmonary vasodilators is hampered by the lack of selectivity. Inhaled nitric oxide produces selective pulmonary vasodilation; however, it requires a special device, and weaning can cause rebound. OralSildenafil Citrate (Viagra) is a phosphodiesterase type V inhibitor.Sildenafil Citrate (Viagra) can produce sustained pulmonary vasodilatation in patients with hypoxic or primary pulmonary hypertension; however, experience with postoperative pulmonary hypertension is limited. We report our initial experience with eight patients who received oralSildenafil Citrate (Viagra) as adjunctive therapy for postoperative pulmonary hypertension METHODS: We reviewed the charts of eight adult patients with postoperative pulmonary hypertension who received oralSildenafil Citrate (Viagra) (25 to 50 mg) to facilitate weaning of IV (milrinone, nitroglycerine, and sodium nitroprusside) and inhaled (nitric oxide) pulmonary vasodilators. Hemodynamic data were recorded before and 30 and 60 minutes after the initial dose of sildenafil. RESULTS: After the initial dose of sildenafil, mean pulmonary artery pressure was reduced by 20% and 22% at 30 and 60 minutes, respectively (p < 0.05). Pulmonary vascular resistance index decreased by 49% and 44% at 30 and 60 minutes, respectively (p < 0.05).Sildenafil Citrate (Viagra) had no clinically significant effects on cardiac index, mean arterial pressure, or systemic vascular resistance. Subsequent doses ofSildenafil Citrate (Viagra) were administered at regular intervals, allowing successful weaning of concomitant pulmonary vasodilators. CONCLUSIONS: OralSildenafil Citrate (Viagra) is an effective agent for treatment of postoperative pulmonary hypertension and can be used to facilitate weaning of inhaled and IV pulmonary vasodilators

Influence ofSildenafil Citrate (Viagra) on copulatory behaviour in sluggish or normal ejaculator male rats: a central dopamine mediated effect?

The present study investigates the effects induced bySildenafil Citrate (Viagra) (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 thatSildenafil Citrate (Viagra) 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 Citrate (Viagra) 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

KF31327, a new potent and selective inhibitor of cyclic nucleotide phosphodiesterase 5.

The effects of KF31327 (3-ethyl-8-[2-(4-hydroxymethylpiperidino)benzylamino]-2,3-dihydro-1H-imidazo[4,5-g]quinazoline-2-thione dihydrochloride) on phosphodiesterase 5 (cyclic GMP-specific phosphodiesterase) activity and platelet aggregation were investigated and compared with those of sildenafil, a well-known phosphodiesterase 5 inhibitor. KF31327 inhibited phosphodiesterase 5 from canine trachea (K(i)=0.16 nM) more potently thanSildenafil Citrate (Viagra) (K(i)=7.2 nM). The kinetic analysis revealed that KF31327 was a non-competitive inhibitor. In the presence of nitroglycerin (nitric oxide generator), both compounds inhibited the collagen-induced aggregation of rabbit platelets at less than 0.1 microM, augmenting intracellular cyclic GMP level without affecting cyclic AMP. In contrast, in the absence of nitroglycerin, a higher concentration (10 microM) of KF31327 was required to inhibit platelet aggregation and increased both cyclic nucleotide levels. However, 10 microMSildenafil Citrate (Viagra) did not affect aggregation despite elevation of cyclic GMP comparable to that in the presence of nitroglycerin. These results indicate that in the presence of nitroglycerin, the inhibition of platelet aggregation by KF31327 is due to the elevation of cyclic GMP, whereas the mechanism underlying the inhibition without nitroglycerin might be related to a rise in intracellular cyclic AMP

IntracavernosalSildenafil Citrate (Viagra) facilitates penile erection independent of the nitric oxide pathway.

Sildenafil, in nanomolar serum levels, is an effective phosphodiesterase type 5 inhibitor, and facilitates penile erection only during sexual stimulation. However, there is limited information on the pharmacological activity of this agent when tissue levels approach millimolar concentrations following intracavernosal injection. The aim of this study was to investigate whetherSildenafil Citrate (Viagra) causes penile erection in the absence of active neurogenic input. Organ bath preparations of rabbit penile cavernosal tissue strips were contracted with 1 microM phenylephrine and exposed to increasing concentrations ofSildenafil Citrate (Viagra) in the absence or presence of the nitric oxide (NO) synthase inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME; 0.6 mM).Sildenafil Citrate (Viagra) caused dose-dependent relaxation of rabbit cavernosal smooth muscle at high concentrations (>0.1 microM) with little or no effect at concentrations below 0.1 microM. The addition of L-NAME did not affect this response. In a separate protocol,Sildenafil Citrate (Viagra) dose response determinations were performed in the presence of the guanylyl cyclase inhibitor, 1H-[1,2,4]-oxadiazolo-[4,3-a]-quinoxalin-1-one (ODQ; 3 microM) or vehicle (50% dimethyl sulfoxide [DMSO]). Relaxation toSildenafil Citrate (Viagra) in the presence of DMSO was significantly enhanced relative toSildenafil Citrate (Viagra) alone. ODQ treatment partially attenuated relaxation to sildenafil, but failed to completely inhibit the response. In cavernosal tissue strips,Sildenafil Citrate (Viagra) elevated basal cyclic guanosine monophosphate (cGMP) levels twofold (0.54 vs. 1.10 pmol/mg prot). To further investigate these observations, anesthetized rabbits were injected intracavernosally withSildenafil Citrate (Viagra) (0.3-1.3 mg). In the absence of pelvic nerve stimulation, the magnitude and duration of the intracavernosal pressure increased in a dose-dependent fashion in response to sildenafil, approaching the systemic arterial pressure at higher doses. Intracavernosal administration of L-NAME, at doses that inhibited pelvic nerve stimulated penile erection, did not alter the response to intracavernosalSildenafil Citrate (Viagra) at 1.3 mg. Sildenafil, at the doses tested, did not significantly change the systemic arterial pressure. These data suggest that intracavernosal sildenafil, at tissue levels approaching millimolar concentrations, can cause relaxation of vascular smooth muscle and penile erection by a novel mechanism independent of the classical NO/cGMP pathway

Combined treatment with intravenous prostacyclin andSildenafil Citrate (Viagra) in patients with pulmonary hypertension: report of 4 cases

BACKGROUND AND OBJECTIVE: Here we report the experience obtained from a combined treatment with intravenous (i.v) prostacyclin and oralSildenafil Citrate (Viagra) in patients with severe pulmonary hypertension (PHT) who had a poor response to prior treatment with prostacyclin alone. PATIENTS AND METHOD:Sildenafil Citrate (Viagra) was added to the treatment in four patients with PHT (primary in two patients and secondary to collagenosis in the other two) with no adequate response to i.v. prostacyclin treatment. The clinical course, 6minutes walking test and echocardiogram were evaluated. RESULTS: InitialSildenafil Citrate (Viagra) dose was 12.5 mg three times daily, which was increased up to 50 mg three times daily in one patient and up to 50 mg four times daily in the other three. The symptoms of right heart failure were controlled in all cases. Before the start ofSildenafil Citrate (Viagra) administration, two patients had class III dyspnea and two patients had class IV dyspnea. Two patients converted to class I (previously class III and IV), and the other two converted to class II. The distance walked within 6 minutes increased (average increase 55%) and systolic pulmonary artery pressure decreased in all patients (average reduction 27%). Effects ofSildenafil Citrate (Viagra) were substained. The only side effect seen was mild headache. CONCLUSIONS: Our experience supports the value ofSildenafil Citrate (Viagra) in the treatment of PHT and suggests that combined treatment is useful for rescuing patients who fail to respond to initial treatment with i.v. prostacyclin

Effect ofSildenafil Citrate (Viagra) on ocular haemodynamics.

PURPOSE: To study the effect of sildenafil, which is an effective agent for the treatment of Erectile Dysfunction, on ocular haemodynamics. METHODS: In this prospective study we examined the effect of a single oral dose of 50 mg Sildenafil Citrate (Viagra) in a group of healthy young male volunteers, by using colour Doppler ultrasound imaging to measure haemodynamic variables in the central retinal artery (CRA), short temporal posterior ciliary artery (STPCA) and ophthalmic artery (OA). The following examinations were performed on both eyes immediately before and 1 h after a single oral dose of 50 mg sildenafil: visual acuity, intraocular pressure (IOP), colour vision, anterior segment, fundus appearance, resting heart rate, blood pressure and colour Doppler measurements. RESULTS: AfterSildenafil Citrate (Viagra) administration, peak systolic velocity, mean velocity and end-diastolic velocity significantly increased in the OA of both eyes. All Dopper indices remained non-significant for the CRA and STPCA of both eyes.Sildenafil Citrate (Viagra) did not cause any significant change in IOP, colour vision, visual acuity, systolic blood pressure or diastolic blood pressure. However, heart rate measurements increased significantly afterSildenafil Citrate (Viagra) administration compared with baseline (p = 0.003). CONCLUSION: The increased flow velocity in the ophthalmic artery seems to be due to a vasodilator effect ofSildenafil Citrate (Viagra)