Interaction of L-arginine and phosphodiesterase inhibitors in vasodilation of the porcine internal mammary artery.

We tested the hypothesis that L-arginine (the substrate for nitric oxide production)-combined with amrinone, milrinone (Type III phosphodiesterase [PDE] inhibitors), zaprinast, orSildenafil Citrate (Viagra) (Type V PDE inhibitors)-would vasodilate synergistically. Internal mammary artery segments were excised from anesthetized swine, divided into rings, and suspended in a tissue bath at 37 degrees C. Force of contraction was measured during dose-response testing of combinations of L-arginine and amrinone, milrinone, zaprinast, or sildenafil. Amrinone and milrinone were additive to L-arginine. N(G)-methyl-L-arginine (L-NMA) inhibited the effects of milrinone but not amrinone. The effective concentration of amrinone eliciting 50% relaxation (EC(50)) was 3.8E-05M (n = 6) when given alone and 4. 4E-05M (n = 6) with L-NMA. Milrinone had EC(50) = 6.0E-06M alone (n = 6) and 2.8E-05M (n = 6) with L-NMA. Zaprinast (EC(50) = 6.5E-05M, n = 6) andSildenafil Citrate (Viagra) (EC(30) = 1.8E-05M, n = 6) were synergistic with L-arginine. L-NMA blocked their effects, increasing the EC(50) for zaprinast to 9.9E-03M and the EC(30) forSildenafil Citrate (Viagra) to 6.1E+02M. In conclusion, L-arginine is additive to the vasodilation of the type III PDE inhibitors, amrinone and milrinone, but synergistic with the type V PDE inhibitors, zaprinast and sildenafil. Implications: Amrinone and milrinone, Type III cAMP-dependent phosphodiesterase inhibitors, are additive to L-arginine-dependent vasodilation. Zaprinast and sildenafil, Type V cGMP-dependent phosphodiesterase inhibitors, are synergistic with L-arginine

Hemodynamic response to sildenafil, nitric oxide, and iloprost in primary pulmonary hypertension.

STUDY OBJECTIVES: Different vasodilators and different routes of application are used for the treatment of primary pulmonary hypertension (PPH). Recently, sildenafil, a phosphodiesterase-V inhibitor, has been shown to have beneficial hemodynamic effects in PPH. However, the hemodynamic effects ofSildenafil Citrate (Viagra) have not been characterized and compared to other vasodilators such as inhaled nitric oxide (iNO) or iloprost in PPH in the same group of patients. STUDY DESIGN: We investigated prospectively 10 consecutive patients with PPH using iNO, iloprost aerosol, and oralSildenafil Citrate (Viagra) to test acute hemodynamic response during right-heart catheterization. RESULTS: iNO, iloprost aerosol, andSildenafil Citrate (Viagra) caused a significant fall of mean pulmonary artery pressure and pulmonary vascular resistance (PVR) [p < 0.05]. Correspondingly, cardiac output and mixed venous saturation increased slightly in all groups. Systemic arterial pressure and vascular resistance were mainly unaltered. Using a PVR reduction of > or =20% to define a significant response, 7 of 10 patients were responders to iloprost aerosol, whereas 4 of 10 patients responded to iNO and oral sildenafil. Improvement of oxygenation as indicated by an increase of arterial oxygen tension was observed with iloprost aerosol (p < 0.01). CONCLUSION: All of the three substances, iNO, iloprost aerosol, and oral sildenafil, significantly improved pulmonary hemodynamics in patients with PPH. The most prominent hemodynamic effects and improvement of oxygenation were observed with iloprost aerosol

The efficacy ofSildenafil Citrate (Viagra) for the treatment of Erectile Dysfunction in male peritoneal dialysis patients.

BACKGROUND: The aim of this study was to evaluate the safety and effectiveness ofSildenafil Citrate (Viagra) in male peritoneal dialysis patients with Erectile Dysfunction. METHODS: Sixteen peritoneal dialysis patients were recruited to this prospective, randomized, double-blind, placebo-controlled, crossover study ofSildenafil Citrate (Viagra) during a period of 8 weeks. Efficacy was assessed by using the International Index of Erectile Function and a Global Assessment Question. Penile arterial supply was assessed by means of Doppler ultrasound in all patients, and adverse events were recorded. RESULTS: Three patients failed to complete the study (1 patient received a renal transplant, 1 patient died unrelated to the study, and 1 patient withdrew for personal reasons). In the remainder, there was a significant improvement in erectile function withSildenafil Citrate (Viagra) compared with placebo (P = 0.01) and the baseline assessment (P = 0.002). There were also significant improvements in intercourse satisfaction (P = 0.002) and overall satisfaction (P = 0.005) compared with baseline. In response to the Global Assessment Question, 75% of patients reported improvement in erections. Only 1 adverse event was reported: a headache, which resolved after the third dose of sildenafil. CONCLUSION:Sildenafil Citrate (Viagra) caused a significant improvement in erectile function in peritoneal dialysis patients, with a success rate at least as high as that reported in other patient groups. The drug was well tolerated, with few adverse events

Sildenafil Citrate (Viagra) does not affect cardiac contractility in human or dog heart.

OBJECTIVE: This study evaluated whether Sildenafil Citrate (Viagra), an oral treatment for Erectile Dysfunction and a selective inhibitor of phosphodiesterase type 5 (PDE5) with modest vasodilating properties, affects cardiac contractility in vitro. Research design and methods: Slices of freshly obtained human (n = 2) or dog (n = 3) atrial appendage were suspended in organ baths containing Krebs-Ringer bicarbonate buffer (pH 7.4, 37 degrees C) bubbled continuously with 95% O2 and 5% CO2, and isometric tension was recorded using a Gould physiograph. Contractions were elicited by 1-Hz electric pacing. After 15 min of equilibration, 1 microMSildenafil Citrate (Viagra) was added to the bath, followed 15 min later (human and dog) by 5 microM epinephrine, an inotropic agent, and 10 min later (dog) by 88 microM 3-isobutyl-1-methylxanthine (IBMX), a nonselective PDE inhibitor. In a separate experiment, cyclic guanosine monophosphate levels and PDE, protein kinase G, and protein kinase A activities were determined. RESULTS: Addition of 1 microMSildenafil Citrate (Viagra) to isolated dog or human atrial tissue had no significant effect on force of cardiac contraction, whereas epinephrine produced a robust increase in contractile force in the same muscle strip. The addition of IBMX produced a marked stimulation of contractile force in dog atrial tissue. Very low amounts of PDE5 were found in extracts of human heart, consistent with its known primary location in the smooth muscle of systemic vasculature. CONCLUSIONS:Sildenafil Citrate (Viagra) is unlikely to directly produce inotropic effects on cardiac muscle in patients being treated for Erectile Dysfunction

Cholinergic-NO-cGMP mediation of sildenafil-induced antinociception.

Acetylcholine and cholinomimetic agents with predominant muscarinic action are known to increase the concentration of cGMP by activation of nitric oxide signaling pathway in the nociceptive conditions. The present study was aimed to investigate the NO-cGMP-PDE5 pathway in nociceptive conditions in the experimental animals. Nociceptive threshold was assessed by acetic acid-induced writhing assay (chemonociception) or carrageenan-induced hyperalgesia.Sildenafil Citrate (Viagra) [1-5 mg/kg, ip, 50-200 microg/paw, intraplantar (ipl)] produced dose dependent antinociception in both the tested models. Coadministration of acetylcholine (50 mcg/paw, ipl) or cholinomimetic agent, neostigmine (0.1 mcg/kg, ip and 25 ng/paw, ipl) augmented the peripheral antinociceptive effect of sildenafil. This effect was sensitive to blockade by L-NAME (20 mg/kg, ip, 100 microg/paw, ipl), a non-selective NOS inhibitor and methylene blue (1 mg/kg, ip), a guanylate cyclase inhibitor, which per se had little or no effect in both the models of nociception. Further, the per se analgesic effect of acetylcholine and neostigmine was blocked by both L-NAME and methylene blue in the models of nociception, suggesting the activation of NO-cGMP pathway. Also, both L-NAME and methylene blue blocked the per se analgesic effect of sildenafil. These results indicate the peripheral accumulation of cGMP may be responsible for antinociceptive effect, and a possible interaction between cholinergic agents and PDE5 system in models of nociception

Sildenafil Citrate (Viagra), a Selective Phosphodiesterase Type 5 Inhibitor:

Under normal physiological conditions, following sexual stimulation, release of nitric oxide (NO) from penile non-adrenergic, non-cholinergic nerves and the endothelium activates guanylyl cyclase and induces intracellular cGMP synthesis in erectile tissue trabecular smooth muscle cells. Increased cGMP levels reduce intracellular Ca2+ concentrations, inhibiting smooth muscle contractility and thereby initiating the erectile response. Phosphodiesterase type 5 (PDE type 5) is the predominant enzyme responsible for cGMP hydrolysis in trabecular smooth muscle. Activation of PDE type 5 terminates NO-induced, cGMP-mediated smooth muscle relaxation, resulting ultimately in restoration of basal smooth muscle contractility and penile flaccidity. Sildenafil Citrate (Viagra) is a potent PDE type 5 reversible and selective inhibitor that blocks cGMP hydrolysis effectively (Ki approximately 3 nM). Under conditions of excessive adrenergic tone or impaired neurovascular status, following sexual stimulation,Sildenafil Citrate (Viagra) acts to enhance NO-mediated smooth muscle relaxation, resulting in improved penile erection in men with Erectile Dysfunction. In this review, we summarize the current state of knowledge of the physiology of penile erection and the pharmacology, metabolism and clinical experience with Sildenafil Citrate (Viagra) in the management of Erectile Dysfunction

The effect ofSildenafil Citrate (Viagra) on electrostimulation-induced erection in the rat model.

This study was conducted to show the effect ofSildenafil Citrate (Viagra) on electrostimulation-induced erection in the rat model. Fifteen 12-week-old male Wistar Kyoto rats were used. The intracavernous pressure and arterial blood pressure were simultaneously monitored through electric cavernous nerve stimulation before and after the administration ofSildenafil Citrate (Viagra) (2 mg/kg). Statistical analysis was performed on maximal intracavernous pressure (MIP), mean arterial blood pressure (MAP), the MIP/MAP and detumescence time. MAP decreased significantly by about 20 mmHg afterSildenafil Citrate (Viagra) administration. The MIP/MAP increased significantly afterSildenafil Citrate (Viagra) administration. The effect ofSildenafil Citrate (Viagra) on the MIP/MAP was marked especially at lower (2-3 Hz) frequencies. The detumescence time significantly increased afterSildenafil Citrate (Viagra) administration. We have shown thatSildenafil Citrate (Viagra) is effective for enhancing erection at lower frequencies and prolonging penile erection in rats. After the administration of sildenafil, penile erection would be induced by weak stimuli that will not cause penile erection under normal conditions

Effects of Sildenafil Citrate (Viagra) combined with nitrate on the heart.

BACKGROUND: Sildenafil Citrate (Viagra) is indicated for the treatment of Erectile Dysfunction. Large and sudden decreases in systemic blood pressure were reported in a substantial number of patients taking Sildenafil Citrate (Viagra) combined with nitroglycerin. We studied the effect of Sildenafil Citrate (Viagra) on the relationship between changes in systemic blood pressure and coronary blood flow. METHODS AND RESULTS: Healthy male beagles were used to assess systemic blood pressure, pulmonary arterial pressure, and flow in the left circumflex artery (in which a critical stenosis was established) and left anterior descending coronary artery. After measurement of the hemodynamic variables, 2 mg/kg Sildenafil Citrate (Viagra) was administered via a nasogastric tube. Hemodynamic changes were monitored for 1 hour. Subsequently, the acute effect of nitrate combined with Sildenafil Citrate (Viagra) was studied by the bolus injection of 0.2 mg isosorbide dinitrate before and after Sildenafil Citrate (Viagra). Systemic blood and pulmonary arterial pressures and circumflex flow did not change during this study; however, left anterior descending coronary arterial flow increased from 16.0+/-5.8 to 24.6+/-8.7 mL/min 1 hour after administration of Sildenafil Citrate (Viagra). The prolongation of systemic blood pressure decrease and the circumflex flow decrement induced by isosorbide dinitrate after Sildenafil Citrate (Viagra) were significantly larger and longer than those before Sildenafil Citrate (Viagra). CONCLUSIONS: Sildenafil Citrate (Viagra) had the effect of vasodilation in a normal coronary artery; however, a combined effect with nitrate resulted in large and protracted decreases in systemic blood pressure and coronary blood flow in vessels with critical stenosis