|show drug details|
|urinary tract infection||0.025999999|
|coronary artery disease||0.0010|
|loss of vision||0.0010|
|transient ischemic attack||0.0010|
|upper respiratory tract infection||0|
|transient global amnesia||0|
|lower respiratory infection||0|
|liver function tests abnormal||0|
|pain in limb||0|
PDE5 inhibitor sildenafil citrate augments endothelium-dependent vasodilation in smokers.. Masashi Kimura; Yukihito Higashi; Keiko Hara; Kensuke Noma; Satoshi Sasaki; Keigo Nakagawa; Chikara Goto; Tetsuya Oshima; Masao Yoshizumi; Kazuaki Chayama (2003) Hypertension display abstract
Smoking is associated with endothelial dysfunction. The purpose of this study was to determine the effect of sildenafil, an inhibitor of phosphodiesterase type 5 (PDE5), on endothelial function in smokers. We evaluated the forearm blood flow (FBF) responses to acetylcholine (ACh), an endothelium-dependent vasodilator, and to sodium nitroprusside (SNP), an endothelium-independent vasodilator, before and after oral sildenafil administration (100 mg) with a strain-gauge plethysmograph in 10 young healthy male smokers and 10 young healthy male nonsmokers. FBF response to ACh was lower in smokers than in nonsmokers. The vasodilatory effects of SNP were similar in both groups. Sildenafil increased the FBF response to ACh from 9.3+/-2.0 to 12.5+/-3.5 mL/min per 100 mL tissue in smokers and from 12.6+/-5.6 to 19.6+/-8.4 mL/min per 100 mL tissue in nonsmokers, and it increased the response to SNP from 13.3+/-3.9 to 15.1+/-4.3 mL/min per 100 mL tissue in smokers and from 14.8+/-5.2 to 18.4+/-6.0 mL/min/100 mL tissue in nonsmokers (P
Absence of clinically important HERG channel blockade by three compounds that inhibit phosphodiesterase 5--sildenafil, tadalafil, and vardenafil.. R Dustan Sarazan; William J CrumbJr; Charles M BeasleyJr; Jeffrey T Emmick; Kenneth M Ferguson; Christine A Strnat; Peter J Sausen (2004) European journal of pharmacology display abstract
Compounds that inhibit phosphodiesterase 5 (PDE5) have been developed for the treatment of erectile dysfunction. Because men with erectile dysfunction frequently have comorbid cardiovascular disease, they may have limited cardiac repolarization reserve and be at risk of arrhythmia if treated with medications that prolong ventricular repolarization. The human ether-a-go-go related gene (HERG) channel is important for repolarization in human myocardium and is a common target for drugs that prolong the QT interval. We studied the ability of three compounds that inhibit PDE5--sildenafil, tadalafil, and vardenafil--to block the HERG channel. Using a whole cell variant of the patch-clamp method, the HERG current was measured in a stably transfected human embryonic kidney cell line expressing the HERG channel. The compounds produced dose-dependent reductions in HERG current amplitude over a concentration range of 0.1 to 100 microM. The IC50 values were 12.8 microM for vardenafil and 33.3 microM for sildenafil. Because the maximum soluble concentration of tadalafil (100 microM) produced only a 50.9% inhibition of the HERG current amplitude, the IC50 value for tadalafil could not be determined with the Hill equation. Tadalafil had the weakest capacity to block the HERG channel, producing a 50.9% blockade at the maximum soluble concentration (100 microM), compared with 86.2% for vardenafil (100 microM) and 75.2% for sildenafil (100 microM). In conclusion, the concentrations of the PDE5 inhibitors required to evoke a 50% inhibition of the HERG current were well above reported therapeutic plasma concentrations of free and total compound. None of the three compounds was a potent blocker of the HERG channel.
cGMP-phosphodiesterase antagonists inhibit Ca2+-influx in Dictyostelium discoideum and bovine cyclic-nucleotide-gated-channel.. Daniel F Lusche; Hiroshi Kaneko; Dieter Malchow (2005) European journal of pharmacology display abstract
We used antagonists of cGMP-phosphodiesterases to examine the role of cGMP for light-scattering oscillations and cAMP-induced Ca(2+)-influx in Dictyostelium discoideum, however, SCH 51866 (cis-5,6a,7,8,9,9a-hexahydro-2-[4-(trifluoromethyl)phenylmethyl]-5-methyl-cyclopent[4,5]imidazo[2,1-b]purin-4(3H)-one) and sildenafil citrate (1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1-H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine citrate) were poor inhibitors of cGMP-hydrolysis. Instead, SCH 51866 (IC(50) = 16 microM) and sildenafil, blocked chemoattractant (cAMP)-induced Ca(2+)-influx as determined with a Ca(2+)-specific electrode. SCH 51866 (150 microM) affected neither spontaneous cGMP transients during light-scattering-oscillations nor cAMP-mediated K(+)-efflux. SCH 51866 and sildenafil are competitive inhibitors of cGMP phosphodiesterases. However, the activity of cGMP-dependent protein kinase Ialpha (PKGIalpha) was not altered by SCH 51866 (150 microM). By contrast, patch-clamp measurements of bovine cone cGMP-gated-channels (cyclic-nucleotide-gated-channel, CNGA3), stably expressed in human embryonic kidney cells, HEK 293 cells, revealed reversible, competitive and dose-dependent inhibition of sodium currents by SCH 51866 (IC(50) = 25 microM) and sildenafil, but not by another inhibitor of cGMP-phosphodiesterases, UK 114,542. The possibility that D. discoideum cells also express a cGMP-regulated channel is supported by our finding that LY 83583 (6-(phenylamino)-5,8-quinolinedione) (35 microM), known to inhibit cyclic-nucleotide-gated-channels as well as guanylyl-cyclases, reduced cAMP-induced Ca(2+)-influx in D. discoideum, but did not affect cAMP-induced cGMP accumulation. Utilizing a PDED null strain that exhibits a prolonged and elevated cGMP transient following receptor activation, we found that the inhibition of Ca(2+)-influx by SCH 51866 in the wildtype was absent in the mutant. Our results show that SCH 51866 and sildenafil are antagonists of a Ca(2+)-permeable channel (CNGA3) and that both compete with cGMP for a regulatory site of Ca(2+)-influx in D. discoideum.
Phosphodiesterase 5 and effects of sildenafil on cerebral arteries of man and guinea pig.. Christina Kruuse; Tejvir S Khurana; Sergei D Rybalkin; Steffen Birk; Ulla Engel; Lars Edvinsson; Jes Olesen (2005) European journal of pharmacology display abstract
Sildenafil (Viagra), a selective inhibitor of phosphodiesterase 5 (PDE5), induces headache and migraine. Although previously supposed to be a "vascular" headache, no significant cerebral artery dilatation was found in vivo. Thus, we hypothesised that PDE5 may not be present or that sildenafil is less effective on the cGMP hydrolysis in cerebral arteries, and that sildenafil may not be an effective dilator of cerebral arteries under baseline conditions. We evaluated the presence of PDE5 mRNA and protein in human arteries. Furthermore, the effects of two selective PDE5 inhibitors, sildenafil and UK-114,542, and a PDE1 inhibitor UK-90,234 on cGMP hydrolysis were investigated in human and guinea pig cerebral arteries. The vasoactive responses of the compounds were evaluated in guinea pig basilar arteries in vitro, with concomitant measurements of cAMP and cGMP. PDE5 was found in human middle cerebral arteries. Sildenafil and UK-114,542 inhibited cGMP hydrolysis concentration-dependently in both species. In guinea pig arteries, sildenafil induced an endothelium-dependent vasodilatation only at concentrations above 10 nM, which was augmented by sodium nitroprusside and attenuated by reduction of cGMP, but was cGMP independent at high concentrations. UK-114,542 was more and UK-90,234 was less potent than sildenafil. In conclusion, PDE5 is present in human and guinea pig cerebral arteries, and is inhibited by sildenafil at micromolar levels. Sildenafil in vitro is a poor dilator of guinea pig cerebral arteries unless a nitric oxide donor is co-administered, corresponding to the previous findings in vivo.