sildenafil-citrate and Ventricular-Fibrillation

This study is to clarify whether sildenafil, which is a selective inhibitor of the isoform 5 of the enzyme phosphodiesterase, improves macrocirculation or/and microcirculation during ventricular fibrillation (VF) and cardiopulmonary resuscitation (CPR) so as to improve outcomes of resuscitation.. Sixteen female pigs were used. After anesthesia, the abdominal cavity was opened to observe the mesenteric microcirculation. Following the guidelines, we determined microvascular flow index, perfused vessel density and proportion of perfused vessels both for large(diameter >20 μm)and small (diameter <20 μm) microvessels. Sildenafil (0.5 mg/kg) or saline was given at 30 minutes before inducing VF. After 8 min VF, 4 min CPR was started and then defibrillation was attempted.. Compared with saline, sildenafil reduced the shocks and duration of CPR (all P < .05), and improved coronary perfusion pressure (CPP) during CPR and 24-hour survival (all P < .05). Sildenafil significantly improved microcirculatory parameters in large microvessel and decreased the lactic acid level during VF and CPR (all P < .05), but the differences in small microvessel were not significant (all P > .05). Microvascular flow index in both large and small microvessels were closely correlated to each other (r = 0.91, P < .01), and to CPP during CPR ([r = .88, P < .01] and [r = .70, P < .05], respectively).. Sildenafil increases the success of resuscitation through improving macrocirculation and microcirculation during VF and CPR. There is a close relationship between microvascular flow and CPP during CPR.

Topics: Animals; Blood Flow Velocity; Cardiopulmonary Resuscitation; Electric Countershock; Female; Mesentery; Microcirculation; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Swine; Ventricular Fibrillation

Pre-clinical studies in swine have demonstrated that a supratherapeutic concentration of sildenafil citrate decreased defibrillation efficacy and facilitated cardiac arrhythmia. We therefore, decided to investigate the effects of Kaempferia parviflora (KP) extract on these parameters in the swine heart. The underlying assumption was that in the heart, KP might be producing effects similar to sildanafil citrate as KP has long been used in southeast Asian traditional medicine to correct erectile dysfunction.. The study was conducted as the defibrillation study, and ventricular fibrillation (VF) induction study. In both studies, the defibrillation threshold (DFT), the upper limit of vulnerability (ULV) and VF threshold were determined before and after KP extract administration.. In both studies KP extract at high concentrations (100 and 50 mg/kg) significantly increased the DFT and ULV, without altering the VF threshold. At these concentrations, systolic and diastolic blood pressures were also attenuated.. High concentrations of KP extract attenuated defibrillation efficacy and increased cardiac vulnerability to arrhythmia in a normal swine heart. When used in appropriate concentrations, its blood pressure lowering effect may be useful in hypertensive states. Further studies need to be done to elucidate its mechanism of action.

Topics: Animals; Arrhythmias, Cardiac; Blood Pressure; Electric Countershock; Electrophysiological Phenomena; Heart; Heart Conduction System; Piperazines; Plant Extracts; Purines; Sildenafil Citrate; Sulfones; Swine; Ventricular Fibrillation; Zingiberaceae

Sildenafil citrate at supratherapeutic levels has been reported to decrease defibrillation efficacy. However, its effects on ventricular fibrillation induction and the upper limit of vulnerability (ULV) have not been investigated. We tested the hypothesis that sildenafil citrate reduces the ventricular fibrillation threshold (VFT) and increases the ULV.. Twenty-one pigs (25-30 kg) were randomly assigned into 3 groups of 7 pigs each. A solution containing 100 mg (group 100) or 50 mg (group 50) sildenafil citrate or 100 cc saline (group control) was infused intravenously in each pig. A train of 10 S1s was delivered from an RV electrode, and an S2 stimulus was delivered at the peak of the T wave of the last S1 activation to determine the VFT and ULV, before and after drug administration.. The 100 mg sildenafil citrate significantly (P<0.03) decreased VFT, accounting for approximately 36% by peak voltage and approximately 52% by total energy, and significantly (P<0.009) increased ULV, accounting for approximately 28% by peak voltage, and approximately 56% by total energy.. Supratherapeutic concentrations of sildenafil citrate significantly decreased the VFT and increased the ULV, resulting in an expansion of the VF induction window during the vulnerable period.

Topics: Animals; Electric Countershock; Heart Conduction System; Humans; Phosphodiesterase Inhibitors; Piperazines; Purines; Random Allocation; Sildenafil Citrate; Sulfones; Swine; Ventricular Fibrillation

A previous study demonstrated that supra-therapeutic concentration of sildenafil citrate attenuates defibrillation efficacy. However, the effect of combined sildenafil and NTG administration on defibrillation efficacy is not known.. The present study investigated whether sildenafil administration at the therapeutic level increases the defibrillation threshold (DFT) when combined with NTG.. Twenty-four pigs (20-25 kg) were randomized into four groups. After the control DFT was obtained, a stock solution of 50-mg (group 1, therapeutic concentration) and 100-mg (group 2, supratherapeutic concentration) of sildenafil, and 100-mL of saline (groups 3 and 4) were infused at 2 mL/min. Then, NTG was administered in groups 1-3 at 5 microg/min, with an increment of 5 microg/min every 5 min. The DFT was determined again after NTG was infused for 20 minutes.. In group 1, the DFT (402 +/- 33V, 11 +/- 2J) was not different from the control (404 +/- 28V, 11 +/- 2J). In group 2, the DFT (521 +/- 18V, 19 +/- 1J) was higher (p < 0.004) than that in the control group (444 +/- 31V, 14 +/- 2J). Saline did not alter the DFT either individually or in combination with NTG.. Supratherapeutic dose of sildenafil-NTG combination significantly increased the DFT (17% of peak voltage, 37% of total energy). This effect on DFT appears to be driven by sildenafil and not NTG.

Topics: Animals; Electric Countershock; Heart Ventricles; Hemodynamics; Myocardium; Nitric Oxide; Nitroglycerin; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Swine; Ventricular Fibrillation

Although fatal arrhythmia and sudden death have been reported in patients taking sildenafil citrate, its effect on defibrillation efficacy has not been investigated. The aim of this study was to test the hypothesis that sildenafil citrate increases the shock strength required to successfully defibrillate during ventricular fibrillation (VF).. A total of 26 pigs (20-25 kg) were randomly assigned into three groups. In each group, the defibrillation threshold (DFT) was determined at the beginning of the study using a three-reversal up/down protocol. Each shock (RV-SVC, biphasic) was delivered after 10 seconds of VF. Group 1 (n = 10) received 50 mg and group 2 (n = 10) received 100 mg of sildenafil citrate intravenously at a rate of 2 mL/minute for 50 minutes. Group 3 (n = 6) received 100 mL of saline intravenously at the same rate as in group 1. The DFT was determined again after the drug (drug-DFT) and saline (saline-DFT) administration. For 100-mg sildenafil citrate infusion, the DFT (483 +/- 39 V, 18 +/- 3 J) was significantly (P < 0.003 and P < 0.01, respectively) higher than the control-DFT (407 +/- 123 V, 13 +/- 7 J). This sildenafil citrate infusion increased the DFT approximately 19% by voltage, and approximately 38% by total energy. After 50-mg sildenafil citrate infusion, the DFT (454 +/- 28 V, 15 +/- 2 J) was not different than the control DFT (449 +/- 28 V, 15 +/- 2 J). Saline infusion (391 +/- 18 V, 12 +/- 1 J) did not alter the control DFT (399 +/- 22 V, 12 +/- 1 J).. The 100-mg sildenafil citrate infusion, representing a supra-therapeutic plasma level, significantly increased the DFT. This finding indicates that VF occurring during supra-therapeutic sildenafil citrate treatment would require a stronger shock to successfully defibrillate.

Topics: Animals; Blood Pressure; Electric Countershock; Heart Rate; Infusions, Intravenous; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Swine; Ventricular Fibrillation

Topics: Animals; Blood Pressure; Electric Countershock; Erectile Dysfunction; Heart Rate; Humans; Infusions, Intravenous; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Swine; Ventricular Fibrillation

Sildenafil (Viagra) prolongs repolarisation in cardiac muscle, an effect that could lead to ventricular fibrillation (VF). Sildenafil (2 mg kg(-1)) was given by mouth to 12 mongrel dogs and, 24 h later, these dogs were anaesthetised, thoracotomised and subjected to a 25 min occlusion of the anterior descending coronary artery. Haemodynamic parameters were similar in this and the control group, but there were fewer and less serious ventricular arrhythmias during occlusion in the sildenafil group (VF 17 vs 60%; ventricular premature beats 140+/-52 vs 437+/-127% and episodes of ventricular tachycardia 4.0+/-3.2 vs 19.3+/-7.7%, all P<0.05). However, reperfusion VF and indices of ischaemia severity (epicardial ST-segment mapping, inhomogeneity) were not modified by the drug. Sildenafil increased the QT interval, especially during ischaemia. Our conclusion is that ischaemia-induced ventricular arrhythmias are reduced by sildenafil, but this protection is less pronounced than that following cardiac pacing or exercise.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Coronary Vessels; Dogs; Electrocardiography; Hemodynamics; Myocardial Reperfusion Injury; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Stroke Volume; Sulfones; Tachycardia, Ventricular; Ventricular Dysfunction, Left; Ventricular Fibrillation; Ventricular Premature Complexes

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.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Carbolines; Cation Transport Proteins; Cell Line; Cyclic Nucleotide Phosphodiesterases, Type 5; Dose-Response Relationship, Drug; Ether-A-Go-Go Potassium Channels; Heart Rate; Humans; Imidazoles; Male; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Potassium Channels, Voltage-Gated; Purines; Sildenafil Citrate; Sulfones; Tachycardia, Ventricular; Tadalafil; Triazines; Vardenafil Dihydrochloride; Ventricular Fibrillation

The effects of sildenafil (Viagra), a specific inhibitor of phosphodiesterase 5, on ischemic myocardium was examined using an isolated rat heart model. Rats were pretreated with sildenafil at doses ranging from 0.001 mg to 0.5 mg/kg body weight. After 60 min, isolated hearts were subjected to ischemia for 30 min followed by 2 h of reperfusion. The results demonstrated that at 0.05 mg/kg (and to some extent at 0.01 mg/kg), sildenafil provided significant cardioprotection as evidenced by improved ventricular recovery, a reduced incidence of ventricular fibrillation and decreased myocardial infarction. At higher doses, it caused a significant increase in the incidence of ventricular fibrillation while at very low doses it had no effect on cardiac function. As expected, sildenafil increased cyclic 3',5'-monophosphate (cGMP) content in the heart. The results demonstrate for the first time that within a narrow dose range, sildenafil can protect the heart from ischemia/reperfusion injury, probably through a cGMP-signaling pathway.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Cardiotonic Agents; Cyclic GMP; Disease Models, Animal; Dose-Response Relationship, Drug; Electrocardiography; In Vitro Techniques; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Ventricular Fibrillation; Ventricular Function

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.

Topics: Action Potentials; Animals; Female; Male; Nitric Oxide Donors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Swine; Tachycardia, Ventricular; Ventricular Dysfunction, Right; Ventricular Fibrillation