sildenafil-citrate and Hyperemia

Early studies showed beneficial effects of phosphodiesterase 5 inhibitors on cardiovascular function in heart failure (HF) patients, but the RELAX trial observed no improvement in exercise capacity with sildenafil treatment in subjects with HF and preserved ejection fraction.. A subgroup of participants in the RELAX trial (n=48) underwent comprehensive noninvasive cardiovascular assessment before and after treatment with sildenafil or placebo in a prospective ancillary study. Left ventricular contractility was assessed by peak power index and stroke work index. Systemic arterial load was assessed by arterial elastance (Ea) and right ventricular afterload by pulmonary artery systolic pressure. Endothelial function was assessed by reactive hyperemia index after upper arm cuff occlusion. Compared with placebo (n=25), sildenafil (n=23) decreased Ea (-0.29±0.28 mm Hg/mL versus +0.02±0.29, P=0.008) and tended to improve reactive hyperemia index (+0.30±0.45 versus -0.17±0.30, P=0.054). In contrast, left ventricular contractility was reduced by 11% to 16% with sildenafil compared with placebo (ΔPWR/EDV -52±70 versus +0±40 mm Hg/s, P=0.006; ΔSW/EDV +0.3±5.8 versus -6.0±5.1 mm Hg, P=0.04). Sildenafil had no effect on pulmonary artery systolic pressure.. In subjects with HF and preserved ejection fraction, sildenafil displayed opposing effects on ventricular and vascular function. We speculate that beneficial effects of phosphodiesterase 5 inhibitors in the systemic vasculature and endothelium were insufficient to improve clinical status or that the deleterious effects on left ventricular function offset any salutary vascular effects, contributing to the absence of benefit observed with sildenafil in subjects with HF and preserved ejection fraction in the RELAX trial.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00094302.

Topics: Aged; Arterial Pressure; Endothelium, Vascular; Exercise Tolerance; Female; Heart Failure; Hemodynamics; Humans; Hyperemia; Male; Middle Aged; Myocardial Contraction; Phosphodiesterase 5 Inhibitors; Piperazines; Prospective Studies; Purines; Sildenafil Citrate; Sulfonamides; Time Factors; Treatment Outcome; Vasodilation; Vasodilator Agents; Ventricular Function, Left

  Sildenafil is a type 5 phosphodiesterase inhibitor that has a theoretical ability to increase hyperemia following a short bout of ischemia. We tested if oral sildenafil increases skin PORH in healthy volunteers..   We assessed forearm skin PORH (occlusion of blood flow for five minutes) in ten healthy volunteers 120minutes following the oral administration of 50 or 100mg of sildenafil. Cutaneous blood flow on the forearm was monitored using LDF..   The PORH peak, expressed as a percentage of baseline, was clearly increased with 100mg sildenafil: 746% (95% CI 447-1044) versus 484% (95% CI 354-613) with 50mg sildenafil, and 468% (95% CI 347-588) without sildenafil (p=0.03 for 100mg versus 50mg and control). Oral sildenafil at 50mg increased the AUC of PORH on the forearm compared with control: 4568PU.sec (95% CI: 2252-6883) with 50mg sildenafil versus 1030 PU.sec (95% CI 737-1322) without sildenafil (p=0.006). Likewise, 100mg sildenafil increased the AUC (5271PU.sec (95% CI -81-10,623), albeit bordering on significance (p=0.07). Neither dose increased maximal LTH..   Acute sildenafil administration at 50 and 100mg enhances skin hyperemia following a short bout of ischemia.

Topics: Administration, Oral; Adolescent; Adult; Blood Flow Velocity; Dose-Response Relationship, Drug; Female; Humans; Hyperemia; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Skin; Sulfones; Time Factors

Sildenafil, a specific inhibitor of phosphodiesterase 5A (PDE5A), is currently tested as a treatment for severe Raynaud's phenomenon. Here, we tested whether sildenafil, alone or combined with local sodium nitroprusside (SNP) delivered through skin iontophoresis, increased forearm cutaneous blood conductance in healthy volunteers, and to assess how well this combination was tolerated.. Ten healthy volunteers were enrolled. Variations in cutaneous vascular conductance (CVC) following oral administration of 50 or 100 mg of sildenafil with or without SNP iontophoresis were expressed as a percentage of maximal CVC, and were monitored using laser Doppler imaging. SNP iontophoresis was performed on the ventral surface of the forearm, 1 h after application of lidocaine/prilocaine cream.. Sildenafil at 100 mg, but not 50 mg, increased overall responses (area under the curve) (44%) and peak responses (29%) to SNP iontophoresis. Sildenafil at 100 mg, but not 50 mg, increased baseline CVC (75%). Incidence of headache was not changed when SNP iontophoresis was combined with sildenafil. One episode of symptomatic arterial hypotension occurred in a volunteer given 50 mg sildenafil, 30 min after the beginning of SNP iontophoresis.. Oral sildenafil at 100 mg potentiated local skin hyperaemia induced by SNP iontophoresis, with no increased incidence of headaches. The combination of oral specific PDE5A inhibitor and nitrates administered through skin iontophoresis deserves further investigation in diseases such as severe Raynaud's phenomenon, with particular attention to the incidence of arterial hypotension.

Topics: Administration, Oral; Adult; Dose-Response Relationship, Drug; Drug Synergism; Female; Forearm; Humans; Hyperemia; Iontophoresis; Male; Nitroprusside; Piperazines; Purines; Regional Blood Flow; Sildenafil Citrate; Skin; Sulfones; Vasodilator Agents

Maximum skin hyperaemia (MH) induced by heating skin to > or = 42 degrees C is impaired in individuals at risk of diabetes and cardiovascular disease. Interpretation of these findings is hampered by the lack of clarity of the mechanisms involved in the attainment of MH.. MH was achieved by local heating of skin to 42-43 degrees C for 30 min, and assessed by laser Doppler fluximetry. Using double-blind, randomized, placebo-controlled crossover study designs, the roles of prostaglandins were investigated by inhibiting their production with aspirin and histamine, with the H1 receptor antagonist cetirizine. The nitric oxide (NO) pathway was blocked by the NO synthase inhibitor, NG-nitro-L-arginine methyl esther (L-NAME), and enhanced by sildenafil (prevents breakdown of cGMP).. MH was not altered by aspirin, cetirizine or sildenafil, but was reduced by L-NAME: median placebo 4.48 V (25th, 75th centiles: 3.71, 4.70) versus L-NAME 3.25 V (3.10, 3.80) (p = 0.008, Wilcoxon signed rank test). Inhibition of NO production (L-NAME) resulted in a more rapid reduction in hyperaemia after heating (p = 0.011), whereas hyperaemia was prolonged in the presence of sildenafil (p = 0.003). The increase in skin blood flow was largely confined to the directly heated area, suggesting that the role of heat-induced activation of the axon reflex was small.. NO, but not prostaglandins, histamine or an axon reflex, contributes to the increase in blood flow on heating and NO is also a component of the resolution of MH after heating.

Topics: Aspirin; Cetirizine; Cross-Over Studies; Cyclic GMP; Cyclooxygenase Inhibitors; Double-Blind Method; Female; Histamine; Histamine H1 Antagonists, Non-Sedating; Hot Temperature; Humans; Hyperemia; Laser-Doppler Flowmetry; Male; Microcirculation; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Phosphodiesterase Inhibitors; Piperazines; Prostaglandins; Purines; Reference Values; Regional Blood Flow; Sildenafil Citrate; Skin; Sulfones; Ultrasonography

Sildenafil, a treatment for erectile dysfunction, is a specific phosphodiesterase type 5 (PDE 5) inhibitor that enhances nitric oxide (NO)-mediated vasodilation in the corpus cavernosum by inhibiting cyclic guanosine monophosphate breakdown. Since PDE 5 is widely expressed in the vasculature, we examined the hypothesis that sildenafil could enhance NO-mediated vasodilation in other vascular beds and improve endothelial function.. NO-mediated responses to acetylcholine (endothelium-dependent) and nitroglycerin (endothelium-independent) were measured in healthy men in the dorsal hand vein (n = 13), after the administration of either sildenafil 50 mg or placebo. Flow-mediated dilation of the brachial artery and forearm postischemic reactive hyperemia were measured before and after sildenafil 50 mg, isosorbide dinitrate 5 mg, and placebo in a double-blind, randomized, crossover study (n = 11).. In the hand vein, sildenafil administration increased sensitivity to local nitroglycerin. The 50% effective dose decreased approximately 4-fold from 13.5 ng/min (range, 6.9-26.6 ng/min) to 2.7 ng/min (range, 1.1-6.4 ng/min) (P =.025). Sildenafil decreased the maximum venoconstriction induced by phenylephrine from 81% +/- 3% to 74% +/- 3% (P =.025). Sildenafil did not significantly affect the maximal venodilatory response to acetylcholine (35% +/- 7% after placebo versus 32% +/- 8% after sildenafil) (P =.7). In the arterial vasculature, flow-mediated dilation before (2.4% +/- 1%) and after (2.8% +/- 1.4%) sildenafil (P =.8) and postischemic reactive hyperemia area under the curve before (1807 +/- 393 mL. min. s/100 mL) and after (1467 +/- 257 mL. min. s/100 mL) sildenafil were not different (P =.8). Resting heart rate, blood pressure, and resting brachial artery diameter were unchanged after sildenafil administration. Isosorbide dinitrate, an endothelium-independent vasodilator, caused a significant increase in resting brachial artery diameter from 0.53 +/- 0.01 cm to 0.56 +/- 0.02 cm (P =.005), without altering flow-mediated dilation.. In healthy men sildenafil increased sensitivity to nitroglycerin, an exogenous NO donor, approximately 4-fold but did not affect endothelium-dependent, NO-mediated responses in either the hand vein or forearm vasculature. Differential vascular responses to sildenafil may localize its enhancement of endogenous NO-mediated vasodilation to vascular beds such as the corpus cavernosum.

Topics: Acetylcholine; Adult; Brachial Artery; Dose-Response Relationship, Drug; Double-Blind Method; Hand; Humans; Hyperemia; Male; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Plethysmography; Purines; Regional Blood Flow; Sildenafil Citrate; Sulfones; Vasodilation; Veins

Previous work has shown nitric oxide (NO) contributes to ~15% of the hyperemic response to dynamic exercise in healthy humans. This NO-mediated vasodilation occurs, in part, via increases in intracellular cyclic guanosine monophosphate (cGMP), which is catabolized by phosphodiesterase. We sought to examine the effect of phosphodiesterase-5 (PDE-5) inhibition on forearm blood flow (FBF) responses to dynamic handgrip exercise in healthy humans and the role of NO. We hypothesized exercise hyperemia would be augmented by sildenafil citrate (SDF, PDE-5 inhibitor). We further hypothesized any effect of SDF on exercise hyperemia would be abolished with intra-arterial infusion of the NO synthase (NOS) inhibitor L-N. FBF (Doppler ultrasound) was assessed at rest and during 5 min of dynamic forearm handgrip exercise at 15% of maximal voluntary contraction under control (saline) conditions and during 3 experimental protocols: (1) oral SDF (n = 10), (2) intra-arterial L-NMMA (n = 20), (3) SDF and L-NMMA (n = 10). FBF responses to intra-arterial sodium nitroprusside (NTP, NO donor) were also assessed.. FBF increased with exercise (p < 0.01). Intra-arterial infusion of L-NMMA resulted in a reduction in exercise hyperemia (17 ± 1 to 15 ± 1 mL/dL/min, p < 0.01). Although the hyperemic response to NTP was augmented by SDF (area under the curve: 41 ± 7 vs 61 ± 11 AU, p < 0.01), there was no effect of SDF on exercise hyperemia (p = 0.33).. Despite improving NTP-mediated vasodilation, oral SDF failed to augment exercise hyperemia in young, healthy adults. These observations reflect a minor contribution of NO and the cGMP pathway during exercise hyperemia in healthy young humans.

Topics: Adult; Blood Pressure; Enzyme Inhibitors; Exercise; Female; Hand Strength; Hemodynamics; Humans; Hyperemia; Male; Nitric Oxide; Nitroprusside; Nucleotides, Cyclic; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Vasodilation; Young Adult

Aging is associated with an altered regulation of blood flow to contracting skeletal muscle; however, the precise mechanisms remain unclear. We recently demonstrated that inhibition of cGMP-binding phosphodiesterase 5 (PDE5) increased blood flow to contracting skeletal muscle of older but not young human subjects. Here we examined whether this effect of PDE5 inhibition was related to an improved ability to blunt α-adrenergic vasoconstriction (functional sympatholysis) and/or improved efficacy of local vasodilator pathways. A group of young (23 ± 1 yr) and a group of older (72 ± 1 yr) male subjects performed knee-extensor exercise in a control setting and following intake of the highly selective PDE5 inhibitor sildenafil. During both conditions, exercise was performed without and with arterial tyramine infusion to evoke endogenous norepinephrine release and consequently stimulation of α1- and α2-adrenergic receptors. The level of the sympatholytic compound ATP was measured in venous plasma by use of the microdialysis technique. Sildenafil increased (P < 0.05) vascular conductance during exercise in the older group, but tyramine infusion reduced (P < 0.05) this effect by 38 ± 9%. Similarly, tyramine reduced (P < 0.05) the vasodilation induced by arterial infusion of a nitric oxide (NO) donor by 54 ± 9% in the older group, and this effect was not altered by sildenafil. Venous plasma [ATP] did not change with PDE5 inhibition in the older subjects during exercise. Collectively, PDE5 inhibition in older humans was not associated with an improved ability for functional sympatholysis. An improved efficacy of the NO system may be one mechanism underlying the effect of PDE5 inhibition on exercise hyperemia in aging.

Topics: Adenosine Triphosphate; Age Factors; Aged; Aging; Blood Flow Velocity; Blood Vessels; Humans; Hyperemia; Infusions, Intra-Arterial; Male; Microdialysis; Muscle Contraction; Muscle, Skeletal; Nitric Oxide Donors; Phosphodiesterase 5 Inhibitors; Receptors, Adrenergic, alpha-1; Receptors, Adrenergic, alpha-2; Regional Blood Flow; Sildenafil Citrate; Sympathetic Nervous System; Sympathomimetics; Tyramine; Vasoconstriction; Vasodilation; Young Adult

Bone healing is still one of the most important problems of the oral and maxillofacial surgery procedures. This study was designed to evaluate the effect of sildenafil citrate (which is used for erectile dysfunction) on bone defect healing in an experimental animal model.. A total of 42 male Wistar-albino rats were randomly assigned to the control group (n=21) or the study group (n=21). The control group was fed on a standard laboratory diet until 12 h before surgery, whereas the study group received Sildenafil citrate via orogastric tube 10 mg/kg once a day for 30 days. Under anaesthesia, a 3 x 3 x 2 mm depth defect was made on tibia of each rat. 7 animals from each group were euthanised on postoperative days 7,15 and 30. Bone samples were taken for examination, histologically on day 7, by 3D dental tomography on day 15, and for bone strength resistance on day 30.. Statistically significant differences were determined between the groups from the inflammatory and repair phase, with the healing process being more advanced in the Sildenafil group.. Sildenafil citrate can be used as a supporting factor to accelerate the healing process of bone. In future comprehensive studies will need to demonstrate the Sildenafil citrate affect on bone defect healing.

Topics: Animals; Bone and Bones; Hyperemia; Male; Nitric Oxide Synthase; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Rats; Rats, Wistar; Regional Blood Flow; Sildenafil Citrate; Sulfones; Tibia; Tibial Fractures; Tomography, X-Ray Computed

Sildenafil, a selective inhibitor of phosphodiesterase type 5, produces relaxation of isolated epicardial coronary artery segments by causing accumulation of cGMP. Because shear-induced nitric oxide-dependent vasodilation is mediated by cGMP, this study was performed to determine whether sildenafil would augment the coronary resistance vessel dilation that occurs during the high-flow states of exercise or reactive hyperemia. In chronically instrumented dogs, sildenafil (2 mg/kg per os) augmented the vasodilator response to acetylcholine, with a leftward shift of the dose-response curve relating coronary flow to acetylcholine dose. Sildenafil caused a 6. 7 +/- 2.1 mmHg decrease of mean aortic pressure, which was similar at rest and during treadmill exercise (P < 0.05), with no change of heart rate, left ventricular (LV) systolic pressure, or LV maximal first time derivative of LV pressure. Sildenafil tended to increase myocardial blood flow at rest and during exercise (mean increase = 14 +/- 3%; P < 0.05 by ANOVA), but this was associated with a significant decrease in hemoglobin, so that the relationship between myocardial oxygen consumption and oxygen delivery to the myocardium (myocardial blood flow x arterial O(2) content) was unchanged. Furthermore, sildenafil did not alter coronary venous PO(2), indicating that the coupling between myocardial blood flow and myocardial oxygen demands was not altered. In addition, sildenafil did not alter the peak coronary flow rate, debt repayment, or duration of reactive hyperemia that followed a 10-s coronary occlusion. The findings suggest that cGMP-mediated resistance vessel dilation contributes little to the increase in myocardial flow that occurs during exercise or reactive hyperemia.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Acetylcholine; Analysis of Variance; Animals; Coronary Vessels; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Dogs; Dose-Response Relationship, Drug; Endothelium, Vascular; Hemodynamics; Hyperemia; Infusions, Intra-Arterial; Oxygen Consumption; Phosphodiesterase Inhibitors; Physical Conditioning, Animal; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents