Sildenafil Improves Coronary Artery Patency in a Canine Model of Platelet-Mediated Cyclic Coronary Occlusion After Thrombolysis

Lewis, Gregory D.; Witzke, Christian; Colón-Hernández, Pedro; Guerrero, J. Luis; Bloch, Kenneth D.; Semigran, Marc J.

doi:10.1016/j.jacc.2005.11.060

Cited by 17 publications

(10 citation statements)

References 38 publications

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“…Third, the improved neurological outcome noted in our study may reflect an activity of sildenafil other than its influence on vasospasm. For example, sildenafil inhibits platelet aggregation, 29–30 and could thus reduce formation of microthrombi, which have also been implicated in the pathophysiology of DCI after SAH. 31 Finally, the manner in which sildenafil reduces SAH-induced neuronal cell death was not addressed in our study.…”

Section: Discussionmentioning

confidence: 99%

Phosphodiesterase 5 Inhibition Attenuates Cerebral Vasospasm and Improves Functional Recovery After Experimental Subarachnoid Hemorrhage

et al. 2012

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Background Cerebral vasospasm is an independent predictor of poor outcome after subarachnoid hemorrhage (SAH). The nitric oxide-cyclic GMP (NO-cGMP) vasodilatory pathway is strongly implicated in its pathophysiology. Preliminary studies suggest that phosphodiesterase 5 (PDE5) – an enzyme that degrades cGMP – may play a role, as the PDE5 inhibitor sildenafil was found to reduce vasospasm after SAH. However, several questions that are critical when considering translational studies remain unanswered. Objective To elucidate the mechanism of action of sildenafil against vasospasm, and to assess whether sildenafil attenuates SAH-induced neuronal cell death, improves functional outcome after SAH, or causes significant physiological side effects when administered at therapeutically relevant doses. Methods SAH was induced via endovascular perforation in male C57BL6 mice. Beginning two hours later, mice received sildenafil citrate (0.7, 2 or 5mg/kg P.O. BID) or vehicle. Neurological outcome was assessed daily. Vasospasm was determined on post-SAH Day 3. Brain PDE5 expression and activity, cGMP content, neuronal cell death, arterial blood pressure (BP), and intracranial pressure (ICP) were examined. Results We found that PDE5 activity (but not expression) is increased after SAH, leading to decreased cGMP levels. Sildenafil attenuates this increase in PDE5 activity and restores cGMP levels after SAH. Post-SAH initiation of sildenafil was found to reduce vasospasm, decrease neuronal cell death, and markedly improve neurological outcome, without causing significant physiological side effects. Conclusion Sildenafil–an FDA-approved drug with a proven track record of safety in humans –is a promising new therapy for vasospasm and neurological deficits following SAH.

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Section: Discussionmentioning

confidence: 99%

Phosphodiesterase 5 Inhibition Attenuates Cerebral Vasospasm and Improves Functional Recovery After Experimental Subarachnoid Hemorrhage

et al. 2012

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“…Indeed, although it is generally acknowledged that drugs such as aspirin and the thienopyridines can effectively reduce thrombosis in ACS, they are significantly less effective at inhibiting the strong platelet activations associated with thrombolysis or in-stent thrombosis (7,8); the latter represent a significant cause of acute myocardial infarctions and sudden cardiac death (2)(3)(4)(5). In this context, recent attention has shifted to using selective PDE5 inhibitors such as sildenafil citrate (Viagra) for prevention of thrombosis (10,11). Although the use of PDE5 inhibitors for anti-platelet therapeutics is consistent with the widely accepted idea that increases in intracellular cGMP result in inhibition of platelet aggregation, scattered recent reports have suggested that sildenafil might have proaggregatory effects and that these prothrombotic effects could limit their utility (12).…”

Section: Discussionmentioning

confidence: 99%

“…Although anti-platelet agents, including aspirin or thienopyridines, can reduce thrombosis in ACS or at stents, their weak potencies rarely eliminate platelet-mediated re-occlusions in response to strong platelet activation signals, including those associated with thrombolysis (7,8). The anti-platelet actions of the selective cyclic nucleotide phosphodiesterase 5 (PDE5) inhibitors, including sildenafil citrate (Viagra), was suggested to represent a therapeutic option in controlling ACS and in-stent thrombosis (9)(10)(11). Although the anti-platelet actions of sildenafil support the use of PDE5 inhibitors as anti-thrombotic agents, other reports suggest that sildenafil might have proaggregatory effects (12).…”

mentioning

confidence: 99%

Compartmentation and compartment-specific regulation of PDE5 by protein kinase G allows selective cGMP-mediated regulation of platelet functions

Wilson

Elbatarny²,

Crawley³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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It is generally accepted that nitric oxide (NO) donors, such as sodium nitroprusside (SNP), or phosphodiesterase 5 (PDE5) inhibitors, including sildenafil, each impact human platelet function. Although a strong correlation exists between the actions of NO donors in platelets and their impact on cGMP, agents such as sildenafil act without increasing global intra-platelet cGMP levels. This study was undertaken to identify how PDE5 inhibitors might act without increasing cGMP. Our data identify PDE5 as an integral component of a protein kinase G1␤ (PKG1␤)-containing signaling complex, reported previously to coordinate cGMP-mediated inhibition of inositol-1, 4, 5-trisphosphate receptor type 1 (IP 3R1)-mediated Ca 2؉ -release. PKG1␤ and PDE5 did not interact in subcellular fractions devoid of IP 3R1 and were not recruited to IP3R1-enriched membranes in response to cGMP-elevating agents. Activation of platelet PKG promoted phosphorylation and activation of the PDE5 fraction tethered to the IP 3R1-PKG complex, an effect not observed for the nontethered PDE5. Based on these findings, we elaborate a model in which PKG selectively activates PDE5 within a defined microdomain in platelets and propose that this mechanism allows spatial and temporal regulation of cGMP signaling in these cells. Recent reports indicate that sildenafil might prove useful in limiting in-stent thrombosis and the thrombotic events associated with the acute coronary syndromes (ACS), situations poorly regulated with currently available therapeutics. We submit that our findings may define a molecular mechanism by which PDE5 inhibition can differentially impact selected cellular functions of platelets, and perhaps of other cell types.calcium ͉ PKG

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“…Sildenafil may have a biphasic effect on platelets, consisting of an initial transient stimulatory response that promotes platelet aggregation and a subsequent inhibitory response that limits the size of thrombi [67]. Ex vivo inhibition of platelet aggregation despite aspirin therapy has also been observed [68]. Sildenafil also increases the threshold for activation of the platelet glycoprotein IIb/IIIa receptor without an effect on platelet degranulation [19].…”

Section: Effects Of Selective Pde5 Inhibition On Cardiac and Vascularmentioning

confidence: 99%

Cardiovascular Effects of Phosphodiesterase Type 5 Inhibitors

Vlachopoulos

Ioakeimidis

Rokkas

et al. 2009

The Journal of Sexual Medicine

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Introduction Phosphodiesterase type 5 (PDE5) inhibitors are widely used as first-line therapy for erectile dysfunction (ED). Their efficacy and safety combined with an increasing understanding of cyclic guanosine monophosphate (cGMP)-regulated mechanisms have triggered a number of attempts to determine their effects on the cardiovascular system and their potential benefits in cardiovascular conditions. Aim To review and discuss recent findings regarding the cardiovascular effects of PDE5 inhibitors and to highlight current and future clinical applications beyond ED. Main Outcome Measures Results of preclinical and clinical studies evaluating the cardiovascular effects of PDE5 inhibitors are analyzed and critically put into perspective. Methods Extensive PubMed literature search reviewing relevant data on effects and mechanisms of PDE5 inhibitors on the cardiovascular system. Results In recent years, extensive but very heterogeneous preclinical and clinical evidence has been reported. PDE5 inhibition has proven collateral benefits for a multitude of risk factors or diseases associated with or accompanying ED. However, these agents appear to have the potential of expanding their indications. To date, PDE5 inhibition has been shown to be effective for the treatment of idiopathic pulmonary artery hypertension, and sildenafil is approved for this indication. Importantly, accumulating data show that the therapeutic potential extends to the myocardium, the coronary and peripheral arteries, subliclinical inflammation, oxidative stress, thrombosis, neurological recovery, and pathways of fibrosis. Thus, the spectrum of patients who may benefit has expanded to include, for instance, patients with heart failure or coronary artery disease. Conclusions PDE5 inhibitors are an exciting class of drugs with pleiotropic effects. Current or future PDE5 inhibitors are a conceptually attractive therapeutic strategy with potential clinical applications in a variety of cardiovascular conditions.

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Sildenafil Improves Coronary Artery Patency in a Canine Model of Platelet-Mediated Cyclic Coronary Occlusion After Thrombolysis

Abstract: Sildenafil improves coronary patency in a canine model of platelet-mediated coronary artery thrombosis, likely via inhibition of platelet aggregation.

Cited by 17 publications

References 38 publications

Phosphodiesterase 5 Inhibition Attenuates Cerebral Vasospasm and Improves Functional Recovery After Experimental Subarachnoid Hemorrhage

Phosphodiesterase 5 Inhibition Attenuates Cerebral Vasospasm and Improves Functional Recovery After Experimental Subarachnoid Hemorrhage

Compartmentation and compartment-specific regulation of PDE5 by protein kinase G allows selective cGMP-mediated regulation of platelet functions

Cardiovascular Effects of Phosphodiesterase Type 5 Inhibitors

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