Sildenafil Increases Sympathetically Mediated Vascular Tone in Humans

Dopp, John M.; Agapitov, Alexei V.; Sinkey, Christine A.; Haynes, William G.; Phillips, Brian N.

doi:10.1093/ajh/hpt018

Cited by 14 publications

(17 citation statements)

References 39 publications

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“…While sildenafil citrate is not associated with clinically significant changes in systemic hemodynamic parameters (Jackson et al 1999), it may cause increases in muscle sympathetic nerve activity (MSNA) and plasma norepinephrine (Dopp et al 2013; Phillips et al 2000). Enhanced vasoconstriction due to an increase in MSNA could partially mask any increase in exercise hyperemia as a result of sildenafil citrate.…”

Section: Discussionmentioning

confidence: 99%

Potentiation of the NO-cGMP pathway and blood flow responses during dynamic exercise in healthy humans

Limberg

Malterer

Kellawan³

et al. 2016

Eur J Appl Physiol

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Purpose 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-NG-monomethyl arginine (L-NMMA). Methods FBF (Doppler ultrasound) was assessed at rest and during 5 minutes 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. Results 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). Conclusions 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.

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Section: Discussionmentioning

confidence: 99%

Potentiation of the NO-cGMP pathway and blood flow responses during dynamic exercise in healthy humans

Limberg

Malterer

Kellawan³

et al. 2016

Eur J Appl Physiol

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“…Although at first sight this is surprising, it is notable that PDE5 inhibition by sildenafil does not reverse hypertension induced by chronic inhibition of NOS in the rat 28 and second, in humans, it is associated with increased sympathetic outflow 29 and increased sympathetically mediated vascular tone. 30 Central actions of sildenafil increasing sympathetic outflow may offset local peripheral vasodilation and explain why local intra-arterial administration of sildenafil induces forearm vasodilation 31,32 but systemic administration does not. 30,33 It is possible that increased α-adrenergic activity inhibits nNOS-mediated vasodilation, as has been shown for eNOS responses, 34 and that this outweighs any effects on cGMP.…”

Section: Discussionmentioning

confidence: 99%

“…30 Central actions of sildenafil increasing sympathetic outflow may offset local peripheral vasodilation and explain why local intra-arterial administration of sildenafil induces forearm vasodilation 31,32 but systemic administration does not. 30,33 It is possible that increased α-adrenergic activity inhibits nNOS-mediated vasodilation, as has been shown for eNOS responses, 34 and that this outweighs any effects on cGMP. Increased sympathetic outflow in hypertensive subjects could explain both the blunted nNOS response to mental stress and the lack of effect of sildenafil to further enhance high sympathetic outflow, and hence lack of effect to influence nNOS responses in these subjects.…”

Section: Discussionmentioning

confidence: 99%

Impaired Neuronal Nitric Oxide Synthase–Mediated Vasodilator Responses to Mental Stress in Essential Hypertension

et al. 2015

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Abstract-Neuronal NO synthase (nNOS) regulates blood flow in resistance vasculature at rest and during mental stress.To investigate whether nNOS signaling is dysfunctional in essential hypertension, forearm blood flow responses to mental stress were examined in 88 subjects: 48 with essential hypertension (42±14 years; blood pressure, 141±17/85±15 mm Hg; mean±SD) and 40 normotensive controls (38±14 years; 117±13/74±9 mm Hg). A subsample of 34 subjects (17 hypertensive) participated in a single blind 2-phase crossover study, in which placebo or sildenafil 50 mg PO was administered before an intrabrachial artery infusion of the selective nNOS inhibitor S-methyl-l-thiocitrulline (SMTC, 0.05, 0.1, and 0.2 μmol/min) at rest and during mental stress. In a further subsample (n=21) with an impaired blood flow response to mental stress, responses were measured in the presence and absence of the α-adrenergic antagonist phentolamine. The blood flow response to mental stress was impaired in hypertensive compared with normotensive subjects (37±7% versus 70±8% increase over baseline; P<0.001). SMTC blunted responses to mental stress in normotensive but not in hypertensive subjects (reduction of 40±11% versus 3.0±14%, respectively, P=0.01, between groups). Sildenafil reduced the blood flow response to stress in normotensive subjects from 89±14% to 43±14% (P<0.03) but had no significant effect in hypertensive subjects. Phentolamine augmented impaired blood flow responses to mental stress from 39±8% to 67±13% (P<0.02). Essential hypertension is associated with impaired mental stress-induced nNOS-mediated vasodilator responses; this may relate to increased sympathetic outflow in hypertension. nNOS dysfunction may impair vascular homeostasis in essential hypertension and contribute to stress-induced cardiovascular events. (Hypertension. 2015;65:903-909.

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“…The PDE5 inhibitor sildenafil citrate reduces vagal activation and increases sympathetic modulation in men with chronic heart failure (Piccirillo et al 2002), although this probably occurs through its reflex vasodilatory action. Moreover, sildenafil significantly increases plasma noradrenaline concentration in healthy middle-aged men (Dopp et al 2013) and alleviates functional muscle ischaemia in boys with Duchenne muscular dystrophy in a dose-dependent manner (Nelson et al 2014). Lee et al (2015) recently found that PDE9A protein expression is upregulated during hypertrophy and cardiac failure.…”

Section: Pdes As Therapeutic Targets In Cardiac Dysautonomiamentioning

confidence: 99%

“…Moreover, sildenafil significantly increases plasma noradrenaline concentration in healthy middle‐aged men (Dopp et al . ) and alleviates functional muscle ischaemia in boys with Duchenne muscular dystrophy in a dose‐dependent manner (Nelson et al . ).…”

Section: Introductionmentioning

confidence: 99%

Cyclic nucleotide regulation of cardiac sympatho‐vagal responsiveness

Paterson

2016

The Journal of Physiology

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Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are now recognized as important intracellular signalling molecules that modulate cardiac sympatho‐vagal balance in the progression of heart disease. Recent studies have identified that a significant component of autonomic dysfunction associated with several cardiovascular pathologies resides at the end organ, and is coupled to impairment of cyclic nucleotide targeted pathways linked to abnormal intracellular calcium handling and cardiac neurotransmission. Emerging evidence also suggests that cyclic nucleotide coupled phosphodiesterases (PDEs) play a key role limiting the hydrolysis of cAMP and cGMP in disease, and as a consequence this influences the action of the nucleotide on its downstream biological target. In this review, we illustrate the action of nitric oxide–CAPON signalling and brain natriuretic peptide on cGMP and cAMP regulation of cardiac sympatho‐vagal transmission in hypertension and ischaemic heart disease. Moreover, we address how PDE2A is now emerging as a major target that affects the efficacy of soluble/particulate guanylate cyclase coupling to cGMP in cardiac dysautonomia.

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Sildenafil Increases Sympathetically Mediated Vascular Tone in Humans

Abstract: Sildenafil increased sympathetically mediated vascular tone in middle-aged healthy men. Alpha-adrenergic-mediated vasoconstriction may offset vasodilation during PDE-5 inhibition and may explain the significant hypotension observed in patients taking alpha-blockers with sildenafil.

Cited by 14 publications

References 39 publications

Potentiation of the NO-cGMP pathway and blood flow responses during dynamic exercise in healthy humans

Potentiation of the NO-cGMP pathway and blood flow responses during dynamic exercise in healthy humans

Impaired Neuronal Nitric Oxide Synthase–Mediated Vasodilator Responses to Mental Stress in Essential Hypertension

Cyclic nucleotide regulation of cardiac sympatho‐vagal responsiveness

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