CLINICAL STUDY
Acute type 5 phosphodiesterase inhibition with sildenafil enhances flow-mediated vasodilation in patients with chronic heart failure
Stuart D. Katz, MDa,
Kujtim Balidemaj, MDa,
Shunichi Homma, MDb,
Henry Wu, MDb,
Jie Wang, MD, PhDa and
Simon Maybaum, MDa
a Division of Circulatory Physiology, Columbia Presbyterian Medical Center, New York, New YorkUSA
b Division of Cardiology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA
Manuscript received August 13, 1999;
revised manuscript received March 7, 2000,
accepted April 14, 2000.
Reprint requests and correspondence: Dr. Stuart D. Katz, Columbia Presbyterian Medical Center, Division of Circulatory Physiology, Room MHB5-435, 177 Fort Washington Avenue, New York, New York 10032
sdk8{at}columbia.edu
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Abstract
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OBJECTIVES
To determine the acute effects of type 5 phosphodiesterase inhibition with sildenafil on flow-mediated vasodilation in the brachial artery of patients with chronic heart failure.
BACKGROUND
Impaired endothelium-dependent, flow-mediated vasodilation in patients with heart failure is partly attributable to hyporesponsiveness of cyclic guanosine monophosphate (cGMP) mediated vasorelaxation effector mechanisms in vascular smooth muscle. The effect of inhibition of cGMP degradation with sildenafil, a specific type 5 cGMP phosphodiesterase inhibitor, on flow-mediated dilation in heart failure is unknown.
METHODS
Flow-mediated vasodilation after release of 1, 3 and 5 min of transient arterial occlusion was measured in the brachial artery with high resolution two-dimensional ultrasound imaging in 48 patients with chronic heart failure before and 1 h after randomized, double-blind assignment to a single oral dose of sildenafil 12.5, 25 or 50 mg or matching placebo.
RESULTS
In response to oral administration of a single dose of study drug, the change in flow-mediated vasodilation after release of 1, 3 and 5 min of arterial occlusion was significantly greater in patients receiving sildenafil 25 mg (3.3 ± 1.9, 3.8 ± 1.8 and 4.0 ± 1.8%, respectively, p < 0.05) and patients receiving sildenafil 50 mg (3.7 ± 1.3, 4.1 ± 1.1, 3.9 ± 1.3%, respectively, p < 0.05) than that of patients receiving placebo (0.7 ± 1.1, 0.2 ± 1.2, 0.6 ± 0.8%, respectively).
CONCLUSIONS
Acute type 5 phosphodiesterase inhibition with sildenafil 25 and 50 mg increases endothelium-dependent, flow-mediated vasodilation in patients with chronic heart failure when compared with placebo.
The vascular endothelium plays an important role in the normal regulation of peripheral vasomotor tone in conduit and resistance blood vessels (1). Nitric oxide, released by vascular endothelial cells in response to hormonal agonists and shear stress, induces vasorelaxation by increasing production of the second messenger cyclic guanosine monophosphate (cGMP) via the activation of soluble guanylate cyclase in vascular smooth muscle (2).
Agonist-induced and shear stress-induced nitric oxide-mediated vasodilation are decreased in the skeletal muscle circulation of patients with heart failure when compared with age-matched normal subjects (3,4). Impaired nitric oxide mediated vasodilation in heart failure is partly attributable to hyporesponsiveness of vasorelaxation effector mechanisms in vascular smooth muscle (5–7). The vasodilatory responses to administration of endothelium-independent cGMP-mediated vasodilatory agents such as nitroglycerin, nitroprusside (soluble guanylate cyclase activators) and atrial and brain natriuretic peptides (particulate guanylate cyclase activators) are decreased in patients with congestive heart failure when compared with normal subjects (6,8).
Vascular smooth muscle responses to cGMP-dependent vasodilatory stimuli are regulated by the activity of vascular smooth muscle phosphodiesterase, which catalyzes hydrolyzation of cGMP to inactive products (9). Seven isozymes of phosphodiesterases have been identified in mammalian tissues (10). Type 5 phosphodiesterase is the predominant isozyme that contributes to regulation of cGMP content in vascular smooth muscle (9,10). Sildenafil is a specific inhibitor of type 5 phosphodiesterase that has been approved for the treatment of erectile dysfunction in humans (11–14). The effect of type 5 phosphodiesterase inhibition with sildenafil on endothelium-dependent vasodilation in patients with heart failure is unknown.
Accordingly, the present randomized, double-blind, placebo-controlled study was undertaken to assess the acute effects of type 5 phosphodiesterase inhibition with three doses of sildenafil on flow-mediated endothelium-dependent vasodilation in the forearm circulation of ambulatory patients with chronic congestive heart failure. The study was designed to test the hypothesis that acute inhibition of cGMP degradation with sildenafil will increase flow-mediated vasodilation in the brachial artery when compared with placebo.
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Methods
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Patient population.
Thirty-nine men and nine women with symptomatic congestive heart failure were studied. Patients between the ages of 21 and 75 years with chronic heart failure for >3 months duration, stable symptoms compatible with New York Heart Association class II or III and left ventricular ejection fraction <40%, determined by radionuclide angiography or echocardiography, were eligible for the study. Criteria for exclusion were systolic blood pressure <90 mm Hg, heart rate <50 beats per minute, therapy with long-acting nitrate preparations, history of intolerance of sildenafil and myocardial infarction, unstable angina, stroke or open heart surgery within the preceding 12 months. Patients were receiving stable doses of diuretics (n = 48), angiotensin-converting enzyme inhibitors (n = 48), digoxin (n = 46) and beta-adrenergic receptor antagonists (n = 28) for at least four weeks before the study. All cardiac medications were discontinued at least 12 h before the study.
Eight men and four women without a history of cardiovascular disease served as normal control subjects to provide a comparison group for baseline pretreatment measurements in heart failure patients. Normal subjects did not receive the study drug. Normal subjects were nonsmokers with no history of cardiovascular or other chronic disease. The mean age of the normal subjects (49 ± 5 years) did not differ from that of the heart failure patients. The protocol was approved by the ethical review committee at Columbia Presbyterian Medical Center. All subjects gave written informed consent before participation.
Brachial artery ultrasound imaging.
Flow-mediated, endothelium-dependent vasodilation in response to transient arterial occlusion was determined with ultrasonographic imaging of the brachial artery with an 11 MHz linear array ultrasound transducer connected to an ATL Apogee 800 plus duplex ultrasound machine (Advanced Technology Laboratories, Bothell, Washington) adapted from previously published methods (15,16). The axial resolution of the 11 MHz transducer is capable of detection of changes in brachial artery diameter of <0.1 mm. Arterial diameter (cm) was determined as the internal dimension of the vessel wall, from trailing edge to leading edge of the anterior and posterior intimal markings, respectively (to confirm full alignment of the ultrasound beam with the maximum anterior-posterior diameter of the brachial artery in its long axis). Brachial artery blood flow velocity was determined with a 1.2 mm pulsed Doppler ultrasound sampling volume placed in the center of the image of the vessel lumen with internal software correction for the incident angle of 60°. Mean blood flow velocity (cm/s) was determined by calculation of the area under the hand-traced curve of the velocity spectral display. Brachial artery diameter and blood flow velocity were measured at rest and after release of transient arterial occlusion induced by inflation of a forearm blood pressure cuff to suprasystolic pressure for 1, 3 and 5 min. Submaximal (1 and 3 min occlusions) and maximal (5 min occlusion) vasodilatory stimuli were utilized to determine whether a ceiling effect in response to a maximal stimulus might mask drug effects apparent at submaximal stimuli. Sequential occlusions were performed at 5 to 15 min intervals, when blood flow velocity and arterial diameter had returned to baseline. Blood flow velocity was measured for 15 s immediately upon release of the occluding cuff; the mean velocity of the first five beats after release was averaged. Brachial artery diameter was measured at end-diastole 60 to 75 s after release of the occluding cuff; five diameter measurements were averaged. Flow-mediated dilation was determined as the percent change in brachial artery diameter after cuff release compared with the resting brachial artery diameter.
Study design.
This was a prospective, double-blind study of three ascending doses of sildenafil versus placebo. The study drug consisted of a single oral dose of sildenafil (12.5, 25 or 50 mg) or matching placebo prepared by the Columbia Presbyterian Medical Center Research Pharmacy from sildenafil citrate tablets (Viagra, Pfizer U.S. Pharmaceuticals, New York, New York). Treatment assignment was randomly allocated within three blocks of 16 patients (12 sildenafil, 4 placebo in each block) in ascending dose order. Subjects were studied in the postabsorptive state. Brachial artery diameter and blood flow velocity were measured in the supine position at rest and after release of 1, 3 and 5 min of transient arterial occlusion before and 1 h after oral ingestion of study drug (to correspond to peak plasma concentration after oral dosing [17]) by an investigator blinded to treatment assignment. Seated blood pressure was determined in triplicate before and 1 h after the study drug with the cuff method. Mean arterial pressure was calculated from a standard formula. Heart rate and rhythm were electrocardiographically monitored throughout the study.
Data analysis.
Values are expressed as mean ± SEM. The primary end point of the study was a change in flow-mediated vasodilation from pretreatment values after oral administration of sildenafil when compared with placebo. Secondary end points were mean blood flow velocity and tolerability/safety parameters (heart rate, blood pressure, and reported adverse events). Differences in flow mediated dilation before and after study drug were analyzed with a repeated measures analysis of variance model with two within group factors (arterial occlusion time, before/after study drug) and one between group factor (treatment assignment). Dunnett’s test was used for post-hoc comparison of treatment groups receiving the three doses of sildenafil versus placebo. A two-tailed p value <0.05 was considered statistically significant.
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Results
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Clinical characteristics.
The clinical characteristics of the four treatment groups (sildenafil 12.5, 25, 50 mg and placebo) are presented in Table 1. No significant differences were present among the treatment groups. Two patients (one assigned to placebo and one assigned to sildenafil 25 mg) were excluded from the final analysis due to suboptimal ultrasound images of the brachial artery.
Flow-mediated dilation.
Brachial artery diameter at rest did not differ among the four treatment groups (0.36 ± 0.02 cm placebo, 0.41 ± 0.01 cm sildenafil 12.5 mg, 0.41 ± 0.02 cm sildenafil 25 mg, 0.40 ± 0.02 cm sildenafil 50 mg) before study drug administration and did not significantly change after study drug administration. Before study drug administration, flow-mediated dilation after release of 1 and 5 min of arterial occlusion did not significantly differ among the four treatment groups, whereas by chance, the pretreatment flow-mediated vasodilation after 3 min of arterial occlusion was lower in the patients assigned to receive 50 mg sildenafil when compared with those assigned to receive 12.5 mg sildenafil or placebo (p < 0.05, Table 2). Pretreatment flow-mediated vasodilation was not significantly correlated with treatment response (r = 0.24, p = NS). After study drug administration, the change in flow-mediated dilation from pretreatment values significantly increased in patients receiving sildenafil 25 mg and patients receiving sildenafil 50 mg (both p < 0.05) but not in patients receiving sildenafil 12.5 mg when compared with patients receiving placebo (Fig. 1, Table 2).
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Table 2 Flow-Mediated Vasodilation (Percent Change in Brachial Artery Diameter) After Release of 1, 3 and 5 Min of Transient Arterial Occlusion Before and After Study Drug Administration in Patients With Heart Failure According to Treatment Assignment
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Figure 1 Change (means ± SEM) in flow-mediated dilation (FMD, %) from pretreatment values after release of 1, 3 and 5 min of arterial occlusion in patients treated with placebo (closed squares), sildenafil 12.5 mg (open squares), sildenafil 25 mg (open circles) and sildenafil 50 mg (open triangles).
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Mean blood flow velocity.
Mean brachial artery blood flow velocity did not differ among the four treatment groups at rest (7.8 ± 0.6 cm/s placebo, 5.5 ± 0.5 cm/s sildenafil 12.5 mg, 7.2 ± 1.0 cm/s sildenafil 25 mg, 7.5 ± 0.5 cm/s sildenafil 50 mg) before study drug administration and did not significantly change after study drug administration. Before study drug administration, mean brachial artery blood flow velocity after release of 1, 3 and 5 min of arterial occlusion did not differ among the treatment groups (Table 3). After study drug administration, mean brachial artery blood flow velocity did not differ among the treatment groups (Table 3).
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Table 3 Mean Brachial Artery Blood Flow Velocity (cm/s) After Release of 1, 3 and 5 Min of Transient Arterial Occlusion Before and After Study Drug Administration in Patients With Heart Failure According to Treatment Assignment
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Tolerability.
Mean arterial pressure did not differ among the four treatment groups before or after study drug administration (Table 4). Heart rate was significantly lower in patients assigned to placebo when compared with the other treatment groups before and after study drug administration (Table 4). This finding may be related to a nonsignificant trend towards increased frequency of use of beta-adrenergic receptor antagonists as background therapy in patients assigned to placebo. Pretreatment heart rate did not significantly correlate with treatment response (r = 0.20, p = NS). In a post-hoc analysis, flow-mediated vasodilation after release of 1, 3 or 5 min of arterial occlusion did not differ in patients with or without background beta-adrenergic receptor antagonist therapy. The study drug was generally well-tolerated. Reported side effects were flushing in seven patients (three treated with sildenafil 12.5mg, three treated with sildenafil 25 mg and one patient treated with sildenafil 50 mg) and mild headache and lightheadedness in one patient treated with placebo.
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Table 4 Heart Rate and MAP Before and After Study Drug Administration in Patients With Heart Failure According to Treatment Assignment
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Normal controls.
Resting brachial artery diameter (0.40 ± 0.02 cm) in normal subjects did not differ from that of patients with heart failure. Resting brachial artery mean blood flow velocity (8.6 ± 0.6 cm/s) was significantly greater in normal subjects when compared with that of patients with heart failure (p < 0.05). Flow-mediated vasodilation after release of 1, 3 and 5 min of transient arterial occlusion (2.8 ± 0.8, 4.2 ± 0.7 and 6.1 ± 1.0%, respectively) and mean brachial artery blood flow velocity after release of 1, 3 and 5 min of transient arterial occlusion (30.4 ± 2.4, 52.6 ± 5.0 and 58.4 ± 6.6 cm/s, respectively) were significantly greater in normal subjects when compared with that of patients with heart failure (both p < 0.05).
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Discussion
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The present data demonstrate a significant increase in flow-mediated dilation in the brachial artery after administration of sildenafil 25 and 50 mg when compared with placebo in ambulatory patients with chronic heart failure. These findings suggest that type 5 phosphodiesterase inhibition with sildenafil acutely improves endothelium-dependent vasodilation in patients with chronic heart failure.
Sildenafil mechanism of action.
Sildenafil is a specific inhibitor of type 5 phosphodiesterase, the predominant isozyme for cGMP degradation in smooth muscle, including human vascular smooth muscle (18). The clinical benefits of sildenafil in erectile dysfunction are mediated by enhanced cGMP-dependent effects related to nitric oxide signaling in corpus cavernosum (11,19,20). Flow-mediated dilation is partly mediated by activation of soluble guanylate cyclase in vascular smooth muscle in response to shear stress-induced endothelial release of nitric oxide (2). Zaprinast, a type 5 phosphodiesterase inhibitor not available for clinical use, enhances endothelium-dependent, nitric oxide-mediated vasodilation in isolated rat aortic rings, in the intact lamb and cat pulmonary circulation with experimental pulmonary hypertension and in the cat hindlimb circulation (21–24). Increased flow-mediated vasodilation in this study is likely due to a direct effect of sildenafil on the brachial artery since the stimulus for flow-mediated dilation, mean blood flow velocity (the predominant physiological determinant of shear stress), did not differ among treatment groups before and after study drug administration. Absence of a change in mean blood flow velocity after sildenafil indicates a primary effect on conduit vessel function (6). The drug-induced increase in flow-mediated vasodilation was observed in response to submaximal (1 and 3 min occlusions) and maximal (5 min occlusion) vasodilatory stimuli. The absence of a ceiling effect in response to a maximal stimulus is in accord with recent studies, which demonstrated improvement in flow-mediated vasodilation in response to 5 min of arterial occlusion after acute administration of ascorbic acid and quinaprilat (25,26).
Mechanisms of endothelial dysfunction in heart failure.
Endothelium-dependent vasodilation in response to hormonal agonists and shear stress is decreased in the skeletal muscle circulation of patients with chronic heart failure when compared with that of normal subjects (3,4,6). The current finding of decreased flow-mediated vasodilation when compared with normal subjects before administration of the study drug is concordant with these past studies. Decreased flow-mediated dilation in patients with heart failure can be attributed to decreased shear stress signal (since mean blood flow velocity was decreased when compared with normal subjects) and reduced activity of the L-arginine-nitric oxide metabolic pathway (27). In addition, impaired vasodilation in response to endothelium-derived nitric oxide in patients with heart failure is partly attributable to hyporesponsiveness of vasorelaxation effector mechanisms in vascular smooth muscle. Previous studies of the vasodilatory responses to intraarterial administration of activators of soluble guanylate cyclase, nitroglycerin and nitroprusside in patients with heart failure have yielded conflicting findings. While some investigators have reported normal vasodilatory responses (3,28), the majority have demonstrated that the vasodilatory responses to nitrosovasodilators are significantly decreased in patients with heart failure when compared with normal subjects (5–7,29–32). The vasodilatory responses to intraarterial administration of atrial natriuretic peptide and brain natriuretic peptide, which mediate vasodilation through activation of particulate guanylate cyclase in vascular smooth muscle, are also attenuated in patients with heart failure when compared with normal subjects (8). In contrast, the vasodilation responses to intraarterial administration of the cyclic adenosine monophosphate dependent vasodilators, isoproterenol and phentolamine, did not differ in patients with congestive heart failure when compared with normal subjects (28,29). Taken together, these observations suggest a specific defect in cGMP-mediated vasodilation is present in the vascular smooth muscle of patients with congestive heart failure.
Role of type 5 phosphodiesterase.
Impaired cGMP-mediated vasodilation in heart failure may be due to decreased synthesis of cGMP (via both soluble and particulate guanylate cyclase pathways), increased degradation of cGMP by phosphodiesterase or downstream abnormalities in the cGMP signal transduction pathway (9). In isolated glomeruli from dogs with heart failure induced by rapid ventricular pacing, cGMP accumulation in response to atrial natriuretic peptide and sodium nitroprusside is decreased when compared with normal controls and is associated with increased phosphodiesterase hydrolyzing activity of cGMP (33). Neurohormonal activation in heart failure may contribute to alterations in cGMP metabolism since, in cultured rat mesangial cells, angiotensin II attenuates the effects of atrial natriuretic peptide on cGMP accumulation, in part, by increasing phosphodiesterase hydrolyzing activity (34).
Study limitations.
Interpretation of the current findings is limited by the short duration of therapy and the relatively small number of patients in each treatment group. Small group differences in pretreatment values of flow-mediated vasodilation and heart rate are unlikely to explain our findings because neither of these variables correlated with treatment response. All patients in the study had compensated chronic heart failure and were receiving therapy consisting of several different classes of medications. Although medications were discontinued before the measurements, an effect of medications on the current findings cannot be excluded. Consistent with the findings of recent large survival trials (35,36), co-morbid conditions, which may influence endothelium-dependent, flow-mediated dilation, were present in this study population. Background medication use and prevalence of co-morbid conditions are unlikely to account for the current findings since baseline clinical characteristics did not differ among the four treatment groups. Since normal subjects did not receive sildenafil in this study, our findings cannot determine whether improved flow-mediated vasodilation after sildenafil was a nonspecific effect or related to reversal of a pathophysiological mechanism present in heart failure.
Conclusions.
This study demonstrated that a single oral dose of sildenafil 25 and 50 mg acutely increases flow-mediated endothelium-dependent vasodilation in the brachial artery of patients with chronic heart failure when compared with placebo. Due to the small number of patients per treatment group, these findings require confirmation in larger studies. Sildenafil was well-tolerated in the study population without significant changes in heart rate or blood pressure. The most frequently reported side effect, flushing, in seven patients (15%) is comparable to the incidence of flushing reported in controlled clinical trials of other patient populations (37). Since its introduction into clinical practice for the treatment of erectile dysfunction, sildenafil has been rarely associated with adverse cardiovascular events (38). Further studies are warranted to characterize the safety and efficacy of longer term type 5 phosphodiesterase inhibition in the treatment of endothelial dysfunction in chronic heart failure.
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Footnotes
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Dr. Katz is partially supported by a NIH K24 HL04024 career development grant.
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D. A. Kass, H. C. Champion, and J. A. Beavo
Phosphodiesterase Type 5: Expanding Roles in Cardiovascular Regulation
Circ. Res.,
November 26, 2007;
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[Abstract]
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G. D. Lewis, J. Lachmann, J. Camuso, J. J. Lepore, J. Shin, M. E. Martinovic, D. M. Systrom, K. D. Bloch, and M. J. Semigran
Sildenafil Improves Exercise Hemodynamics and Oxygen Uptake in Patients With Systolic Heart Failure
Circulation,
January 2, 2007;
115(1):
59 - 66.
[Abstract]
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I. H. Zucker, H. D. Schultz, W. Wang, M. Guazzi, A. C. Scott, C. E. Negrao, M. U. P. B. Rondon, E. S. Prakash, A. L. Clark, A. Crisafulli, et al.
Increased mechanoreceptor/metaboreceptor stimulation explains the exaggerated exercise pressor reflex seen in heart failure
J Appl Physiol,
January 1, 2007;
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498 - 501.
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E. R. Schwarz, S. Rastogi, V. Kapur, N. Sulemanjee, and J. J. Rodriguez
Erectile Dysfunction in Heart Failure Patients
J. Am. Coll. Cardiol.,
September 19, 2006;
48(6):
1111 - 1119.
[Abstract]
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H. Zheng, M. Patel, K. Hryniewicz, and S. D. Katz
Association of extended work shifts, vascular function, and inflammatory markers in internal medicine residents: a randomized crossover trial.
JAMA,
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W. Kiowski, H. Brunner, and C. Schalcher
Sex, the heart, and heart failure.
Seminars in Cardiothoracic and Vascular Anesthesia,
September 1, 2006;
10(3):
256 - 258.
[Abstract]
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M. Clozel, P. Hess, M. Rey, M. Iglarz, C. Binkert, and C. Qiu
Bosentan, sildenafil, and their combination in the monocrotaline model of pulmonary hypertension in rats.
Experimental Biology and Medicine,
June 1, 2006;
231(6):
967 - 973.
[Abstract]
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S D Robinson, C A Ludlam, N A Boon, and D E Newby
Phosphodiesterase type 5 inhibition does not reverse endothelial dysfunction in patients with coronary heart disease
Heart,
February 1, 2006;
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[Abstract]
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R. Fries, K. Shariat, H. von Wilmowsky, and M. Bohm
Sildenafil in the Treatment of Raynaud's Phenomenon Resistant to Vasodilatory Therapy
Circulation,
November 8, 2005;
112(19):
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[Abstract]
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B. A. Borlaug, V. Melenovsky, T. Marhin, P. Fitzgerald, and D. A. Kass
Sildenafil Inhibits {beta}-Adrenergic-Stimulated Cardiac Contractility in Humans
Circulation,
October 25, 2005;
112(17):
2642 - 2649.
[Abstract]
[Full Text]
[PDF]
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A. Das, L. Xi, and R. C. Kukreja
Phosphodiesterase-5 Inhibitor Sildenafil Preconditions Adult Cardiac Myocytes against Necrosis and Apoptosis: ESSENTIAL ROLE OF NITRIC OXIDE SIGNALING
J. Biol. Chem.,
April 1, 2005;
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[Abstract]
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G. J. Gross
Sildenafil and Endothelial Dysfunction in Humans
Circulation,
February 15, 2005;
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M. L. Bots, J. Westerink, T. J. Rabelink, and E. J.P. de Koning
Assessment of flow-mediated vasodilatation (FMD) of the brachial artery: effects of technical aspects of the FMD measurement on the FMD response
Eur. Heart J.,
February 2, 2005;
26(4):
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[Abstract]
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S. D. Katz, K. Hryniewicz, I. Hriljac, K. Balidemaj, C. Dimayuga, A. Hudaihed, and A. Yasskiy
Vascular Endothelial Dysfunction and Mortality Risk in Patients With Chronic Heart Failure
Circulation,
January 25, 2005;
111(3):
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[Abstract]
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M. Guazzi, G. Tumminello, F. Di Marco, C. Fiorentini, and M. D. Guazzi
The effects of phosphodiesterase-5 inhibition with sildenafil on pulmonary hemodynamics and diffusion capacity, exercise ventilatory efficiency, and oxygen uptake kinetics in chronic heart failure
J. Am. Coll. Cardiol.,
December 21, 2004;
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[Abstract]
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S. G. Raja and S. H. Nayak
Sildenafil: Emerging Cardiovascular Indications
Ann. Thorac. Surg.,
October 1, 2004;
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[Abstract]
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R. C Kukreja, R. Ockaili, F. Salloum, and L. Xi
Sildenafil-induced cardioprotection in rabbits
Cardiovasc Res,
December 1, 2003;
60(3):
700 - 701.
[Full Text]
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C. Vlachopoulos, K. Hirata, and M. F O'Rourke
Effect of sildenafil on arterial stiffness and wave reflection
Vascular Medicine,
November 1, 2003;
8(4):
243 - 248.
[Abstract]
[PDF]
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T. Reffelmann and R. A. Kloner
Therapeutic Potential of Phosphodiesterase 5 Inhibition for Cardiovascular Disease
Circulation,
July 15, 2003;
108(2):
239 - 244.
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M. Kimura, Y. Higashi, K. Hara, K. Noma, S. Sasaki, K. Nakagawa, C. Goto, T. Oshima, M. Yoshizumi, and K. Chayama
PDE5 Inhibitor Sildenafil Citrate Augments Endothelium-Dependent Vasodilation in Smokers
Hypertension,
May 1, 2003;
41(5):
1106 - 1110.
[Abstract]
[Full Text]
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G. Jackson
Phosphodiesterase type 5 inhibition in cardiovascular disease: experimental models and potential clinical applications
Eur. Heart J. Suppl.,
December 1, 2002;
4(suppl_H):
H19 - H23.
[Abstract]
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J. P. J. Halcox, K. R. A. Nour, G. Zalos, R. Mincemoyer, M. A. Waclawiw, C. E. Rivera, G. Willie, S. Ellahham, and A. A. Quyyumi
The effect of sildenafil on human vascular function, platelet activation, and myocardial ischemia
J. Am. Coll. Cardiol.,
October 2, 2002;
40(7):
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[Abstract]
[Full Text]
[PDF]
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E. A. Bocchi, G. Guimaraes, A. Mocelin, F. Bacal, G. Bellotti, and J. F. Ramires
Sildenafil Effects on Exercise, Neurohormonal Activation, and Erectile Dysfunction in Congestive Heart Failure: A Double-Blind, Placebo-Controlled, Randomized Study Followed by a Prospective Treatment for Erectile Dysfunction
Circulation,
August 27, 2002;
106(9):
1097 - 1103.
[Abstract]
[Full Text]
[PDF]
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C. Desouza, A. Parulkar, D. Lumpkin, D. Akers, and V. A. Fonseca
Acute and Prolonged Effects of Sildenafil on Brachial Artery Flow-Mediated Dilatation in Type 2 Diabetes
Diabetes Care,
August 1, 2002;
25(8):
1336 - 1339.
[Abstract]
[Full Text]
[PDF]
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H. Zheng, C. Dimayuga, A. Hudaihed, and S. D. Katz
Effect of Dexrazoxane on Homocysteine-Induced Endothelial Dysfunction in Normal Subjects
Arterioscler Thromb Vasc Biol,
July 1, 2002;
22(7):
e15 - 18.
[Abstract]
[Full Text]
[PDF]
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A. M. Arruda-Olson, D. W. Mahoney, A. Nehra, M. Leckel, and P. A. Pellikka
Cardiovascular Effects of Sildenafil During Exercise in Men With Known or Probable Coronary Artery Disease: A Randomized Crossover Trial
JAMA,
February 13, 2002;
287(6):
719 - 725.
[Abstract]
[Full Text]
[PDF]
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S. D. Katz, D. V. Parums, B. G. Phillips, M. Kato, C. A. Pesek, V. K. Somers, M. Winnicki, D. Davison, and K. Narkiewicz
Sympathetic Activation by Sildenafil Response
Circulation,
November 27, 2001;
104
(22):
e119 - e120.
[Full Text]
[PDF]
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R D Rakhit and M S Marber
Nitric oxide: an emerging role in cardioprotection?
Heart,
October 1, 2001;
86(4):
368 - 372.
[Full Text]
[PDF]
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Abstract
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