EXPERIMENTAL STUDY
Sildenafil citrate (Viagra) does not exacerbate myocardial ischemia in canine models of coronary artery stenosis
Karin Przyklenk, PhD, FACCa and
Robert A. Kloner, MD, PhD, FACCa
a Heart Institute, Good Samaritan Hospital, and Department of Medicine, Section of Cardiology, University of Southern California, Los Angeles, California, USA
Manuscript received April 11, 2000;
revised manuscript received July 17, 2000,
accepted September 11, 2000.
Reprint requests and correspondence: Dr. Karin Przyklenk, Heart Institute/Research, Good Samaritan Hospital, 1225 Wilshire Boulevard, Los Angeles, California 90017-2395
karinp{at}dnamail.com
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Abstract
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OBJECTIVES
Our aim was to determine whether sildenafil citrate (Viagra) unfavorably alters coronary perfusion in canine models of coronary artery stenosis.
BACKGROUND
Concern has been raised that sildenafil may exacerbate ischemia in patients with coronary artery disease. However, the effects of sildenafil on coronary perfusion are largely unexplored.
METHODS
Using anesthetized dogs, a micromanometer constrictor was applied to either an intact coronary artery (model of stable hypoperfusion: Protocol 1) or a site of arterial injury (model of recurrent platelet-mediated thrombosis: Protocol 2). After monitoring coronary flow for 1 h, dogs received two escalating, clinically relevant doses of sildenafil or placebo. Perfusion was assessed during the initial hour pretreatment, for 1 h following dose 1 and 1 h following dose 2 by measuring the area of the flow-time profile, normalized to baseline flow x 60 min. Interaction between sildenafil and adenosine-mediated inhibition of platelet aggregation was evaluated by in vitro platelet aggregometry (Protocol 3).
RESULTS
In Protocol 1, flow-time area was maintained at 50% to 60% of baseline in both placebo- and sildenafil-treated groups. In Protocol 2, controls exhibited an expected modest, temporal adenosine-mediated improvement in flow-time area (from 40 ± 5% to 61 ± 7%; p < .05) while in contrast, perfusion in sildenafil-treated dogs remained unchanged (37 ± 6% vs. 33% to 35% before vs. after treatment). In vitro aggregometry confirmed that sildenafil rendered platelets refractory to the inhibitory effects of adenosine receptor stimulation.
CONCLUSIONS
Sildenafil did not exacerbate ischemia in canine models of coronary stenosis. However, in the setting of recurrent thrombosis, sildenafil-treated dogs were apparently unresponsive to the platelet inhibitory effects of endogenous adenosine.
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Abbreviations and Acronyms
| | cAMP | = adenosine 3',5'-cyclic monophosphate | | cGMP | = guanosine 3',5'-cyclic monophosphate | | CBF | = coronary blood flow | | CFVs | = cyclic variations in coronary blood flow | | LAD | = left anterior descending coronary artery | | NO | = nitric oxide | | PDE 5 | = phosphodiesterase 5 | | RMBF | = regional myocardial blood flow |
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Since its release in 1998, sildenafil citrate (Viagra) has gained widespread popularity as the first pharmacologic agent prescribed for the treatment of erectile dysfunction (1,2). Although Viagra is clearly contraindicated in patients concurrently using nitrates, guidelines issued by the American Heart Association and American College of Cardiology have suggested caution in administering Viagra to all patients with coronary artery disease and active ischemia as the drug may, in theory, compromise coronary perfusion by causing coronary vasodilation and initiating "coronary steal," and/or as a secondary consequence of hypotension due to systemic vasodilation (1). Indeed, although most safety profiles have been benign (2–6), one preliminary study suggests that Viagra per se may have adverse cardiovascular consequences (7).
Despite these potential concerns, the effects of sildenafil on coronary and myocardial tissue perfusion in the setting of coronary artery stenosis remain largely unexplored (5,8). Our aim was to determine, using the anesthetized dog, whether sildenafil unfavorably alters coronary perfusion and patency in two clinically relevant models: 1) in the setting of stable hypoperfusion through a narrowed but intact coronary artery (mimicking clinical instances of "hibernating" myocardium); and 2) in a model of unstable angina, characterized by recurrent platelet-mediated thrombosis and variable coronary blood flow through a damaged and stenotic coronary artery. We found no evidence that sildenafil exacerbated ischemia in either model. However, in the model of recurrent thrombosis, sildenafil appeared to block the modest, temporal, adenosine-mediated improvement in coronary patency typically observed in placebo-control animals (9). This unexpected finding was supported by in vitro platelet aggregometry: although coronary perfusion was not worsened with sildenafil treatment, our preliminary findings suggest the agent may render platelets refractory to the well-described platelet inhibitory effects of adenosine receptor stimulation.
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Methods
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This study conforms to the Position of the American Heart Association on Research Animal Use.
Surgical preparation.
Twenty-six purpose-bred dogs (14–22 kg) were anesthetized with sodium pentobarbital (30 mg/kg IV), intubated and ventilated with room air. After cannulating the left carotid artery (for measurement of hemodynamics) and jugular vein (for drug administration), the heart was exposed through a left thoracotomy. Two adjacent segments of the mid-LAD (left anterior descending coronary artery) were isolated: the first served as the site of later coronary stenosis while the second was instrumented with a Doppler flow probe for continuous measurement of mean CBF. In addition, in dogs enrolled in Protocol 1, a cannula was positioned in the left atrial appendage for later injection of radiolabeled microspheres (141Ce or 103Ru) for measurement of regional myocardial blood flow (RMBF). Arterial pressure and coronary blood flow (CBF) were continuously recorded on a chart recorder.
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Protocol 1: coronary artery stenosis  stable coronary flow
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Coronary perfusion in the setting of coronary artery stenosis was assessed in 12 dogs. After 10 min of stabilization and baseline measurement of hemodynamics and CBF, a micomanometer constrictor was positioned around the LAD and tightened such that mean CBF was reduced to  50% of baseline. This application of a stenosis on an undamaged artery results in maintenance of stable coronary hypoperfusion, and represents a model of "short-term myocardial hibernation" (10,11).
CBF and hemodynamics were monitored for 1 h after placement of the stenosis and, at 45 min post-stenosis, RMBF was assessed. After this 1-h pretreatment period, each dog was randomly assigned to receive either an escalating dose of sildenafil citrate (Viagra; Pfizer Inc., New York, New York) or placebo (n = 6 per group). Specifically, Viagra tablets were crushed and 0.7 mg/kg sildenafil was dissolved in 10 ml saline (12) and given IV over 2 min (dose 1), approximating, on a mg/kg basis, the clinical dose of 50 mg administered to a 70 kg patient. At 2 h post-stenosis, the drug-treated cohort received a second, identical 0.7 mg/kg dose. As the plasma half-life of sildenafil is 4 h (1,4), the cumulative dose during the final hour of observation was 1.4 mg/kg (100 mg per 70 kg patient). Controls received two matched 10 ml doses of saline. CBF and hemodynamics were monitored in all dogs throughout the 2 h following treatment and, at 45 min after dose 2, a second measurement of RMBF was obtained. At 3 h post-stenosis, all dogs were euthanized under deep anesthesia by intracardiac injection of KCl, and the hearts were excised and stored in formalin.
Endpoints and analysis.
Heart rate, mean arterial pressure and CBF were quantified at baseline, immediately upon application of the stenosis, at 30 and 60 min post-stenosis (pretreatment), during IV administration of each dose at the time (typically within 1 min) at which the maximal hemodynamic response to sildenafil was observed and at 30 and 60 min after each dose.
Coronary perfusion throughout the 1-h pretreatment period, the 1 h following dose 1, and the 1 h following dose 2 was assessed by measuring the area of the flow-time profile (i.e., by computerized planimetry of the chart recording). Flow-time area in each hourly interval was then normalized for each dog to its baseline CBF x 60 min (9,13).
RMBF
was measured in subendo- and subepicardial tissue blocks cut from the center of the stenotic LAD bed and from the remote, normally perfused circumflex bed using routine methods (10).
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Protocol 2: coronary artery injury + stenosis cyclic variations in coronary blood flow (CFVs)
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Fourteen dogs were enrolled to assess coronary perfusion in the setting of coronary artery injury + stenosis. Baseline measurement of CBF and hemodynamics were obtained as described for Protocol 1, and in addition, 4.5 ml of venous blood was drawn for assessment of in vitro platelet aggregation. The isolated LAD segment was then compressed with a wax-coated hemostat to induce arterial injury (9,13) and a micromanometer constrictor was positioned at the site of injury and tightened such that CBF was reduced to 50% of its baseline value. This scenario of coronary artery injury + stenosis triggers the rapid (within <5 min) development of CFVs caused by the repeated spontaneous formation and dislodgement of platelet-rich thrombi, and mimics the repeated ischemia seen in instances of unstable angina (9,13,14).
CBF and hemodynamics were recorded for 1 h after injury + stenosis. Dogs were then randomized to receive sildenafil (n = 7) or saline (n = 7) as described for Protocol 1 and were monitored for 2 h following treatment. Additional blood samples were drawn for measurement of in vitro platelet aggregation at 30 min after each dose. At 3 h post-stenosis, the animals were euthanized under deep anesthesia as detailed in Protocol 1.
Endpoints and analysis.
Heart rate and mean arterial pressure
were measured as described in Protocol 1. CBF was assessed at baseline and immediately following injury + stenosis, before the onset of CFVs.
In vitro platelet aggregation
was assessed by whole blood impedance aggregometry (13,15). Briefly, each 4.5 ml blood sample was immediately mixed with 0.5 ml of 3.8% sodium citrate. Blood aliquots (0.5 ml) were diluted with an equal volume of sterile 0.9% saline, maintained at 37°C, and the increase in impedance (in ohms: an index of platelet aggregation) at 10 min following the addition of 10 µg collagen (a dose that elicits maximal aggregation in our canine model [13,15]) was recorded.
CFVs
were analyzed by measuring both their frequency and mean nadir during each 1-h interval. A CFV was defined as a slow decrease followed by an abrupt (within 20 s) increase in CBF, with an amplitude  50% of the post-stenotic CBF value (9,13).
Coronary patency
during each hourly interval was assessed by measuring % flow-time area (area of the flow-time profile normalized to baseline flow x 60 min, as described in Protocol 1), and the duration (in minutes) of total thrombotic occlusion (CBF = 0) (9).
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Protocol 3: effect of adenosine A2 receptor agonist on in vitro platelet aggregation
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To obtain insight as to whether the modest difference in coronary patency seen in sildenafil-treated dogs in Protocol 2 may be due to a difference in the response of the platelets to adenosine, we used whole-blood impedance aggregometry to assess the effects of sildenafil, the adenosine A2 receptor agonist CGS 21680 (16), and sildenafil + CGS on in vitro platelet aggregation.
The effects of exogenous sildenafil were evaluated in baseline blood samples obtained from one dog. Either sildenafil (14 µg per 1 ml blood, approximating the total cumulative in vivo dose of 1.4 mg/kg), CGS 21680 (final concentration of 10 µM), sildenafil + CGS, or a comparable volume of saline (control: no drug) were added to blood aliquots prepared as described for Protocol 2. Sildenafil and CGS were added to the aliquots at 30 min and 10 min, respectively, before initiating platelet aggregation with collagen (10 µg).
To assess the effects of in vivo sildenafil treatment, baseline blood samples were drawn from four dogs—two control and two sildenafil-treated—entered into Protocol 1. Paired aliquots were prepared, with CGS 21680 (10 µM) added to one tube and saline added to the second. Aggregation in response to collagen was measured for each sample, and the % difference in response (i.e., [aggregation in the CGS-treated sample – aggregation in the "no drug" sample]/[aggregation in the "no drug" sample] x 100%) was determined. At 30 min following dose 2, additional blood samples were obtained from all four dogs and assessment of platelet aggregation in paired vehicle- and CGS-treated samples was repeated.
Statistical analysis.
For Protocols 1 and 2, all variables were compared using two-factor analysis of variance (for group and time) with replication followed by Newman–Keuls post-hoc test. A p value of <0.05 was considered statistically significant. For Protocol 3, qualitative comparisons of platelet aggregation were made among control, sildenafil-, CGS- and sildenafil + CGS-treated aliquots. All results are presented as mean ± SEM (standard error of the mean).
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Results
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Protocol 1: coronary artery stenosis stable coronary flow.
Hemodynamics
Heart rate was not altered by sildenafil and did not differ between groups (Table 1). Sildenafil did, however, trigger an acute reduction in mean arterial pressure (1,4): for dose 1, the maximum decrease, seen 38 ± 6 s into the 2-min IV administration of sildenafil, was 28 ± 3 mm Hg while, for dose 2, a maximum decrease in pressure of 24 ± 4 mm Hg was observed at 39 ± 6 s into treatment. This effect was transient, with arterial pressure typically recovering to pretreatment values within 5 min and no differences seen between groups at 30 and 60 min following either dose.
Severity of coronary stenosis
Coronary blood flow averaged 14–15 ml/min at baseline and was reduced to 7–8 ml/min upon application of the stenosis (p = ns between groups; Table 1).
Coronary perfusion
CBF was depressed versus baseline, but did not differ versus the stenotic value, in all dogs during the 3 h of observation (p = ns between groups; Table 1). Similarly, flow-time area, the overall index of vessel patency, averaged 50% to 60% of baseline throughout the protocol in both control and drug-treated cohorts (p = ns; Fig. 1A).
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Figure 1 Results (group means ± SEM) for Protocol 1: coronary artery stenosis stable coronary flow. (A) % Flow-time area and (B) Regional myocardial blood flow (RMBF) in endocardial (Endo) and epicardial (Epi) segments of the stenotic left anterior descending coronary artery bed for control and sildenafil-treated dogs. Black bars indicate controls; white bars indicate sildenafil. PreTreat = data obtained during the initial hour before randomization and treatment.
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Regional myocardial blood flow
RMBF in the subendo- and subepicardial halves of the stenotic LAD bed was similar in both groups before randomization and was not altered by either sildenafil or placebo (Fig. 1B). In addition, RMBF in the normally perfused circumflex territory did not differ between groups either before treatment or after dose 2 (data not shown).
Protocol 2: coronary artery injury + stenosis CFVs.
Hemodynamics
There were no group differences in heart rate at any time during the protocol (Table 1). Mean arterial pressure, was, by chance, higher at baseline in dogs later randomized to receive sildenafil; however, the drug-treated group exhibited the same transient reductions in mean pressure as described for Protocol 1.
Severity of coronary stenosis
Baseline CBF averaged 12 ml/min and was reduced to 5.5 ml/min in both groups upon application of the stenosis (p = ns; Table 1).
In vitro platelet aggregation
Maximal platelet aggregation in response to 10 µg collagen was 12–14 ohms at baseline and was not altered by treatment with sildenafil or vehicle (Fig. 2A).
CFVs
All dogs exhibited 6–8 CFVs during the initial hour following injury + stenosis, with no change in frequency following administration of sildenafil or saline (data not shown).
The mean nadir of the CFVs averaged 1.7–2.0 ml/min before randomization and 1.4–2.7 ml/min during the final hour of treatment (p = ns between groups or over time; data not shown).
Coronary patency
The mean duration of total thrombotic occlusion was 16–20 min during the initial hour of observation and 11–13 min following dose 2 (p = ns between groups or over time; data not shown).
Flow-time area, the overall index of vessel patency, was comparable in both groups before treatment, averaging 40 ± 5% and 37 ± 6% of baseline in dogs later randomized to receive placebo and sildenafil (Fig. 2B). In control animals, flow-time area showed the expected modest increase over time (9), to a mean of 61 ± 7% of baseline during the final hour of observation (p < 0.05 vs. pretreatment). In contrast, in sildenafil-treated dogs, flow-time area remained unchanged at 33% to 35% following administration of dose 1 and dose 2 (p = ns vs. pretreatment; p < 0.05 vs. control following dose 2; Fig. 2B).
Protocol 3: effect of adenosine A2 receptor agonist on in vitro platelet aggregation.
As expected, exogenous addition of sildenafil to blood aliquots had no effect on in vitro platelet aggregation (17) (Fig. 3A), whereas adenosine A2 receptor stimulation with CGS 21680 elicited a 25% reduction in platelet aggregation (18) (Fig. 3). However, in samples exposed to both sildenafil and CGS, the platelet inhibitory effects of CGS 21680 were not manifest. This apparent refractoriness to A2 receptor stimulation was seen both with exogenous addition of sildenafil to blood aliquots (Fig. 3A) and with in vivo sildenafil treatment (Fig. 3B).
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Figure 3 Whole-blood impedance aggregometry: Protocol 3. (A) Original recordings of in vitro platelet aggregation (i.e., increase in impedance) in blood aliquots exogenously treated with sildenafil, the adenosine A2 agonist CGS 21680, sildenafil + CGS 21680, and no drug (control). Arrows indicate addition of collagen (10 µg); bar = 2 min. (B) % Change in impedance (mean ± SEM) seen in CGS 21680-treated aliquots versus paired "no drug" samples. Data were obtained at baseline and after dose 2 in two vehicle-treated and two sildenafil-treated dogs. Black bars indicate controls; white bars indicate sildenafil.
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Discussion
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Our results demonstrate that sildenafil does not exacerbate myocardial ischemia in canine models of short-term "hibernation" and unstable angina. However, in the model of recurrent platelet-mediated thrombosis, sildenafil did abrogate the modest, temporal adenosine-mediated improvement in coronary patency seen in placebo controls. This latter observation, together with our results obtained using in vitro platelet aggregometry, suggests that sildenafil-treated dogs may be unresponsive to the platelet inhibitory effects of adenosine receptor stimulation.
Sildenafil in models of stable coronary hypoperfusion.
Sildenafil elicits smooth muscle relaxation and vasodilation by selective inhibition of guanosine 3',5'-cyclic monophosphate (cGMP)-specific phosphodiesterase 5 (PDE 5), thereby amplifying cGMP-mediated signaling initiated by the release of nitric oxide (NO). Indeed, inhibition of PDE 5, present in high concentrations in the corpus cavernosum, represents the mechanism by which sildenafil facilitates penile erection, and amplification of cGMP-mediated signaling by sildenafil is responsible for its profound and deleterious potentiation of the hypotensive effect of nitrates (1,2).
Sildenafil may also trigger coronary vasodilation: PDE 5 is present in coronary vascular smooth muscle (17) and, under conditions of reduced coronary blood flow, NO (the substrate for cGMP-mediated signaling) is liberated from ischemic myocardium (19). Although vasodilation in the vascular bed distal to a coronary stenosis may improve blood flow to the hypoperfused territory, sildenafil could, alternatively, exacerbate ischemia due to either coronary steal or as a result of hypotension due to systemic vasodilation. However, we found no deterioration in coronary perfusion with sildenafil in the setting of stable hypoperfusion. These data are consistent with two reports showing no decrease in coronary blood flow with sildenafil in men with coronary artery disease (5) or in conscious dogs with coronary artery stenosis subjected to treadmill exercise (8). Our current study extends these observations and demonstrates that sildenafil is also benign with respect to myocardial tissue perfusion (RMBF) in this model of short-term "hibernation."
Sildenafil in the setting of coronary artery injury + stenosis and CFVs.
Protocol 1 revealed that sildenafil does not cause a vasodilatory-induced reduction in coronary perfusion distal to a narrowed but intact coronary artery. However, many patients with coronary disease exhibit arterial damage at the site of coronary stenosis (14); this serves as a powerful substrate for the activation, adhesion and aggregation of platelets and initiates the well-characterized development of CFVs caused by recurrent spontaneous formation/dislodgement of platelet-rich thrombi at the site of injury + stenosis (9,13,14). Nitric oxide and upregulation of cGMP-mediated signaling, in addition to initiating vasodilation, is also well recognized as a potent inhibitor of platelet aggregation (13,20). Platelets are rich in PDE 5 (19,21), and in fact PDE 5 inhibitors have been proposed as a novel class of antiplatelet drugs (21). Thus, in contrast to the potential deleterious effects of PDE 5-mediated vasodilation, these data suggest that sildenafil may, in theory, attenuate the development of CFVs—and thus improve patency—in the setting of coronary artery injury + stenosis by cGMP-mediated inhibition of platelet aggregation.
As anticipated from our previous studies (9), dogs in the control group of Protocol 2 exhibited a modest temporal improvement in coronary patency during the 3-h protocol, apparently triggered by release of adenosine from ischemic/reperfused myocardium during early episodes of spontaneous thrombotic occlusion/reperfusion and resultant partial inhibition of platelet aggregation via stimulation of platelet adenosine A2 receptors (9,22,23). However, as further expected, this endogenous release of adenosine is not sufficient to prevent platelet aggregation (9): this is supported by the lack of temporal variation in in vitro aggregation in response to a maximal stimulus (10 µg collagen) between the final versus first hour of the protocol.
Sildenafil did not attenuate maximal in vitro platelet aggregation; this is consistent with previous observations in which sildenafil was added exogenously to platelet-rich plasma (17) and with results in blood samples obtained from Viagra-treated men (5). Moreover, in contrast to our premise, sildenafil did not improve in vivo coronary patency when compared with data obtained before treatment, or versus time-matched placebo controls. In fact, although patency did not deteriorate with sildenafil treatment, the typical modest improvement in % flow-time area over time was not manifest in sildenafil-treated dogs.
Confounding effect of sildenafil on in vitro, adenosine A2-mediated inhibition of platelet aggregation.
The lack of a temporal improvement in vessel patency in the sildenafil-treated cohort prompted us to investigate the possibility that sildenafil may render platelets refractory to the inhibitory effects of adenosine. Support for this concept was obtained in Protocol 3, in which we found that sildenafil appeared to abrogate the ability of CGS 21680 to attenuate in vitro platelet aggregation. However, the mechanisms by which sildenafil (which presumably augments platelet cGMP content via inhibition of PDE 5 [17,21]) might block A2-mediated inhibition of platelet aggregation (achieved by stimulation of adenylate cyclase and upregulation of adenosine 3',5'-cyclic monophosphate [cAMP] [21]) are unclear. There is evidence of "cross-talk" between cGMP- and cAMP-mediated signaling (21,24) but, contrary to the implications of our study, sildenafil potentiated (rather than blocked) cAMP production in an isolated cardiac muscle preparation (24). Further in vitro studies, focusing on possible interactions among sildenafil, cGMP- and cAMP-mediated signaling in platelets are needed to resolve this issue.
Summary and future directions.
Sildenafil did not worsen coronary perfusion or exacerbate myocardial ischemia in our experimental models of coronary artery stenosis. However, in the setting of recurrent platelet-mediated thrombosis, sildenafil did exert an unexpected and apparently confounding effect on adenosine-mediated inhibition of platelet aggregation.
These results were obtained in short-term experiments employing acute canine models and, although the data are consistent with the current guidelines recommending caution in administering Viagra to patients with active ischemia (1), confirmation of the clinical relevance of our observations will require further study. Second, the mechanism(s) by which sildenafil alters the response of platelets to adenosine remains to be elucidated. Finally, the question of whether Viagra may attenuate the efficacy of other purinergic anti-platelet agents (i.e., ticlopidine, clopidogrel or dipyridamole) has, to date, not been explored (1) and may, on the basis of our current results, warrant future investigation.
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Footnotes
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Supported by an IRB/RAC grant (to K.P.) from Good Samaritan Hospital.
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F. Salloum, C. Yin, L. Xi, and R. C. Kukreja
Sildenafil Induces Delayed Preconditioning Through Inducible Nitric Oxide Synthase-Dependent Pathway in Mouse Heart
Circ. Res.,
April 4, 2003;
92(6):
595 - 597.
[Abstract]
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R. Ockaili, F. Salloum, J. Hawkins, and R. C. Kukreja
Sildenafil (Viagra) induces powerful cardioprotective effect via opening of mitochondrial KATP channels in rabbits
Am J Physiol Heart Circ Physiol,
September 1, 2002;
283(3):
H1263 - H1269.
[Abstract]
[Full Text]
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Abstract
Methods
p < 0.05 vs. PreTreat.