Anesth Analg 2002;94:1505-1509
© 2002 International Anesthesia Research Society
ANESTHETIC PHARMACOLOGY
Sildenafil (Viagra®) Augments Sodium Nitroprusside-Induced But Not Nitroglycerin-Induced Hypotension in Dogs
Kyung Y. Yoo, MD PhD*,
Hak S. Kim, MD*,
Jai-Dong Moon, MD PhD
, and
JongUn Lee, MD PhD
*Department of Anesthesiology and Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju, South Korea
Address correspondence and reprint requests to Kyung Yeon Yoo, MD, PhD, Department of Anesthesiology, Chonnam National University Medical School, 5 Hak-dong, Gwangju 501-746, Korea. Address e-mail to kyyoo{at}chonnam.ac.kr
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Abstract
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We investigated whether sildenafil citrate (Viagra®) may reduce the dose of nitrovasodilators to induce deliberate hypotension. Ten mongrel dogs were acutely instrumented with a femoral artery catheter and a pulmonary artery catheter. Sodium nitroprusside (SNP; 1–16 µg · kg-1 · min-1) or nitroglycerin (NTG; 2–32 µg · kg-1 · min-1) was IV given to induce hypotension. The study consisted of two occasions, in a random order, in each animal: one with sildenafil pretreatment (1 mg/kg IV followed by 0.3 mg · kg-1 · h-1) and the other without to serve as a control. Hemodynamic variables were continuously monitored. Plasma cyclic guanosine monophosphate (cGMP) concentrations were measured by radioimmunoassay. Both SNP and NTG produced dose-dependent decreases in mean arterial blood pressure without affecting the heart rate in the presence as well as in the absence of sildenafil. Systemic vascular resistance index and mean pulmonary arterial pressure were also decreased. The magnitude of mean arterial blood pressure and systemic vascular resistance index reductions caused by SNP was augmented by sildenafil, whereas that caused by NTG was not affected. Neither SNP nor NTG alone altered the plasma cGMP concentrations. Sildenafil increased the plasma cGMP concentration, which was further increased by SNP but not affected by NTG. These results indicate that sildenafil may reduce the dose of SNP in producing deliberate hypotension in the dog. The potentiation of SNP-induced hypotension by sildenafil may be related to an augmented accumulation of cGMP.
IMPLICATIONS: Sildenafil may reduce the dose of sodium nitroprusside required to induce deliberate hypotension and hence the potential for cyanide toxicity.
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Introduction
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Deliberate hypotension, as an adjunct to anesthesia, is frequently used to minimize blood loss and to improve the quality of the surgical field (1,2). Among others, sodium nitroprusside (SNP) and, less frequently, nitroglycerin (NTG) have been used to induce hypotension because they are rapid in onset and short in duration of action (3). However, deliberate hypotension with SNP may be associated with tachyphylaxis. If tachyphylaxis ever occurs, the dosage of SNP may have to be increased, with the resultant potential hazard of cyanide toxicity (4). However, the major disadvantage with NTG is the lack of potency (5).
The vasodilator effect of both SNP and NTG is mediated by a release of nitric oxide (NO), which in turn activates soluble guanylyl cyclase and increases the formation of cyclic guanosine monophosphate (cGMP) (6). The effect of cGMP is then terminated by its degradation catalyzed by phosphodiesterases. Sildenafil citrate (Viagra®; Pfizer, New York, NY), which has been recently introduced into clinical practice for the treatment of erectile dysfunction (7), is a selective inhibitor of type 5 phosphodiesterase. Therefore, there may be a potential interaction between sildenafil and NO donors in the systemic circulation where type 5 phosphodiesterase is abundant (8). A synergistic interaction between sildenafil and NO donors has indeed been demonstrated in isolated human vessels (9) and isolated rabbit aorta (10), as well as in patients with stable angina taking NO donors (11,12). This study was designed to evaluate whether sildenafil may reduce the dose of nitrovasodilators required to induce hypotension and hence the risk of systemic toxicity.
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Methods
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The study was approved by the Institutional Committee of Laboratory Animal Care and Use. Ten healthy mongrel dogs of either sex, weighing 19–27 kg, were studied on two occasions in a random order, 1 wk apart each: one without sildenafil pretreatment to serve as control, and the other with sildenafil pretreatment (Sildenafil group). After an overnight fasting, animals were anesthetized with thiopental sodium 20–25 mg/kg IV. After tracheal intubation, anesthesia was maintained with enflurane (1.4% end-tidal) and 50% nitrous oxide in oxygen via positive-pressure ventilation. Tidal volume and respiratory rate were adjusted to maintain PaCO2 between 30 and 35 mm Hg, as determined by repeated measurements and by use of an end-tidal CO2 monitor. To obtain muscle relaxation, vecuronium bromide 0.1 mg/kg was initially used as a bolus, followed by continuous infusion at 0.05 mg · kg-1 · h-1. Body temperature and electrocardiogram were continuously monitored. Lactated Ringer’s solution was administered at 5 mL · kg-1 · h-1.
Catheters were placed into the left femoral artery to continuously monitor the blood pressure and to take blood samples and into the cephalic vein to serve as a route for drug and fluid administration. A 7.5F oximetric flow-directed pulmonary artery catheter was inserted through the right femoral vein for the measurement of right atrial pressure, pulmonary arterial pressure (PAP), pulmonary artery occlusion pressure, and cardiac output (CO). CO was measured continuously with the continuous CO monitor (13).
After baseline hemodynamic measurements, dogs received either sildenafil (1 mg/kg IV followed by 0.3 mg · kg-1 · h-1) or an equivalent volume (20 mL) of normal saline over 15 min. Hemodynamic measurements were repeated 5 min later. Incremental doses of SNP (1, 2, 4, 8, and 16 µg · kg-1 · min-1) or NTG (2, 4, 8, 16, and 32 µg · kg-1 · min-1) were then administered for 15 min at each dose, and hemodynamic measurements were obtained at the end of each dose. In an effort to avoid rebound hypertension, the final SNP dose was gradually decreased over 30 min (14). The order of the infusions of SNP and NTG was at random. Approximately 30 min after cessation of SNP or NTG infusion, when hemodynamics became stable, an infusion protocol as in the first trial was performed with the other drug. The anesthesia then was discontinued, catheters were removed, and the animals were allowed to recover. One week later, the procedure was repeated with pretreatment of saline or sildenafil. Heart rate (HR) was continuously monitored from lead II of the electrocardiogram by using a tachometer. Pressure transducers were connected to a biomedical amplifier, and data were continuously recorded at 150 Hz on a personal computer by using an analog-to-digital interface with a data acquisition system. Sildenafil (Viagra) was obtained as tablets, and they were dissolved in 50 mL of saline to infuse into the cephalic vein with an infusion pump. The total volume of fluid administered during the study was approximately 750 mL. Mean arterial blood pressure (MAP) and mean PAP were determined electronically. Cardiac index (CI), stroke volume index (SVI), systemic vascular resistance index (SVRI), and pulmonary vascular resistance index were calculated with standard formulae.
The arterial blood was obtained for measurement of plasma cGMP levels before and 5 min after the injection of sildenafil and during the infusion of SNP (16 µg · kg-1 · min-1) or NTG (32 µg · kg-1 · min-1). The cGMP was determined by equilibrated radioimmunoassay. Standards and samples were introduced in a final volume of 100 µL of 50 mmol/L sodium acetate buffer (pH 4.8). One hundred microliters of dilute cGMP antiserum (Calbiochem-Novabiochem, San Diego, CA) and iodinated cGMP (10,000 cpm/100 µL, specific activity = 2,200 Ci/mmol; DuPont-New England Nuclear, Wilmington, DE) were added and incubated for 24 h at 4°C. The bound form was separated from the free form by charcoal suspension. Plasma cGMP concentrations are expressed as picomoles of cGMP generated per milliliter of plasma.
Data are expressed as mean ± SD. Hemodynamic changes during SNP or NTG administration were analyzed by two-way repeated-measures analysis of variance followed by Bonferroni’s multiple comparison test as appropriate, and the relationship between dose of SNP and MAP was analyzed by linear regression analysis. A value of P < 0.05 was considered statistically significant.
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Results
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The basal hemodynamic variables did not significantly differ between the Sildenafil and Control groups. IV bolus injection of sildenafil transiently decreased MAP and increased CI and HR, in which baseline values were resumed within 5–10 min (Tables 1 and 2).
SNP caused dose-dependent decreases of MAP, which was augmented by sildenafil. A linear relationship was noted between the log dose of SNP and MAP. The two regression lines plotted in the absence and presence of sildenafil were parallel with different intercepts, showing a 2.2-fold potentiation by sildenafil (Fig. 1). In contrast, NTG-induced decreases in MAP were not affected by sildenafil (26% ± 9% in controls versus 27% ± 12% in the Sildenafil group with the largest dose of NTG used).
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Figure 1. Effects of sodium nitroprusside (SNP) on mean arterial blood pressure (MAP) after treatment with saline (control) or sildenafil. Values are mean ± SD of 10 dogs. B = before pretreatment; S = after saline or sildenafil pretreatment. The solid line is MAP = 95.4 - 28.5 x (log dose SNP) (r = 0.82, P < 0.01); the dotted line is MAP = 84.8 - 27.9 x (log dose SNP) (r = 0.83, P < 0.01). *P < 0.05 versus Control group.
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Both SNP and NTG decreased SVRI without significant changes in HR in the Control and Sildenafil groups. The magnitude of decreases in SVRI was augmented by sildenafil during SNP infusion, but not during NTG infusion. During SNP infusion, CI and SVI were decreased significantly in the Control group, but not in the Sildenafil group. However, they did not significantly differ between the two groups throughout the study. During NTG infusion, CI and SVI remained unchanged throughout the study. The mean PAP was decreased by NTG as well as by SNP, the degree of which was not affected by sildenafil.
Sildenafil alone increased the plasma cGMP concentrations (37%–40% over the basal), whereas neither SNP nor NTG alone significantly altered them. The sildenafil-induced increase of cGMP concentrations was augmented by SNP (60% over the value achieved by sildenafil alone), but not by NTG (Tables 1 and 2).
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Discussion
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SNP and NTG are often used to induce deliberate hypotension. However, each drug is associated with its own limitations: SNP with metabolic acidosis and cyanide poisoning when large doses are used (3,4) and NTG with the lack of potency (5). Therefore, any pharmacological adjuncts to potentiate their vasodilator action may be useful. This study demonstrated that sildenafil caused a 2.2-fold potentiation of the hypotensive effect of SNP in association with an enhanced accumulation of cGMP. However, sildenafil did not affect the hypotensive effect of NTG, where the accumulation of cGMP also remained unaffected.
The absence of an interaction of sildenafil with NTG in this study may be contradictory to previous findings, which demonstrated a synergism in patients taking nitrates for stable angina (11,12). In a number of previous reports, it has been established that nitrate-induced dilator responses and patterns within different vascular beds (arteries, veins, arterioles, and different organs) in animals closely reflect those observed in human subjects (15). A synergistic interaction between NTG and sildenafil was observed in conscious chronically instrumented dogs (16). Furthermore, the interaction between sildenafil and NTG was not affected by the order of the two drugs administered (11). Therefore, the contradictory results in this study may not be attributed to differences in animal species or the order of drug administration.
In the systemic circulation, SNP has effects on capacitance as well as resistance vessels, whereas NTG has an effect primarily on the capacitance vessels (17). The failure of sildenafil to interact with NTG may then be attributed to a lack of its effect on resistance vessels. However, in this study, SVRI was decreased by NTG as well as by SNP, suggesting that both drugs were effective on the resistance vessels. Therefore, their site of action may not account for the lack of interaction between sildenafil and NTG.
However, several studies have shown that NO causes vasodilation via cGMP-independent as well as cGMP-dependent pathways (18,19). The absence of a significant interaction of sildenafil with NTG on the plasma cGMP concentration may indicate a cGMP-independent effect of NTG. Alternatively, enflurane may have affected the interaction, because volatile anesthetics inhibit the NO-cGMP pathway (20). The release of cGMP into the circulation during the use of sildenafil and NTG, a less potent nitrovasodilator than SNP, is likely to be dissipated under enflurane anesthesia.
Although SNP decreased both CI and SVRI in the Control group, it decreased only SVRI in the presence of sildenafil. Therefore, the hemodynamic effect of sildenafil on SNP-induced hypotension appears to be related primarily to an enhanced reduction in SVRI. SNP may reduce CI because of a decrease of preload resulting from venodilation. A synergistic interaction between SNP and sildenafil on capacitance vessels would further reduce CI. However, CI remained unaltered in the presence of sildenafil during SNP infusion which may, at least in part, be related to systemic arterial vasodilation (greater reduction in afterload). Phillips et al. (21) have demonstrated that sildenafil markedly increases the sympathetic neural activity both at rest and under stress in humans. Furthermore, sildenafil increased cyclic adenosine monophosphate concentrations in isolated human heart (22). It is also likely that unchanged CI may reflect a positive inotropic effect of sildenafil.
After oral administration in awake volunteers, Moreland et al. (23) found that blood sildenafil level peaked in 60–120 minutes, and its plasma half-life was estimated to be 4–4.5 hours. Moreover, sildenafil alone, even at a large dose, had modest effects on blood pressure in healthy volunteers (24). In this context, when a prolonged SNP infusion is anticipated, an oral pretreatment of sildenafil would safely reduce the dose of SNP and hence the potential for cyanide toxicity. However, further studies will be needed to clarify the issue.
In summary, we observed that sildenafil may reduce the dose of SNP, but not that of NTG, to produce deliberate hypotension in the dog. The potentiation of hypotension by sildenafil may be related to an enhanced reduction of SVRI through its actions to increase the accumulation of cGMP.
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Acknowledgments
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Supported by a research grant (2001G0301) from Korea Science and Engineering Foundation through Hormone Research Center.
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Accepted for publication February 5, 2002.
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Abstract
Introduction
