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Anesth Analg 2000;90:840-846
© 2000 International Anesthesia Research Society

CARDIOVASCULAR ANESTHESIA

Interaction of L-Arginine and Phosphodiesterase Inhibitors in Vasodilation of the Porcine Internal Mammary Artery

Arthur W. Wallace, MD, PhD, and Wynnis L. Tom, BS

Department of Anesthesiology, San Francisco Veterans Administration Medical Center and Department of Anesthesiology, University of California–San Francisco, San Francisco, California

Address correspondence and reprint requests to Arthur Wallace, MD, PhD, VAMC Anesthesia (129), 4150 Clement St., San Francisco, CA 94121. Address e-mail to awallace{at}best.com


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We tested the hypothesis that L-arginine (the substrate for nitric oxide production)—combined with amrinone, milrinone (Type III phosphodiesterase [PDE] inhibitors), zaprinast, or sildenafil (Type V PDE inhibitors)—would vasodilate synergistically. Internal mammary artery segments were excised from anesthetized swine, divided into rings, and suspended in a tissue bath at 37°C. Force of contraction was measured during dose-response testing of combinations of L-arginine and amrinone, milrinone, zaprinast, or sildenafil. Amrinone and milrinone were additive to L-arginine. NG-methyl-L-arginine (L-NMA) inhibited the effects of milrinone but not amrinone. The effective concentration of amrinone eliciting 50% relaxation (EC50) was 3.8E-05M (n = 6) when given alone and 4.4E-05M (n = 6) with L-NMA. Milrinone had EC50 = 6.0E-06M alone (n = 6) and 2.8E-05M (n = 6) with L-NMA. Zaprinast (EC50 = 6.5E-05M, n = 6) and sildenafil (EC30 = 1.8E-05M, n = 6) were synergistic with L-arginine. L-NMA blocked their effects, increasing the EC50 for zaprinast to 9.9E-03M and the EC30 for sildenafil to 6.1E+02M. In conclusion, L-arginine is additive to the vasodilation of the type III PDE inhibitors, amrinone and milrinone, but synergistic with the type V PDE inhibitors, zaprinast and sildenafil.

Implications: Amrinone and milrinone, Type III cAMP-dependent phosphodiesterase inhibitors, are additive to L-arginine-dependent vasodilation. Zaprinast and sildenafil, Type V cGMP-dependent phosphodiesterase inhibitors, are synergistic with L-arginine.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
One of the possible etiologies of vasospasm and subsequent myocardial ischemia is impaired endothelium-dependent flow (1). Endothelial cells contribute to the control of local vascular tone by formation of nitric oxide (NO) (2). In patients with atherosclerotic arteries, endothelium-dependent relaxations fail to occur in response to NO-dependent factors (3). The basal secretion of NO is lower (3), and NO-dependent factors that cause vasodilation in normal arteries result in vasoconstriction in atherosclerotic vessels (4). This paradoxical effect is thought to be caused by an inability of the endothelium to synthesize adequate amounts of NO (5), causing unopposed vasoconstriction.

L-arginine is the precursor of endothelium-derived NO. Increasing levels of L-arginine may increase NO production and augment endothelium-dependent vasodilation. Infusions of L-arginine have been shown to improve vascular function in patients with hypercholesterolemia (2,5) and atherosclerosis (6,7). We previously demonstrated that L-arginine infusion caused a relatively selective coronary vasodilation after coronary artery bypass (8). Unfortunately, the dose involved approached levels of 10-2 M (8). We designed the present study to find compounds that may be able to amplify the vascular effects of L-arginine and prevent vasospasm. We tested for synergism between the vasodilatory actions of L-arginine and four phosphodiesterase (PDE) inhibitors: amrinone (Type III inhibitor), milrinone (Type III inhibitor), zaprinast (Type V inhibitor), and sildenafil (Type V inhibitor).


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Tissue Preparation
After approval by our institutional animal care and use committee, domestic swine (30–80 kg) were sedated with ketamine, mask induced with isoflurane, intubated, and a midline sternotomy performed. Segments of internal mammary artery (IMA) were dissected out and used immediately. Fat and connective tissue were removed from the vessel. Each segment was sliced into 2 mm rings.

Tension Measurement
Vessels were mounted on stainless-steel hooks and suspended in a Radnoti glass chamber tissue bath (Radnoti Glass Technology, Inc., Monrovia, CA) in a HEPES buffer solution (9,10) maintained at 37°C. The buffer was a salt nutrient solution consisting of 130 mM NaCl, 4.7 mM KCl, 14.9 mM NaHCO3, 1.18 mM KH2PO4, 1.17 mM MgSO4, 1.6 mM CaCl2 · 2H2O, 0.03 mM CaNa2 EDTA, 5.5 mM glucose, and 25 mM HEPES, with pH 7.40 ± 0.05 (Sigma Chemical Company, St. Louis, MO). The chambers were connected with tubing to a source of gas (5% CO2/95% O2), a water bath (Fisher Isotemp Refrigerated Circulator Model 910, Fisher Scientific, Pittsburgh, PA), and a drainage system.

A chart recorder/amplifier (GRASS Model 7 Polygraph, GRASS Instrument Company, Quincy, MA) was used to record vessel tension measured by calibrated force transducers (GRASS Force-Displacement Transducer FT03, GRASS Instrument Company). Five rings were used per trial. The vessel rings were allowed to stabilize in the chambers in HEPES buffer at 37°C for 60 min. A resting tension of 2 g (initially defined by preliminary studies) was then applied to each of the five rings, which were then allowed to stabilize at this constant tension. Test compounds were added directly into the tissue bath solution to generate dose response data. The vessel was preconstricted with epinephrine (6.8 mM), and a new stable tension was reached (approximately 10 min). Vessels that did not exhibit a stable tension during set up were discarded. Each of the five rings were then exposed to a different dose of PDE inhibitor (differing by 1.0 log10 unit steps), followed by the same concentration of L-arginine. The L-arginine concentration was then increased in 1.0 log10 unit steps. After each addition, the vessel was allowed to stabilize before the addition of the next vasoactive drug (approximately 15 min between additions).

NO Synthase Inhibitor Experiments
Vessel segments were prepared in the same manner as described. The NO synthase inhibitor NG-methyl-L-arginine (L-NMA) was added to the chamber (500 µM) and the vessels allowed to equilibrate for 30 min. Vessels were preconstricted with epinephrine (6.8 mM) before the dose-response curves were generated. Increasing concentrations (in 1.0 log10 unit steps) of amrinone, milrinone, zaprinast, sildenafil, or L-arginine were added. Vasodilators were not combined, but administered in separate trials. After each addition, the vessel was allowed to stabilize before the addition of a higher concentration of vasoactive drug (approximately 15 min between additions). The same experiment was also performed without L-NMA present for comparison.

Drugs
The following drugs were used: epinephrine (Adrenalin, 1 mg/mL; Parke-Davis, Morris Plains, NJ); L-arginine hydrochloride (SigmaUltra, Sigma Chemical Company, St. Louis, MO); amrinone lactate (Inocor, 5 mg/mL; Sanofi Winthrop Pharmaceuticals, New York, NY); milrinone lactate (Primacor, 1 mg/mL; Sanofi Winthrop Pharmaceuticals, New York, NY); zaprinast (Sigma Chemical Company, St. Louis, MO); sildenafil (Viagra, Pfizer Pharmaceuticals, New York, NY); and L-NMA (Sigma Chemical Company, St. Louis, MO). The amrinone ampules and milrinone ampules were serially diluted in distilled water. L-arginine, zaprinast, and the NO synthase inhibitor L-NMA were dissolved and serially diluted in distilled water. Sildenafil was dissolved, filtered, and then serially diluted in 0.9% sodium chloride solution. The concentrations of each drug are expressed as final molar concentrations in the buffer bath solution.

Percent dilation resulting from the addition of test compounds was calculated as the percentage of the constriction induced by epinephrine. We defined the difference between basal tension and that induced by epinephrine as 100%. Results are expressed as mean percentage ± standard error. If tone decreased below baseline unpreconstricted levels, a relaxation response greater than 100% was calculated.

Vasodilation induced by L-arginine and the PDE inhibitors was assessed using linear regression of the log10 of concentration versus percent dilation data. To test for interaction between L-arginine and an individual PDE inhibitor, the percent dilation was plotted against the log10 of the L-arginine concentration for each of five concentrations of PDE inhibitor used. Linear regression lines were fitted to the data. The slopes of the regression lines were tested (SAS System, SAS Institute, Cary, NC) to characterize the effect of increasing concentrations of PDE inhibitor. Interaction was established by significance of the second term (b1) in the equation: Go


where b = slope of linear regression line for percent dilation versus log10 L-arginine concentration, b0 and b1 = regression terms, and D1–D7 = dummy variables for different vessel segments (11).

For comparison of dose-response curves, the effective concentration of vasodilator agent eliciting 50% relaxation (EC50) values were calculated from each concentration-relaxation curve using a logistic curve-fitting equation: Go


where E is response, M is maximal relaxation, A is concentration, K is EC50 concentration, and p is the slope variable (12). The nonlinear regression was performed using SigmaPlot (Version 4.01, SPSS, Inc., Chicago, IL). The EC30 value is correspondingly defined for 30% relaxation. EC50 and EC30 values in the presence and absence of inhibitor (L-NMA) were compared using analysis of variance (SigmaStat Version 2.03, SPSS, Inc., Chicago, IL). A probability value of P < 0.05 was considered significant for all statistical analyses.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
L-arginine and the four PDE inhibitors induced statistically significant concentration-dependent vasodilation in the isolated IMA rings (Fig. 1a, Table 1). L-arginine, amrinone, milrinone, zaprinast, and sildenafil are each statistically significant in dilating epinephrine-precontracted vessel rings (Table 1). At maximum administered doses, zaprinast, amrinone, and milrinone completely reversed epinephrine-induced contraction. Sildenafil was less potent, however, reversing contraction by approximately 40%.



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  		Figure 1. Internal mammary artery rings preconstricted with epinephrine (6.8 mM). Data are expressed as the mean ± SE, with n = number of vessel segments. a, Log concentration-response curves for L-arginine (n = 6, •), amrinone (n = 6, {blacksquare}), milrinone (n = 6, {blacktriangleup}), zaprinast (n = 6, {circ}), and sildenafil (n = 6, {square}). b, Log concentration-response curves for L-arginine (n = 6, •), amrinone (n = 6, {blacksquare}), milrinone (n = 6, {blacktriangleup}), zaprinast (n = 6, {circ}), and sildenafil (n = 6, {square}) in the presence of L-NMA. Compared with curves for the vasodilators in the absence of L-NMA (a), a significant decrease (P < 0.05) in dilation was observed for L-arginine, milrinone, zaprinast, and sildenafil. PDE = cyclic nucleotide phosphodiesterase, L-NMA = NG-methyl-L-arginine.

 

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  		Table 1. Response to L-Arginine and Phosphodiesterase Inhibitors Individually With and Without L-NMA in Porcine IMA Segments
 
As seen in Fig. 2a, the slope of the regression line for the graph of percent dilation vs log10 L-arginine concentration does not change significantly as the concentration of the PDE III inhibitor amrinone changes (interaction term not significant by linear regression). The same is true for milrinone (Fig. 2b). However, the slope changes significantly as the concentration of zaprinast or sildenafil changes (Fig. 2, c and d) (P < 0.05).



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  		Figure 2. Internal mammary artery rings preconstricted with epinephrine (6.8 mM). Data are expressed as the mean ± SE, with n = number of vessel segments. a, L-arginine in combination with amrinone (n = 8; no amrinone, •); 4.3E-07M amrinone, {circ}; 4.3E-06M amrinone, {blacktriangledown}; 4.3E-05M amrinone, {triangledown}; and 4.3E-04M amrinone, {blacksquare}). The regression lines shifted upward in a parallel manner as the concentration of amrinone was increased. b, L-arginine in combination with milrinone (n = 10; no milrinone, •; 2.4E-07M milrinone, {circ}; 2.4E-06M milrinone, {blacktriangledown}; 2.4E-05M milrinone, {triangledown}; and 2.4E-04M milrinone, {blacksquare}). The regression lines shifted upward in a parallel manner as the concentration of milrinone was increased. c, L-arginine in combination with zaprinast (n = 8; no zaprinast, •; 4.8E-07M zaprinast, {circ}; 4.8E-06M zaprinast, {blacktriangledown}; 4.87E-05M zaprinast, {triangledown}; and 4.8E-04M zaprinast, {blacksquare}). The slopes of the regression lines increased as the concentration of zaprinast was increased. d, L-arginine in combination with sildenafil (n = 10; no sildenafil, •; 2.6E-07M sildenafil, {circ}; 2.6E-06M sildenafil, {blacktriangledown}; 2.6E-05M sildenafil, {triangledown}; and 2.6E-04M sildenafil, {blacksquare}). The slopes of the regression lines increased as the concentration of sildenafil was increased.

 
The NO synthase inhibitor L-NMA did not alter the effects of amrinone (EC50 = 3.8E-05M, n = 6 with amrinone alone and 4.4E-05M, n = 6 with amrinone and L-NMA; P value not significant when analysis of variance [ANOVA] performed on concentration curves) (Table 1) (Fig. 1b). It did, however, influence the relaxant response to milrinone (EC50 = 6.0E-06M, n = 6 with milrinone alone and 2.8E-05M, n = 6 with milrinone and L-NMA; P < 0.05 on concentration curves). Interaction between L-NMA and milrinone was significant (ANOVA, P < 0.05). L-NMA greatly decreased the effects of zaprinast and sildenafil, compared with the drugs administered alone (ANOVA on concentration curves, P < 0.05 for both inhibitors). The EC50 value for zaprinast alone was 6.5E-05M (n = 6); but, with L-NMA, it increased to 9.9E-03M (n = 6). Since the concentrations of sildenafil we used achieved a maximum relaxation of approximately 40%, EC30 values were calculated for sildenafil. The EC30 value for sildenafil alone was 1.8E-05M (n = 6), and with L-NMA it increased dramatically to 6.1E+02M. L-arginine (EC50 = 1.6 M when given alone, n = 6) vasodilation was completely blocked by L-NMA.

Below about 1E-05M, the two PDE V inhibitors, zaprinast and sildenafil, cause similar amounts of IMA vasodilation. Above 1E-05M, however, zaprinast appears to be the more potent vasodilator.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
PDE inhibitors were studied as possible agents to amplify the vasodilatory effects of L-arginine. We found dose-related vasodilation by the four PDE inhibitors tested. The effects of Type III PDE inhibitors (amrinone or milrinone) were additive to the dose-related vasodilation caused by L-arginine. The effects of Type V PDE inhibitors (zaprinast or sildenafil) were synergistic with L-arginine. Our results suggest that since PDE V inhibitors augment the effects of L-arginine, they have the potential to be used in combination with L-arginine.

Vasospasm is common during coronary artery bypass graft surgery and may contribute to early myocardial ischemia, increasing perioperative morbidity and mortality (13). Various types of vasodilators have been used to prevent or reverse vasospastic events, but prophylactic therapy has not reduced risk (14–19). One possible agent for the prevention of vasospasm is the nitrovasodilator, L-arginine that is metabolized by NO synthase into NO (9). NO rapidly diffuses out of the endothelial cells and into adjacent smooth muscle cells. Binding of NO to guanylate cyclase causes an immediate increase in cyclase catalytic activity, producing guanosine 3'-5'-cyclic monophosphate (cGMP) (20). Elevation in levels of cGMP results in vasodilation of vascular smooth muscle (21).

L-arginine, because of its role as the substrate of NO synthase, has been studied for possible augmentation of endothelium-dependent vasodilation. It is a peripheral vasodilator in healthy humans (22) and enhances endothelium-dependent vasodilation in patients with hypercholesterolemia (2,5) and coronary artery disease (23). After coronary artery bypass, L-arginine is a coronary vasodilator, with minimal systemic vascular effects (8). The dose of L-arginine needed, however, is high (10-2 M) (2,8). We examined the possibility of amplifying the effects of L-arginine by testing for synergism between L-arginine and PDE inhibitors. This experiment is a step in the effort to develop L-arginine as a prophylactic therapy for the prevention of vasospasm.

PDE inhibitors antagonize cyclic nucleotide PDE, which hydrolyze cyclic nucleotides (21). PDEs have been classified into at least six major families: PDE I, PDE II, PDE III, PDE IV, PDE V, and PDE VI (21,24). The PDE V subtype specifically hydrolyzes cGMP (21). Inhibition of PDE Vs decreases the breakdown of cGMP and promotes vascular smooth muscle relaxation (Fig. 3). Two PDE V-specific inhibitors, zaprinast and sildenafil, were tested for possible synergism with the NO precursor L-arginine. The effects of L-arginine in combination with PDE inhibitors have not been previously reported. We investigated their efficacy for in vitro reversal of epinephrine-induced vasoconstriction in healthy porcine IMA so that normal endothelial function was present. The concentrations of L-arginine needed for in vitro vasodilation were similar to those found in vivo (25). Synergism between L-arginine and zaprinast and between L-arginine and sildenafil was found and results from decreased breakdown of cGMP in the face of increased production.



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  		Figure 3. Schematic of the nitric oxide biochemical pathway. L-NMA = NG-methyl-L-arginine, L-NAME = NG-nitro-L-arginine methyl ester, L-NMMA = NG-monomethyl-L-arginine, NADPH = nicotine-adenine-dinucleotide phosphate, 5'-AMP = adenosine monophosphate, ATP = adenosine triphosphate, cAMP = adenosine 3'-5'-cyclic monophosphate, 5'-GMP = guanosine monophosphate, GTP = guanosine triphosphate, cGMP = guanosine 3'-5'-cyclic monophosphate.

 
Both of the biological second messengers, cGMP and adenosine 3'-5'-cyclic monophosphate (cAMP), cause vasodilation. Although the two mechanisms have been considered to be independent, there are some reports of an interaction between cGMP and cAMP-mediated vasodilators (14,26). Because the PDE III class of PDEs preferentially hydrolyzes cyclic AMP and is competitively inhibited by cyclic GMP (21), it is possible that a PDE III inhibitor may have some synergism with L-arginine. Increasing levels of cGMP from L-arginine could inhibit PDE III and cause a synergistic dilation. We found that L-arginine, combined with amrinone, is not synergistic (Table 2). Whereas each drug causes significant vasodilation (Table 1), the effects of L-arginine and amrinone are merely additive. The same is true for L-arginine with milrinone. This is demonstrated in the parallel vertical displacement between the regression lines as the concentration of amrinone or milrinone was increased (Fig. 2, a and b). Thus, although cGMP inhibits Type III PDEs, increased levels of cGMP from increased L-arginine levels are only additive to the effects of PDE III inhibitors.


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  		Table 2. Effect of L-Arginine and Phosphodiesterase Inhibitors in Combination
 
Sildenafil is the only Type V PDE inhibitor available for clinical use. Sildenafil is not as potent a vasodilator as the other PDE inhibitors (40% reversal of contraction by 4.3E-04M sildenafil versus complete reversal by the other three). Sildenafil is a potent relaxant of the corpus cavernosum (24), but less effective on the vasculature (27). Sildenafil demonstrates synergistic vasodilation with nitroglycerine (27) and L-arginine. Sildenafil has been shown to have a 240-fold more potent effect on human corpus cavernosum tissue (24) than zaprinast. In contrast, zaprinast is a more potent vasodilator.

The NO synthase inhibitor L-NMA was given to test the effects of L-arginine and the four PDE inhibitors under conditions in which NO production is impaired. L-arginine vasodilation was blocked by L-NMA. L-NMA did not inhibit amrinone-induced vasodilation and is consistent with previous reports (28). We found a significant interaction (ANOVA, P < 0.05), but no synergism between L-NMA and milrinone. The EC50 of milrinone was not significantly different 6.0E-06M (confidence interval: 8.5E-05 to 2.3E-07) vs 2.8E-05M (confidence interval: 5.4E-05 to 1.3E-05) in the presence of L-NMA. Previous studies have varied in their characterization of milrinone. Milrinone-induced vasodilations were not affected by NG-monomethyl-L-arginine (21), but were attenuated by NG-nitro-L-arginine methyl ester (12). The present study is suggestive that the effects of milrinone can be influenced by NO production.

The inhibition of the response to sildenafil and zaprinast by L-NMA clearly demonstrates cGMP-mediated vasodilation and is consistent with earlier reports (29,30).

Vessel segments from healthy animals were preconstricted with a pharmacological dose (6.8 mM) of epinephrine to create a large change in vessel tone against which the vasodilators, L-arginine and the PDE inhibitors, could function. Some preconstricting agent is required during in vitro testing of vasodilators and many have been used, including epinephrine (31), norepinephrine (32), potassium (32), prostaglandin F2a (33), phenylephrine (32), and many others. As long as the choice of preconstrictor provides complete vasoconstriction and does not block the mechanism of action of the vasodilator, there is no difference in calculated EC50 for the vasodilator (34–36).

We used porcine IMA samples for two reasons. We initially attempted to use human IMA samples, but many had been exposed to papaverine and the samples were too small to obtain five rings per sample. Porcine and human vascular biology are similar, but the limitation of the use of animal models apply.

This study did not consider clinically used NO donors nitroprusside and nitroglycerin, because the hypothesis to be tested was whether a PDE inhibitor could augment the effects of L-arginine. Other investigators have demonstrated synergism between nitroglycerine and zaprinast (29) or sildenafil (27). It is usually not clinically necessary to augment the effects of nitroprusside and nitroglycerin because their therapeutic range is associated with low doses of drug. L-arginine may be useful clinically because its effect is regulated by NO synthase, and it may be more selective in efficacy than nitroprusside or nitroglycerin. We speculate that the observed synergistic interaction between sildenafil and L-arginine could be deleterious (by causing excessive vasodilation) or beneficial (combinations of L-arginine and sildenafil may be useful for preventing vasospasm). Resolution of the clinical importance of this synergistic interaction will require further studies.

In conclusion, our study has shown that two Type V PDE inhibitors, zaprinast and sildenafil, act synergistically with L-arginine in vasodilation of the internal mammary artery in vitro. When L-arginine and PDE V inhibitors are used in combination, a reduced dose results in significant vasodilation.


   Acknowledgments
 
This study was supported by the Foundation for Anesthesia Education and Research, Young Investigation Award (Rochester, NY).

We would like to thank Dr. Brian Cason for the loan of tissue bath equipment and bench space. We would like to thank Dr. Stan Glantz for advice on statistical methods.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication December 16, 1999.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2000 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press