Pharmacology 1990;41:280-285
Vasodilatory Effects of Lidocaine on Epicardial Porcine Coronary Arteries Neal S. Perlmutter3, Richard A. Wilson3, Scott W. Edgar3, Wendy 9 Sanders3, Barry H. Greenberg3, Ralph Tanzb “Division o f Cardiology, Department of Medicine, and bDepartment o f Pharmacology, Oregon Health Sciences University, Portland, Oreg., USA
Key Words. Lidocaine • Coronary blood flow • Vasodilation
Introduction Although intravenous lidocaine is com monly used for the treatment of life-threat ening ventricular arrhythmias, it has other important cardiovascular effects. We have observed intravenous lidocaine (1.5-4.0 mg/ kg) to produce large increases in coronary blood flow in open-chest swine in our labo ratory [1]; others have observed similar ef fects in patients with recent myocardial in farction [2], Lidocaine has been shown to produce systemic arterial vasodilation in dogs [3] and man [4] over a wide dose range, and the coronary flow effects have been pos
tulated to result from drug-induced systemic vasodilation, with secondary reflex tachy cardia and an associated increase in myo cardial oxygen consumption. Gould et al. [2] questioned this observation, however, after measuring coronary blood flow by ru bidium clearance in men before and after lidocaine injection. They noted that lido caine does not appreciably change cardiac pressures, heart rate or velocity of contrac tion, all of which are major determinants of myocardial oxygen consumption, and felt that lidocaine more likely causes coronary vasodilation by direct action on vascular smooth muscle.
Downloaded by: Stockholm University Library 130.237.165.40 - 1/18/2019 10:10:10 PM
Abstract. To investigate the mechanism of lidocaine’s effect to cause vasorelaxation, swine epicardial mid-right coronary arterial rings were placed under constant (5 g) tension in a muscle bath, precontracted with 35 mmol/1 KC1 and exposed to increasing concentrations of lidocaine (3-2,000 pg/ml). At a concentration of 10 pg/ml, mild vasoconstriction oc curred, increasing tension 1.9 ± 0.1 % above baseline. Vasodilation began to occur at 30 pg/ ml and was maximal at 2,000 pg/ml. reducing tension 97.5 ± 0.2% below baseline. Vasodi lation was not altered significantly by removal of endothelium or by pretreatment with propranolol or indometacin.
281
Lidocainc and Vasodilation
Fig. 1. Effect o f lidocainc on coronary artery tension: the effect of cumulative concentrations o f lidocaine (1-2,000 pg/ml) added to the media bathing a porcine coro nary arterial ring precontracted with 35 mmol/1 KC1.
Materials and Methods Tissue Preparation Hearts from male and female pigs (30-45 kg) were obtained fresh from Carlton Packing Company in Carlton, Oreg.. USA, and placed in iced, pregassed Krebs-Henselcit (KH) solution for transportation to the laboratory. The KH solution contained the following (mmol/1): KC1, 4.75; KH:P 0 4. 1.19; M gS 0j-7H ;0, 1.19; CaCI2-2H ;0 , 1.27; NaCI, 118; NaHCCh, 25, and glucose, 5.56. The right coronary' artery was dissected free, cleaned of adherent connec tive and adipose tissue and then transversely cut into arterial rings 4 -6 mm in length and 4 -5 mm in resting diameter. Care was taken to avoid stretching the rings and to preserve endothelial integrity. The arterial rings were carefully mounted on gently curved, stainless steel hooks and suspended in a 20-ml KH bath. The lower hook was fixed to the bottom of the bath, while the upper hook was at tached to a force transducer (Grass FT.03) and mounted on a micrometer apparatus. Changes in iso metric force were recorded on a polygraph (Grass 7). The bathing solution was continuously aerated with a mixture of 95% 02/5% CO:, and temperature was maintained at 37 °C.
Pharmacologic Studies For each experiment, rings were mounted under 5 g o f resting tension and were allowed to equilibrate in the bath for 90 min. Following equilibration, rings were depolarized twice with KH solution containing 35 mmol/1 KC1. After reaching a stable constricted plateau with 35 mmol/1 KC1, lidocaine was added to the bath solution, in 0 .1-ml increments, to produce increasing bath concentrations o f 3, 10, 30, 100, 300, 600, 1,000 and 2,000 pg/ml. Each concentration was allowed to remain in contact with the arterial rings, until the maximal response had been observed and cumulative isometric responses to lidocaine mea sured (fig. 1). In order to investigate the effects o f the endothe lium on vasoactive properties o f lidocaine, cumula tive dose-response measurements were obtained in experiments where some of the rings were devoid of their endothelium. Endothelial cells were removed from the rings by rubbing the luminal surface with the tip o f a wooden toothpick for 15-30 s. The effective ness o f this procedure in removing the endothelium has been documented previously by electron-micro scopic studies [5]. Removal o f the endothelium was then confirmed physiologically by demonstrating the inability of adenosine triphosphate (ATP. 10"8 - 10-6 mol/1) to induce arterial smooth muscle relaxation [6). After all drug testing had been completed, the ability of hemoglobin (10-5 mol/1) to augment arterial tone only in vessels with intact endothelium [7] was also confirmed. In separate experiments, the cumulative lidocaine dose-response measurements were also obtained from coronary artery rings which were pretreated with either propranolol (3 X 10-6 mol/1) or indometacin (1 X 10"5 mol/1). Dose-response measurements were initially obtained for lidocaine alone without antago-
Downloaded by: Stockholm University Library 130.237.165.40 - 1/18/2019 10:10:10 PM
Although lidocaine has been shown to cause peripheral arterial vasodilation, the di rect effect of lidocaine on coronary- artery vasoactivity has not been demonstrated. This study was designed to examine the di rect effects of lidocaine on vasoactivity in porcine coronary artery rings.
Perlmuttcr/Wilson/Edgar/Sanders/Grecnberg/Tanz
282
Fig. 2. Lidocaine dose response on coronary vasorelaxation: doseresponse curve for lidocaine show ing the percent of arterial ring tone induced by 35 mmol/l KCI versus lidocaine concentration (3-2,000 pg/ml). 0% equals the initial 5 g of resting tension, and 100% equals the maximum precontraction by 35 mmol/l KCI. • = Control re sponse to lidocaine (with endothe lium intact); A = response to lido caine (with endothelium removed).
Drugs All test solutions o f lidocaine hydrochloride (Ab bott Laboratories), propranolol hydrochloride (Ayerst Laboratories), indometacin (Sigma Chemical) and ATP (Sigma Chemical) were prepared from stock solutions on the day o f the experiment, using serial dilutions. Test solutions were administered in 0.1-ml increments to the bath solution by a micropipet. All reported drug doses were equivalent to the final bath concentrations o f the drug. Bovine hemoglobin type 1 (Sigma Chemical) con tains a mixture o f oxyhemoglobin and the oxidized derivative, methemoglobin. Pure hemoglobin (oxyhe moglobin) was prepared by adding to a solution o f 1 mmol/l o f commercial hemoglobin in distilled wa ter, a 10-fold molar excess of the reducing agent, sodium dithionite (Na 2Si 0 4 ). Sodium dithionite was then removed by dialysis against 100 volumes o f dis tilled water for 2 h at 4 °C. The purity o f the solutions o f hemoglobin was determined spectrophotometrically. The solutions were frozen in aliquots at - 2 0 °C and stored for up to 14 days.
Data Analysis Relaxation was determined by measuring the cu mulative reduction in induced tone in the arterial seg ments and expressed as the percentage o f the contrac tion induced by 35 mmol/l KCI. A value of 0% indi cates initial resting tension (5 g), and a value o f 100% indicates the isometric tension generated by exposure to 35 mmol/l KCI. Values greater than 100% indicate that vasoconstriction had occurred in response to an agent. Data are expressed as means ± SEM. Compar isons between lidocaine dose-response curves in con trol rings and in rings without endothelium, and with antagonist pretreatment, were performed using analy sis o f variance. A p value o f less than 0.05 was consid ered to be significant.
Results Lidocaine resulted in a relaxation of por cine coronary arterial rings. A typical poly graph recording of isometric tension in re sponse to increasing lidocaine concentrations (3-2,000 |ig/ml) is shown in figure 1. Doseresponse curves for all initial arterial rings
Downloaded by: Stockholm University Library 130.237.165.40 - 1/18/2019 10:10:10 PM
nist pretreatment. After a 30-min reequilibration pe riod, the dose-response measurements were repeated following pretreatment with one o f these antago nists.
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283
Table 2. Effect o f indometacin on lidocaine-induced vasorelaxation (percent o f KCI-induced con traction)
Lidocaine pg/ml
Without propranolol pretreatment (n = 6)
With propranolol pretreatment (n = 6)
Lidocaine pg/ml
Without indometacin pretreatment (n = 6)
With indometacin pretreatment (n = 6)
10 30 100 300 600 1,000
102.0±0.97 95.7± 0.59 82.2 + 2.33 44.2 + 3.32 15.5 ± 1.54 6.2 ±0.79
101.2 + 0.47 9 8 .0 ± 0 .5 6 86.3 ± 1.56 44.5 ±3.23 14.6± 1.59 6.6 ± 1.41
10 30 100 300 600 1.000
I01 .0 ± 0 .6 0 95.3 ± 0 .5 0 83.5 ±2.00 46.1 ±3.45 15.3 ±2.87 6.1 ± 1.65
98.7 ±2.97 97.9 ±0.92 78.6 ±5.13 38.6 ±4.21 I2.4± 1.94 5.9± 0.68
tested at these concentrations are shown in figure 2 (closed circles). A biphasic doseresponse relationship was noted. Increasing the lidocaine concentration from 3 to 10 pg/ ml caused mild vasoconstriction, indicated by an increase in ring tension from 100.4 ± 0.04 to 101.9 ± 0.1 % (p < 0.05) of the con traction induced by 35 mmol/l KCl, respec tively. Vasodilation occurred at 30 pg/ml (95.7 ± 0.1% of the contraction induced by 35 mmol/l KCl) and increased to a maximum at 2,000 pg/ml (2.5 ± 0.2% of the contrac tion induced by 35 mmol/l KCl). The doseresponse curve is steepest around the con centration of 300 pg/ml. with appropriately larger standard error values in this range. Endothelial cell removal produced no ef fect on the lidocaine dose-response relation ship (fig. 2, p > 0.25); curves appear nearly identical in sets of rings with and without endothelium. Pretreatment with propranolol (3 X 10~6 mol/1) or indometacin (1 X 10 '5 mol/1) pro duced no effect on the lidocaine dose-re sponse relationship, either (tables 1, 2, re spectively; p > 0.25 for each intervention).
Discussion This study demonstrates that lidocaine produced coronary vasodilation on isolated porcine coronary arterial rings. Although va soconstriction occurred at levels sometimes seen during steady-state infusion in man (24 pg/ml at steady state) [8], a more marked vasodilation occurred at higher doses, such as may be seen during bolus injection. A rapid intravenous bolus injection of lido caine (2-3 mg/kg over 30 s) can produce ini tial plasma levels of 20-48 pg/ml in animal studies [9], In humans, a 50-mg intravenous bolus of 1% lidocaine given over 60 s may result in an initial plasma concentration of 1-7 pg/ml at 60s after injection [10], In creasing the dose, the rate of injection and the concentration of lidocaine would be ex pected to increase the initial plasma concen trations even more. Blood sampling sooner and more frequently may also identify higher levels than previously observed. Although the vascular effects of lidocaine have been studied in both animals and man under a variety of conditions, many of these
Downloaded by: Stockholm University Library 130.237.165.40 - 1/18/2019 10:10:10 PM
Table 1. Effect o f propranolol on lidocaine-induced vasorelaxation (percent o f KCI-induced con traction)
prior results appear conflicting. Some in vivo studies have demonstrated that lidocaine produces vasodilation, as indicated by an increase in peripheral arterial blood flow [3, 11] and an increase in coronary arterial blood flow [1,2]. Other in vivo studies have indicated that lidocaine either produces va soconstriction [11, 12] or no vascular effect at all [4, 13]. Gould et al. [2] demonstrated that lidocaine increased coronary blood flow as assessed by serial rubidium clearance measurements in men before and after lido caine injection. There are several possible explanations for the differences between past and current studies. Species specificity may explain some of the differences in observed vasoactivity. Lidocaine has been found to produce vaso constriction in dogs [13] but vasodilation in humans [2]. Differences in the concentration of lidocaine achieved in the blood may also explain the conflicting results of previous studies as our data suggest that a biphasic vasoconstriction-vasodilation may occur at low and high lidocaine levels, respectively. The current study is an in vitro investiga tion, in contrast to the in vivo studies de scribed above. Advantages to the in vitro techniques utilized here include more con sistent, precise drug delivery to the artery, more quantitative assessment of arterial va soconstriction and vasodilation, and re moval of the artery from the hemodynamic and autonomic systemic effects which lido caine has been shown to produce, thus re vealing any direct activity. The mechanism of lidocaine-induced cor onary vasodilation remains to be deter mined. However, the results of this study suggest that the mechanism is not dependent upon endothelial factors, (3-adrenergic acti vation or prostaglandin metabolites, given
Perlmutter/Wilson/Edgar/Sanders/Greenberg/Tanz
that vasodilation could not be reduced with endothelial removal or administration of ap propriate blocking agents. These results may have therapeutic impli cations. Lidocaine is frequently given to pa tients with suspected myocardial infarction as prophylaxis against ventricular arrhyth mias. Coronary vasodilation in this setting, if produced by lidocaine, could help alleviate myocardial ischemia and thereby decrease ischemia-induced arrhythmias or potentially reduce the size of myocardial infarction.
Acknowledgements N.S.P. is a Research Fellow supported by the National Institutes o f Health Institutional Training grant No. 5T32HL07596-03. S.W.E. and W.S. were supported by summer research fellowships o f the American Heart Association, Oregon Affiliate. The authors gratefully acknowledge the expert secretarial assistance o f John Davis.
References 1 Gee D, Wilson RA, Angello DA: Acute effect o f lidocaine on coronary blood flow and myocardial function. Angiology 1990;41:30-35. 2 Gould L. Reddy CVR, Hayt DB, et al: Lignocaine: Effects on coronary blood flow in patients with recent myocardial infarction. Br Heart J 1973;36: 566-569. 3 Austen WG, Morgan JM: Cardiac and peripheral vascular effects of lidocaine and procainamide. Am J Cardiol 1985;16:701-707. 4 Schumacher RR, Lieberson AD. Childress RH, et al: Hemodynamic effects o f lidocaine in patients with heart disease. Circulation 1968;37:965-972. 5 Carrier GO. White RE. Kirby ML: Histamine induced relaxation o f rat aorta: Importance o f Hi receptor and vascular endothelium. Blood Vessels 1984;21:180-183. 6 DeFeadis FV: Studies on endothelium-dependent vasorelaxation. Gen Pharmacol 1985;17:1-4. 7 Martin W, Villani GM, Jothianandan D, et al:
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284
Lidocaine and Vasodilation
9
10
11
12 Thomsen JH. Terry W. Stenlund RR. et al: The effects of lidocaine on systemic and coronary he modynamics. Arch lnt Pharmacodyn 1971:194: 83-92. 13 Okamura T, Sunamori M, Suzuki A: Protective effect oflidocaine in reperfused ischemic myocar dium. Jpn Circ J 1982;46:657-662.
Received: March 21, 1990 Accepted: June 19, 1990 Richard A. Wilson, MD Division of Cardiology, L-462 Oregon Health Sciences University 3181 S.W. Sam Jackson Park Road Portland. OR 97201-3098 (USA)
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8
Selective blockade of endothelium-dependent and glyceryl trinitrate-induced relaxation by hemoglo bin and by methylene blue in the rabbit aorta. J Pharmacol Exp Ther 1984;232:708-716. Laurikainen E, Arstila M, Pekkarinen A, et at; Optimum dosage of lidocaine. lnt J Clin Pharma col Ther Toxicol 1983;23:16-19. Vogt B. Martin C. Meesmann W: Prophylactic lidocaine: Concentration in plasma and myocar dial tissue and antifibrillatoric efficacy during early ischemia in dogs and pigs. J Cardiovasc Pharmacol 1988;12:571-578. Thomson PD, Rowland M, Melmon K.L: The influence o f heart failure, lower disease and renal failure on the disposition of lidocaine in man. Am Heart J 1971;82:417-421. Johns RA. DiFazio CA. Longnecker DE: Lido caine constricts or dilates rat arterioles in a dosedependent manner. Anesthesiology 1984;62:141 — 144.
285
Vasodilatory Effects of Lidocaine on Epicardial Porcine Coronary Arteries Neal S. Perlmutter3, Richard A. Wilson3, Scott W. Edgar3, Wendy 9 Sanders3, Barry H. Greenberg3, Ralph Tanzb “Division o f Cardiology, Department of Medicine, and bDepartment o f Pharmacology, Oregon Health Sciences University, Portland, Oreg., USA
Key Words. Lidocaine • Coronary blood flow • Vasodilation
Introduction Although intravenous lidocaine is com monly used for the treatment of life-threat ening ventricular arrhythmias, it has other important cardiovascular effects. We have observed intravenous lidocaine (1.5-4.0 mg/ kg) to produce large increases in coronary blood flow in open-chest swine in our labo ratory [1]; others have observed similar ef fects in patients with recent myocardial in farction [2], Lidocaine has been shown to produce systemic arterial vasodilation in dogs [3] and man [4] over a wide dose range, and the coronary flow effects have been pos
tulated to result from drug-induced systemic vasodilation, with secondary reflex tachy cardia and an associated increase in myo cardial oxygen consumption. Gould et al. [2] questioned this observation, however, after measuring coronary blood flow by ru bidium clearance in men before and after lidocaine injection. They noted that lido caine does not appreciably change cardiac pressures, heart rate or velocity of contrac tion, all of which are major determinants of myocardial oxygen consumption, and felt that lidocaine more likely causes coronary vasodilation by direct action on vascular smooth muscle.
Downloaded by: Stockholm University Library 130.237.165.40 - 1/18/2019 10:10:10 PM
Abstract. To investigate the mechanism of lidocaine’s effect to cause vasorelaxation, swine epicardial mid-right coronary arterial rings were placed under constant (5 g) tension in a muscle bath, precontracted with 35 mmol/1 KC1 and exposed to increasing concentrations of lidocaine (3-2,000 pg/ml). At a concentration of 10 pg/ml, mild vasoconstriction oc curred, increasing tension 1.9 ± 0.1 % above baseline. Vasodilation began to occur at 30 pg/ ml and was maximal at 2,000 pg/ml. reducing tension 97.5 ± 0.2% below baseline. Vasodi lation was not altered significantly by removal of endothelium or by pretreatment with propranolol or indometacin.
281
Lidocainc and Vasodilation
Fig. 1. Effect o f lidocainc on coronary artery tension: the effect of cumulative concentrations o f lidocaine (1-2,000 pg/ml) added to the media bathing a porcine coro nary arterial ring precontracted with 35 mmol/1 KC1.
Materials and Methods Tissue Preparation Hearts from male and female pigs (30-45 kg) were obtained fresh from Carlton Packing Company in Carlton, Oreg.. USA, and placed in iced, pregassed Krebs-Henselcit (KH) solution for transportation to the laboratory. The KH solution contained the following (mmol/1): KC1, 4.75; KH:P 0 4. 1.19; M gS 0j-7H ;0, 1.19; CaCI2-2H ;0 , 1.27; NaCI, 118; NaHCCh, 25, and glucose, 5.56. The right coronary' artery was dissected free, cleaned of adherent connec tive and adipose tissue and then transversely cut into arterial rings 4 -6 mm in length and 4 -5 mm in resting diameter. Care was taken to avoid stretching the rings and to preserve endothelial integrity. The arterial rings were carefully mounted on gently curved, stainless steel hooks and suspended in a 20-ml KH bath. The lower hook was fixed to the bottom of the bath, while the upper hook was at tached to a force transducer (Grass FT.03) and mounted on a micrometer apparatus. Changes in iso metric force were recorded on a polygraph (Grass 7). The bathing solution was continuously aerated with a mixture of 95% 02/5% CO:, and temperature was maintained at 37 °C.
Pharmacologic Studies For each experiment, rings were mounted under 5 g o f resting tension and were allowed to equilibrate in the bath for 90 min. Following equilibration, rings were depolarized twice with KH solution containing 35 mmol/1 KC1. After reaching a stable constricted plateau with 35 mmol/1 KC1, lidocaine was added to the bath solution, in 0 .1-ml increments, to produce increasing bath concentrations o f 3, 10, 30, 100, 300, 600, 1,000 and 2,000 pg/ml. Each concentration was allowed to remain in contact with the arterial rings, until the maximal response had been observed and cumulative isometric responses to lidocaine mea sured (fig. 1). In order to investigate the effects o f the endothe lium on vasoactive properties o f lidocaine, cumula tive dose-response measurements were obtained in experiments where some of the rings were devoid of their endothelium. Endothelial cells were removed from the rings by rubbing the luminal surface with the tip o f a wooden toothpick for 15-30 s. The effective ness o f this procedure in removing the endothelium has been documented previously by electron-micro scopic studies [5]. Removal o f the endothelium was then confirmed physiologically by demonstrating the inability of adenosine triphosphate (ATP. 10"8 - 10-6 mol/1) to induce arterial smooth muscle relaxation [6). After all drug testing had been completed, the ability of hemoglobin (10-5 mol/1) to augment arterial tone only in vessels with intact endothelium [7] was also confirmed. In separate experiments, the cumulative lidocaine dose-response measurements were also obtained from coronary artery rings which were pretreated with either propranolol (3 X 10-6 mol/1) or indometacin (1 X 10"5 mol/1). Dose-response measurements were initially obtained for lidocaine alone without antago-
Downloaded by: Stockholm University Library 130.237.165.40 - 1/18/2019 10:10:10 PM
Although lidocaine has been shown to cause peripheral arterial vasodilation, the di rect effect of lidocaine on coronary- artery vasoactivity has not been demonstrated. This study was designed to examine the di rect effects of lidocaine on vasoactivity in porcine coronary artery rings.
Perlmuttcr/Wilson/Edgar/Sanders/Grecnberg/Tanz
282
Fig. 2. Lidocaine dose response on coronary vasorelaxation: doseresponse curve for lidocaine show ing the percent of arterial ring tone induced by 35 mmol/l KCI versus lidocaine concentration (3-2,000 pg/ml). 0% equals the initial 5 g of resting tension, and 100% equals the maximum precontraction by 35 mmol/l KCI. • = Control re sponse to lidocaine (with endothe lium intact); A = response to lido caine (with endothelium removed).
Drugs All test solutions o f lidocaine hydrochloride (Ab bott Laboratories), propranolol hydrochloride (Ayerst Laboratories), indometacin (Sigma Chemical) and ATP (Sigma Chemical) were prepared from stock solutions on the day o f the experiment, using serial dilutions. Test solutions were administered in 0.1-ml increments to the bath solution by a micropipet. All reported drug doses were equivalent to the final bath concentrations o f the drug. Bovine hemoglobin type 1 (Sigma Chemical) con tains a mixture o f oxyhemoglobin and the oxidized derivative, methemoglobin. Pure hemoglobin (oxyhe moglobin) was prepared by adding to a solution o f 1 mmol/l o f commercial hemoglobin in distilled wa ter, a 10-fold molar excess of the reducing agent, sodium dithionite (Na 2Si 0 4 ). Sodium dithionite was then removed by dialysis against 100 volumes o f dis tilled water for 2 h at 4 °C. The purity o f the solutions o f hemoglobin was determined spectrophotometrically. The solutions were frozen in aliquots at - 2 0 °C and stored for up to 14 days.
Data Analysis Relaxation was determined by measuring the cu mulative reduction in induced tone in the arterial seg ments and expressed as the percentage o f the contrac tion induced by 35 mmol/l KCI. A value of 0% indi cates initial resting tension (5 g), and a value o f 100% indicates the isometric tension generated by exposure to 35 mmol/l KCI. Values greater than 100% indicate that vasoconstriction had occurred in response to an agent. Data are expressed as means ± SEM. Compar isons between lidocaine dose-response curves in con trol rings and in rings without endothelium, and with antagonist pretreatment, were performed using analy sis o f variance. A p value o f less than 0.05 was consid ered to be significant.
Results Lidocaine resulted in a relaxation of por cine coronary arterial rings. A typical poly graph recording of isometric tension in re sponse to increasing lidocaine concentrations (3-2,000 |ig/ml) is shown in figure 1. Doseresponse curves for all initial arterial rings
Downloaded by: Stockholm University Library 130.237.165.40 - 1/18/2019 10:10:10 PM
nist pretreatment. After a 30-min reequilibration pe riod, the dose-response measurements were repeated following pretreatment with one o f these antago nists.
Lidocaine and Vasodilation
283
Table 2. Effect o f indometacin on lidocaine-induced vasorelaxation (percent o f KCI-induced con traction)
Lidocaine pg/ml
Without propranolol pretreatment (n = 6)
With propranolol pretreatment (n = 6)
Lidocaine pg/ml
Without indometacin pretreatment (n = 6)
With indometacin pretreatment (n = 6)
10 30 100 300 600 1,000
102.0±0.97 95.7± 0.59 82.2 + 2.33 44.2 + 3.32 15.5 ± 1.54 6.2 ±0.79
101.2 + 0.47 9 8 .0 ± 0 .5 6 86.3 ± 1.56 44.5 ±3.23 14.6± 1.59 6.6 ± 1.41
10 30 100 300 600 1.000
I01 .0 ± 0 .6 0 95.3 ± 0 .5 0 83.5 ±2.00 46.1 ±3.45 15.3 ±2.87 6.1 ± 1.65
98.7 ±2.97 97.9 ±0.92 78.6 ±5.13 38.6 ±4.21 I2.4± 1.94 5.9± 0.68
tested at these concentrations are shown in figure 2 (closed circles). A biphasic doseresponse relationship was noted. Increasing the lidocaine concentration from 3 to 10 pg/ ml caused mild vasoconstriction, indicated by an increase in ring tension from 100.4 ± 0.04 to 101.9 ± 0.1 % (p < 0.05) of the con traction induced by 35 mmol/l KCl, respec tively. Vasodilation occurred at 30 pg/ml (95.7 ± 0.1% of the contraction induced by 35 mmol/l KCl) and increased to a maximum at 2,000 pg/ml (2.5 ± 0.2% of the contrac tion induced by 35 mmol/l KCl). The doseresponse curve is steepest around the con centration of 300 pg/ml. with appropriately larger standard error values in this range. Endothelial cell removal produced no ef fect on the lidocaine dose-response relation ship (fig. 2, p > 0.25); curves appear nearly identical in sets of rings with and without endothelium. Pretreatment with propranolol (3 X 10~6 mol/1) or indometacin (1 X 10 '5 mol/1) pro duced no effect on the lidocaine dose-re sponse relationship, either (tables 1, 2, re spectively; p > 0.25 for each intervention).
Discussion This study demonstrates that lidocaine produced coronary vasodilation on isolated porcine coronary arterial rings. Although va soconstriction occurred at levels sometimes seen during steady-state infusion in man (24 pg/ml at steady state) [8], a more marked vasodilation occurred at higher doses, such as may be seen during bolus injection. A rapid intravenous bolus injection of lido caine (2-3 mg/kg over 30 s) can produce ini tial plasma levels of 20-48 pg/ml in animal studies [9], In humans, a 50-mg intravenous bolus of 1% lidocaine given over 60 s may result in an initial plasma concentration of 1-7 pg/ml at 60s after injection [10], In creasing the dose, the rate of injection and the concentration of lidocaine would be ex pected to increase the initial plasma concen trations even more. Blood sampling sooner and more frequently may also identify higher levels than previously observed. Although the vascular effects of lidocaine have been studied in both animals and man under a variety of conditions, many of these
Downloaded by: Stockholm University Library 130.237.165.40 - 1/18/2019 10:10:10 PM
Table 1. Effect o f propranolol on lidocaine-induced vasorelaxation (percent o f KCI-induced con traction)
prior results appear conflicting. Some in vivo studies have demonstrated that lidocaine produces vasodilation, as indicated by an increase in peripheral arterial blood flow [3, 11] and an increase in coronary arterial blood flow [1,2]. Other in vivo studies have indicated that lidocaine either produces va soconstriction [11, 12] or no vascular effect at all [4, 13]. Gould et al. [2] demonstrated that lidocaine increased coronary blood flow as assessed by serial rubidium clearance measurements in men before and after lido caine injection. There are several possible explanations for the differences between past and current studies. Species specificity may explain some of the differences in observed vasoactivity. Lidocaine has been found to produce vaso constriction in dogs [13] but vasodilation in humans [2]. Differences in the concentration of lidocaine achieved in the blood may also explain the conflicting results of previous studies as our data suggest that a biphasic vasoconstriction-vasodilation may occur at low and high lidocaine levels, respectively. The current study is an in vitro investiga tion, in contrast to the in vivo studies de scribed above. Advantages to the in vitro techniques utilized here include more con sistent, precise drug delivery to the artery, more quantitative assessment of arterial va soconstriction and vasodilation, and re moval of the artery from the hemodynamic and autonomic systemic effects which lido caine has been shown to produce, thus re vealing any direct activity. The mechanism of lidocaine-induced cor onary vasodilation remains to be deter mined. However, the results of this study suggest that the mechanism is not dependent upon endothelial factors, (3-adrenergic acti vation or prostaglandin metabolites, given
Perlmutter/Wilson/Edgar/Sanders/Greenberg/Tanz
that vasodilation could not be reduced with endothelial removal or administration of ap propriate blocking agents. These results may have therapeutic impli cations. Lidocaine is frequently given to pa tients with suspected myocardial infarction as prophylaxis against ventricular arrhyth mias. Coronary vasodilation in this setting, if produced by lidocaine, could help alleviate myocardial ischemia and thereby decrease ischemia-induced arrhythmias or potentially reduce the size of myocardial infarction.
Acknowledgements N.S.P. is a Research Fellow supported by the National Institutes o f Health Institutional Training grant No. 5T32HL07596-03. S.W.E. and W.S. were supported by summer research fellowships o f the American Heart Association, Oregon Affiliate. The authors gratefully acknowledge the expert secretarial assistance o f John Davis.
References 1 Gee D, Wilson RA, Angello DA: Acute effect o f lidocaine on coronary blood flow and myocardial function. Angiology 1990;41:30-35. 2 Gould L. Reddy CVR, Hayt DB, et al: Lignocaine: Effects on coronary blood flow in patients with recent myocardial infarction. Br Heart J 1973;36: 566-569. 3 Austen WG, Morgan JM: Cardiac and peripheral vascular effects of lidocaine and procainamide. Am J Cardiol 1985;16:701-707. 4 Schumacher RR, Lieberson AD. Childress RH, et al: Hemodynamic effects o f lidocaine in patients with heart disease. Circulation 1968;37:965-972. 5 Carrier GO. White RE. Kirby ML: Histamine induced relaxation o f rat aorta: Importance o f Hi receptor and vascular endothelium. Blood Vessels 1984;21:180-183. 6 DeFeadis FV: Studies on endothelium-dependent vasorelaxation. Gen Pharmacol 1985;17:1-4. 7 Martin W, Villani GM, Jothianandan D, et al:
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Received: March 21, 1990 Accepted: June 19, 1990 Richard A. Wilson, MD Division of Cardiology, L-462 Oregon Health Sciences University 3181 S.W. Sam Jackson Park Road Portland. OR 97201-3098 (USA)
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