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Anesth Analg 1999;89:604
© 1999 International Anesthesia Research Society

CARDIOVASCULAR ANESTHESIA

Propofol-Induced Alterations in Myocardial ß-Adrenoceptor Binding and Responsiveness

Weiguo Zhou, MD*, H. Jerrel Fontenot, MD, PhD*, Shi-Nan Wang, MD{dagger}, and Richard H. Kennedy, PhD*,{dagger},{ddagger}

Departments of *Anesthesiology, {dagger}Pharmacology & Toxicology, and {ddagger}Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas

Address correspondence and reprint requests to Richard H. Kennedy, PhD, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, 4301 West Markham St., Slot# 522, Little Rock, AR 72205. Address e-mail to kennedyrichardh{at}exchange.uams.edu


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Propofol (iv) depresses cardiovascular function in both humans and animals. However, the mechanism underlying this action has not been well described. The present study was designed to test the hypothesis that this effect of propofol results in part from an antagonism of adrenergic control of the heart. Experiments examined effects of propofol on: 1) [3H]CGP12177 (a ß-adrenoceptor antagonist) binding in rat myocardial membranes; and 2) the inotropic and chronotropic actions of isoproterenol in rat left atrial muscle and right atria, respectively. Propofol (25–200 µM) increased the apparent dissociation constant for [3H]CGP12177 without affecting binding site density. Similarly, 200 µM propofol increased the 50% effective concentration values for the dose-dependent positive chronotropic and inotropic actions of isoproterenol in right and left atria, and depressed the maximum increase in spontaneous rate elicited by this ß-adrenoceptor agonist. Other experiments demonstrated that propofol does not alter muscarinic receptor binding as monitored using [3H]quinuclidinylbenzilate. In conclusion, these results indicate that propofol can decrease cardiac ß-adrenoceptor responsiveness; however, the concentrations of propofol required suggest that this action contributes to the cardiovascular depression produced by this anesthetic only during large-dose bolus injection.

Implications: Experiments in membranes and cardiac preparations isolated from rat heart demonstrate that relatively high concentrations of propofol (25–200 µM) are required to antagonize ß-adrenoceptor binding and tissue responsiveness.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Propofol (2,6-di-isopropylphenol) is a potent iv anesthetic that has gained widespread popularity for the induction and maintenance of anesthesia. However, the use of this anesthetic has been limited somewhat by its adverse cardiovascular effects that include decreases in cardiac output and arterial pressure (1–4). Comparative studies have shown that the hemodynamic effects of propofol are generally more pronounced than those elicited by other iv anesthetics traditionally used for induction (1,5).*Furthermore, direct cardiac depressant effects of propofol have been observed in myocardium from both animals and humans (5,6).{dagger}

Propofol's negative inotropic effect may be the result of several actions. Reports suggest that the depressed myocardial contractility is not mediated via effects on potassium currents (7) or decreases in sarcoplasmic reticular calcium release (8). However, propofol releases nitric oxide (9), acts as a calcium-channel blocker in vascular preparations (10), and activates protein kinase C (11), all of which could serve as mechanisms of the negative inotropic effect. Previous studies in our laboratory have suggested that the cardiodepressant effect elicited by high doses of propofol is associated with a decrease in voltage-dependent calcium influx via L-type calcium channels (12).

In addition, it is possible that the cardiovascular effects of propofol in vivo are mediated in part by antagonism of neurohumoral control. Volatile anesthetics, such as halothane, have been reported to depress myocardial function by interfering with the ß-adrenoceptor system (13). Propofol depresses sympathetic nerve activity and the baroreceptor response to decreases in blood pressure (14,15); however, possible interactions involving ß-adrenoceptors and their signal transduction pathways have received little attention (16). The present study was designed to determine if propofol acts at the level of the myocardium to antagonize the response to catecholamines. Experiments monitored effects of the anesthetic on: 1) cardiac actions of the ß-adrenoceptor agonist isoproterenol; and 2) ß-adrenoceptor binding in membranes prepared from rat ventricular myocardium.


   Methods
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 Abstract
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 Methods
Results
 Discussion
 References
 
All experiments were conducted in accordance with institutional guidelines and the Guide for the Care and Use of Laboratory Animals published by the U.S. Department of Health and Human Services, NIH Publication No. 86-23.

Membrane Preparation
Partially purified membranes from rat ventricular myocardium were prepared using a modification of a previously described procedure (12). Briefly, hearts were isolated from male Sprague-Dawley rats weighing 300–350 g and perfused immediately through the aorta with Krebs-Henseleit (KH) buffer (saturated with 95% O2/5% CO2). After the perfusate was free of blood, the ventricles were homogenized in 50 mM Tris-HCl:2 mM MgSO4 (pH 7.3 [4°C]), using three 30-s bursts of a Polytron at a setting of 6, followed by 6 strokes of a manual glass/glass homogenizer. The homogenate was centrifuged at 800g for 20 min. The resulting pellet was discarded, and the supernatant was centrifuged at 2,500g for 20 min. From this second supernatant, a pellet was isolated by two sequential centrifugations at 30,000g for 20 min, with intermediate washing of the pellet using the homogenizing buffer. The final membrane pellet was resuspended in 50 mM Tris-HCl:2 mM MgSO4 buffer to make a final suspension of 1 mg protein/mL. Protein concentration was determined by the method of Bradford (17) using bovine serum albumin as the standard.

Radioligand Binding Assay
Initial experiments characterized [3H]CGP12177 (ß-adrenoceptor antagonist) binding. Membranes (250 µl final volume) were incubated with varying concentrations of [3H]CGP12177 (\F0.01–4 nM) in the presence (25–200 µM) and absence of propofol. After 30 min at 37°C, the reaction mixture was diluted with 3.5 mL of ice-cold buffer (50 mM Tris-HCl:2 mM MgSO4) and immediately filtered through GF/C filters using a vacuum filtration manifold. The filters were washed three times with 3.5 mL each of the buffer, and the radioactivity remaining on the filters was measured by liquid scintillation spectrometry. Specific [3H]CGP12177 binding was defined as the difference between binding monitored in the presence and absence of 10 µM of unlabeled nadolol. All samples were processed in triplicate.

Experiments were also designed to determine if propofol alters muscarinic receptor binding to rat ventricular membranes. [3H]Quinuclidinylbenzilate ([3H]QNB) binding was examined in the presence and absence of the anesthetic. The assay mixture (250 µl final volume) contained membrane protein and increasing concentrations of [3H]QNB. After incubation at 37°C for 30 min, the reaction was terminated using the filtration and washing methods previously described. Atropine (5 µM) was used to define nonspecific binding. All samples were processed in triplicate.

Analysis of Binding Data
Binding data were analyzed using a microcomputer version of LIGAND (18). Saturation binding was evaluated to calculate binding site density (Bmax) and the apparent dissociation constant (Kd); a one-site model provided the best fit for all experiments.

Isolated Right and Left Atrial Preparations
Male Sprague-Dawley rats weighing 300–350 g were anesthetized with halothane (Halocarbon Laboratories, Inc., Hackensack, NJ), and hearts were removed and immediately perfused through the aorta with a KH solution of the following composition (in mM): 118.0 NaCl, 25.0 NaHCO3, 4.8 KCl, 1.2 MgSO4, 1.4 CaCl2, and 11.1 glucose. The solution was buffered to pH 7.4 by saturation with 95% O2/5% CO2 gas, and temperature was maintained at 37°C.

After all detectable blood was washed from the hearts, entire right and left atria were isolated and bathed in the KH solution previously described (37°C). Right atria were allowed to beat spontaneously; pacemaker frequency was monitored via tachographs (using signals from bipolar contact electrodes) and recorded continuously on a polygraph (Grass Model 7, Grass Instrument Co., Quincy, MA). Left atria were paced via platinum contact electrodes at a frequency of 1.5 Hz by 1.0-ms square wave pulses set at 125% threshold voltage. Force of resting tension and isometric contraction were monitored by force-displacement transducers (Grass Model FT-03) and recorded continuously on a polygraph. A length–tension relationship was determined for each left atrial preparation, and resting tension was subsequently maintained at that which elicited 90% of maximum observed contractile force. All atria were equilibrated for 90 min in the buffer solution before experiments were begun; during this period, the medium was replaced every 15 min.

Experiments were designed to evaluate the effect of propofol on the dose-dependent actions of isoproterenol. Cumulative dose-response curves for the adrenergic agonist were obtained by sequential addition of drug to the bathing medium; the next higher concentration of agonist was added to the KH solution only after the tissue reached a steady-state response at the previous level. When used, propofol (200 µM) was added to the bathing medium 15 min before exposure to isoproterenol.

Statistical Analysis
Data were evaluated by Student's t-test (when comparing two groups) or analysis of variance with post hoc comparison of individual groups (when comparing more than two groups) using Sigmastat (Jandel Scientific, San Rafael, CA). Differences were considered statistically significant when P < 0.05. All data are expressed as means ± SEM. The 50% effective concentration (EC50) values (the concentration of agonist eliciting a half-maximum response) were obtained by graphical evaluation of individual concentration-response curves.

Materials
Propofol (2,6-di-isopropylphenol) was purchased from Aldrich Chemical Co. (Milwaukee, WI). Since this drug can be added slowly to aqueous solutions without precipitating, it was not necessary to use lipid emulsions and solvent controls in the present experiments. [3H]CGP12177 (42.5 Ci/mmol) and [3H]QNB (40 Ci/mmol) were purchased from Du Pont (Boston, MA). Other chemicals were obtained from Sigma Chemical Co. (St. Louis, MO).


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Radioligand Binding Studies
As indicated in Fig. 1, [3H]CGP12177 binding to rat ventricular membranes showed a single population of high-affinity binding sites. Propofol antagonized this binding in a competitive manner, decreasing the slope of the Scatchard plot while having no effect on the x-intercept (Fig. 1). As shown in Table 1, the Kd for [3H]CGP12177 binding was increased by propofol in a concentration-dependent fashion (25–200 µM), whereas the Bmax was not significantly altered. Propofol did not affect the nonspecific binding of [3H]CGP12177, which ranged from 20% to 40% of total binding in the current studies.



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  		Figure 1. Representative plots showing saturation binding and Scatchard analysis (inset) of [3H]CGP12177 binding to rat ventricular membranes in the absence (open circles) and presence (closed circles) of 100 µM propofol.

 

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  		Table 1. Effects of Propofol on Specific [3H]CGP12177 Binding to Partially Purified Membranes Prepared from Rat Ventricular Myocardium
 
The effect of propofol on muscarinic receptor binding was determined using [3H]QNB. In contrast to its antagonism of [3H]CGP12177 binding, 100 µM propofol had no effect on the Kd or Bmax for [3H]QNB (Table 2).


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  		Table 2. Effects of 100 µM Propofol on [3H]QNB Binding to Partially Purified Membranes Prepared from Rat Ventricular Myocardium (n = 4/group)
 
Isolated Tissue Studies
Experiments in isolated cardiac preparations were performed to determine if observed effects of propofol on [3H]CGP12177 binding were paralleled by an antagonism of tissue responsiveness to ß-adrenoceptor stimulation. Inotropic actions of isoproterenol were compared in isolated atrial muscle in the presence and absence of 200 µM propofol. As reported previously (12), propofol caused a decrease in the contractility recorded before exposure to isoproterenol; developed tension was reduced from 0.41 ± 0.12 to 0.19 ± 0.05 g (P = 0.026) in preparations treated with propofol. In addition, as shown in Fig. 2, the anesthetic shifted the dose-response curve for the inotropic effect of isoproterenol to the right (the EC50 value was increased from 5.48 ± 1.09 to 16.39 ± 3.19 nM; P = 0.015) while having no significant effect on the increase in developed tension elicited by this agonist (1.56 ± 0.24 vs 1.88 ± 0.17 g in the presence and absence of 200 µM propofol, respectively; P = 0.303). Lower concentrations of propofol (100 µM and below) had no significant effect on the inotropic action of isoproterenol in these atrial preparations.



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  		Figure 2. Effects of isoproterenol on developed tension in rat left atrial muscle in the presence (closed circles; n = 6) and absence (open circles; n = 6) of 200 µM propofol. Preparations were bathed in oxygenated Krebs-Henseleit buffer (37°C) and paced at 1.5 Hz. Propofol was added to the treated group 15 min before isoproterenol. Dose-response curves were obtained by cumulative addition of agonist. Vertical bars represent SEM.

 
Propofol (200 µM) also decreased the spontaneous rate in isolated right atria (from 406 ± 5 to 318 ± 1 bpm in preparations treated with the anesthetic; P < 0.001) and antagonized the positive chronotropic action of isoproterenol. As shown in Fig. 3, the anesthetic shifted the dose-response curve to the right (EC50 values: 4.87 ± 0.80 vs 14.03 ± 3.61 nM; P = 0.048) and depressed the magnitude of the increase in rate (218 ± 6 vs 154 ± 10 bpm; P < 0.001). This effect of propofol was not observed at propofol concentrations of 100 µM and below.



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  		Figure 3. Effects of isoproterenol on spontaneous rate in rat right atria in the presence (closed circles; n = 6) and absence (open circles; n = 6) of 200 µM propofol. Preparations were bathed in oxygenated Krebs-Henseleit buffer (37°C), and rate was monitored by bipolar electrodes. Propofol was added to the treated group 15 min before isoproterenol. Dose-response curves were obtained by cumulative addition of agonist. Vertical bars represent SEM.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Current results indicate that propofol acts in a dose-dependent, competitive manner (25–200 µM) to antagonize ß-adrenoceptor binding in rat myocardial membranes. In addition, the positive chronotropic and inotropic actions of the ß-adrenoceptor agonist isoproterenol were antagonized by the anesthetic, with this antagonism observed at 200 µM propofol, but not at concentrations of 100 µM and below. In terms of the inotropic action of isoproterenol, the antagonistic effect of propofol was "competitive," causing a rightward shift in the dose-response curve with no change in efficacy. Similarly, propofol increased the Kd value for [3H]CGP12177 binding without affecting Bmax. Consistent with current results, previous experiments by Lejay et al. (16) in rat left ventricular papillary muscle showed that the positive inotropic effect of isoproterenol is not antagonized by either 4.5 or 45 µM propofol. Neither the magnitude of the inotropic response to isoproterenol nor its EC50 values were altered by propofol in this previous study. In contrast, Lejay et al. (16) found that 45 µM propofol eliminated the positive inotropic response to the {alpha}-adrenoceptor agonist phenylephrine.

In contrast to the competitive nature of the antagonism observed when examining the inotropic response to isoproterenol, propofol's antagonism of the chronotropic effect of this ß-adrenoceptor agonist was characterized by both rightward and downward shifts in the dose-response curve. The mechanism of the decrease in maximum obtainable spontaneous rate cannot be discerned from current data; however, since propofol's effects on inotropic responsiveness and [3H]CGP12177 binding were competitive, it would seem that the noncompetitive antagonism of the chronotropic response was not mediated via interactions at the ß-adrenoceptors.

Plasma concentrations of propofol for clinical use range from 3 to 90 µM (~0.7–20 µg/mL). A typical plasma concentration of propofol during general anesthesia is considered to be 35 µM (19). In dogs, propofol plasma concentrations can be as high as 200 µM after administration of common doses (20). Since it has been estimated that this drug is 97%–99% protein bound (21), the effective free plasma concentration is probably near 1 µM (perhaps 6 µM in dogs). Thus, the concentrations of propofol we used are greater than those associated with the anesthesia achieved by continuous propofol infusion. For example, a significant increase in the Kd for [3H]CGP12177 binding was first observed at a concentration of 25 µM propofol with a twofold increase in Kd occurring at a concentration greater than 150 µM. EC50 values for the chronotropic and inotropic actions of isoproterenol were increased approximately threefold by 200 µM propofol. These values suggest that the Ki for propofol at myocardial ß-adrenoceptors is 100–150 µM and indicate that this antiadrenergic action plays little, if any, role in the cardiac depression observed during continuous infusion. However, it is conceivable that plasma concentrations of free propofol approach ß-adrenoceptor blocking doses during bolus injection (22). A recent study by Schnider et al. (23) showed that bolus injection of 2 mg/kg propofol can result in peak plasma levels greater than 40 µg/mL (>180 µM) in humans.

In summary, results of the current study suggest that large-dose bolus injection of propofol may depress cardiac function in part via antagonism of ß-adrenoceptor binding and thus receptor activation via catecholamines. This action is probably not elicited by the plasma concentrations maintained during routine continuous infusion of this anesthetic. Nonetheless, this effect of propofol appears to be selective for ß-adrenoceptors, since the anesthetic had no effect on muscarinic receptor binding when evaluated at identical concentrations.


   Acknowledgments
 
This work was supported in part by a grant from the Arkansas Affiliate of the American Heart Association.


   Footnotes
 
* Boyle WA, White PF, Rendig SV. Negative inotropic effects of propofol versus etomidate and thiopental on rabbit papillary muscle [abstract]. Anesth Analg 1989;68:S35. Back

{dagger} Epema AH, Gelissen HPMM, Henning RH, et al. Negative inotropic effects of etomidate, ketamine and propofol in isolated human atrial muscle [abstract]. Anesthesiology 1994;81:A396. Back


   References
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 Methods
 Results
 Discussion
 References
 

  1. Grounds AM, Twigley AJ, Carli F, et al. The hemodynamic effects of intravenous induction. Comparison of the effects of thiopentone and propofol. Anaesthesia 1985;40:735–40.[Web of Science][Medline]
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  8. Puttick RM, Terrar DA. Differential effects of propofol and enflurane on contraction dependent on calcium derived from the sarcoplasmic reticulum of guinea pig isolated papillary muscles. Anesth Analg 1993;77:55–60.[Abstract/Free Full Text]
  9. Petros AJ, Bogle RG, Pearson JD. Propofol stimulates nitric oxide release from cultured porcine aortic endothelial cells. Br J Pharmacol 1993;109:6–7.[Web of Science][Medline]
  10. Chang KS, Davis RF. Propofol produces endothelium-independent vasodilation and may act as a Ca2+ channel blocker. Anesth Analg 1993;76:24–32.[Abstract/Free Full Text]
  11. Hemmings HC, Adamo AIB. Effects of halothane and propofol on purified brain protein kinase C activation. Anesthesiology 1994;81:147–55.[Web of Science][Medline]
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  13. Marty J, Nivoche Y, Nimier M, et al. The effects of halothane on the human beta-adrenergic receptor of lymphocyte membranes. Anesthesiology 1987;67:974–8.[Web of Science][Medline]
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Accepted for publication May 21, 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 1999 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press