An investigation of the cardiotoxic action of vancomycin in the isolated working rat heart

Toxic m Vmo Vol 3, No

0887-2333/89 $3.00 + 0 00

I, pp 27-32, 1989

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AN INVESTIGATION OF THE CARDIOTOXIC ACTION OF VANCOMYCIN IN THE ISOLATED WORKING RAT HEART K. F. JIM and W. D. MATTHEWS* Department of Investtgattve Toxtcology, Smith Kline & French Laboratories, Research and Development Dtvtston, P.O. Box 1539, King of Prussta, PA 19406-0939, USA (Received 23 June 1988)

Abstract-The mechamsm of cardrotoxic actton of vancomycm was exammed m preparattons of Isolated working rat hearts and spontaneously beatmg right atria Vancomycin produced a concentrattondependent decrease m aortrc flow, coronary flow and heart rate m the Isolated workmg rat heart, wtth no stgnificant effect on other haemodynamic parameters. At 5 mu, vancomycm produced a statrsttcally srgnificant decrease (compared wtth control values) in aortic flow (24.1 k 7.5%) and m the basal heart rate (34.3 k 3 5%) after 15 mm mcubatton Coronary flow was also reduced by 23.5 f 9.2% Prolonged exposure of the preparation to SmM-vancomycm produced a marked time-dependent bradycardta accompanied by a time-dependent increase m the leakage of lactic dehydrogenase (LDH) mto the perfuston medium. Moreover, a correlatton (r = -0.94) was found between the trme-dependent bradycardta and LDH leakage Induced by Vancomycm In the Isolated spontaneously beatmg nght atna pretreated with atropme, vancomycm (5 mM) also produced a ttme-dependent bradycardta stmtlar to that found in the isolated workmg rat heart. Moreover, 4sCa2+ -flux studtes indtcated that vancomycm had no significant effect on the Wa2 + uptake into the right atria1 muscle These data suggest that. (1) vancomycm has a direct and acute cardrotoxic action at high concentrattons ( > 1 mt.r), (2) time-dependent bradycardta 1s a senstttve functional index for the cardtotoxtcrty induced by vancomycin; (3) the bradycardta elicited by vancomycm is due neither to the release of acetylcholine from the parasympathetic nerves mnervatmg the heart nor to blockade of Ca*+ entry

1979; Waters & Rosenberg, 1981; Wold & Turmpseed, 1981). The mechanism by which vancomycin produces haemodynamic changes is unknown. Wold & Tumipseed (1981) suggested that the hypotension induced by vancomycin in the dog was mediated by the release of histamine. In another study, direct vasodilatory action of vancomycin in a preparation of isolated dog hindhmb was reported (Cohen et al. 1970). Recently, it has been suggested that the hypotenston elicited by vancomycin may be the result a direct myocardial depressant effect (Mellor, 1983). The study reported here was designed to determine whether vancomycin produced a direct deleterious effect on cardiac function and to explore possible mechanisms of cardiotoxtcity using the isolated working rat heart and preparations of spontaneously beating right atria.

INTRODUCrION Vancomycin is a glycopeptide antibiotic that was marketed in 1956 because of its efficacy against resistant penicillase-producmg Staphylococci (McCormick et al. 1956). It was shown to be more active against Gram-positive than against Gram-negative bacteria, with a minimum inhibitory concentration of 0.25 pg/ml for the Streptococci (Lightbown, 1964). It is difficult for bacteria to develop resistance to vancomycin (Perkins, 1982), and this may be because of its mode of action, by which it sequesters mtermediates of peptidoglycan synthesis rather than interfering directly with one of the biosynthetic enzymes. Intravenous admunstration of vancomycin has been shown to be associated with various toxicities including nephrotoxicity (Dean et al. 1985, Farber & Moellering, 1983; Marre et al. 1984 & 1985; Mellor et al. 1985; Wold & Turnipseed, 1981), ‘red-neck’ (Pau & Khakoo, 1985) and ‘red-man syndrome’ (Garrelts & Peterte, 1985), cardiac arrest (Dajee et al. 1984; Glicklich & Figura, 1984; Mayhew & Deutsch, 1985), ototoxictty (Mellor et al. 1984 & 1985), neutropenia (Fat-well et al. 1984; Sorrel1 et al. 1982), and hypotension (Dajee et al. 1984; Newfield & Roizen,

MATERIALSAND

*To whom correspondence should be addressed Abbreuiatrons: EGTA = ethylene glycol bis-@-ammoethyl ether), LDH = lactate dehydrogenase; LVP = left peak ventrtcular pressure, NADH = fl-mcotinamide adenine drnucleotide, disodtum salt; Na,EDTA = ethylenediamine tetraacenc actd, dtsodmm salt, PSS = phosphate-buffered saline. 27

METHODS

Materials. Vancomycin HCl was purchased from Eli Lilly (Indianapolis, IN); 45CaC1, (48.29 mCi/mg) was obtained from Du Pont Co. (Wilmington, DE); fi-nicotinamide adenine dinucleotide (NADH, disodium salt), sodium pentobarbttal, atropme sulphate, and all other chemical reagents were obtained from Sigma Chemical Co. (St Louis, MO); heparin (sodium solution) was purchased from U.S. Biochermcal Corp. (Cleveland, OH). Preparation of isolated working rat heart. Male Sprague-Dawley rats (250-300 g; Charles River Breeding Laboratories Inc., Wilmington, MA) were

K. F JIM and W. D. MATTHEWS

28

inJected with heparin (180 U/kg body weight, tp) and sodium pentobarbital (50 mg/kg, tp). Once anaesthetized, the heart was rapidly excised and transferred to a beaker containing ice-cold modified Krebs buffer (KB) composed of (mM). NaCl (118), KC1 (4.7) CaCl,. 2H,O (2.5), MgCl,. 6H,O (1 2), NaHCO, (25 0), Na, HPO, (1 .O), ethylenedtaminetetraacetic acid, disodium salt (Na,EDTA, 0 5) and glucose (11 0), pH 7.4. The pencardial sac and surrounding tissues were removed. The aorta was isolated and cut Just before its bifurcation. The heart was then wetghed The aorta was connected to a cannula from the perfusion apparatus (total volume 200 ml; Fig. 1) and a small mctsion was made m the pulmonary artery to facihtate coronary flow. The heart was perfused in a retrograde fashion with buffer at 37°C and contmuously aerated with 95% 0,/S% CO,. A small hole was made in the ostium of the left atrium which was then cannulated. The pulmonary vein was hgated As the heart was workmg, buffer entered the left atrium at a fixed left atria1 filling pressure of IO-cm water, and ventncular output was ejected through the aorta against a pressure of 70-cm water Coronary flow was collected from the effluent through the small mctsion m the pulmonary artery. Both the coronary flow and aortic flow were returned to the constant head reservon via an auxiliary reservoir. Buffer interchange between the reservoir was driven by two Cole-Palmer peristaltic pumps. Buffer was drawn through a Milhpore filter (AP Prefilter, M&pore Corp , Bedford, MA) interposed between the two reservoirs (Fig. 1). Aorttc flow was measured volumetrically over a l-mm period. Coronary outflow was determined by collectmg perfusate in a T-shaped plastic cylinder connected to a Gould P23ID pressure transducer. The coronary flow rate was derived from the rate of rise of pressure recorded on the Beckman Dynagraph R612 recorder. Left peak ventricular pressure (LVP),

left ventricular contractility (dp/dt,,,) and heart rate were recorded by msertmg a 23-gauge needle mto the left ventricle. The needle was connected via a polyethylene tube to a Statham P23 pressure transducer. was differentiated from the pressure The dpldt,,, signal via a Beckman dp/dt coupler wired directly to the LVP channel of the recorder. Heart rate was recorded via a Beckman cardiotachometer coupler connected to the LVP channel. Physiological parameters were recorded at 15-min Intervals. A buffer change was made routinely at least once every 15 mm unless otherwise stated. Preparations with LVP < 80mm Hg or cardiac output (aorttc flow + coronary flow) < 40 ml/min were not used m these studies Preparation of spontaneously beatzng rzght atria Male Sprague-Dawley rats were anaesthetized with sodium methohexttal (50 mg/kg body weight, ip; Eh Lilly & Co., Indianapolis, IN). The heart was rapidly excised and put into ice-cold physiological sahne (PSS) of the following composition (mM): NaCl(ll8), KC1 (4.7), CaCl,. 2H,O (2.5), MgCl,. 6H,O (1.2) NaHCO, (25.0), Na,HPO, (l.O), Na,EDTA (0.03), glucose (1 l.O), and atropme sulphate (0.001) pH 7 4 The right atrium was removed and suspended between two stamless-steel hooks under a resting tension of 1 g m lo-ml Jacketed glass baths contammg PSS at 37°C and aerated with 95% 0,/5% CO, The upper hook was attached to a force transducer (Grass FT03C), and the lower hook was attached to a fixed ttssue holder. Isometric tension was recorded on a Dynagraph recorder (Beckman R612). Heart rate (beats/mm) was counted from the tension tracings with a paper speed set at 10 mm/set. Vancomyczn studies. Vancomycin was prepared by making a stock solution of 50 mM m buffer, pH 6 6 Subsequent dilutions were made wtth either Krebs buffer or PSS The pH of buffer containing 5 mM-vancomycm was 7 2-7.3. After I-hr equihbration at 37°C the effect of vancomycm on the

-7Ocm

Resarvolr ill--

for Inltlal

Auxlllary

ROIOlV0lr Filter

-

Perl~~ttlc Pump8 Fig 1 Perfusion apparatus for the isolated working rat heart

t0cm Ocm

Cardiotoxicity of vancomycin isolated working rat heart was determined. Vancomycin was administered cumulatively with the concentration increased every 15 min just after physiological parameters were measured. In separate experiments, after 1 hr equilibration period, the preparation was exposed to 5 muvancomycin. Phystological parameters were then recorded every 15 min for 2 hr. During each measurement period, a l-ml aliquot of the perfusion buffer was taken for the determination of lactic dehydrogenase (LDH) activity. The protocol was repeated in the isolated spontaneously beating right atrium in the presence of atropine (0.001 mM) to block the muscarmic choline& receptors. Assay of LDH activity. LDH activity was assayed using a modification of Bergmeyer’s method (1974). Briefly, each sample (0.5 ml) was mixed with 1 ml of a reagent buffer composed of (final concentration) pyruvic acid (1.21 mM), NADH (0.19 mM), and Tns HCl (66.80 mM), pH 7.4. The LDH activity was determined by measuring the consumption of NADH as estimated by the fall in absorbance at 340nm. 45Ca2’JIux studies. The right atrium was isolated as described prevrously After equilibration at 37°C for 1 hr 45Ca2+ (1 pCi/ml) was added to the tissuebath containing the atrium m the absence and presence of vancomycm. After 5-min incubation, the 45Ca2+ exchange process was terminated by removing the atrium from the radioactive buffer. The atrium was then put into ice-cold (O.S’C) Ca2+ free PSS containing 2 mh+EGTA for 30 min in order to remove extracellular membrane-bound 45Ca2+ (Meishen et al. 1981). The atrium was blotted with Whatman filter paper (no. 4) weighed, and put into a scintillation vial containing 1Oml ScintiVerse II (Fisher Scientific Co., Fairlawn, NJ) scintillation

Table LVP* 15 30 45 60 15 90 105 120 I35 150 165

cocktail. After overnight incubation at room temperature, the 4sCaZ+ taken up by the tissue was determined by counting m a Beta Trac 6895 liquid scintillation counter (Tracer Analytic Inc., Elk Grove Village, IL). The tissue 45CaZ+ uptake was then calculated as previously described (Jim et al. 1985). Statistical analyses. All results were expressed as means + SEM. The difference between two mean values was analysed by Student’s t test for unpaired observations. For multiple comparisons, Dunnett’s test (Bruning & Kuntz, 1977) was used. Differences were considered to be statistically significant at P < 0.05. RESULTS

Table 1 illustrates the stability of the preparations of isolated working rat hearts. Cardiac function was relatively stable for at least 3 hr at 37°C under the defined experimental conditions. All studies were completed within 2-3 hr. In addition, the values for the various cardiac parameters measured were similar to those that have been reported previously for the working rat heart in vitro (Morgan et al. 1980; Neely et al. 1967). Vancomycin produced a concentration-dependent decrease in aortic flow, heart rate and coronary flow in the isolated working rat heart (Table 2). At 5 mM it produced statistically significant decreases (in comparison with controls) in aortic flow (24.1 + 7.5%) and in the basal heart rate (34.3 f 3.5%) after 15 min incubation; a reduction (23.5 + 9.2%) in coronary flow was also observed, but this decrease did not reach statistical significance. No significant effects on these parameters were observed at vancomycin concentrations < 5 mM. Since heart rate was the

I Stablhty of the Isolated workmg rat heart Wpmt

101 7 * I2 0 1050+115 IO5 0 + 8 7 100.0&76 98 3 f 6.1 967f60 950+50 950550 943+44 927*60 917k60 8llil3

29

6600 k 72 I 6661 f 851 6600 5 833 6133k811 6133k811 6000 + 833 5933 k 769 586-l+ 706 5733 k 169 5661+ 819 5533 + 769 5333 + 851

Heart rate (beats/mm)

Aortlc flow (ml/mm)

Coronary flow

254 f 17 26Ok28 272 f I7 270 f 21 270 f IR 214 f 16 268 + 16 264*12 268 + 16 268 + 19 266k18 264fl8

541+93 54.7 f 9 3 533+96 53 3 f 9.6 52 0 f 10.1 52.0 + IO I 50 7 + 10.7 507+107 49.3 * 1I 4 493*114 46.3 _+13 5 44.0* 140

127k42 II 7k42 127+42 12Oi35 13.0 +4 0 120+35 l27+37 l23+43 133k38 137k42 14.7 * 5 2 150f5 I

(ml/mm)

*Left peak ventncular pressure (mm Hg) tLeft ventncular contractlhty (maxlmal rate of nse of left ventncular pressure, mm Hg/sec) Values are means -f SEM for groups of three hearts. Table 2 Effect of 15 mm exoosure to vancomvcm on the ohvslolomcal oarameters of the Isolated workmg rat heart Vancomycm concn (mM) 0 (control) 0.01 01 1 5

LVPT 105.0 f 103.8 * 103 8 f 105.0 f 116 3 +

20 1.3 1.3 2.0 8.0

dp/dt,,.S 6200 f 469 6200 5 529 6200 -+ 523 6050 & 602 7400 + 94s

Heart rate (beats/mm)

Aort~c flow (ml/mm)

Coronary tlow (ml/min)

268 f 15 268 * 15 264_+14 250*1s 176+ 13’

68 5 + 1.5 68 5 f 7.5 69Oi66 64.0*49 52.0 f 2 8’

98*09 95*06 9.5 * 0.5 8.5 + 0.6 1 5 f 0.9

tLeft ventncular pressure (mm Hg) $Left ventncular contract&y (maxlmal rate of nse of 1eR ventncular pressure, mm Hg/sec). Values are means f SEM for groups of four hearts, and those marked wth an asterisk differ sigmficantly (Student’s from the corresponding control value (*P < 0 OS).

I test)

K. F JIM and W. D. MATTHEWS

30

Rg. 2. Effect of vancomycm (5 mht) on the basal heart rate in the Isolated working rat heart (A, vancomycin-treated hearts; A, control hearts) Values are means for groups of three hearts and range bars Indicate SEM. The values marked with asterisks differ sigmficantly (Student’s r-test) from the control values (*P < 0 05) The basal heart rates were 296 f 7 beats/mm (controls) and 302 f beats/min (vancomycm-treated hearts). A. parameter that was most sensitive to vancomycm m this preparation (Table 2) only changes m the basal heart rate induced by vancomycin were monitored in subsequent studies. Prolonged exposure of the preparation to vancomycm (5 mM) induced a marked time-dependent decrease m heart rate accompanied by a time-dependent increase of LDH leakage into the perfusion medium (Figs 2 & 3). Vancomycm decreased the heart rate by 52.6 + 4.9% and increased the LDH activity m the medium by 3.3 + 1.3-fold after 2 hr mcubatton with vancomycm. Moreover, a good correlation (r = -0.94) was found between the time-dependent brady-

-60 0.5 LDH

1.0 activity

1.5

2.0

(mUltipl6S

3.0

2.5 Of

basal

3 5 Vah6)

Frg. 4. Correlatron between the trme-dependent bradycardra and leakage of lactate dehydrogenase (LDH) induced by vancomycin (5 mM) m the isolated workmg rat heart. Data were obtamed from Figs 2 & 3. The hne was drawn from linear regression analysis. y = - 15.79x-6 97, r = -0 94.

functtonal

5.0 r 3

Yj

4.0

1

cardia and LDH leakage induced by vancomycm (Fig. 4). In the absence of vancomycm, over the duration of the experiments there was no significant change m the basal heart rate, and only a slight increase m the release of LDH (Figs 2 and 3). In order to investigate further the possible mechanism(s) of vancomycin-induced bradycardia, the effect of the compound on isolated spontaneously beating right atrta was examined. These experiments were conducted in the presence of atropine (0.001 mM) m order to eliminate any contnbution of release of acetylcholine to the bradycardta. The preparation of isolated right atrium was considered to be stable for at least 3 hr at 37°C smce the spontaneous heart rate was essentially constant durmg that time (data not shown). Vancomycm produced a concentrationdependent bradycardia in this preparation (Fig. 5). Vancomycin at 5 mM Induced a decrease (29 4 f 2.8%) m the heart rate after 15 min mcubatton that was comparable with the effect observed in the

r,

10

20

30

40

60

60

70

60

60

100

110

I

it

120

Time (min)

Ftg. 3. Effect of vancomycin (5m~) on leakage of lactate dehydrogenase (LDH) in the isolated workmg rat heart (0, vancomycin-treated hearts; 0, control hearts). Values are means for groups of three hearts and range bars indicate SEM. The values marked with asterisks differ significantly (Student’s r test) from the control values (*P < 0.05). The basal LDH acttvrtres were 5.29 f 3.12 mu/ml (controls) and 1.39 f 0.53 mu/ml (vancomycm-treated hearts).

Ftg. 5. Cumulatrve concentratton-response curve for vancomycin m the isolated spontaneously beating right atna of rat heart in the presence of atropine (1 PM). The Isolated atria were exposed to vancomycm for 15 mm. Values are means for groups of four isolated atna, and range bars mdmate SEM

Cardiotoxicity of vancomycin Table 3 Effect of vancomycl” on %a2+ uptake in the wlated right atna of rat hearts Vancomycln concn (mh4) 0 (control) 5

Uptake of ‘%a’+ (mmol/kg wet wt) 017*001 0.16kOOl

Basal heart rate (% change) -2051

0 + 127*

Values are means + SEM for groups of four Isolated atria and the value marked wth a” astensk ddfers slgnlficantly (Student’s f test) from the control value (P < 0 OS) The ‘%a2 + uptake and changes m the basal heart rate were detenmned after 5-mm mcubatton of the atria wth vancomya”.

isolated working heart (Fig. 5; Table 2). A timedependent bradycardia caused by vancomycin (5 mM) also was observed (data not shown). After 1 hr incubation with vancomycin, a decrease in heart rate of 39.2 f 6.2% was measured. Influx of Ca* + is involved in the generation of the diastolic depolarization and hence the pacemaker potential of the spontaneously beating atria1 muscle (Sperelakis, 1984). The effect of vancomycin on the influx of 45Ca2+ was examined in the spontaneously beating nght atria. Table 3 shows that vancomycin had no significant effect on the 45Ca2c uptake at a concentration that reduced heart rate by 20%. DISCUSSION

Rapid iv admmistration of vancomycin has been reported to produce alterations in the functions of the cardiovascular system (Marre et al. 1985; Mayhew & Deutsch, 1985; Mellor et af. 1985; Sorrel et al. 1982; Wold & Turnipseed, 1981). Mayhew & Deutsch (1985) reported that iv administration of vancomycm (250 mg) to a 2-yr-old female child (10 kg body weight) resulted in cardiac arrest with a marked bradycardia of 40 beats/min. The mechanism of the observed cardiotoxicity was unclear. Vancomycin administration was also shown to produce a dosedependent hypotension in dogs (Wold & Turnipseed, 181). At a dose of 20 mg/kg body weight, vancomycin induced a decrease of 34.8 mm Hg m mean blood pressure which was prevented by pretreatment with the antihistamine methapyrilene. This suggests that the release of histamine might mediate the hypotension caused by vancomycin. In another study, infusion of vancomycin (500mg over 30 min) to a 64-yr-old man resulted in a decrease in blood pressure from 135/85 to 80/60 (Waters & Rosenberg, 1981). Administration of a peripheral vasoconstrictor, such as methoxamine, did not return the blood pressure to normal. However, the hypotension was reversed to normal by calcium chloride (350 mg) given iv. The study reported here was designed to investigate the direct cardiotoxic action of vancomycin in the isolated working heart, an in vitro model that is useful for the evaluation of cardiac function in the absence of regulation by the central nervous system. Vancomycin (5 mM) elicited a bradycardia that was time dependent. At present, the mechanism of bradycardia produced by vancomycin is unclear. The rat atrium has been shown to contain a high density of muscarinic receptors (Reinhardt & Roskoski, 1983). Activation of muscanmc receptors by acetylcholine released from parasympathetic nerves by vancomycin

31

may account for the observed bradycardia. However, this seems unlikely since the bradycardia elicited by vancomycin in the isolated right atria was not prevented by atropine, a muscarinic receptor antagonist (Fig. 5). Previous studies have illustrated that aminoglycoside antibiotics (gentamycin, neomycin, streptomycin) could produce profound depression of cardiac function (Adams, 1975; Cohen et al. 1970). Other studies in arterial (Adams et al. 1973; Goodman et al. 1974) and myocardial (Adams & Durrett, 1978) preparations indicated that these compounds interfered with Ca* + movement through Ca2 + channels in the membrane. Thus, it is possible that vancomycin may have calcium-antagonistic activity at the slow Ca*+ channels at the sarcolemma of the heart and that such activity may mediate the vancomycininduced bradycardia. However, this mechanism is unlikely since the 45Ca2+ uptake in the isolated right atria was unaffected by vancomycin treatment at a concentration that reduced the heart rate by 20% (Table 3). Moreover, vancomycin did not cause any changes in the contractile tension of the isolated nght atna. In contrast, streptomycin (1 mM) or verapamil (0.01 mM) produced bradycardia and a decrease in contractile tension in the same preparation (K. Jim, unpublished observations, 1986). However, inhibitory actions on other ionic conductances at the sarcolemma cannot be excluded by these experiments. The time-dependent bradycardia correlated with a time-dependent increase in LDH leakage into the perfusion medium. Leakage of LDH has been shown to indicate myocardial cellular damage (Waldenstrom et al. 1977), and the time-dependent bradycardia may be a consequence of cardiac muscle inJury produced by vancomycm In conclusion, the results of this study indicate that the cardiotoxic action of vancomycin does not involve the release of acetylcholine from the vagus nerves or the inhibition of Caz+ influx into cardiac muscle. It may involve a direct cytotoxic effect on the cardiac myocyte. Vancomycin at high concentrations (> 1 mM) can produce a direct cardiotoxic action which is mamfested as time-dependent bradycardia and LDH release in a preparation of the isolated working rat heart. Acknowledgemenrs-The authors are grateful for the excellent techmcal asststance of Gregory S. Ladies for the isolated workmg rat heart studies. Helpful suggestrons and comments from Dr William R. Hewitt are also gratefully acknowledged.

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Sperelakis N. (1984) The slow action potenttal and properties of the myocardial slow channels. In Physiology and Pathophyslology of the Heart Edited by N Sperelakts. pp 1591186. Ma&us NiJhoff, Boston Waldenstrom A. P.. Hialmarson A. C.. Jodal M & Waldenstrom J (1977j. Significance of enzyme release from ischemic isolated rat heart Acta med. stand. 201, 525-532 Waters B. G & Rosenberg M. (1981) Vancomycm-Induced hypotenston. Oral Surg. Oral Med Oral Path. 52, 239-240

Wold J. S. & Turmpseed S. A (1981) Toxicology of vancomycin m laboratory animals. Rev. znfect Dzs. 3, (Suppl.), S224-S229.