Anesth Analg 1999;88:710
© 1999 International Anesthesia Research Society
CARDIOVASCULAR ANESTHESIA
Isoflurane and Sodium Nitroprusside Reduce the Depressant Effects of Protamine Sulfate on Isolated Ischemic Rat Hearts
Edith Hochhauser, PhD*,
Pinchas Halpern, MD
,
Victor Zolotarsky, MD*,
Tatyana Krasnov, MSc*,
Jaqueline Sulkes, PhD
, and
Bernardo Vidne, MD*
*Cardiac Research Laboratory of the Department of Cardiothoracic Surgery, Felsenstein Medical Research Center;
Department of Epidemiology, Rabin Medical Center, Petach Tikva; and
Department of Emergency Medicine, Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel
Address correspondence and reprint requests to Prof. B. A. Vidne, Department of Cardiothoracic Surgery, Rabin Medical Center, Beilinson Campus, Petach Tikva 49100, Israel.
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Abstract
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The administration of protamine sulfate (protamine) to reverse the action of heparin is associated with adverse reactions. We studied the effects of protamine and isoflurane on isolated, perfused rat hearts previously subjected to cardioplegic ischemia. Hearts were perfused with oxygenated Krebs-Henseleit (KH) solution for 30 min, then subjected to cardioplegic ischemia for 30 min (KCl 16 mEq/L at 31°C) and 5 min reperfusion. Drug exposure lasted 15 min, and the recovery period was 60 min. Test groups were control, protamine (10 µg/mL), isoflurane (1.5%), protamine + isoflurane, sodium nitroprusside (SNP) (2.5 ng/mL), and SNP + protamine. Left ventricular developed pressure (LVP), coronary flow, and myocardial oxygen consumption were depressed by protamine to 30% ± 4%, 47% ± 4%, and 39% ± 4% of baseline (P < 0.001 versus control), respectively. Isoflurane and SNP afforded partial protection from the effects of protamine: LVP was 57% ± 5% and 51% ± 3% of baseline, respectively (P < 0.05 versus protamine alone and control); coronary flow was 70% ± 6% and 97% ± 12% of baseline, respectively (P < 0.05 versus protamine alone; P < 0.05 for isoflurane versus control); and O2 consumption was 69% ± 6% and 88% ± 15% of baseline, respectively (P < 0.05 versus protamine; P < 0.05 for isoflurane versus control). In this model, protamine-induced myocardial depression and coronary vasoconstriction were less pronounced in the presence of either isoflurane or SNP.
Implications: We examined the interactions of isoflurane, sodium nitroprusside, and protamine in a rat heart model and found that both isoflurane and sodium nitroprusside partially protect the heart from the depressant effects of protamine. This finding is significant, as these drugs are often used in heart surgery.
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Introduction
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The IV administration of protamine sulfate (protamine) to reverse the action of heparin is associated with several adverse reactions in humans and animals, such as systemic hypotension, decreased cardiac output, bradycardia, and pulmonary hypertension (1,2). A direct negative inotropic effect of protamine has been demonstrated in different experimental models (i.e., in vivo models, as well as investigations of isolated beating hearts, myocardial strips, and isolated cardiomyocytes) (3–5). Protamine reduces oxygen consumption of isolated rabbit hearts (3). Our group has previously demonstrated that the isolated rat heart recovering from cardioplegic ischemia is more vulnerable to the cardiodepressant action of protamine sulfate than the nonischemic heart (6).
The volatile anesthetic isoflurane has a myocardial depressant action. Its negative inotropic effect has been demonstrated in humans, in experimental animals, and in the isolated myocardium of various mammals (7,8). Isoflurane depresses myocardial contraction less than either halothane or enflurane in both humans and rats (7,8). It enhances the functional recovery of ischemic rat myocardium (9) and is cardioprotective in the stunned myocardium dog model, partly through activation of the adenosine receptor (10). Volatile anesthetics protect the ischemic rabbit myocardium from infarction by activation of adenosine receptor and protein kinase C (11). Isoflurane depresses left ventricular function and increases coronary flow to the same extent, with and without cardioplegic ischemia (8).
Chemical cardioplegia is in wide clinical use for protection of the myocardium during global ischemia. However, myocardial cells may be injured during periods of prolonged aortic cross-clamping (12), rendering the postcardioplegic heart more vulnerable to cardiodepressant drugs. It is therefore of interest to explore the effects of various cardioactive drugs on the postcardioplegia heart (8).
Isoflurane is often administered after the discontinuation of cardioplegia (13), at the same time that protamine is administered for reversal of heparin action. Thus, simultaneous exposure to both protamine and isoflurane is common clinical practice.
We investigated the interaction of isoflurane and protamine on mechanical performance, coronary vascular tone, and oxygen consumption of the heart after ischemic cardioplegia. An isolated rat heart model was used to eliminate the influences of the extrinsic humoral and autonomic nervous systems. When it was evident that hearts perfused with both isoflurane and protamine functioned better than those exposed to protamine alone, and with significant effects on coronary resistance, we also evaluated the effects of a pure vasodilator, sodium nitroprusside (SNP) (14) combined with protamine, using the same protocol.
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Methods
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Animal care complied with the Principles of Laboratory Animal Care and the Guide for the Care and Use of Laboratory Animals. Forty-one male Wistar rats weighing 250–300 g were anesthetized with diethyl ether. Their hearts were rapidly excised and mounted on the stainless steel cannula of a perfusion apparatus. Retrograde aortic perfusion was initiated at a perfusion pressure of 100 cm H2O with oxygenated Krebs-Henseleit solution (KH) filtered (5 µm) in a nonrecirculating manner in the concentrations of (in mM) NaCl 118, KCl 4.7, CaCl2 2.5, MgSO4 · 7H2O 1.2, KH2PO4 1.2, glucose 11.1, NaHCO3 25, as accepted in the literature (15). The perfusate was continuously oxygenated with 95% O2 and 5% CO2, resulting in a pH of 7.35–7.40. PO2 and PCO2 values in the perfusion medium were 550–650 and 25–30 mm Hg, respectively. Temperature was maintained at 37 ± 0.5°C (30 ± 0.5°C during ischemia) by placing a thermostated water jacket around the perfusate reservoir and the isolated heart.
Epicardial pacing wires were connected to the right ventricle and the aortic cannula. Pacing was begun after completion of the preparation at 300 bpm (5 V, 10-ms duration), using an external Harvard stimulator (Edenbridge, Kent, England). A latex balloon filled with water was inserted into the left ventricular cavity through a small incision in the left atrium and connected to a Statham Medical P132284 pressure transducer (Mennen Medical, Inc., Clarence, NY). The balloon was tied and inflated to a volume producing a diastolic pressure of 0–5 mm Hg, which was continuously monitored throughout the experiment. The pulmonary artery was cannulated to obtain perfusate samples for pH, PO2, and PCO2. AT-CODAS Software (Dataq Instr. Inc., Akron, OH) was used to calculate the maximal rate of the increase and decline of the left ventricular pressure (dP/dtmax). Coronary flow was measured by collecting the effluent flow into a calibrated beaker for 1 min. Perfusate afferent and efferent gases were measured after 30 min of stabilization, after 15 min of drug perfusion, and at the end of reperfusion. Samples were withdrawn from the aortic inflow port and the right ventricle using a tiny polyethylene catheter inserted through a pulmonary artery incision. Specific oxygen consumption was calculated by multiplying the arteriovenous oxygen content difference by the coronary flow, and the product was divided by the dry weight of the hearts (15). All recordings were made at fixed intervals every 5 min when the different drugs were tested and every 10 min in the recovery period (Fig. 1). Creatine phosphokinase (CPK) was measured spectrophotometrically in the coronary effluent at the first minute of reperfusion after ischemia and was multiplied by coronary flow per minute to obtain absolute enzyme leakage values. At the end of each experiment, the heart was weighed after it had been dried in an oven at 80°C.
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Figure 1. Experimental protocol. Group 1 = no drug (control); Group 2 = protamine 10 µg/mL; Group 3 = isoflurane 1.5%; Group 4 = protamine 10 µg/mL and isoflurane 1.5%; Group 5 = sodium nitroprusside (SNP) 2.5 ng/mL; Group 6 = protamine 10 µg/mL and SNP 2.5 mg/mL. An initial stabilization period was allowed in all groups by perfusion with KH for 30 min (37°C). Cardioplegic solution containing KH with KCl 16 mEq/L was administered for 2 min. Thereafter, all groups were subjected to 30 min of ischemia (31°C). The hearts were then perfused for 5 min with KH solution, after which drugs were administered for 15 min and the hearts were reperfused for a 60-min recovery period.
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A concentration of 10 µg/mL protamine was chosen for study because that concentration has a significant effect on contractility but still allows sufficient experimental time, whereas higher concentrations result in excessively rapid deterioration of left ventricular pressure (6). Administration of protamine directly after ischemia sometimes results in deterioration of contractility as a consequence of arterioventricular block and ventricular fibrillation. Therefore, the heart was perfused 5 min after ischemia when complete recovery was established.
Isoflurane was equilibrated in an oxygenating chamber by passing a gas mixture of 95% O2/5% CO2 (2 L/min) through a vaporizer for at least 30 min before mounting the heart. Isoflurane was introduced by switching to a perfusate equilibrated with isoflurane through bubbling at vaporizer settings corresponding to 1.5 vol%, which is equivalent to 1 minimum alveolar anesthetic concentration in rats (16). The output of the vaporizer was measured using an anesthetic monitor. The mean isoflurane concentration was 0.50 ± 0.01 mM, which remained stable during the 15-min period of cardiac perfusion. Isoflurane concentrations in the perfusate were measured at each interval. Perfusate solution (1 mL) was collected at the aortic inflow port into 1-mL sealed vials for isoflurane concentration measurements using the gas chromatography technique (17).
We conducted a dose-finding pilot study before the main experiments and found that SNP at a concentration of 2.5 ng/mL resulted only in coronary vasodilation, without any cardiac contractility effect. Experiments were performed as follows: Group 1 (n = 8), no-drug control; Group 2 (n = 7), protamine; Group 3 (n = 7), isoflurane; Group 4 (n = 8), isoflurane and protamine; Group 5 (n = 5), SNP; Group 6 (n = 6), SNP and protamine.
An initial stabilization period was allowed in all groups by perfusion with KH for 30 min. Cardioplegic solution containing KH with KCl 16 mEq/L was administered for 2 min. All groups were subjected to 30 min of cardioplegic ischemia, after which the hearts were perfused with KH solution for 5 min. The various drugs were then administered for 15 min, and the hearts were reperfused for a 60-min recovery period (Fig. 1).
Results are expressed as means ± SEM. Statistically significance differences in mean values between variables were assessed by analysis of variance with repeated measurements using the multiple comparison option of Duncan. The same analysis was performed at each point in time between groups; P < 0.05 was considered significant. Values during the stabilization period were defined as 100%.
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Results
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Table 1 presents all hemodynamic and oxygen consumption values of all the groups tested in absolute values. Baseline values, measured 30 min after stabilization, were similar in all groups. CPK leakage into the coronary effluent during the first minute after reperfusion was similar in all groups (1707–1850 IU/min). According to this variable, all groups experienced myocardial damage during ischemia to the same extent. In Groups 1 and 5, LVP remained stable throughout the experiment. SNP did not affect contractile variables in the treated groups compared with control. Figure 2 presents the percent changes in LVP. All measured variables demonstrated that hearts in the studied groups recovered completely within 5 min after cardioplegic ischemic, before drug administration. Protamine administered alone produced a significant depression of LVP after 5 min (to 43% ± 5% of baseline; P < 0.001), with further deterioration at 15 min (to 30% ± 4% of baseline; P < 0.001). When protamine was administered together with either isoflurane or SNP, the depression after 15 min was significantly less, i.e., to only 57% ± 5% and 51% ± 3%. Isoflurane alone depressed LVP to 77% ± 3% of baseline (P < 0.05 versus control). This depression was markedly less than that produced by protamine (P < 0.05). Hearts exposed to protamine alone recovered very slowly, with LVP values of 62% ± 8% of baseline, compared with 82% ± 4% for the control hearts after 60 min of reperfusion. The addition of isoflurane or SNP to protamine resulted in significantly rapid recovery to baseline values (within 10 min, compared with 40 min for protamine alone).
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Figure 2. Changes in left ventricular isovolumic developed pressure (LVP) expressed as a percentage of baseline values of the tested groups. Hearts were perfused as described in the text. Each symbol represents the mean ± SEM. P < 0.001.
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The changes in the maximal rate of increase of LVP (+dP/dtmax) are presented in Figure 3 (upper panel). The pattern of changes in +dP/dtmax was similar to that seen with LVP. Thus, protamine administration significantly reduced +dP/dtmax after 15 min (to 21% ± 3% of baseline). Isoflurane alone depressed +dP/dtmax to 75% ± 3% of baseline (P < 0.05 versus control). The addition of either isoflurane or SNP to protamine partially prevented the depression of +dP/dtmax (to 55% ± 6% and 47% ± 3%; P < 0.05). After 60 min, the values were 78% ± 3% and 82% ± 6%, respectively, compared with 81 ± 5% for controls.
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Figure 3. Changes in positive and negative derivative of left ventricular pressure of the isolated heart are presented in the upper and lower panels, respectively (dP/dtmax). Results are expressed as a percentage of baseline values. Each symbol represents the mean ± SEM. P < 0.001.
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The changes of maximal rate of LVP decrease (-dP/dtmax) are presented in Figure 3 (lower panel). Administration of protamine caused significant depression of -dP/dtmax (to 14% ± 3%; P < 0.05) versus controls. In Groups 4 and 6, the reduction of -dP/dtmax was significantly less pronounced (to 55% ± 5% and 43% ± 3%; P < 0.05 versus protamine). During the first 10 min of reperfusion with KH solution, full recovery of -dP/dtmax was achieved in all groups except Group 2 (protamine alone), which recovered to only 56% ± 5% (P < 0.05 versus control) after 60 min of reperfusion.
Changes in coronary flow are presented in Figure 4. Isoflurane and SNP alone increased coronary flow to 120% ± 9% and 131% ± 7% of baseline at 15 min (P < 0.01 versus control), with recovery being similar to that of controls. Protamine exposure resulted in significant reduction of coronary flow (47% ± 4% of baseline; P < 0.05). Although the administration of isoflurane together with protamine only mitigated the reduction of coronary flow to 70% ± 6% of baseline (P < 0.05 versus protamine group), SNP completely prevented the reduction in coronary flow due to protamine (97% ± 10%). However, when SNP and protamine administration were discontinued, coronary flow declined significantly, to values similar to those seen with protamine alone, although they recovered later. In the reperfusion period, coronary flow recovered in all hearts to statistically similar values after 30 min, although Groups 2 and 6 had lower coronary flow values.
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Figure 4. Changes in coronary flow rate expressed as a percentage of baseline values of the isolated heart. Each symbol represents the mean ± SEM. P < 0.001.
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Protamine exposure significantly reduced oxygen consumption (to 39% ± 4% of baseline versus control; P < 0.05) (Figure 5). Isoflurane or SNP alone had no statistically significant effect on oxygen consumption. The addition of isoflurane or SNP to protamine attenuated the reduction in oxygen consumption caused by protamine (to 69% ± 6% [P < 0.05 versus control] or to 88% ± 15% of baseline, respectively). In the reperfusion period, oxygen consumption recovered during the first 20 min in all groups.
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Figure 5. Changes in oxygen consumption expressed as a percentage of baseline values of the isolated heart. Each symbol represents the mean ± SEM. P < 0.001.
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Discussion
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Protamine administered during open heart surgery often causes adverse hemodynamic effects (1,2). Isoflurane also has dose-dependent myocardial depressant properties (7). We previously demonstrated that isolated rat hearts subjected to cardioplegic ischemia were more vulnerable to protamine (6) and that isoflurane depressed the amplitude of myocardial contraction to a similar extent with and without previous cardioplegic ischemia (8). In the present study, myocardial contractility (LVP, dP/dtmax) was significantly reduced by protamine during both drug administration and the recovery period. The addition of isoflurane does not enhance, but rather partially mitigates, the cardiodepressant actions of protamine. SNP was used to test whether the cardioprotective effect of isoflurane was due to its vasodilatory effect; by virtue of its being a pure vasodilator (14), we demonstrated that it also ameliorated the deleterious affects of protamine.
The exact mechanism of myocardial depression induced by protamine is open to conjecture. Protamine may increase inward leakage of calcium due to a generalized increase in membrane ionic conductance, resulting in intracellular calcium overload (6). Microscopic examination of a left ventricle that had been previously perfused with fluorescein-labeled protamine revealed that protamine could traverse the vascular compartment of the myocardium in an isolated rabbit heart. Protamine may then come into direct contact with the myocyte and directly affect myocyte contractile processes (18). Protamine, which is highly positively charged, binds nonspecifically at or near ion channels, thus altering their structure and impairing their function (1). Intracellular calcium overload at rest may inhibit calcium influx during each depolarization, thus inhibiting calcium-activated calcium release from the sarcoplasmic reticulum, consequently diminishing contraction strength of the myocardium (6). Isolated myocyte contractile function, as seen by the velocity of shortening and lengthening, was markedly decreased by protamine (18,19). Ischemia and reperfusion result in sarcolemmal injury, causing calcium overload (20). Myocytes, which are capable of compensating for calcium overload produced by either protamine or ischemia alone, may not be able to compensate for the calcium influx caused by their combined effects. Although LVP and +dP/dtmax recovered within 40 min, -dP/dtmax was still depressed compared with controls. Thus, -dP/dtmax may be more affected than +dP/dtmax. These findings were supported by Hird et al. (19), who attributed the difference between contraction and relaxation to the fact that calcium release is passive during contraction, whereas calcium sequestration during relaxation is an active, energy-dependent process. Ischemia may aggravate this dependency (12).
In this study, isoflurane alone depressed LVP and +dP/dtmax by approximately 20%. Studies at the subcellular level and of contractility suggest that isoflurane inhibits calcium flux into the heart cells through both calcium channels and Na+/Ca+2 exchange and that it stimulates calcium uptake by the sarcoplasmic reticulum (21,22). This is believed to decrease the amount of calcium available for contractile activation (7). Thus, both protamine and isoflurane depress myocardial contraction by the impairment of uptake and release of calcium. The combination of these two drugs was less depressant than protamine alone during both drug exposure and recovery. Protamine and isoflurane seem to act as mutual antagonists: protamine causes an increase of intracellular calcium, and isoflurane induces the opposite effect, thus preventing calcium overload in the sarcolemma. Unlike Hird et al. (18,19), who found that protamine depresses myocyte ß-adrenergic responsiveness and the inotropic effects of ouabain, the combined depressant effects of isoflurane and protamine were not synergistic in our study. Because it is a cardioprotective drug, isoflurane partially protects against the negative inotropic effects of protamine (9–11). We observed that protamine caused a significant reduction in coronary flow. Isoflurane is well known for its vasodilatory effect (10,23). When isoflurane was added to protamine, it attenuated this reduction in coronary flow. Protamine reduced oxygen consumption in an isolated heart experimental model (3). Our findings show that the reduction of oxygen consumption caused by protamine was proportionally equal to the reduction in coronary flow (almost 60% in both) and that isoflurane attenuated the reduction in oxygen consumption.
The question arises as to whether the effects of isoflurane in counteracting protamine-induced myocardial depression are due to its coronary vasodilatory property or to other properties. In a follow-up experiment, we investigated the interaction of SNP with protamine. Interestingly, although SNP completely reversed the coronary vasoconstriction produced by protamine, it only partially reversed the myocardial depression (to 51% ± 3% of baseline, compared with 30% ± 4% of baseline for protamine alone; P < 0.05). Thus, vasoconstriction alone does not fully explain the effects of protamine, and the vasodilatory effects of isoflurane do not solely explain its protective action against protamine. Interestingly, although contractility is only partially maintained by SNP in the presence of protamine, both coronary flow and oxygen consumption are fully recovered. Similar dissociation of oxygen utilization from hemodynamic effects was shown by Wakefield et al. (24), who used protamine alone or protamine and the prostacycline analog, iloprost. Iloprost completely blocked the oxygen consumption decline that accompanies protamine exposure without similarly altering the hemodynamic changes. In the present study, when both protamine and SNP were stopped, coronary flow decreased to levels similar to those seen with protamine alone. This effect is probably due to the longer half-life of protamine. Thus, both isoflurane and SNP attenuated the negative inotropic effects of protamine sulfate, the first by being a coronary vasodilator and a cardioprotective drug (9–11), and the latter by being a pure vasodilator (14).
Some potential limitations of the present study must be noted. It is possible that the concentration of protamine used in the study was high compared with clinically relevant serum concentrations. However, the amount of protamine in the blood bound to heparin and to blood proteins, or that remaining in its free form, is still unknown (5,19). The true concentration of unbound protamine is also unknown. However, the frequency of side effects of protamine is significant at usual clinical doses (25). Studies examining the effects of protamine on the myocardium have used concentrations as high or higher than those used in the present study, without any binding proteins in the perfusion system (5,18,19).
In summary, the results of the present study suggest that, in the isolated rat heart previously subjected to cardioplegic ischemia, both isoflurane and SNP afford partial protection against protamine-induced myocardial depression and coronary vasoconstriction.
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Accepted for publication December 15, 1998.
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Abstract
Introduction
