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Am J Physiol Heart Circ Physiol 275: H8-H14, 1998;
0363-6135/98 $5.00
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Vol. 275, Issue 1, H8-H14, July 1998

The role of coronary flow and adenosine in postischemic recovery of septic rat hearts

Jitka A. Ismail and Kathleen H. McDonough

Department of Physiology, Louisiana State University Medical Center, New Orleans, Louisiana 70112

    ABSTRACT
Top
Abstract
Introduction
Methods
Results
Discussion
References

Sepsis depresses myocardial function but prevents subsequent ischemia-reperfusion injury. Elevated coronary flow (CF) and endogenous adenosine may be important factors in the complete recovery of postischemic myocardial function observed in septic rat hearts. The purpose of this study was to determine the effects of manipulating CF and of antagonizing adenosine receptors on the postischemic recovery of left ventricular developed pressure (LVDP) in septic and control rat hearts. The relationship between CF and LVDP in septic rat hearts before ischemia was depressed compared with control. However, this relationship was unaltered by ischemia in septic hearts, whereas in control hearts it was severely depressed. Preventing the elevation of CF during reperfusion did not significantly affect the recovery of LVDP in septic rat hearts. Adenosine antagonism by 8-phenyltheophylline (0.1 and 1 nM) prevented the elevated CF during reperfusion, and the higher dose significantly depressed postischemic function. We conclude that elevated CF did not contribute to the recovery of postischemic LVDP in septic rat hearts but that endogenous adenosine may provide protection from ischemia.

cardioprotection; ischemia; reperfusion

    INTRODUCTION
Top
Abstract
Introduction
Methods
Results
Discussion
References

SEPSIS (18, 19) and endotoxemia (20, 23, 27-29) significantly impair left ventricular (LV) function. Paradoxically, septic hearts (18) completely recover preischemic LV developed pressure (LVDP) during reperfusion, whereas recovery of hearts from endotoxin-treated animals is incomplete but improved compared with control hearts (27, 28). McDonough and Causey (18) suggested that the elevated coronary flow (CF) observed during reperfusion may contribute to the full recovery of LVDP. We hypothesized that the relationship between CF and ventricular function is altered in septic rat hearts and that elevated CF during reperfusion may be responsible for the enhanced recovery of preischemic function.

Adenosine, a vasodilator (3) and mediator of the improved recovery of myocardial function after preconditioning and ischemia (1, 2, 5, 8, 10, 13, 21, 25, 31), could play a role in sepsis-induced cardioprotection. Preconditioning, first described by Murry et al. (25) as brief periods of ischemia followed by reperfusion before sustained ischemia, protects the heart from damage during sustained ischemia. There are several possible mechanisms for adenosine-mediated cardioprotection, including diminished metabolic demand (3, 21), delayed onset of ischemic contracture (14, 16), decreased production of superoxide anions and hydrogen peroxide by stimulated neutrophils (3, 10, 16), and phosphorylation of ATP-sensitive K+ channels, myosin light chains, and/or other intracellular proteins by protein kinase C (PKC; 5, 10, 12, 21). Furthermore, infusion of adenosine into healthy hearts before ischemia mimics the effects of preconditioning and reduces myocardial infarct size compared with that observed in untreated control hearts (2, 3, 11, 16, 25). Adenosine A1 receptors, found on cardiomyocytes and vascular smooth muscle cells, are known to mediate negative chronotropy, dromotropy, and inotropy, and A2 receptors, located on endothelial and vascular smooth muscle cells, mediate coronary vasodilation (3). Adenosine-mediated cardioprotection may occur via A1 receptors (5, 10, 13, 14, 16, 20, 21, 31) and/or A3 (1, 2, 17) receptors, which are also found on cardiomyocytes. However, the contribution of the A3 receptor is confusing because of species differences (8, 15, 21, 31). We hypothesized that, because adenosine confers myocardial protection comparable to that of preconditioning, adenosine may contribute to the recovery of LVDP after prolonged ischemia in septic rat hearts via enhanced CF and/or other effects.

There were three objectives to this study: 1) to determine the effects of varying CF in septic and control rat hearts on pre- and postischemic LVDP; 2) to assess the role of elevated CF in the recovery of postischemic LVDP in septic rat hearts by maintaining a constant CF before ischemia and during reperfusion, thus preventing the elevation of CF; and 3) to delineate the involvement of endogenously released adenosine on the recovery of LVDP using the adenosine receptor antagonist 8-phenyltheophylline (8-PT).

    METHODS
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Abstract
Introduction
Methods
Results
Discussion
References

Surgical procedures and perfusion. Seventy-one male Sprague-Dawley rats weighing 250-275 g purchased from Hilltop (Raleigh, NC) were used in these experiments. They were housed in the animal care facility (maintained at a constant temperature with a 12:12-h light-dark cycle) for ~1 wk and were provided Purina rat chow and water ad libitum before use in these experiments. The rats were used in accordance with the standards prescribed by the National Institutes of Health and the Institutional Animal Care and Use Committee of the Louisiana State University Medical Center.

At the time of study, the rats were anesthetized with ketamine-Rompun (10 mg/100 g and 1 mg/100 g, respectively), and a sterilized polyethylene catheter (PE-50) was inserted into the dorsal subcutaneous space. The catheter was used for administration of 1 ml sterile saline (control) or 1 ml Escherichia coli (septic), a sterile inoculum containing ~1010 E. coli (American Type Culture Collection E11775). One injection was made at the time of surgery and another injection 5 h later (18). There were no mortalities.

Twenty-two to twenty-six hours after the induction of sepsis, control and septic rats were weighed and colonic temperature was measured with a thermistor probe. The rats were then anesthetized with pentobarbital sodium (0.1 ml/100 g), and the thorax was opened to expose the heart. Hearts were excised and immediately submersed in cold Krebs-Henseleit bicarbonate buffer [KHB; containing (in mM) 118 NaCl, 4.7 KCl, 2.4 MgSO4, 1.2 KH2PO4, 25 NaHCO3, 0.5 NaEDTA, 2.8 CaCl2, and 5 glucose; pH 7.4]. The aorta was attached to a metal cannula, and perfusion was initiated from a Langendorff column. A latex balloon tied onto the end of a 4-Fr dual-lumen catheter was guided through the left atrial appendage into the LV. Silk sutures were tied around the small portion of the end of the balloon protruding from the apex and also around the catheter at the atrial appendage to prevent slippage. Approximately 100 µl of water were injected into the balloon such that diastolic pressure was maintained at ~10 mmHg. Constant preload permitted assessment of systolic and diastolic pressure changes throughout the experiment. All hearts were stabilized for 15 min under constant pressure with nonrecirculated KHB equilibrated with a 95% O2-5% CO2 gas mixture. Temperature was maintained at 37°C by a heating pump (Haake D1), which circulated the heated water through a water jacket that encased the heart (18). After control perfusion, global ischemia was achieved by terminating retrograde CF for 35 min, and hearts were subsequently reperfused for 25-30 min. CF (as it dripped off the heart) was measured before ischemia and every 30 s for the first 5 min of reperfusion and every 5 min thereafter. Coronary perfusion pressure (CPP) and LV pressure were recorded with a Grass polygraph (Grass Instruments; model 7). LVDP was calculated as systolic pressure minus diastolic pressure, and rate-pressure product (RPP) was calculated as LVDP multiplied by heart rate (HR).

Variable CF. CF was physically manipulated to assess the relationship between CF and LVDP before and after ischemia in control and septic rat hearts. After the stabilization, hearts were switched to constant-flow perfusion using a Masterflex pump system (Cole-Parmer Instruments; model 7014-20). CF was initially set at the same rate as that observed under constant pressure during the stabilization period. Next, CF was incrementally decreased to approximately 4 and 8 ml/min, increased to the original flow, and then increased to approximately 15, 20, and 28 ml/min. The CF was then returned to the original flow rate and allowed to equilibrate before ischemia. During the first 15 min of reperfusion, hearts were perfused at their original flow rate and then the sequence of flow changes was repeated. Flow was maintained at each level until function stabilized (usually 5 min). The hearts were not paced.

Constant-flow perfusion. To prevent the elevation of CF during reperfusion, we maintained a constant CF in some hearts with a constant-flow perfusion pump. The rate for constant-flow perfusion in control and septic rat hearts, both before and after ischemia, was set to that measured during the initial constant-pressure stabilization period. After stabilization, some hearts were switched to constant flow and allowed to equilibrate for 15 min before ischemia and then reperfused at that same flow rate. The other hearts were perfused under constant pressure before and after ischemia for statistical comparison. Hearts were not paced.

Adenosine antagonism. To assess the effects of adenosine receptor antagonism on the recovery of CF and LVDP in control and septic rat hearts, we added the nonselective antagonist 8-PT to the perfusate. After the stabilization period, perfusion was switched to constant flow (approximating the flow observed under constant pressure) for 5 min while the perfusate in the Langendorff column was switched to buffer containing the drug. Hearts were subsequently perfused with this buffer under constant pressure for 30 min before ischemia and during the entire reperfusion period. Hearts were paced when HR fell below 300 beats/min.

Drugs. 8-PT was purchased from Sigma.

Statistics. Means ± SE were calculated for each parameter. Student's t-tests, paired t-tests, and one-way ANOVA (Excel and SigmaStat) were use to analyze the data. Differences were considered statistically significant at P < 0.05.

    RESULTS
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Abstract
Introduction
Methods
Results
Discussion
References

Variable CF. Before ischemia, there was a linear relationship between CF and LVDP in control rat hearts at CF between 4 and 20 ml/min, continuing to rise less steeply above 20 ml/min (Fig. 1A). However, in the septic group, this relationship was displaced downward and to the right and did not increase after 20 ml/min (Fig. 1A). The relationship between CF and LVDP was unaltered by ischemia in the septic group (Fig. 1B). However, postischemic LVDP was severely depressed at every level of CF in the control group and was not different from the postischemic septic group at each CF.


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  		Fig. 1.   Effects of varying coronary flow (CF) on preischemic (A) and postischemic (B) left ventricular developed pressure (LVDP) in control (n = 7) and septic (n = 6) rat hearts. The preischemic relationship between CF and LVDP in septic rat hearts was significantly depressed compared with control, and this was unaltered by ischemia. The postischemic relationship between CF and LVDP was severely depressed in control hearts.

Constant-flow perfusion. The effects of 35 min of ischemia and 25 min of reperfusion on CF, CPP, LVDP, and RPP in control and septic rat hearts perfused with either constant pressure or constant flow are presented in Table 1. In the control constant-pressure group, the postischemic CF decreased 41%, LVDP decreased 30%, and RPP was decreased 43% from the preischemic values. In the septic constant-pressure group, CF and LVDP were not significantly different from preischemic values at 25 min of reperfusion. However, between 5 and 15 min of reperfusion, the untreated septic rat hearts exhibited elevated CF up to a maximum of 139% of initial flow (Fig. 2). Hearts from untreated control rats had a maximum recovery of CF of only 66%.

                              
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  		Table 1.   Effects of constant pressure vs. constant flow in control and septic rat hearts on CF, CPP, LVDP, and RPP


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  		Fig. 2.   Recovery of CF (% of preischemia) in untreated control (n = 8) and septic (n = 9) rat hearts perfused under constant pressure after 35-min ischemia. Recovery of CF in septic rat hearts was significantly elevated and greater than that of control hearts.

When CF was maintained at the preischemic level during reperfusion, control hearts recovered higher LVDP than that observed under constant-pressure reperfusion (81 vs. 70% of preischemic level; Table 1). However, LVDP was still significantly decreased from the preischemic value. Before ischemia, LVDP in the septic group was higher in the constant-flow group than in the constant-pressure group. However, there was still complete recovery of function after ischemia in both septic groups (constant-pressure group, 107%; constant-flow group, 97%). The percent recovery of LVDP in both septic groups was higher than in both of the control groups. Because HR tended to be depressed during the reperfusion period in all four groups, the RPP was calculated to normalize the recovery of LVDP to HR. The percent recovery of RPP was better in the septic group than in the control group.

Adenosine antagonism. The effects of 0.1 and 1.0 nM 8-PT on CF, LVDP, HR, and RPP in control and septic rat hearts are presented in Table 2. In the 0.1 nM 8-PT-treated group, predrug CF was significantly higher in the control hearts than in the septic rat hearts but decreased by ~20% in both groups after 30-min perfusion with the drug. Predrug LVDP in the control group was higher than in the septic group; however, after 30 min of perfusion with the adenosine antagonist, LVDP and RPP decreased 13% in the control group, whereas neither parameter changed significantly in the septic group.

                              
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  		Table 2.   Effects of 0.1 and 1.0 nM 8-PT on CF, LVDP, and RRP in control and septic hearts (constant pressure) before and after ischemia and reperfusion

The recovery of CF (% of preischemic value) in 0.1 nM 8-PT-treated control and septic rat hearts, respectively, after 35 min of ischemia is presented in Fig. 3, A and B. During reperfusion, CF in the control group was significantly depressed compared with preischemic levels, comparable to that observed in untreated control hearts. Reperfusion CF in the septic group did not exhibit the elevation noted in the untreated group but did recover 100% at 25 min of reperfusion. Postischemic LVDP and RPP in the control hearts were significantly depressed compared with preischemic levels, whereas the septic group recovered completely by 25 min of reperfusion (LVDP: P = 0.067; RPP: P = 0.062; Table 2).


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  		Fig. 3.   Recovery of CF (% of preischemia) in untreated (n = 8), 0.1 nM (n = 7), and 1.0 nM (n = 6) 8-phenyltheophylline (8-PT)-treated control (A) and septic rat hearts (B; n = 9, 7, and 6, respectively) after 35-min ischemia. Recovery of CF in control hearts was not significantly altered by either concentration (0.1 or 1.0 nM) of the adenosine antagonist 8-PT. Elevated CF in septic hearts was blocked by both concentrations of 8-PT; recovery at 25-min reperfusion was not significantly depressed.

In the 1.0 nM 8-PT study, predrug CF in control and septic rat hearts was not significantly different. In both groups, CF decreased after a 30-min perfusion with 1.0 nM 8-PT; however, cardiac function decreased only in the control group (LVDP decreased 14% and RPP decreased ~20%). In contrast to the low dose, the high dose of 8-PT did affect recovery of postischemic ventricular function in septic rat hearts: LVDP and RPP were significantly decreased (66 and 62% of preischemic function, respectively). Postischemic LVDP in the control group was also significantly depressed, as had been previously seen in the untreated control hearts.

There was no significant difference in the recovery of CF, as a percentage of predrug flow, among the 0.1 and 1.0 nM 8-PT-treated control hearts (0.1 nm, 59%; 1.0 nM, 54%) and the untreated control group (59%; same data as constant-pressure group). Similarly, there was no difference in recovery between the two 8-PT-treated septic groups at 25 min of reperfusion (0.1 nM, 76%; 1.0 nM, 77%); however, the untreated septic group recovered 100% of preischemic CF. LVDP, as a percentage of predrug LVDP, was similar in control rat hearts with or without 8-PT (untreated, 70%; 0.1 nM, 66%; 1.0 nM, 69%). However, there were significant differences among the untreated, 0.1 nM 8-PT-treated, and 1.0 nM 8-PT-treated septic rat hearts in the recovery of LVDP. The untreated and 0.1 nM 8-PT treated septic rat hearts recovered 107 and 81% (P = 0.062), respectively, of predrug LVDP, whereas 1.0 nM 8-PT-treated hearts recovered only 62%. Similar trends were observed when the RPP of the three groups was compared. All three control groups recovered to a similar extent (untreated, 57%; 0.1 nM 8-PT treated, 64%; 1.0 nM 8-PT treated, 60%), whereas 1.0 nM 8-PT caused a significant decrease in the recovery of the septic group [untreated, 95 ± 10%; 0.1 nM 8-PT treated, 76 ± 8% (P = 0.062); 1.0 nM 8-PT treated, 61 ± 13%].

    DISCUSSION
Top
Abstract
Introduction
Methods
Results
Discussion
References

Sepsis (18) and endotoxemia (20, 27) depress myocardial function but protect the heart from further injury due to ischemia and reperfusion. Previous studies by McDonough and Causey (18) demonstrated that myocardial function after 50 min of ischemia in septic hearts is not significantly depressed. They proposed that this was, at least in part, due to the elevated CF observed during early reperfusion (18). After 20 min of ischemia in an endotoxin model, CF and LVDP recovered better than controls but not to preischemic levels; however, the role of CF was not addressed (20). The results of the present study indicated that the relationship between CF and LVDP was altered in septic rat hearts and that elevated CF during reperfusion was not necessary for the full recovery of postischemic function.

The goal of the first experiment was to establish the relationship between CF and LVDP in pre- and postischemic control and septic rat hearts. Before ischemia, LVDP in septic rat hearts increased with flow between 4 and 20 ml/min, but further increasing flow resulted in a slight decrease in LVDP (Fig. 1A). Preischemic LVDP in control rat hearts was more dependent on flow and varied linearly with CF between 4 and 20 ml/min and continued to rise (less steeply) at CF above 20 ml/min. LVDP was significantly higher at every CF in the control group than in the septic group. Ischemia severely depressed the relationship between CF and LVDP in control rat hearts, but septic rat hearts were relatively unaffected (Fig. 1B).

It is well documented that oxygen consumption is linearly related to CF in normal hearts (29). The linear relationship between CF and LVDP in control hearts implies that LVDP and oxygen consumption are proportional, whereas in septic hearts this relationship is dramatically altered. Characteristics of sepsis, such as mismatched oxygen supply and demand, impaired capacity of the vasculature to respond to the metabolic needs of the myocardium (24, 29), and compromised myocardial function (18, 19, 29), may explain why there is an abnormal relationship between flow and function before ischemia that remained unaffected by 35 min of ischemia. The postischemic dysfunction of the control hearts may have been due to impaired release of Ca2+ from the sarcoplasmic reticulum, decreased contractile protein sensitivity to Ca2+, and lactate accumulation (25, 26, 30). The resultant alterations in Ca2+ handling and myosin ATPase inactivation would prevent normal actin-myosin interactions, leading to the observed decrease in contractility (30). Also, ATP depletion, metabolic enzyme inhibition, acyl carnitine and lysophosphatidylcholine accumulation, and the activation of proteases and phospholipases contribute to arryhthmias and necrosis characteristic of ischemic injury (30).

To further examine the altered relationship between flow and function in hearts from septic rats, we prevented the increase in CF (139%) observed in postischemic septic rat hearts under constant-pressure perfusion by maintaining constant-flow perfusion. CF during the stabilization period and preischemic LVDP in septic rat hearts subsequently perfused with constant flow were higher than in the constant-pressure group. Although our septic animals were studied in the hyperdynamic phase (they were febrile and had ocular exudate and diarrhea), the sepsis in this group was probably less severe. Despite these differences, there was still complete recovery of postischemic function in septic rat hearts perfused with constant CF (constant-pressure group, 107%; constant-flow group, 97%). These data indicate that the elevated CF was not required for the recovery of postischemic function in septic rat hearts and supported our hypothesis that sepsis alters the relationship between CF and LVDP. Furthermore, these results suggest that severe myocardial depression is not necessary for sepsis-induced cardioprotection to occur. Similarly, Meng et al. (23) have shown that endotoxin causes a maximal decrease in CF and LVDP at 6 h, but at 12 through 24 h, CF is significantly elevated compared with baseline and saline-treated rats; LVDP returns to baseline levels by 24 h (23). As observed in septic rats, endoxemia appears to cause a similar alteration in the relationship between CF and LVDP. In the endotoxin model after 20 min of ischemia, the recovery of LVDP is improved, but not to preischemic levels, and the role of CF is unclear (20).

Control rat hearts under constant-pressure perfusion recovered only 59% of preischemic CF and 70% of preischemic LVDP, and the maximum recovery of flow was 66%. Under constant-flow perfusion, control hearts recovered slightly better function (81%), but LVDP was still significantly lower than the preischemic value. The increase in postischemic recovery of LVDP was probably due to the increased postischemic flow afforded by maintaining constant preischemic flow. Vessels that would have collapsed under constant-pressure perfusion may have been perfused when CF was maintained constant, thus enhancing oxygen and substrate delivery and metabolite removal. This finding was in accordance with the well-documented observation that an increase in coronary perfusion augments cardiac function (Gregg's phenomenon) (6). This effect is also observed in control hearts before ischemia and in septic hearts, although to a much lesser extent. Increasing perfusion pressure by increasing CF may stretch the muscle fibers, enhancing filament overlap and increasing cardiac function via the Frank-Starling mechanism (6).

The function(s) and mediator(s) of the elevated CF observed during reperfusion of the septic heart have not yet been identified. Therefore, we investigated one potential mediator in order to gain some insight into the mechanism of sepsis-induced cardioprotection. Adenosine, a potent vasodilator, increases in response to imbalances in metabolic supply and demand (3, 8, 24) and alpha 1-adrenergic-mediated increases in 5'-nucleotidase activity via PKC (11, 12). Recently it has been found that adenosine is an important determinant of hepatopsplanchnic vascular tone during sepsis (24). To examine the contribution of endogenous adenosine to the elevated CF and recovery of postischemic LVDP in the septic rat myocardium, we added the nonselective adenosine receptor antagonist 8-PT (0.1 or 1.0 nM) to the perfusate. This drug is one of the methylxanthines that are known to inhibit phosphodiesterase, the enzyme that catalyzes the breakdown of cAMP to AMP, and to stimulate the release of catecholamines at high concentrations (3, 14), both of which would cause an increase in cAMP and thus increase contractility. Previous studies have used this drug in the micromolar range (9). However, in preliminary studies, we found that 0.1 and 1.0 nM 8-PT were sufficient concentrations to block the negative chronotropic action of adenosine (determined by percent inhibition studies in naive animals; data not shown), and, in fact, we observed decreases in LVDP in control hearts after 30 min of perfusion (Table 2).

The lower concentration of 8-PT decreased preischemic CF in both control and septic rat hearts 20 and 19%, respectively. The decrease in LVDP in the control group (13%) paralleled the decrease in CF; however, there was no significant decrease in LVDP in the septic group, again supporting the hypothesis that the relationship between CF and LVDP is altered by sepsis. Postischemic CF in the control group was 74% of preischemic flow, and the recovery of LVDP in this group was 76%. This was not significantly different from the recovery in untreated hearts, indicating that the low dose of 8-PT did not exacerbate myocardial ischemia and reperfusion damage. In the septic group, the elevated CF typically observed during reperfusion was prevented by 0.1 nM 8-PT. The recovery of CF was not significantly decreased compared with preischemia (96%), but it was decreased compared with the predrug CF (76%). The LVDP at 25 min of reperfusion was not significantly different from the preischemic value or from the predrug value. These results suggested that limiting the increase in CF (probably by blocking adenosine A2 receptors) with 0.1 nM 8-PT did not affect the recovery of LVDP, further emphasizing that the recovery of LVDP was not dependent on CF in septic rat hearts.

The high dose of 8-PT (1.0 nM) decreased CF in the control rat hearts by 32% and LVDP by 14% but did not significantly decrease these parameters in the septic group. However, 1.0 nM 8-PT did prevent the elevation of CF during reperfusion in septic rat hearts. CF at 25 min of reperfusion was 87 ± 10% of preischemic CF, not significantly different from septic hearts treated with the low dose. However, the recovery of LVDP was significantly impaired, recovering only 66% of preischemic function (62% of predrug). These results indicated that the endogenous production of adenosine caused the increase in CF during reperfusion and contributed to the protection of the septic rat heart from ischemia-reperfusion injury.

In addition to its action as a vasodilator, adenosine has been shown to be involved in preconditioning (1, 2, 5, 8, 10, 13, 21, 25, 31). Stimulation of A1 receptors (5, 10, 13, 14, 16, 20, 21, 31) and/or A3 receptors (1, 2, 17) has many protective effects, such as decreasing intracellular Ca2+ (30) and oxidative injury (3, 10, 16), ultimately limiting infarct size (2, 3, 11, 16, 25) and postischemic dysfunction (8, 13). Although it is unknown which component(s) is/are directly responsible for the complete recovery of the septic rat heart, adenosine released during sepsis may have activated intracellular biochemical pathways similar to those activated by preconditioning. Both the adrenergic and purinergic systems appear to be involved in preconditioning of the rat myocardium (22, 31). Acute adenosine or phenylephrine preconditioning subsequent to delayed preconditioning with endotoxin in vivo (24 h before in vitro studies) improves postischemic functional recovery (20). Transient ischemia of hearts from rats pretreated with endotoxin further enhanced the improved recovery of aortic flow and decreased creatine kinase release observed with either treatment alone (28). During sepsis, there is an increase in circulating catecholamines (7), which, in addition to increasing adenosine via 5'-nucleotidase activation (11, 12), may be a trigger for activation of additional protective mechanisms. Increased catalase activity has been shown to occur in adenosine-treated rat myocytes (17) and endotoxemic hearts (4), but no significant increases were found in septic hearts after ischemia and reperfusion; however, levels were not measured before ischemia (18). Heat shock proteins have also been found in hearts of rats pretreated with endotoxin and may be a component of the protection afforded against infarction (27). Perhaps diminished cardiac function during sepsis may have diverted energy toward activation of cellular processes that would provide protection against further insults.

In view of the many factors contributing to ischemia-reperfusion injury and sepsis-endotoxemia-induced dysfunction, in addition to the various purported mechanisms of preconditioning, it is likely that multiple pathways are converging. The potential interaction of adenosine, intracellular messengers, heat shock proteins, and antioxidant enzymes may lead to sepsis-induced cardioprotection.

    FOOTNOTES

Address for reprint requests: K. H. McDonough, Dept. of Physiology, Louisiana State Univ. Medical Center, 1901 Perdido St., New Orleans, LA 70112.

Received 13 November 1997; accepted in final form 6 March 1998.

    REFERENCES
Top
Abstract
Introduction
Methods
Results
Discussion
References

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Am J Physiol Heart Circ Physiol 275(1):H8-H14
0002-9513/98 $5.00 Copyright © 1998 the American Physiological Society


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