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J Appl Physiol 100: 541-547, 2006. First published October 13, 2005; doi:10.1152/japplphysiol.00350.2005
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Myocardial hypoperfusion/reperfusion tolerance with exercise training in hypertension

Patricia O. Reger,1 Mary F. Barbe,3,5 Mamta Amin,5 Brian F. Renna,1 Leigh Ann Hewston,1 Scott M. MacDonnell,1 Steven R. Houser,2,4 and Joseph R. Libonati1,2,4

Departments of 1Kinesiology, 2Physiology, 3Cell Biology, 4Cardiovascular Research Center, and 5Department of Physical Therapy, Temple University, Philadelphia, Pennsylvania

Submitted 25 March 2005 ; accepted in final form 20 September 2005


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
The purpose of this study was to examine whether exercise training, superimposed on compensated-concentric hypertrophy, could increase myocardial hypoperfusion-reperfusion (H/R) tolerance. Female Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) (age: 4 mo; N = 40) were placed into a sedentary (SED) or exercise training (TRD) group (treadmill running; 25 m/min, 1 h/day, 5 days/wk for 16 wk). Four groups were studied: WKY-SED (n = 10), WKY-TRD (n = 10), SHR-SED (n = 10), and SHR-TRD (n = 10). Blood pressure and heart rate were determined, and in vitro isolated heart performance was measured with a retrogradely perfused, Langendorff isovolumic preparation. The H/R protocol consisted of a 75% reduction in coronary flow for 17 min followed by 30 min of reperfusion. Although the rate-pressure product was significantly elevated in SHR relative to WKY, training-induced bradycardia reduced the rate-pressure product in SHR-TRD (P < 0.05) without an attenuation in systolic blood pressure. Heart-to-body weight ratio was greater in both groups of SHR vs. WKY-SED (P < 0.001). Absolute and relative myocardial tolerance to H/R was greater in WKY-TRD and both groups of SHR relative to WKY-SED (P < 0.05). Endurance training superimposed on hypertension-induced compensated hypertrophy conferred no further cardioprotection to H/R. Postreperfusion 72-kDa heat shock protein abundance was enhanced in WKY-TRD and both groups of SHR relative to WKY-SED (P < 0.05) and was highly correlated with absolute left ventricular functional recovery during reperfusion (R2 = 0.86, P < 0.0001). These data suggest that both compensated hypertrophy associated with short-term hypertension and endurance training individually improved H/R and that increased postreperfusion 72-kDa heat shock protein abundance was, in part, associated with the cardioprotective phenotype observed in this study.

diastole; heat shock proteins; heart

CHRONIC HYPERTENSION IS A major risk factor for the development of coronary artery disease and is a well-documented precursor for the development of congestive heart failure (24). Chronic hypertension induces pathological, concentric hypertrophy in which there is a parallel addition of sarcomeres that characteristically increases cardiomyocyte cell size and width (21). From a cellular perspective, concentric hypertrophy differs from eccentric hypertrophy in that, with eccentric hypertrophy, cardiomyocytes adapt by increasing sarcomeres in series, thereby inducing an increase in cell length (21, 52). While compensatory concentric hypertrophy is often regarded as an adaptational process to normalize wall stress with hypertension (68), it is frequently manifest with normal or hyperactive systolic performance coupled with diastolic dysfunction, i.e., increased left ventricular (LV) chamber stiffness (16) and an increased susceptibility to ischemia-reperfusion (I/R) injury (3, 5, 17, 23, 32, 60, 69–71).

In general, chronic aerobic exercise training has been shown to protect the myocardium from I/R injury (64, 74). Several studies have shown that training protects the myocardium from hypoxia, anoxia, and I/R injury (6, 7, 10, 11, 14, 15, 36, 37, 39, 41, 44, 46, 47, 50, 55, 63) with higher intensities of exercise shown to confer greater protection (10, 11, 44). Understanding the mechanisms associated with exercise-induced cardioprotection from I/R injury has great clinical relevance. Exercise training has been shown to enhance myocardial antioxidant scavenging (20, 44, 62) and increases the expression of ~70- (HSP70) to 72-kDa heat shock proteins (HSP72), an effect that can occur within a few days after the onset of training (20, 47, 54, 56). The HSP70/72 family are associated with a host of protective mechanisms, including stabilizing and refolding damaged proteins during stressful conditions like ischemia. Thus it has been suggested that HSP72 protection from I/R injury is, in part, mediated via its effects on ATP-sensitive K+ channels (34).

Few data exist with respect to how chronic exercise training impacts I/R tolerance in compensated hypertrophy. Thus the purpose of the present study was to examine whether exercise training superimposed on a model of pressure overload hypertrophy was protective against I/R injury. Our specific hypothesis was that 4 mo of aerobic exercise training (treadmill running) in the spontaneously hypertensive rat (SHR) model would improve LV performance in response to a relative bout of hypoperfusion followed by reperfusion and that this putative effect would be related to the postreperfusion abundance of myocardial HSP72.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Animals and exercise training.   Forty 4-mo-old female Wistar Kyoto rats (WKY; n = 20) and SHR (n = 20) (weighing ~185 g) were obtained from Charles River Laboratories (St. Constant, Quebec). Animals within both the WKY and SHR groups were randomly assigned into either a sedentary (WKY-SED, N = 10; SHR-SED, N = 10) or exercise-trained group (WKY-TRD, N = 10; SHR-TRD, N = 10). All rats were housed three per cage, maintained on a 12:12-h light-dark cycle, and fed ad libitum (18% protein diet, Harlan Teklad Global Diets, Madison, WI). Training consisted of low-intensity endurance running at a speed of 25 m/min, 0% grade, 60 continuous min, 5 days/wk, for a period of 16 wk. SHR-SED and WKY-SED were handled each day. Resting heart rates (HRs) (mean of 25 cardiac cycles) and blood pressures were collected on three occasions (pre-, mid-, and posttraining), utilizing a tail cuff apparatus (XBP1000; Kent Scientific, Torrington, CT). At 8 mo of age, all animals were killed, and functional studies were performed. All animals received humane care in compliance with Temple University Institutional Animal Care and Use Committee and the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH Publication No. 85-23, revised 1985). One rat in the SHR-TRD group did not complete the training protocol and thus was not included in the final hemodynamic analysis.

Isolated rat heart preparation.   Rats were anesthetized with pentobarbital sodium (60 mg/kg ip) and heparinized intravenously (500 units). The heart was excised, trimmed of excess tissue, and rapidly immersed in cold (4°C), Ca2+-free Krebs-Henseleit buffer. Hearts were placed on a Langendorff perfusion apparatus (ML785B2, ADInstruments, Colorado Springs, CO) and perfused at 16 ml/min (STH pump controller ML175, ADInstruments, Colorado Springs, CO) with a modified Krebs-Henseleit solution containing (in mM) 2.0 Ca2+Cl2, 130 NaCl, 5.4 KCl, 11 dextrose, 2 pyruvate, 0.5 MgCl2, 0.5 NaH2PO4, and 25 NaHCO3. The buffer was equilibrated with 95% O2 and 5% CO2, which maintained the pH at 7.35–7.4, as previously described (49).

The coronary flow rate was selected to mimic the in situ perfusion pressure. After coronary perfusion was initiated, the LV was immediately decompressed with an apical puncture via the insertion of a short apical drain. A balloon was inserted into the LV, and the LV balloon volume was adjusted to 10–12 mmHg of LV end-diastolic pressure (LVEDP) for stabilization. Following stabilization, no further alterations in balloon volume were made, and preischemic baseline LV performance was recorded.

After baseline measurements, a relative period of hypoperfusion was established by reducing the coronary flow by 75% of baseline to 4 ml/min. The hypoperfusion flow was designed to mimic clinical coronary syndromes in which coronary lesions often become significant when flow is compromised in excess of 70%. Hypoperfusion, as opposed to no-flow ischemia, allows the heart to continue working through the period of compromised flow (45). Hypoperfusion was maintained for 17 min followed by reperfusion at the baseline coronary flow rate (16 ml/min for 30 min). Recordings and measurements of LV pressure (LVP), the maximum rate of positive and negative change in LVP (±dP/dt), and coronary perfusion pressures were continuously made during both the hypoperfusion and reperfusion periods (Powerlab/8SP, ADInstruments, Colorado Springs, CO). Coronary perfusion pressure was measured at heart level via a fluid-filled pressure transducer. LV-developed pressure was calculated by subtracting the LVEDP from the LV systolic pressure. At the end of the reperfusion period, hearts were arrested, and ~40% of the LV was then removed, frozen in liquid nitrogen, and stored at –80°C until being analyzed for stress proteins.

Gel electrophoresis and Western blotting.   LV tissue was homogenized in phosphate buffer containing protease inhibitors for 30 s with a tissue homogenizer. The tissue was then placed in clean Eppendorf tubes and centrifuged for 15 min for the subsequent removal of the supernatant. Protein concentration was measured using the Pierce protein assay based on the Bradford dye-binding procedure with bovine serum albumin as the standard (12). The protein solution was divided into aliquots and stored at –80°C. At the time of analysis, samples were thawed and recentrifuged, and volumes were transferred to allow 30 µg of total protein per lane on a criterion 10% Tris gel (Bio-Rad). Proteins were separated by SDS-polyacrylamide gel electrophoresis. After electrophoresis, the proteins were then transferred to Western polyvinylidene difluoride (PVDF) membranes (Bio-Rad). Protein transfer was verified by staining the gel in Comassie blue and by the transfer of prestained molecular weight markers (Bio-Rad) on to PVDF membranes. After the PVDF membranes were blocked with nonfat dry milk, they were incubated with a mouse monoclonal antibody reacting to HSP72 (Stressgen Bioreagents). The secondary antibody, a horseradish peroxidase-conjugated rabbit, anti-mouse immunoglobin G (Jackson ImmunoResearch Laboratories) was then applied. The membranes were developed using enhanced chemiluminescence and exposed to X-ray film. The membrane was then stripped using 5x Western Reprobe buffer. Following the recommended washing and blocking, the PVDF membrane was then incubated with an antibody reacting to GAPDH. The application of the secondary antibody and membrane development was performed, as previously described. HSP72 and GAPDH were then quantified by densitometry.

Data analysis.   Animal characteristics and hemodynamics at time of death were compared with one-way ANOVA and least significant difference post hoc analysis. LV performance during hypoperfusion/reperfusion performance was analyzed with ANOVA with repeated measures and Tukey’s post hoc analysis. Myocardial HSP72 protein abundance was compared by using a one-way ANOVA and Tukey’s post hoc analysis. Pearson-product correlations were performed for LV functional recovery and HSP72 protein abundance. All analyses were performed by using SPSS version 12.0 (Chicago, IL). Significance was set at an {alpha}-level of P < 0.05. Statistical tendencies are reported as P < 0.1. Data are reported as means ± SE. Langendorff hearts with significant arrhythmias and/or technical limitations were not included in the final data analysis. The final group sample size for isolated heart studies were as follows: WKY-SED, N = 8; WKY-TRD, N = 9; SHR-SED, N = 7; SHR-TRD, N = 8.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Hemodynamics.   Following 16 wk of exercise training, resting HR values for both WKY-TRD and SHR-TRD were significantly lower than their respective sedentary controls (WKY-SED and SHR-SED) (Table 1). WKY-TRD had a lower HR than both SHR groups (P < 0.01). Systolic blood pressure gradually increased over time in all groups, and, immediately before death, systolic blood pressure, diastolic blood pressure, mean arterial pressure, and rate-pressure product (RPP) were significantly greater in both SHR groups relative to both WKY groups. Training-induced bradycardia in SHR-TRD attenuated the RPP relative to SHR-SED (P < 0.05), whereas RPP was similar between WKY-SED and WKY-TRD.


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  		Table 1. Hemodynamic parameters immediately before death

 
Animal characteristics.   The animal physical characteristics are presented in Table 2. At the time of death, the body weights of both SHR groups were less than those of both WKY groups (P < 0.01). Absolute heart weight (HW) was greater in SHR-TRD vs. WKY-SED (P < 0.01). HW-to-BW ratio was greater in both groups of SHR relative to both groups of WKY (P < 0.001). Absolute tibial length was similar among all groups. However, SHR-TRD showed a greater HW-to-tibial length ratio relative to both WKY-SED and WKY-TRD (P < 0.05).


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  		Table 2. Physical characteristics

 
Isolated heart performance.   In our model, all hearts were perfused at a constant coronary flow rate of 16 ml/min with a crystalloid perfusate, allowing for differences in coronary perfusion pressure to be illustrative of coronary vascular resistance. As Table 3 illustrates, the baseline coronary flow rate of 16 ml/min elicited similar perfusion pressures between both WKY groups, despite the tendency for coronary perfusion pressure to be greater in both SHR groups relative to both groups of WKY. At baseline, LV end-diastolic volume was experimentally fixed to yield an LVEDP of 10–12 mmHg. Mean LV balloon volume was similar in WKY compared with SHR (WKY-SED: 48 ± 7 µl, WKY-TRD: 52 ± 5 µl, SHR-SED: 65 ± 14 µl, and SHR-TRD: 62 ± 15 µl; P = not significant). Baseline Langendorff LV performance was similar across all groups.


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  		Table 3. Absolute LV performance during hypoperfusion and reperfusion

 
Tables 3 and 4 also illustrate the absolute and relative Langendorff LV performance throughout the hypoperfusion/reperfusion protocol. Relative hypoperfusion was induced by decreasing the coronary flow rate by 75% to 4 ml/min in all groups. Hypoperfusion promptly diminished coronary perfusion pressure by ~70% in all groups. After 17 min of hypoperfusion, coronary perfusion pressure started to increase relative to the onset of hypoperfusion and was similar across groups. During reperfusion, there was a consistent rise in coronary perfusion pressure relative to baseline in all groups.


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  		Table 4. Relative LV performance during hypoperfusion/reperfusion (% of baseline)

 
LV developed pressure fell ~80% in all groups during hypoperfusion and was greater (both relative and absolute; P < 0.05) in SHR-SED and SHR-TRD relative to WKY-SED midway through hypoperfusion. LVEDP, +dP/dt, and –dP/dt were similar between groups during hypoperfusion. Reperfusion improved cardiac performance relative to hypoperfusion. However, throughout reperfusion, absolute and relative LV developed pressure, +dP/dt, and –dP/dt (Tables 3 and 4) were most compromised in WKY-SED relative to all of the other groups.

HSP72 abundance.   The HSP72/GAPDH abundance is illustrated in Fig. 1. HSP72/GAPDH abundance was increased in WKY-TRD relative to WKY-SED (P < 0.05). Both SHR groups showed greater HSP72/GAPDH relative to WKY-SED (P < 0.01). Moreover, both absolute and relative LV developed pressure recovery were well correlated with HSP72/GAPDH abundance (R2 = 0.86, P < 0.0001; R2 = 0.60, P < 0.0004, absolute and relative, respectively) (Fig. 2).


Figure 1
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  		Fig. 1. Left ventricular 72-kDa heat shock protein (HSP72)/GAPDH abundance. WKY, Wistar-Kyoto rats; SHR, spontaneously hypertensive rats; SED, sedentary; TRD, exercise trained. Values are means ± SE; N = 4 per group.

 

Figure 2
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  		Fig. 2. Relationship between the absolute developed pressure (Dev P) at the conclusion of reperfusion (i.e., reperfusion 30 min) and left ventricular (LV) HSP72/GAPDH abundance. N = 16.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The major findings of this study are that, in the compensated hypertrophy stage, hearts from SHR animals were more tolerant to hypoperfusion followed by reperfusion. In normotensive WKY animals, endurance training also provided protection from hypoperfusion/reperfusion contractile dysfunction. However, moderate-intensity endurance training superimposed on hypertension conferred no further cardioprotection from hypoperfusion/reperfusion. Postreperfusion-HSP72 abundance was enhanced with both hypertension-induced compensated hypertrophy and endurance training and was well correlated with LV functional recovery during reperfusion. These data suggest that an increased postreperfusion HSP72 abundance is, in part, associated with the cardioprotective phenotype that accompanies short-term hypertension and exercise training.

Our data in WKY animals are not surprising, since several studies have shown that exercise training protects the myocardium from hypoxia, anoxia, and I/R injury (6, 7, 10, 11, 14, 15, 29, 36, 37, 39, 41, 44, 46, 47, 50, 55, 63, 64, 74). Clearly, there is a complex interplay of mechanisms associated with how exercise training may protect the heart from I/R contractile dysfunction (64, 73). Exercise training in normotensive animals has been shown to enhance myocardial antioxidant scavenging (44, 62) and increase the expression of HSP70 to HSP72 (20, 47). Heat shock proteins have also been shown to be capable of regulating ATP-sensitive K+ channel conductance (34). Exercise training has specifically been shown to blunt the responsiveness of the sarcolemmal ATP-sensitive K+ channels to anoxia (36) and improve the myocardial sensitivity to glibenclamide, an ATP-sensitive K+ channel inhibitor (37).

There is an abundance of literature suggesting that HSP72 is not an essential component for cardioprotection (4, 18, 29, 42, 57, 58, 65, 66, 75–77, 83, 84). However, the HSP70/72 family is associated with a host of protective mechanisms, including stabilizing and refolding damaged proteins during ischemic stress (26, 28, 31, 40, 73), and it is possible that the increased postreperfusion abundance of HSP72 observed in the present study may, in part, mechanistically explain the protection observed in WKY-TRD and both groups of SHR.

Although not determined in the present study, exercise training has also been shown to maintain ATP and phosphocreatine content in response to I/R (10, 11), improve sarcoplasmic reticulum Ca2+ transport (59), and upregulate some key glycolytic enzymes (38, 44). ATP is functionally important in protection from I/R injury, in part, by maintaining ionic balance (19, 35). ATP derived from glycolytic metabolism (19) is thought to preferentially fuel Ca2+ uptake by the sarcoplasmic reticulum (82), the Na+/K+ exchanger (27), and the ATP-sensitive K+ channel (51, 80). Moreover, ATP derived from glycolysis plays an important role in actin-myosin rigor bond dissociation (2, 3, 79), a factor critical in regulating myocardial diastolic stiffness (43, 46).

Chronic hypertension negatively impacts both myocardial structure and function by serving as a substrate for the induction of pathological, concentric hypertrophy. With concentric myocardial hypertrophy, sarcomeres are added in parallel, thereby increasing cardiomyocyte cell size and width (21, 24). From a cellular perspective, concentric hypertrophy differs from eccentric hypertrophy in that, with eccentric hypertrophy, cardiomyocytes adapt by increasing sarcomeres in series and thus cell length (21, 52, 53).

While compensatory concentric hypertrophy is often regarded as an adaptational process to normalize wall stress with hypertension (68), recent reports have questioned the necessity of such (33). Certainly, the mechanisms associated with the dichotomous adaptive and maladaptive aspects of myocardial hypertrophy are important to understand. Of significance, concentric hypertrophy secondary to pressure overload is often associated with an increased susceptibility to hypoxic and ischemic injury (3, 13, 17, 22, 23, 32, 43, 48, 60, 69–71, 81). Abnormalities in coronary vasculature (69), as well as biochemical or metabolic alterations intrinsic to the hypertrophic myocardium (3), have been identified as possible sources of the enhanced myocardial susceptibility to ischemia. However, these previous studies typically examined older animals at accelerated phases in the hypertensive pathophysiological cascade. Conversely, studies using relatively young animals during the compensated phase of hypertrophy have shown that the hypertrophied heart is, instead, more tolerant to ischemia and reperfusion secondary to phenotypical changes, which allow the myocardium to be more efficient (78) and tolerant to hypoxic/ischemic stress (25, 30, 72). Tubau et al. (78) suggested that myosin isozyme shifts (from V1 to V2 and V3) with pressure overload may, in part, mechanistically lead to enhanced mechanical efficiency.

The results of the present study show that short-term compensated hypertrophy in the SHR model is protective from hypoperfusion followed by reperfusion. Once again, the finding that postreperfusion HSP72 abundance was increased in SHR may, in part, explain the observed putative protection. An enhanced abundance of HSP72 in the SHR model is consistent with previous reports showing enhanced HSP72 levels in response to heat stress (9, 28).

Interestingly, although our results show that exercise training resulted in greater hypoperfusion/reperfusion contractile performance in WKY-TRD relative to WKY-SED, exercise training superimposed on hypertension did not provide any additional protective effects. The comparable performance between the trained and untrained hypertensive groups is difficult to explain and contrary to our initial hypothesis. One possibility is that the low-intensity training protocol utilized in this study was not a sufficient enough stimulus to elicit a cardioprotective phenotype in the already compensated SHR myocardium. We chose the training intensity of 55% peak O2 uptake to correspond to the preferred training intensity for hypertensive patients (1), and our initial studies in the SHR model have shown that this intensity was effective in improving tolerance to acidosis (67) and enhancing beta-adrenergic responsiveness and signaling (49).

The SHR model was selected for our study because it closely mimics the clinical course of untreated essential hypertension in humans. It has been documented that concentric hypertrophy occurs in SHR between 6 and 12 mo of age, decompensating to heart failure near 15 mo (8). We chose to study these animals at 8 mo of age because compensatory hypertrophy is known to exist at this age without a concomitant increase in interstitial fibrosis (8). The causes of hypertension in SHR are polygenic and do not necessarily reflect the genetic anomalies associated with hypertension in humans. Despite this limitation, the present data suggest that both exercise training and short-term hypertension protect the heart from hypoperfusion/reperfusion, with no further putative effect gained by superimposing exercise training on hypertension. Our data also suggests that the postreperfusion abundance of HSP72 plays a role in this enhanced tolerance to hypoperfusion/reperfusion.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This study was supported by a beginning-grant-in-aide from the American Heart Association, Mid-Atlantic affiliate (J. R. Libonati) and National Heart, Lung, and Blood Institute Grant HL-33921 (S. R. Houser).


   FOOTNOTES
 

Address for reprint requests and other correspondence: J. R. Libonati, Temple Univ., 122 Pearson Hall, 1800 North Broad St., Philadelphia, PA 19122 (e-mail: jlibonat{at}temple.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

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