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Am J Physiol Heart Circ Physiol 294: H1523-H1529, 2008. First published February 8, 2008; doi:10.1152/ajpheart.01241.2007
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Sex Steroids and Gender in Cardiovascular-Renal Physiology and Pathophysiology

Sex differences to myocardial ischemia and β-adrenergic receptor blockade in conscious rats

Heidi L. Lujan and Stephen E. DiCarlo

Department of Physiology, Wayne State University School of Medicine, Detroit, Michigan

Submitted 25 October 2007 ; accepted in final form 4 February 2008


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
We recently documented sex differences in the susceptibility to reperfusion-induced sustained ventricular tachycardia and β-adrenergic receptor blockade in conscious rats. However, the effect of sex on ischemia-induced ventricular arrhythmias and β-adrenergic receptor blockade is underinvestigated. Therefore, we tested the hypothesis that gonadal hormones influence the ventricular arrhythmia threshold (VAT) induced by coronary artery occlusion as well as the response to β-adrenergic receptor blockade. The VAT was defined as the time from coronary occlusion to sustained ventricular tachycardia resulting in a reduction in arterial pressure. Male and female intact and gonadectomized (GnX) rats were instrumented with a radiotelemetry device for recording arterial pressure, temperature, and ECG, as well as a Doppler ultrasonic flow probe to measure cardiac output and a snare around the left main coronary artery. The VAT was determined in conscious rats by pulling on the snare. The VAT was significantly longer in intact females (5.56 ± 0.19) vs. intact males (4.31 ± 0.14 min). This sex difference was abolished by GnX. Specifically, GnX decreased the VAT in females (4.55 ± 0.22) and increased the VAT in males (5.14 ± 0.30 min). Thus male sex hormones increase and female sex hormones decrease the susceptibility to ischemia-induced sustained ventricular tachycardia. β-Adrenergic receptor blockade increased the VAT in intact males and GnX females only. Thus gonadal hormones influence the response to β-adrenergic receptor blockade. Uncovering major differences between males and females in the pathophysiology of the cardiovascular system may result in sex-specific optimization of patient treatments.

cardiovascular risks; arrhythmia

ISCHEMIA-INDUCED TACHYARRHYTHMIAS that culminate in ventricular fibrillation (19) are the leading cause of death in industrially developed countries (36). Despite the clinical relevance of ischemia-induced arrhythmias, very little experimental data are available regarding sex-specific responses. Specifically, Humphreys and colleagues (20), in the pentobarbital sodium-anesthetized rat as well as isolated rat heart, reported that females experienced fewer arrhythmias than males during myocardial ischemia.

Other investigators using different mechanisms to induce arrhythmias also reported a sex difference. For example, Du and colleagues (14), in the in situ perfused rat heart model with chronic infarction and failure, documented that ventricular arrhythmias, triggered by sympathetic activation, were less frequent in female than in male rats. Similarly, Teplitz and colleagues (46), in the pentobarbital sodium-anesthetized rat, reported that male rat hearts are more susceptible than female hearts to epinephrine-induced arrhythmias and more than twice as many male rats died following epinephrine treatment compared with females. Furthermore, ovariectomy increased the susceptibility to epinephrine-induced arrhythmias, whereas castration had a minimal effect in males. These studies, using a variety of models and methods, support the concept that female sex hormones decrease the susceptibility to ventricular arrhythmias.

It is important to reiterate, however, that only one study (20) examined the response to ischemia-induced arrhythmias. In addition, to our knowledge, sex differences in response to myocardial ischemia and β-adrenergic receptor blockade have not been examined in conscious rats. This is an important consideration because anesthetic agents, surgical trauma, and isolated hearts significantly alter the response to myocardial ischemia.

Therefore, we tested the hypothesis that gonadal hormones influence the susceptibility to ischemia-induced sustained ventricular tachycardia as well as the response to β-adrenergic receptor blockade in conscious, chronically instrumented rats. Specifically, we hypothesized that female sex hormones reduce and male sex hormones increase the susceptibility to ischemia-induced tachyarrhythmias.


   MATERIALS AND METHODS
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 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Surgical Procedures

Experimental preparations and protocols were reviewed and approved by the Animal Care and Use Committee of Wayne State University. The studies conformed to American Physiological Society guidelines and principles for research involving animals.

All surgical procedures were performed using aseptic measures. Female (n = 7; age, ~12 wk) and male rats (n = 7; age, ~9 wk) were anesthetized with pentobarbital sodium (50 mg/kg ip), and supplemental doses (10 mg/kg ip) were administered if the rat regained the blink reflex or responded during the surgical procedures. Subsequently, ovariectomy and orchidectomy procedures were performed as recently described (31).

A telemetry device (Data Sciences International PhysioTel C50-PXT; pressure, temperature, and ECG) was implanted at the time of the gonadectomy procedures as well as in intact male (n = 11; age, ~9 wk) and female (n = 12; age, ~12 wk) rats as previously described (7, 40), and a catheter was placed in the intraperitoneal space for the infusion of fluids. The transmitter body, which contains the thermistor, was placed in the intraperitoneal space. The pressure sensor of the telemetry device, located within the tip of a catheter, was inserted into the descending aorta for continuous, nontethered recording of pulsatile arterial blood pressure. The electrical leads from the telemetry device were placed in a modified lead II configuration by placing the negative electrode slightly to the right of the manubrium and the positive electrode at the anterior axillary line along the fifth intercostal space. The animals were allowed to recover at least 4 wk. During the recovery period, the rats were handled, weighed daily, and acclimatized to the laboratory and investigators.

After recovery, the animals were anesthetized as described above, and the hearts were approached via a left thoracotomy through the fourth intercostal space. A coronary artery occluder was made from 5.0-gauge atraumatic prolene suture (8720H, Ethicon), which passed through a polyethylene-50 guide tubing (Clay Adams). The suture was positioned around the left main coronary artery 2 to 3 mm from the origin by inserting the needle into the left ventricular wall under the overhanging left atrial appendage and by bringing it out high on the pulmonary conus (8, 9, 27, 29, 30, 31). The guide tubing with the other end of the occluder was then exteriorized at the back of the neck. The tubing was filled with a mixture of Vaseline and mineral oil to prevent a pneumothorax. Teflon-coated silver-wire electrodes were sutured 2 to 3 mm apart on the surface of the left atrial appendage as previously described (31, 40). In addition, a Doppler ultrasonic flow probe was positioned around the ascending aorta as previously described (23, 31). The electrodes and flow probe lines were tunneled beneath the skin and exteriorized at the back of the neck. At least 1 wk was allowed for recovery. During the recovery periods, the rats were handled, weighed daily, and acclimatized to the laboratory and investigators. Two separate surgeries (gonadectomy plus telemetry or telemetry alone as well as thoracotomy) were separated by at least 4 wk because the animals recover significantly better than if two major surgeries are conducted during one session.

Experimental Procedures

Susceptibility to ischemia-induced arrhythmias. Conscious, unrestrained rats were studied in their home cages (~13,350 cm3) for all experiments. Rats were allowed to adapt to the laboratory environment for approximately 1 h to ensure stable hemodynamic conditions. After the stabilization period, beat-by-beat, steady-state preocclusion hemodynamic variables were recorded over 10–15 s. Subsequently, the left main coronary artery was temporarily occluded by use of the prolene suture. Specifically, acute coronary artery occlusion was performed by pulling up on the suture that was around the left main coronary artery (Fig. 1). Rapid changes in the ECG (peaked T wave followed by S-T segment elevation) and arterial pressure occur within seconds of pulling on the suture, documenting coronary artery occlusion. The occlusion was maintained until the onset of ventricular tachycardia but no longer than 6.5 min to prevent myocardial damage. The ventricular arrhythmia threshold (VAT) was defined as the time from coronary artery occlusion to sustained ventricular tachycardia resulting in a reduction in arterial pressure (Fig. 1). Ventricular tachycardia was defined as sustained ventricular rate (absence of P wave, wide bizarre QRS complex) greater than 1,000 beats/min with a reduction in arterial pressure below 40 mmHg. If the time to sustained ventricular tachycardia exceeded 6.5 min, the occlusion was stopped and 6.5 min was used as the VAT. Normal sinus rhythm appeared upon termination of the occlusion by gently compressing the thorax. Without compressing the thorax, the sustained ventricular tachycardia progresses to ventricular fibrillation. Ventricular fibrillation was defined as a ventricular rhythm without recognizable QRS complex, in which signal morphology changed from cycle to cycle and for which it was impossible to estimate heart rate (HR). In the event when the animal did not resume normal sinus rhythm, cardioversion was achieved (after the rat lost consciousness) with the use of 1 shock (10 J) of direct current.


Figure 1
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  		Fig. 1. Recording of arterial pressure, the ECG, heart rate [HR, in beats/min (bpm)], and cardiac output immediately before and during sustained ventricular tachycardia (V-tach) in an intact, conscious male rat. Note the S-T segment elevation followed by sustained ventricular tachycardia (absence of P wave, rapid, wide QRS complexes, zero cardiac output, and decrease in arterial pressure). Time (x-axis) is the time immediately before (occlusion) and after release of the occlusion (postocclusion).

 
On an alternate day (at least 1 wk apart), the protocol was repeated with cardiac β1-adrenergic receptor blockade [metoprolol (10 mg/kg) (22)]. Cardiac β1-adrenergic receptor blockade was achieved by infusion of the specific β1-adrenergic receptor antagonist metoprolol into the intraperitoneal catheter. Ten minutes after metoprolol administration, the VAT was determined as described above. A crossover design, control and cardiac β1-adrenergic receptor blockade, was used to prevent an order effect.

Determination of reproductive organ body weight and ischemic zone. After the experiments, the rats were euthanized with an overdose of pentobarbital sodium, and the reproductive organs were removed, rinsed clean, and weighed. To determine the size of the ischemic zone, the heart was excised with the occluder intact and perfused via the aorta with 30 ml of 0.9% saline to wash out the blood. Subsequently, the left main coronary artery was occluded by tying the suture. Evans blue dye (100 µl, 0.5%) was perfused via the aorta, allowing the dye to infuse into the nonischemic area of the heart, leaving the ischemic regions unstained. The heart was trimmed, leaving only the right and left ventricles, rinsed to remove the excess blue dye, and weighed. The heart was trimmed again, leaving only the ischemic region. The weight of the ischemic zone was expressed as the percentage of total ventricular weight (8).

To determine whether the occlusion produced a myocardial infarction, the heart was sliced transversally into ~1.0-mm sections and incubated in a 1% solution 2,3,5-triphenyltetrazolium chloride (TTC, Sigma) at 37°C for 20 min. The heart sections were placed between two glass slides and immersed in 10% formalin overnight to enhance the contrast of the stain. TTC staining differentiates viable tissue by reacting with myocardial dehydrogenase enzymes to form a red brick stain. Necrotic tissue, which has lost its dehydrogenase enzymes, does not form a red stain and shows up as pale yellow. This stain has been shown to be a reliable indicator of myocardial infarction (15).

Data Analysis

All recordings were sampled at 2 kHz, and the data were expressed as means ± SE. A three-factor ANOVA with post hoc Tukey method was used to compare the VAT in male and female intact and gonadectomized (GnX) rats in the control and β-adrenergic receptor blockade conditions. A four-factor ANOVA with repeated measures on one factor was used to compare mean arterial blood pressure (MAP), HR, cardiac output, and vascular conductance immediately before the occlusion (preocclusion) and at 4 min of occlusion. This standardized time point was selected to compare identical time points between groups. This was necessary because the VAT was different between groups. Importantly, no animal experienced tachycardia before 4 min of occlusion in the two conditions. Preocclusion and prerelease data were the average of every beat during the last 10–15 s of the period. In addition, a two-factor ANOVA with post hoc Tukey method was used to compare ST elevation and rate-pressure product in the control and β-adrenergic receptor blockade conditions. The ECGs were analyzed off-line to measure the ST segment elevation (voltage difference between the baseline and J point) using the ECG analysis software for Chart [ADInstruments (45)]. The rate-pressure product, an index of myocardial oxygen demand, was calculated as systolic blood pressure x HR/1,000 (21). Unpaired t-tests were used to compare reproductive organ weights between intact and GnX males and females.


   RESULTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Figure 2 presents the VAT for intact and GnX male and female rats in the control and β-adrenergic receptor blockade conditions. The VAT was significantly longer in intact females versus intact males (significant sex difference effect). This sex difference was abolished by GnX (significant sex difference x GnX interaction). Specifically, GnX decreased the VAT in females and increased the VAT in males. β-Adrenergic receptor blockade increased the VAT in intact males and GnX females only (significant drug effect).


Figure 2
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  		Fig. 2. Arrhythmia threshold for intact and gonadectomized (GnX) male and female rats in the control and β-adrenergic receptor blockade (β-Block) conditions. The arrhythmia threshold was significantly longer in intact females and GnX males compared with intact males. In contrast, GnX decreased the ventricular arrhythmia threshold (VAT) in female rats and increased the VAT in males. β-Adrenergic receptor blockade increased the VAT in intact males and GnX females only. *P < 0.05, control intact female vs. control intact male; {dagger}P < 0.05, control intact female vs. control GnX female; {ddagger}P < 0.05, control intact male vs. control GnX male; {dagger}{dagger}P < 0.05, control intact male vs. β-Block intact male; {ddagger}{ddagger}P < 0.05, control GnX female vs. β-Block GnX female.

 
In the control condition, two intact females, zero GnX females, zero intact males, and one GnX male did not experience tachycardia before the 6.5-min occlusion limit. Similarly, with β-adrenergic receptor blockade, four intact females, three GnX females, four intact males, and zero GnX males did not experience tachycardia before the 6.5-min occlusion limit.

Figure 3 presents the ST-segment elevation (Fig. 3, top) and rate-pressure product (Fig. 3, bottom) at 4 min of occlusion for intact and GnX male and female rats in the control and β-adrenergic receptor blockade conditions. There were no sex difference effects, however, as expected coronary artery occlusion elevated the ST segment and rate-pressure product in all groups, and the elevations were reduced with β-adrenergic receptor blockade (significant drug effect). Similar results were obtained when we examined these parameters immediately before the sustained ventricular tachycardia (same relative time point; data not shown).


Figure 3
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  		Fig. 3. ST-segment elevation (top) and rate-pressure product (bottom) at 4 min of occlusion for intact and GnX male and female rats in the control and β-adrenergic receptor blockade conditions. There were no sex difference effects, however, as expected coronary artery occlusion elevated the ST segment and rate-pressure product in all groups and the elevations were reduced with β-adrenergic receptor blockade (significant drug effect). SBP, systolic blood pressure. *P < 0.05, control vs. β-Block.

 
Table 1 presents MAP, HR, cardiac output, and vascular conductance immediately before the occlusion (preocclusion) and at 4 min of occlusion in intact and GnX male and female rats under two experimental conditions of control and β-adrenergic receptor blockade. MAP and HR were significantly different between male and female intact and GnX rats (significant sex difference effect). Specifically, MAP was higher and HR was lower in males. HR, cardiac output, and vascular conductance were significantly different at 4 min of occlusion in all groups compared with preocclusion (significant treatment effect). Specifically, cardiac output and vascular conductance decreased, whereas HR increased during the occlusion. In addition, HR was significantly lower in all groups with β-adrenergic receptor blockade (significant drug effect). Cardiac output was higher in intact males compared with intact females, and GnX reduced cardiac output in males only (significant sex difference x GnX interaction). Finally, there was a significant sex difference by drug and sex difference by GnX interaction for conductance. Specifically, β-adrenergic receptor blockade decreased conductance in males without a change in females. GnX decreased conductance in males and increased conductance in females. Similar results were obtained when we examined these parameters immediately before the sustained ventricular tachycardia (same relative time point; data not shown).


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  		Table 1. MAP, HR, CO, and Cond immediately before the occlusion (preocclusion) and 4 min into the occlusion in female and male intact and GnX rats

 
Table 2 presents body and reproductive organ weights, ventricular weight/body weight ratio and extent of ischemic zone (% of heart weight). As expected, GnX reduced reproductive organ weight in both males and females; however, there were no differences in the ventricular weight-to-body weight ratio or extent of the ischemic zone between groups. Finally, based on the TTC protocol, the occlusion did not cause an infarction in any rat.


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  		Table 2. Body and reproductive organ weights, VW-to-BW ratio, the extent of ischemic zone, and QT interval in female and male intact and GnX rats

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
In this study, we tested the hypothesis that sex difference influences the susceptibility to ischemia-induced sustained ventricular tachycardia as well as the response to β-adrenergic receptor blockade. Specifically, we hypothesized that female sex hormones protect against ischemia-induced tachyarrhythmias and that male sex hormones increase the susceptibility to ischemia-induced tachyarrhythmias. To test this hypothesis, we recorded the VAT induced by myocardial ischemia in conscious male and female intact and GnX rats in the control and β-adrenergic receptor blockade conditions. The major findings of this study include the following. First, the VAT was significantly longer in intact females versus intact males. This sex difference was abolished by GnX. Specifically, GnX decreased the VAT in females and increased the VAT in males. Thus male sex hormones increase and female sex hormones decrease the susceptibility to ischemia-induced sustained ventricular tachycardia. Second, β-adrenergic receptor blockade increased the VAT in intact males and GnX females only. Thus male sex hormones influence the response to β-adrenergic receptor blockade. However, the potential for a ceiling effect (see Limitations) prevents us from making conclusions about female sex hormones and the effect of β-adrenergic receptors.

These results contrast sharply with the influence of sex hormones on the susceptibility to reperfusion-induced arrhythmias in conscious male and female rats (31). Specifically, in that study, male sex hormones were protective against reperfusion-induced sustained ventricular tachyarrhythmia, whereas female sex hormones did not alter the response to myocardial reperfusion. Furthermore, β-adrenergic receptor blockade was only ineffective in the presence of male sex hormones (31). These sex-specific responses to ischemia- versus reperfusion-induced tachyarrhythmias that culminate in ventricular fibrillation support the concept that the mechanism mediating the arrhythmias during ischemia and reperfusion is specific to the insult (3, 32). For example, myocardial ischemia causes the depletion of ATP, an increase in lactate, PCO2, extracellular [K+], and intracellular [Ca2+], as well as a gradual, heterogeneous, progressive decrease in action potential duration, resting membrane potential, maximum rate of rise of voltage of phase 0, and overall action potential amplitude (11, 13, 41). In contrast, reperfusion rapidly reverses the metabolic and electrophysiological consequences of ischemia as well as increases the formation of free radicals. Ischemia-induced arrhythmias may therefore be mediated by the heterogeneity of the developing injury, whereas reperfusion-induced arrhythmias may be mediated by the complex interaction between processes of cellular deterioration and cellular recovery, as well as cellular damage by free radicals. Future research is needed to focus on the specific mechanism mediating arrhythmias during ischemia as well as reperfusion in males and females since understanding these differences may result in sex-specific optimization of patient treatments (10).

Myocardial ischemia causes local-metabolic, nonexocytotic norepinephrine release, which contributes to the incidence of arrhythmias (12, 24, 42, 43). Specifically, arrhythmias coincide with ischemia-induced norepinephrine release, and inhibition of norepinephrine release can prevent the occurrence of ventricular fibrillation (12, 24). Furthermore, increased sympathetic activity contributes to cardiac arrhythmias and increases the susceptibility to ventricular fibrillation (37, 44). These data suggest that blocking adrenergic receptors may protect against ischemia-induced arrhythmias. However, antiarrhythmic effects of the β-adrenergic antagonist are inconsistent (39). In the present study, we documented that the cardioselective β-adrenergic receptor antagonist, metoprolol, reduced the susceptibility to ischemia-induced sustained ventricular tachycardia in intact males and GnX females only. Surprisingly, β-adrenergic receptor blockade was not effective in increasing the VAT in intact females or GnX males. These data may have profound clinical and scientific significance, and, to our knowledge, this question had not been addressed experimentally (2, 18, 26, 33–35).

We used ST-segment shifts and double product (rate-pressure product, Fig. 3) as an index of the severity of myocardial ischemia (25). Although there was no sex difference effect on ST segment or rate-pressure product, β-blockade, as expected, reduced ST segment and rate pressure-product in all groups. These data document that sex hormones did not influence the severity of myocardial ischemia, which is consistent with the similarity in ischemic zone between all groups.

Finally, we documented several sex-specific hemodynamic data before and after β-adrenergic receptor blockade. Specifically, MAP was higher and HR was lower in males. These results are consistent with reports of elevated resting HR in female rats (1, 4, 6). Female rats had a higher sympathetic tonus and intrinsic HR and lower parasympathetic tonus than their male counterparts (6). The higher sympathetic tonus and lower parasympathetic tonus in female rats are consistent with the higher-resting HR compared with the male rats.

In addition, cardiac output was higher in intact males compared with intact females, and GnX reduced cardiac output in males only. These responses are consistent with our recent findings that androgen withdrawal produced a 40% decrease in the velocity of circumferential shortening and a 46% reduction in the rate of myocardial relaxation in intact conscious rats. Furthermore, androgen supplementation completely restored contractile function. These results provided the first evidence that androgen withdrawal and androgen replacement produce dramatic alterations on cardiac performance in conscious animals (16).

Finally, β-adrenergic receptor blockade decreased conductance in males without a change in females, whereas GnX decreased conductance in males and increased conductance in females. The mechanisms responsible for these novel findings are unknown and merit future consideration.

Limitations

There are several limitations to this study that must be considered when evaluating the data. First, although the age of the male and female rats was within 3 wk, the animals were not exactly aged matched. Had the rats been exactly aged matched, the males would have weighed significantly more than the females. Although the weight of the males was higher than the weight of the females, this weight difference did not reach statistical significance (Table 2). This question, age versus weight matched for sex studies, is very important and should be considered when investigating the susceptibility to arrhythmias, because the incidence of cardiac arrhythmias increases progressively with age in humans (28) and animals (5, 17, 38); however, arrhythmic activity is also directly proportional to body weight with larger animals and, hence, larger hearts having more pronounced arrhythmic activity (20). Although we do not know whether we would have observed different responses had the rats been aged matched, Humphreys and colleagues addressed this question and concluded that the lower arrhythmic activity in female rats was not the result of the smaller heart size. It is important to note, however, that the anesthetized model and isolated heart preparation used by Humphreys and colleagues may be different from the conscious model used in our study.

We failed to infuse the vehicle (saline) intraperitoneally in the experiment without β-adrenergic receptor blockade to control for the administration of fluid. It is possible that the administration of 200–300 µl of warm saline could affect the response to the occlusion. This is unlikely, however, since the volume (~2.5% of plasma volume) would not alter autonomic reflexes and normal saline would not alter plasma electrolyte concentrations. However, this limitation should be considered when evaluating the results.

β-Adrenergic receptor blockade did not increase the VAT in intact females or GnX males. It is possible that this was due, in part, to the long control VAT in these groups. Specifically, it may have been impossible to detect a significant increase in VAT with β-adrenergic receptor blockade because we limited our occlusions to 6.5 min (e.g., a ceiling effect). It is important to note however, that in the control condition, only two of the 12 intact females did not display tachycardia before the 6.5-min occlusion limit. In contrast, with β-adrenergic receptor blockade, four of the intact females did not display tachycardia before the 6.5-min occlusion limit. These data suggest that our design (e.g., limiting the occlusion to 6.5 min) may have prevented us from documenting a protective effect of β-adrenergic receptor blockade in intact females. Specifically, had we not limited the occlusion to 6.5 min, the time from those four rats may have been long enough to make a significant difference in the VAT. Thus the design may have created a ceiling effect. This argument cannot be made for the GnX males, however. Specifically, in the control condition, only one of the seven GnX males made it to the 6.5-min occlusion limit. Similarly, with β-adrenergic receptor blockade, none of the GnX males made it to the 6.5-min occlusion limit. Furthermore, none of the 11 intact males and none of the 7 GnX females made it to the 6.5-min occlusion limit in the control condition, documenting the absence of a ceiling effect.

Finally, we removed the gonads of male and female rats. It is important to note that the gonads contain several hormones in addition to estrogen or testosterone. Therefore, future studies need to examine responses following estradiol and testosterone replacement in GnX male and female rats to determine the specific-sex hormone or interaction of hormones responsible for the responses.


   GRANTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This study was supported by National Heart, Lung, and Blood Institute Grants HL-67713 and HL-74122.


   FOOTNOTES
 

Address for reprint requests and other correspondence: H. L. Lujan, Wayne State Univ. School of Medicine, 540 E. Canfield Ave., Detroit, MI 48201 (e-mail: hlujan{at}med.wayne.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
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

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