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1Department of Internal Medicine, University of Iowa, and 2Veterans Affairs Medical Center, Iowa City, Iowa 52242
Submitted 3 February 2004 ; accepted in final form 28 March 2004
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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and interleukin (IL)-1
in the plasma and heart, which was blunted by vagotomy. MI also caused a significant increase in hypothalamic TNF- and IL-1, which was not affected by vagotomy. In contrast, epicardial phenol blocked MI-induced increases in hypothalamic TNF- and IL-1 without affecting increases in the plasma and heart. These findings demonstrate that the appearance of proinflammatory cytokines in the brain after MI is independent of blood-borne cytokines and suggest that cardiac sympathetic afferent nerves activated by myocardial ischemia signal the brain to increase cytokine production. In addition, an intact vagus nerve is required for the full expression of proinflammatory cytokines in the injured myocardium and in the circulation. We conclude that the sympathetic and parasympathetic innervation of the heart both contribute to the acute proinflammatory response to MI.
cardiac sympathetic afferents; cardiac vagal afferents; tumor necrosis factor-; interleukin-1; hypothalamus
and in TNF- levels in the hypothalamus as well as the heart and plasma, beginning as early as 30 min after coronary artery ligation (14). The early appearance of proinflammatory cytokines in the hypothalamus has important implications, because this region of the brain contributes substantially to the altered volume regulation and sympathetic drive that characterize heart failure after MI. Proinflammatory cytokines in the hypothalamus can induce the production of neuroactive substances like prostaglandins E2 (PGE2) (36) and corticotropin-releasing hormone (26), central components of the hypothalamic-pituitary-adrenal axis that increase sympathetic nerve activity (9, 22) as well as circulating catecholamines and glucocorticoids (9).
Because blood-borne proinflammatory cytokines are too large to readily cross the blood-brain barrier, a substantial increase in hypothalamic cytokines early after MI is not easily explained. Active transport of blood-borne proinflammatory cytokines across the blood-brain barrier is one possibility (4). Another is the induction of cytokine synthesis within the blood-brain barrier. For example, stimulation of vagal afferent nerves by an intraperitoneal injection of endotoxin (29) or interleukin (IL)-1 (21) can initiate proinflammatory cytokine synthesis in the brain.
The early increase in hypothalamic cytokines after MI suggests the possibility that a neural signaling mechanism may mediate this response. The heart is innervated by sensory afferent fibers traveling in the vagal and sympathetic nerves (31). These cardiac sensory afferent fibers are sensitive to mechanical and chemical stimuli and, when activated, can induce pronounced centrally mediated cardiovascular reflex responses. The cardiac fibers traveling in the sympathetic nerves also convey the sensation of cardiac pain (12). Myocardial ischemia stimulates fibers traveling in both systems (8, 27). In the present experiments, we tested the hypothesis that activation of cardiac sensory afferents by myocardial ischemia might signal the brain to increase hypothalamic TNF- and IL-1 during acute MI.
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METHODS |
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Adult male Sprague-Dawley rats (3–4 mo old) weighing 350–375 g were obtained from Harlan Sprague Dawley (Indianapolis, IN). They were housed in temperature-controlled (23 ± 2°C) and light-controlled (lights on between 0700 and 1900 hours) animal quarters and were provided with rat chow ad libitum. These studies were performed in accordance with the "Guiding Principles for Research Involving Animals and Human Beings" (1). The experimental procedures were approved by the University of Iowa Institutional Animal Care and Use Committee.
General Preparation
Rats were anesthetized with urethane (1.5 g/kg ip), and supplemental doses of urethane (0.1–0.3 g/kg ip or iv) were given when obvious increases in blood pressure and respiratory rate were observed during surgery or experimental recording. The level of anesthesia was periodically reassessed during the surgical procedures and experimental recording by examining nociceptive reflex responses and by continuously monitoring blood pressure and heart rate (HR). The left femoral artery was cannulated with polyethylene (PE)-50 tubing filled with heparinized saline (20 U/ml) for the recording of arterial pressure, which was monitored with a Hewlett-Packard 7754A chart recorder (HP Medical Products Group; Andover, MA). The left femoral vein was cannulated with PE-50 tubing for the administration of drugs and collection of blood samples. Animals were intubated and mechanically ventilated (model 683, Harvard Rodent Ventilator; Holliston, MA) with room air. The ventilation rate was set between 65 and 70 breaths/min. Core temperature was maintained at 37 ± 0.2°C with a rectal thermometer and a temperature controller (model K-100, Baxter Healthcare; Valencia, CA).
Induction of MI
MI or sham MI (Sham-MI) was induced by ligating the left anterior descending coronary artery or exposing the heart without ligating the vessel, as previously described (18). Before the induction of MI, rats underwent one or both of the following interventions.
Vagotomy. For most experiments, the vagus nerves were isolated bilaterally via a midline cervical incision, and both were sectioned or left intact depending on the protocol. Animals recovered for at least an hour after vagotomy (Vx) or sham vagotomy (Sham-Vx) before MI or Sham-MI.
Phenol painting. For some experiments, the epicardial surface of the left ventricle was painted with a solution of 10% phenol and 70% ethyl alcohol in the distribution of the left anterior descending coronary artery to interrupt the cardiac sympathetic fibers innervating only that region of the heart. The phenol solution was applied with a pointed hand-made cotton swab. Every precaution was taken to prevent the spread of phenol to other parts of the heart and surrounding tissues. In these studies, MI was induced immediately after the application of the phenol solution.
Blood and Tissue Sampling
Two hours after MI, the rats were killed to collect trunk blood and tissues from the heart and brain for the measurement of cytokines. Trunk blood was collected in chilled EDTA tubes. Plasma samples were separated and stored at –70°C until assayed for TNF- and IL-1.
Collection of brain tissue. The hypothalamus was removed as described previously(15) using the posterior part of the optic chiasm as the anterior limit, the anterior part of the mammillary bodies as the posterior limit, and the lateral hypothalamic sulci as the lateral limits. After the brain tissue was removed from the skull, the posterior pituitary was separated from the anterior pituitary by careful dissection. Only the anterior pituitary gland was used to measure tissue levels of cytokines. Tissue samples were also taken from the frontal cortex and brain stem.
Collection of cardiac tissue. The heart was cut into three cross sections. The right and left ventricular tissues were separated, and a small amount of tissue was removed from each ventricle. The left ventricular myocardial tissue was taken in the distribution of the occluded coronary artery.
Measurements
TNF-.
Plasma and tissue TNF- levels were measured using an ultrasensitive rat TNF- ELISA kit (Biosource; Camarillo, CA) according to the manufacturer's instructions. The method has been described previously (13).
IL-1.
Plasma and tissue IL-1 levels were measured using a rat IL-1 ELISA kit (Biosource) according to the manufacturer's instructions. Briefly, a 96-well microplate was coated with an antibody specific for rat IL-1. We added 50 µl of sample and 50 µl of standard diluent buffer to each well in duplicate, incubated it for 3 h at room temperature, and then washed it four times. Subsequently, 100 µl of biotinylated anti-IL-1 antibody solution were added, incubated for 1 h, and then washed; 100 µl of streptavidin-horseradish peroxidase conjugate solution were added, incubated for 30 min, and washed; 100 µl of chromagen solution were added and incubated in the dark for 15–20 min; and the reactions were stopped with HCl and read at 450 nm using an ELISA plate reader. Standardization curves were made with known concentrations of rat IL-1. The minimum detectable concentration of IL-1 was <3 pg/ml.
Statistical Analysis
Values are expressed as means ± SE. Differences between groups in circulating and tissue levels of cytokines and in hemodynamic variables were analyzed using two-way repeated-measures ANOVA followed by a post hoc Fisher's least-significant difference test. Changes in hemodynamic variables from baseline to 5 min after coronary ligation were analyzed with a paired t-test.
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RESULTS |
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Figure 1 shows the effects of vagotomy and phenol painting on circulating levels of TNF- (A) and IL-1 (B) after MI. Plasma TNF- in the Sham-MI + Vx group (1.2 ± 0.4 pg/ml) was similar to baseline plasma TNF- levels before MI or Sham-MI (14, 17) or drug infusion (13) in our previous studies.
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(10.0 ± 2.5 pg/ml) and IL-1 (216.0 ± 18.6 pg/ml) compared with Sham-MI + Vx (TNF-: 1.2 ± 0.4 pg/ml; IL-1: 46.3 ± 8.3 pg/ml) and Sham-MI + Sham-Vx + phenol (TNF-: 1.8 ± 0.8 pg/ml; IL-1: 28.3 ± 5.0 pg/ml). The plasma levels of TNF- in the MI + Sham-Vx rats are comparable to the values we previously reported after MI (14). Compared with MI+ Sham-Vx, MI + Vx had lower (P < 0.05) circulating levels of TNF- (5.2 ± 1.1 pg/ml) and IL-1 (49.4 ± 4.5 pg/ml). The circulating level of TNF- was higher (P < 0.05) in MI + Vx than in Sham-MI + Vx, but the IL-1 level did not differ between these two groups.
Phenol.
Pretreatment with epicardial application of phenol solution had no apparent effect on circulating TNF- and IL-1 levels after MI. Like the MI + Sham-Vx group, MI + phenol rats had higher (P < 0.05) levels of circulating TNF- (10.6 ± 2.5 pg/ml) and IL-1 (282.8 ± 54.6 pg/ml) than the two Sham-MI groups. Phenol pretreatment combined with bilateral cervical vagotomy (MI + Vx + phenol) had no additional effect on circulating TNF- and IL-1, beyond the vagotomy alone (MI + Vx).
In summary, MI induced an eightfold increase in plasma TNF- and a fourfold increase in plasma IL-1. Prior vagotomy blunted the increase in TNF- by half and completely blocked the increase in IL-1. Neither cytokine was affected by regional cardiac sympathetic denervation.
Effects of Vagal and Sympathetic Denervation on Tissue Cytokines After MI
Figures 2 and 3 show the effects of vagotomy and phenol painting on TNF- and IL-1 levels in the brain and heart 2 h after coronary ligation.
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Compared with the Sham-MI + Vx group, rats undergoing MI without pretreatment with vagotomy or phenol (MI + Sham-Vx) had an increase (P < 0.05) in TNF- in the brain and in left and right ventricular myocardium (Fig. 2). The increase in brain TNF- related to MI alone was observed in the hypothalamus and anterior pituitary but not in the cortex or brain stem. Tissue levels of TNF- in the brain and heart of the Sham-MI + Vx group were comparable to those of unoperated sham controls in a prior drug infusion study (13).
Vagotomy.
In rats with bilateral cervical vagotomy (MI + Vx), the TNF- levels induced by MI in the left ventricle (6.0 ± 0.6 pg/mg protein) were less than MI + Sham-Vx (14.4 ± 2.3 pg/mg protein) and no different from Sham-MI + Vx (6.7 ± 0.8 pg/mg protein). In the right ventricle, the TNF- levels induced by MI (7.4 ± 1.1 pg/mg protein) in the vagotomized rats (MI + Vx) were also less than MI + Sham-Vx (12.6 ± 2.2 pg/mg protein) but were higher than Sham-MI + Vx (4.1 ± 0.4 pg/mg protein). TNF- increased (P < 0.05) in the hypothalamus after MI (Sham-MI + Vx: 5.1 ± 0.6 pg/mg protein; MI + Sham-Vx: 8.6 ± 1.5 pg/mg protein), but prior vagotomy did not affect this increase (MI + Vx: 8.5 ± 1.0 pg/mg protein). In the brain stem, the TNF- level in the MI + Vx group was higher than that in the Sham-MI + Vx group but not higher than that in the MI + Sham-Vx group.
Phenol.
Phenol application to the left ventricular epicardium (MI + phenol) had a profound effect on hypothalamic TNF- but no effect on cardiac TNF-. Compared with the MI + Sham-Vx and MI + Vx rats, MI + phenol rats had a significantly (P < 05) lower level of hypothalamic TNF- (4.5 ± 1.1 pg/mg protein), which was not different from the Sham-MI + Vx or Sham-MI + Sham-Vx + phenol groups. Vagotomy in combination with phenol had no significant additional effect. In contrast to vagotomy, phenol painting of the left ventricular epicardium had no significant effect on the levels of TNF- in the left (MI + Sham-Vx: 14.4 ± 2.3 pg/mg protein; MI + phenol: 12.1 ± 2.4 pg/mg protein) and right (MI + Sham-Vx: 12.6 ± 2.2 pg/mg protein; MI + phenol: 16.6 ± 1.9 pg/mg protein) ventricular myocardium after MI.
In summary, prior vagotomy prevented the post-MI increase in TNF- in left ventricular myocardium and blunted the increase in right ventricular myocardium but had no effect on hypothalamic TNF-. In distinct contrast, cardiac sympathetic afferent denervation before MI prevented the increase in hypothalamic TNF- without affecting the rise in TNF- in myocardium or plasma.
IL-1.
The responses of IL-1 to MI before and after vagotomy or phenol painting were generally similar to those of TNF- (Fig. 3). Among the brain tissues tested in this study, an increase in IL-1 after MI was observed only in the hypothalamus.
Vagotomy.
IL-1 levels in the left ventricular myocardium after MI were less (P < 0.05) in MI + Vx (48.7 ± 7.2 pg/mg protein) than in MI + Sham-Vx (107.7 ± 15.9 pg/mg protein) but were higher than in Sham-MI + Vx (17.5 ± 2.7 pg/mg protein). In the right ventricle, however, the IL-1 levels after MI were similar in MI + Vx (67.6 ± 7.5 pg/mg protein) and in MI + Sham-Vx (68.1 ± 13.1 pg/mg protein), but higher than in Sham-MI + Vx (19.1 ± 5.4 pg/mg protein). In the hypothalamus, IL-1 was not significantly different in MI + Sham-Vx (63.1 ± 12.7 pg/mg protein) and MI + Vx (59.0 ± 11.2 pg/mg protein) rats; both were higher than in Sham-MI + Vx (21.5 ± 7.0 pg/mg protein) rats.
Phenol.
Phenol application to the left ventricular epicardium (MI + phenol) had effects on IL-1 that were similar to its effects on TNF-. MI + phenol rats had a significantly (P < 05) lower level of hypothalamic IL-1 (32.2 ± 7.1 pg/mg protein) than MI + Sham-Vx (63.1 ± 12.7 pg/mg protein) rats, which was not different from the Sham-MI + Vx (21.5 ± 7.0 pg/mg protein) or Sham-MI + Sham-Vx + phenol (26.5 ± 4.3 pg/mg protein) groups. Vagotomy in combination with phenol had no significant additional effect. Phenol application to the left ventricular epicardium had no significant effect on the MI-induced levels of IL-1 in the left (MI + Sham-Vx: 107.7 ± 15.9 pg/mg protein; MI + phenol: 126.6 ± 20.6 pg/mg protein) and right (MI + Sham-Vx: 68.1 ± 13.1 pg/mg protein; MI + phenol: 122.3 ± 15.3 pg/mg protein) ventricular myocardium. The rats treated with the combination of phenol painting and vagotomy (MI + Vx + phenol) had myocardial IL-1 levels comparable to those treated with vagotomy alone (MI + Vx).
Thus the effects of vagotomy and sympathetic denervation on tissue IL-1 resembled their effects on tissue TNF-. Vagotomy blunted the rise in left ventricular IL-1 but had no effect on right ventricular or hypothalamic IL-1. Prior cardiac sympathetic denervation prevented the rise in hypothalamic IL-1 without reducing the left or right ventricular levels of IL-1.
Hemodynamic Responses to Coronary Ligation and Sham Coronary Ligation
Coronary artery ligation resulted in a significant (P < 0.05) fall in mean arterial pressure (MAP) in three (MI + Sham-Vx, MI + Vx, MI + Vx + phenol) of the four MI groups and a significant reduction in the magnitude of the pulse pressure (PP) in all four MI groups (Fig. 4 and Table 1). After the initial decreases in MAP and PP, measured 5 min after MI, there were no further significant changes in these variables over the ensuing 2 h. At the conclusion of the 2-h interval, immediately before sample collection, MAP was similar in the MI + Sham-Vx, MI + phenol, and MI + Vx + phenol groups. Animals in the two Sham-MI groups experienced no significant change in MAP or PP over the course of the protocol.
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In summary, the observed differences among groups in the appearance of proinflammatory cytokines in brain and heart tissues after MI were not attributable to differences in hemodynamic responses to coronary ligation.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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and IL-1. Cardiac sensory fibers running with vagus nerves have no influence on brain cytokines, but an intact vagus nerve is necessary for the full expression of TNF- and IL-1 levels in the heart and plasma. Importantly, these studies revealed a dissociation between brain and peripheral cytokine levels, consistent with independent regulation of cytokine levels in the two compartments.
The discovery that cardiac afferent fibers traveling with the sympathetic nerves signal the brain to increase proinflammatory cytokines is consistent with their excitatory role in MI (30, 32) and congestive heart failure (41). For years, we have known that myocardial ischemia activates sensory fibers in the heart (8) that initiate a sympathetically mediated excitatory cardiovascular reflex response (33) and signal the pain of myocardial ischemia (12). It is conceivable that the increase in brain cytokines is linked to the nociceptive function of these cardiac sympathetic afferent fibers, because the central modulation of nociceptive responses is associated with alterations in ambient levels of TNF- and IL-1 in the hypothalamus and brain stem (10, 24). In any case, the appearance of proinflammatory cytokines in the brain would be expected to amplify the sympathetically mediated excitatory responses to MI. In the hypothalamus, for example, proinflammatory cytokines stimulate the synthesis of corticotropin-releasing hormone (26) and of PGE2 (24), central components of the hypothalamic-pituitary-adrenal axis that activate the sympathetic nervous system (9, 22) and increase circulating catecholamines and glucocorticoids (9). Cardiac sympathetic afferent activation in acute MI may therefore serve several functions concurrently: signaling ischemic pain (12), inducing sympathetic drive to the heart via a spinal level reflex (32), and, as suggested by the new findings presented here, inducing increases in proinflammatory cytokines in higher brain centers that augment the sympathoexcitatory response (9, 22).
The conclusion that the cardiac sympathetic afferent nerves are the critical link between myocardial injury and hypothalamic cytokine synthesis rests on the assumption that phenol selectively damaged sympathetic rather than vagal cardiac afferent nerves. The available literature strongly supports that assumption. Phenol application to the epicardial surface has been employed for selective cardiac sympathetic afferent (5, 34, 37) and efferent (11, 28, 35) denervation based on anatomic observations (5) that the cardiac sympathetic afferent fibers course more superficially over the epicardial surface of the heart, whereas vagal afferent fibers run deeper until they reach the epicardial surface in the region of the atrioventricular groove. Most of these studies (5, 34, 35, 37) have been performed in acute preparations like the present one. Phenol can be shown to interrupt the cardiac vagal afferent nerve fibers as well, when applied in the distribution of the atrioventricular groove (5). In the present study, however, phenol was applied only to the anterior left ventricular epicardial surface, well away from the atrioventricular groove and in a region where selective deafferentation of sympathetic afferent fibers would be expected. Finally, despite interruption of sympathetic fibers, left ventricular contractility is not altered in the early hours after regional phenol application (35). This is an important point, because an associated change in left ventricular function, if present, might affect both sympathetic and cardiac vagal afferent discharge. In the present experiments, the conclusion that hypothalamic cytokine production is dependent on activation of sympathetic rather than vagal cardiac afferents is supported by the observation that phenol treatment blocked the increase in hypothalamic cytokine levels after MI, whereas bilateral cervical vagotomy, which interrupts all vagal afferent signals ascending from the heart, had no effect. While it is conceivable that in an acute preparation such as this one phenol might excite sympathetic afferent fibers before interrupting them, the control data argue strongly against such an influence: in the sham-operated rats (Sham-MI + Sham-Vx + phenol), the phenol treatment had no effect on brain cytokines.
A surprising finding of this study was that vagotomy had no effect on hypothalamic proinflammatory cytokine synthesis induced by MI. Activation of vagal afferent nerves by peripherally administered endotoxin (29) and cytokines (21) initiates proinflammatory cytokine synthesis in the brain. Inherent in our hypothesis was the presumption that the cardiac vagal afferent endings in the heart, stimulated during myocardial ischemia by the release of noxious substances (possibly even by TNF- and IL-1) and/or by increased intracardiac pressures and mechanical deformation of the heart wall, might signal the brain to increase cytokine production. Our findings, demonstrating no effect of vagotomy on brain cytokine production, were contrary to that hypothesis. Even more surprising were the effects of vagotomy on peripheral cytokine synthesis. The existing literature demonstrates that vagal efferent stimulation inhibits endotoxin-induced (7) and peripheral tissue injury-induced (6) synthesis of proinflammatory cytokines in peripheral tissues, including the heart (6). In our study, contrary to expectations, the cardiac levels of TNF- and IL-1 during MI were reduced after vagotomy. This observation suggests the hypothesis that myocardial cytokine synthesis induced by tissue injury or mechanical stress within the heart itself might be regulated differently than myocardial cytokine synthesis induced by external stressors, the setting in which vagal efferent modulation of cytokines has been demonstrated (6, 7).
An increase in TNF- after MI in both injured and uninjured cardiac tissues has been reported previously by our laboratory (19) and others (25, 38), but the present study is the first to demonstrate that an intact vagus nerve is required for the full expression of myocardial proinflammatory cytokine synthesis immediately after MI. The specific vagal component(s) required, i.e., the vagal afferent terminals, the vagal efferent fibers, or the intrinsic cardiac nerves, were not determined in these experiments. However, capsaicin-sensitive cardiac vagal afferent terminals contain calcitonin gene-related peptide and substance P, which are released locally under certain conditions (23), including myocardial ischemia (20), and these peptides can enhance the synthesis of proinflammatory cytokines in activated macrophages (42). A variety of peptides may affect the heart by way of the intrinsic cardiac nerves (2), and cardiac responses to these substances are abrogated within a few minutes after cervical vagotomy (3). Collectively, these observations support the view that the intact vagus nerve may affect cytokine synthesis by the ischemic heart in ways that are independent of the recognized ability of vagal efferent stimulation to inhibit endotoxin-induced cytokine production.
The brain (40), heart, and a variety of lymphoid tissues are potential sources of circulating cytokines after MI. A notable finding of this study is that cardiac sympathetic deafferentation with phenol, which prevented the increase in brain TNF- and IL-1 levels after MI, had no effect on plasma levels of these two cytokines. In contrast, vagotomy minimized the plasma cytokine response but had no effect on the central nervous system levels. Taken together, these findings suggest a dissociation between the regulation of brain and peripheral cytokine production after acute MI: cytokines produced in the brain do not appear to be a primary source of circulating cytokine levels, and circulating cytokines do not account for the brain cytokine levels. In previous work, we found that central mineralocorticoid receptors can regulate blood-borne TNF- in normal rats (13) and rats with heart failure (17), but those studies did not establish whether TNF- measured in plasma was of central or peripheral origin. In the present study, the plasma cytokine levels seem to track with those in the myocardium, but both might be influenced by an alternative peripheral source.
Finally, it is noteworthy that the increases in brain TNF- and IL-1 during acute MI are localized to the hypothalamus, at least among the brain tissues tested. This localized response in a brain region that is closely associated with volume regulation, stress responses, and sympathetic drive reinforces the impression that the signal from the heart to the brain is specific and functionally important and not simply a generalized central neural response to myocardial injury or associated hypotension. In previous work, we demonstrated that the hypothalamic region is critical for the cardiovascular adjustments to a large MI (16). By stimulating the production of proinflammatory cytokines within the hypothalamus, the cardiac sympathetic afferent nerves provide an early chemical signal that activates the brain response to acute cardiac injury. The relationship of this early sympathetically mediated rise in hypothalamic cytokines to the augmented sympathetic afferent activity (41) and increased hypothalamic cytokine production in established heart failure (14) remains to be determined.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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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.
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in normal rats. Am J Physiol Regul Integr Comp Physiol 285: R1402–R1409, 2003.
after coronary artery ligation in rats. Am J Physiol Regul Integr Comp Physiol 284: R328–R335, 2003.
(IL-1) mRNA in the brain of rats in response to systemic IL-1. J Neurosci 18: 2247–2253, 1998.
mRNA in mice brain in response to peripheral LPS. Am J Physiol Regul Integr Comp Physiol 268: R1327–R1331, 1995.
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P < 0.05 vs. Sham-MI + Vx.
