Published online before print August 19, 2002, doi: 10.1161/01.HYP.0000031800.83899.EC
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(Hypertension. 2002;40:491.)
© 2002 American Heart Association, Inc.
Scientific Contributions |
Exogenous Angiotensin II Does Not Facilitate Norepinephrine Release in the Heart
From the Department of Internal Medicine (T.W.L., G.A., F.B., A.H.v.d.M.) and Experimental Cardiology, Thoraxcenter (S.d.Z., K.J.D., P.D.V.), Erasmus MC, Rotterdam, The Netherlands.
Correspondence to Thomas W. Lameris, Dept. Internal Medicine I, Room L 264, University Hospital Dijkzigt, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands. E-mail Lameris{at}twl.myweb.nl
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Abstract |
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Studies on the effect of angiotensin II on norepinephrine release from sympathetic nerve terminals through stimulation of presynaptic angiotensin II type 1 receptors are equivocal. Furthermore, evidence that angiotensin II activates the cardiac sympathetic nervous system in vivo is scarce or indirect. In the intact porcine heart, we investigated whether angiotensin II increases norepinephrine concentrations in the myocardial interstitial fluid (NEMIF) under basal conditions and during sympathetic activation and whether it enhances exocytotic and nonexocytotic ischemia-induced norepinephrine release. In 27 anesthetized pigs, NEMIF was measured in the left ventricular myocardium using the microdialysis technique. Local infusion of angiotensin II into the left anterior descending coronary artery (LAD) at consecutive rates of 0.05, 0.5, and 5 ng/kg per minute did not affect NEMIF, LAD flow, left ventricular dP/dtmax, and arterial pressure despite large increments in coronary arterial and venous angiotensin II concentrations. In the presence of neuronal reuptake inhibition and
-adrenergic receptor blockade, left stellate ganglion stimulation increased NEMIF from 2.7±0.3 to 7.3±1.2 before, and from 2.3±0.4 to 6.9±1.3 nmol/L during, infusion of 0.5 ng/kg per minute angiotensin II. Sixty minutes of 70% LAD flow reduction caused a progressive increase in NEMIF from 0.9±0.1 to 16±6 nmol/L, which was not enhanced by concomitant infusion of 0.5 ng/kg per minute angiotensin II. In conclusion, we did not observe any facilitation of cardiac norepinephrine release by angiotensin II under basal conditions and during either physiological (ganglion stimulation) or pathophysiological (acute ischemia) sympathetic activation. Hence, angiotensin II is not a local mediator of cardiac sympathetic activity in the in vivo porcine heart.
Key Words: norepinephrine • angiotensin II • renin-angiotensin system • sympathetic nervous system
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Introduction |
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Activation of the sympathetic nervous system simultaneously leads to activation of the renin-angiotensin system via stimulation of ß-adrenergic receptors within the kidney, resulting in an increased renin release. There is also evidence, albeit conflicting, that the sympathetic nervous system is activated by the renin-angiotensin system.1–13 This activation supposedly occurs through stimulation of angiotensin II receptors within the central nervous system and/or stimulation of presynaptic angiotensin II receptors located at sympathetic nerve terminals. When investigating the sympathetic nervous system and its interaction with the renin-angiotensin system, the heart is of particular interest. First of all, the mammalian heart has a dense sympathetic innervation. Second, all components of the renin-angiotensin system are present in the heart, and most angiotensin II in the heart is formed from locally synthesized angiotensin I.14 Third, in conditions like hypertension, ischemia, and especially heart failure, the renin-angiotensin system and sympathetic nervous system are both activated, and this activation likely contributes to the deterioration of cardiac function.15–17
Evidence that angiotensin II activates the cardiac sympathetic nervous system in vivo is scarce4 or indirect.7,18 In a recent study, Teisman et al4 have shown with the use of the microdialysis technique that "pharmacological" (10-6 mol/L) concentrations of locally applied angiotensin II were associated with an increase in norepinephrine concentrations in the myocardial interstitial fluid (NEMIF) of the in vivo rat heart. In the present study, we determined whether "physiological" (10-10 mol/L) to "pathophysiological" (10-8 mol/L) concentrations of angiotensin II modulate NEMIF in the intact porcine heart. The pig is especially suitable as a model for studying the cardiac sympathetic nervous system because, unlike the rat, the prevailing parasympathetic control of cardiac function is very similar to that in man, which allows for a more reliable extrapolation of the experimental results to the reality of human patients.
To exclude a masking effect of neuronal norepinephrine reuptake and negative feedback through presynaptic -adrenergic receptor stimulation on modulation of NEMIF by angiotensin II, we co-perfused some probes with the U1- inhibitor desipramine and the -adrenergic receptor-blocker phentolamine without provoking systemic hemodynamic effects that also may modulate norepinephrine release.19–21
In those studies that demonstrated interaction between angiotensin II and the sympathetic nervous system, most evidence points toward direct facilitation mediated by presynaptic angiotensin II type 1 (AT1) receptors resulting in either a classic calcium-dependent augmentation of exocytotic norepinephrine release1–3 or in enhanced nonexocytotic release via activation of the Na+/H+ exchanger.22,23 Therefore, we not only investigated the modulation of NEMIF by angiotensin II under basal conditions but also during enhanced exocytotic norepinephrine release evoked by stimulation of the left stellate ganglion. In addition, we monitored norepinephrine release in MIF during reduction of left anterior descending coronary artery (LAD) flow, resulting in both exocytotic and nonexocytotic norepinephrine release,20 while still allowing for intracoronary infusion of angiotensin II.
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Methods |
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Animal Procedures
All experiments were performed in accordance with "Guiding Principles for Research Involving Animals and Human Beings" as approved by the Council of the American Physiological Society and under the regulations of the Animal Care Committee of the Erasmus University Rotterdam.
Crossbred LandracexYorkshire pigs of either sex (30 to 35 kg, n=27) were used. Treatment, surgical procedure, and positioning of catheters and flow probes have been described previously.19,20 In animals subjected to LAD flow reduction, a fluid-filled balloon occluder (In Vivo Metric) was placed around the LAD distal to the Doppler flow probe and attached to a bidirectional roller pump (Ismatec). The voltage output from the Doppler equipment was directed through a custom-built electrical circuit, which steered the roller pump to maintain LAD flow at 30% of baseline values. In animals subjected to sympathetic stimulation, the left stellate ganglion was dissected, and an electrode was inserted into the ganglion, as described by Gootman et al,24 and connected to a nerve stimulator (Grass S9; pulses of 12 V, 10 Hz, and 5 ms).
Microdialysis probes were implanted in the left ventricular (LV) myocardium: 1 in the region perfused by the left circumflex coronary artery (LCx) to determine NEMIF,LCx and 3 in the area perfused by the LAD to determine NEMIF, LAD. To achieve local U1-inhibition, one of the LAD probes was co-perfused with desipramine (100 µmol/L, Sigma),21 while another LAD probe was co-perfused with desipramine and phentolamine (100 µmol/L, Department of Pharmacy, University Hospital Dijkzigt, Rotterdam) to block presynaptic -adrenergic receptor-mediated inhibition of norepinephrine release. The microdialysis technique, probe characteristics, handling of the microdialysis and plasma samples for the measurement of norepinephrine concentrations, and probe recovery have been described previously.19,25 Plasma samples for determination of angiotensin II concentrations (AngII) were rapidly drawn into chilled plastic syringes containing an "inhibitor mix."14
Experimental Protocol
After a 120-minute stabilization period, baseline measurements were obtained over a 30-minute period. Probes were perfused with Ringer’s solution (Baxter) at a flow of 2 µL/min, and dialysate was collected at 10-minute intervals, during which period blood was collected from the aorta and the interventricular coronary vein.19,20 In group I (n=7), the effects of angiotensin II on basal sympathetic norepinephrine release were investigated by infusing angiotensin II (Department of Pharmacy) into the LAD at consecutive infusion rates of 0.05, 0.5, and 5 ng/kg per minute for 20 minutes each. In group II (n=7), we assessed the effects of angiotensin II on enhanced exocytotic norepinephrine release by stimulating the left stellate ganglion before and during infusion of angiotensin II. To investigate the effect of angiotensin II on nonexocytotic norepinephrine release, the LAD flow was reduced by 70% for 60 minutes without (group III, n=6) and during simultaneous infusion of angiotensin II into the LAD (group IV, n=7). After 120 minutes of reperfusion, the LAD perfusion area (area at risk) and infarct size were determined.20
Analytical Procedures
Norepinephrine concentrations in plasma and microdialysis samples were determined by high performance liquid chromatography with fluorometric detection.25 Plasma angiotensin II concentrations were determined with high performance liquid chromatography after Sep-Pak extraction and radioimmunoassay.14
Data Analysis and Statistics
Dialysate norepinephrine concentrations were corrected for probe recovery to yield norepinephrine concentrations in MIF.19,20 Lower limits of detection for norepinephrine in dialysate and plasma were 0.2 and 0.02 nmol/L, respectively.25 Baseline values were determined by averaging the 3 measurements over the 30-minute period before intervention.19,20 Angiotensin II plasma concentrations in the LAD were calculated from angiotensin II infusion rate, coronary plasma flow (LADflowx[1-hematocrit]), and arterial angiotensin II concentrations. Results are expressed as mean±SEM. For statistical analysis two-way analysis of variance, one-way analysis of variance for repeated measures with Dunnett’s multiple comparison test as post hoc test, and Student t test were used as appropriate.
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Results |
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Intracoronary Angiotensin II Infusion and Basal Norepinephrine Concentrations (Group I)
During infusion of angiotensin II, angiotensin II concentrations in the LAD and the coronary vein rose from 12±1 and 13±2 pmol/L at baseline up to 8485±1082 and 4150±329 pmol/L during infusion of 5 ng/kg per minute, respectively (Figure 1), while aortic angiotensin II concentrations increased from 12±1 to 80±9 pmol/L. Despite these large increments in angiotensin II concentrations, there were no significant changes in global hemodynamics (Table 1), NEMIF, or arterial and coronary venous norepinephrine concentrations (Table 2 and Figure 2). However, LAD flow tended to decrease, which necessitated increased myocardial O2 extraction, resulting in a decrease in coronary venous O2 saturation (Table 1).
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), NEMIF,LAD+desipramine+phentolamine (
), NEMIF,LCx (x), arterial (solid bars), and coronary venous (hatched bars) norepinephrine concentrations. AngII indicates intracoronary infusion of angiotensin II (0.5 ng/kg per minute). Data are mean±SEM, n=7.
Intracoronary Angiotensin II Infusion and Norepinephrine Release During Sympathetic Activation (Group II)
Stimulation of the left stellate ganglion caused marked increases in blood pressure (19%), LAD flow (25%), and, in particular, LV dP/dtmax (190%, Table 3 and Figure 3) and caused a rise in NEMIF, particularly in the presence of U1- and -adrenergic receptor blockade where NEMIF, LAD increased from 2.7±0.4 to 7.3±1.2 nmol/L (Table 2 and Figure 3). Concomitant intracoronary infusion of angiotensin II did not affect hemodynamic responses to stimulation, nor did it modify the stimulation-induced increase in NEMIF,LAD (from 2.3±0.3 to 6.9±1.3 nmol/L).
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Intracoronary Angiotensin II Infusion and Norepinephrine Release During Ischemia (Groups III and IV)
Cardiovascular Function
The 70% LAD flow reduction resulted in 10% reductions of mean arterial pressure and cardiac output, whereas LV end-diastolic pressure slightly increased (Table 4). Following reperfusion, mean arterial pressure and cardiac output remained depressed, whereas LV end-diastolic pressure returned to baseline. In addition, heart rate increased and LV dP/dtmax decreased. Angiotensin II infusion during ischemia did not alter the hemodynamic response to ischemia and reperfusion. Because LAD flow was kept at 30% of baseline during ischemia, any effect of angiotensin II on LAD flow was prevented.
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Norepinephrine Concentrations
At baseline, NEMIF,LAD and NEMIF,LCx were similar and 3 times the arterial norepinephrine concentration (P<0.05; Table 2). Under U1-blockade with desipramine, NEMIF,LAD increased approximately 5-fold, irrespective of the presence of -adrenoceptor blockade. NEMIF,LAD tripled during the first 20 minutes of ischemia and continued to rise up to 15-fold at 60 minutes of ischemia (Table 2, Figure 4). Under U1-inhibition, the rate of rise of NEMIF,LAD was attenuated, so that, from 40 minutes of ischemia, NEMIF,LAD in the presence of desipramine was similar to NEMIF,LAD without desipramine. On reperfusion, NEMIF,LAD, NEMIF, LAD in the presence of desipramine, and coronary venous norepinephrine concentrations declined rapidly, with the early rate of decline being most pronounced for NEMIF,LAD without desipramine (Figure 4).
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During ischemia, intracoronary infusion of angiotensin II raised angiotensin II concentrations in the LAD from 9±1 to 2323±231 pmol/L, whereas coronary venous concentrations increased from 13±3 to 408±46 pmol/L, indicating that 80±5% of angiotensin II was extracted over the coronary bed. However, maximum NEMIF,LAD during the 60 minutes of ischemia was not modified by concomitant angiotensin II infusion (Table 2 and Figure 4). Within 120 minutes of reperfusion, NEMIF,LAD and coronary venous norepinephrine concentrations had returned to baseline and were similar for groups III and IV. NEMIF,LCx and arterial norepinephrine concentrations remained unchanged during the course of the experiment in both groups.
Infarct Size
The 70% LAD flow reduction resulted in an ischemic area (area at risk) that composed 32±4% of the LV mass in both groups. Infarct size was 37±7% and 37±4% of the area at risk in groups III and IV, respectively.
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Discussion |
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This study provides no evidence for facilitation of cardiac norepinephrine release by angiotensin II under various experimental conditions in the intact porcine heart, because intracoronary infusion of angiotensin II did not modulate (1) basal sympathetic tone, (2) exocytotic norepinephrine release during sympathetic activation produced by left stellate ganglion stimulation, or (3) exocytotic and nonexocytotic norepinephrine release during myocardial ischemia.
Intracoronary Angiotensin II Infusion and Basal Cardiac Sympathetic Tone
Although the intracoronary angiotensin II infusions in our experiments caused large increments in coronary venous angiotensin II concentrations, no increments in interstitial or coronary venous norepinephrine concentrations were observed (Table 2). Inhibition of norepinephrine neuronal reuptake by co-perfusion of microdialysis probes with desipramine and inhibition of the presynaptic 2-adrenergic receptor-mediated negative feedback of norepinephrine release with phentolamine did not unmask an angiotensin II-mediated increase in NEMIF, LAD.
Although our findings agree with studies that also failed to demonstrate an effect of angiotensin II on basal norepinephrine concentration and norepinephrine spillover,9–11 they are at variance with other studies that have shown angiotensin II to increase basal sympathetic tone.3,4 It could be argued that, in anesthetized animals, facilitation of norepinephrine release by angiotensin II is difficult to demonstrate because of low basal norepinephrine concentrations compared those with awake swine.26 However, Dendorfer and coworkers3 have stated that facilitation of norepinephrine release by angiotensin II is in fact easier to demonstrate when background sympathetic tone is low. An additional possible explanation for the discrepancy between our results and those of Dendorfer3 and Teisman4 is the difference between the dominant sympathetic control of cardiac function in rats and dominant parasympathetic control of cardiac function in pigs and also in humans, which could imply that rat hearts are more sensitive to facilitation of sympathetic activity by angiotensin II.
Angiotensin II may not only facilitate the neuronal release of norepinephrine but may also inhibit its neuronal reuptake.18,27 As neuronal reuptake is an important determinant of NEMIF under baseline conditions as well as during increased sympathetic tone, 19,21 an increase in NEMIF concentration through inhibiting neuronal reuptake by angiotensin II would almost certainly have been detected in this study.
We can also exclude that a putative facilitating effect of angiotensin II on norepinephrine release was masked by a hemodynamically mediated increase in norepinephrine clearance. First, we used intracoronary angiotensin II infusions to prevent significant systemic hemodynamic effects. Second, the tendency of LAD flow to decrease would have favored an increase in NEMIF by blunting norepinephrine clearance. In fact, the angiotensin II-associated increase in norepinephrine observed in some studies might be explained by a decrease in clearance caused by angiotensin II-induced vasoconstriction.4
Intracoronary Angiotensin II Infusion and Norepinephrine Release During Sympathetic Activation
In the present study, sympathetic stimulation was induced by electrical stimulation of the left stellate ganglion, resulting in marked increases in LV dP/dtmax, blood pressure, and LAD flow. These hemodynamic effects were not enhanced by an intracoronary infusion of angiotensin II (Table 3 and Figure 3). Similarly, ganglion stimulation increased NEMIF up to 5-fold. In the presence of U1- and -adrenoceptor blockade, the absolute increase in NEMIF was the most substantial, suggesting an important negative feedback mechanism through presynaptic -adrenergic receptors, most likely of the 2-subtype. Again, infusion of angiotensin II did not augment this increase, irrespective of the presence of U1- and -adrenergic receptor blockade (Table 2 and Figure 3). These results are in agreement with other studies that also failed to demonstrate enhanced norepinephrine release by angiotensin II during sympathetic activation in humans with and without chronic heart failure,10–12 and in particular with Rundqvist et al,8 who demonstrated that intracoronary administration of the angiotensin-converting enzyme (ACE) inhibitor enalaprilat failed to attenuate the increase in cardiac norepinephrine spillover following sympathetic activation. In contrast, other studies using electrical stimulation in vitro,1,2,5 as well as studies in humans, 6,7 did demonstrate angiotensin II-induced augmentation of sympathetic activation. Three of these studies were on the heart.2,5,7 Of the latter, only the study by Saino and colleagues7 investigated augmentation of sympathoneural activation by angiotensin II in the intact (human) heart. However, because they did not measure norepinephrine spillover or norepinephrine concentrations directly but estimated differences in sympathetic activity by comparing responses of coronary blood flow and coronary vascular resistance to the diving and cold-pressure tests, with and without simultaneous intracoronary angiotensin II infusion, it cannot be excluded that vasomotor mechanisms other than -adrenoceptor–mediated vasoconstriction, as a result of facilitated norepinephrine release, are responsible for the observed hemodynamic responses.
Intracoronary Angiotensin II Infusion and Norepinephrine Release During Ischemia
Because angiotensin II has been reported to enhance either nonexocytotic norepinephrine release via activation of the Na+/H+ exchanger22,23 or exocytotic release via classic calcium-dependent facilitation, 1,3 we monitored norepinephrine release in MIF during myocardial ischemia produced by LAD flow reduction, which leads to both exocytotic and nonexocytotic norepinephrine release while still permitting intracoronary infusion of angiotensin II during ischemia. The NEMIF increase during 70% flow reduction (15-fold) was much less than previously described during total occlusion (500-fold),20 not only because ischemia was less severe but also because washout of released norepinephrine is partially preserved during 70% flow reduction. We kept LAD flow constant at 30% of baseline, thereby preventing any potential effects of angiotensin II on flow-induced changes in norepinephrine clearance (Table 4). During flow reduction, concomitant infusion of angiotensin II neither augmented the ischemia-induced increase in NEMIF nor altered its time course (Table 2, Figure 4). Our findings are at variance with the attenuation of ischemia-induced norepinephrine release,23,28,29 as well as the decrease in sympathetic activity in heart failure18,30,31 by ACE-inhibitors or AT1-receptor blockers, which had been reported earlier. Several factors may contribute to these apparent conflicting results. (1) Diffusion limitations for angiotensin II from the bloodstream to the perivascular or myocardial sympathetic nerve terminals could have prevented the infused angiotensin II from reaching the interstitial space and occupying AT1 receptors.8 However, this is unlikely, as we have previously shown that the cardiac tissue concentration of radiolabeled 125I-angiotensin II during 125I-angiotensin II infusion was 75% of its arterial concentration and that most of this angiotensin II is bound to AT1 receptors.14 (2) Although inhibition of the renin-angiotensin system may exert a direct effect on norepinephrine release in chronic heart failure,18,30,31 the decrease in plasma norepinephrine concentrations during treatment of heart failure with ACE-inhibitors or AT1-receptor blockers might also be due to an improvement of cardiac function. (3) The decrease in sympathetic tone with these agents18,23,28–31 might not be mediated through peripheral presynaptic AT1 receptors, but by other mechanisms. For instance, ACE-inhibitors do not only inhibit angiotensin I to angiotensin II conversion, but also limit bradykinin degradation and stimulate prostaglandin formation. Both bradykinin and prostaglandins have been shown to inhibit norepinephrine release.28,32 In addition, the interaction between the renin-angiotensin system and the sympathetic nervous system might be mediated through central AT1 receptors in the brain.33–35 (4) Facilitation of norepinephrine release by presynaptic AT1-receptor activation might be counteracted by presynaptic AT1 receptors, which can inhibit norepinephrine release and are down-regulated in cardiomyocytes of patients with chronic heart failure.22,23,36
Perspectives
In this study in pigs, in which, contrary to rats, cardiac function is predominantly parasympathetically controlled, we did not find evidence for facilitation of cardiac norepinephrine release by exogenous angiotensin II under baseline conditions and during sympathetic activation by either stellate ganglion stimulation or acute ischemia, indicating that angiotensin II is not a local mediator of cardiac sympathetic nerve activity. The design of the study does not exclude facilitation of cardiac norepinephrine release by angiotensin II through stimulation of presynaptic AT1 receptors at sympathetic nerve terminals under pathological conditions such as hypertension and heart failure. In a previous study, we observed an upregulation of AT1 receptors in the remodeled hypertrophied myocardium, as well as increased circulatory concentrations of angiotensin II during exercise, 1 to 3 weeks after infarction.26 If angiotensin II facilitates norepinephrine release via stimulation of presynaptic angiotensin II receptors, the latter model may be particularly suited to address this question, and research to explore this issue is under way. Furthermore, because of intrinsic activation of the renin-angiotensin system, this model is also well suited to explore whether local inhibition of the renin-angiotensin system with AT1-receptor antagonists is associated with a decrease in myocardial norepinephrine release.
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Acknowledgments |
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This study was supported by a grant from the Netherlands Heart Foundation (99.151). Dr Duncker is an Established Investigator (2000D038) of the Netherlands Heart Foundation.
Received February 19, 2002; first decision April 2, 2002; accepted July 22, 2002.
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