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1 Department of Pharmacology, The Panum Institute, University of Copenhagen, DK-2200 Copenhagen N; 2 Department of Medicine M, Glostrup Hospital, University of Copenhagen, DK-2600 Copenhagen; and 3 Department of Clinical Physiology and Nuclear Medicine, Glostrup Hospital, University of Copenhagen, DK-2600, Copenhagen, Denmark
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Simultaneous blockade
of systemic AT1 and AT2 receptors or converting
enzyme inhibition (CEI) attenuates the hypoglycemia-induced reflex
increase of epinephrine (Epi). To examine the role of brain AT1 and AT2 receptors in the reflex regulation
of Epi release, we measured catecholamines, hemodynamics, and renin
during insulin-induced hypoglycemia in conscious rats pretreated
intracerebroventricularly with losartan, PD-123319, losartan and
PD-123319, or vehicle. Epi and norepinephrine (NE) increased 60-and
3-fold, respectively. However, the gain of the reflex increase in
plasma Epi (
plasma Epi/plasma glucose) and the overall Epi and NE
responses were similar in all groups. The ensuing blood pressure
response was similar between groups, but the corresponding bradycardia
was augmented after PD-123319 (P < 0.05 vs. vehicle)
or combined losartan and PD-123319 (P < 0.01 vs. vehicle). The findings indicate 1) brain
angiotensin receptors are not essential for the reflex regulation of
Epi release during hypoglycemia and 2) the gain of
baroreceptor-mediated bradycardia is increased by blockade of brain
AT2 receptors in this model.
losartan; PD-123319; epinephrine; baroreflex
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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INSULIN-INDUCED HYPOGLYCEMIA powerfully stimulates sympathoadrenal activity and hence epinephrine (Epi) release. Thus, in rats, severe hypoglycemia elicits an ~60-fold increase in the plasma concentration of Epi (35). This is considered an important counter-regulatory response during severe hypoglycemia. Therefore, any substance or maneuver that impairs this reflex increase in Epi release may potentially worsen or predispose patients with diabetes mellitus to episodes of hypoglycemia (10).
Several lines of evidence suggest that angiotensin II stimulates or facilitates adrenomedullary Epi release. Thus exogenous angiotensin II stimulates Epi secretion in vivo (24), and high concentrations of angiotensin II stimulate Epi release from isolated perfused adrenals (33). Furthermore, nonselective angiotensin II receptor blockade with [Sar,Ile]-angiotensin abolishes adrenomedullary catecholamine release during insulin-induced hypoglycemia (4). We showed that the increase in plasma Epi concentration during insulin-induced hypoglycemia is unaltered by selective AT1-receptor blockade in both rats and humans (34, 35). However, we also found that simultaneous AT1- and AT2-receptor blockade or systemic ACE-inhibition significantly attenuates the reflex increase in Epi during insulin-induced hypoglycemia (14, 35). This suggests that angiotensin II interacts with Epi release either by an AT2 receptor-mediated action or by a mechanism that involves both AT1 and AT2 receptors. However, these in vivo findings disagree with some in vitro studies on isolated perfused rat adrenal glands, which suggest that AT1-receptor blockade, but not AT2-receptor blockade, attenuates the Epi release elicited by exogenous angiotensin II (33).
Hypothalamic glucose-sensitive sensory neurons project to spinal neural pathways that are paramount for adrenal sympathetic nerve activity and Epi release (17). AT1 and AT2 receptors have been identified in brain areas involved in the central regulation of cardiovascular function (7, 19). Moreover, AT1 and AT2 receptors are present in the spinal cord, and functional studies suggest that both subtypes are involved in the pressor response to intrathecal administration of angiotensin II (22, 23). In the adrenal medulla, the AT2 receptor is abundant and constitutes >90% of the angiotensin receptors (2, 3, 5). Thus angiotensin II may modify the hypoglycemia-induced increase in adrenal sympathetic nerve activity and Epi release through different subtypes of angiotensin receptors at different neural levels involved in this reflex response. This may explain the discrepancies between the above-mentioned in vitro and in vivo studies, because systemic administration of angiotensin receptor antagonists affects receptors in both the central nervous system and in the adrenal medulla (22, 26), whereas only adrenomedullary angiotensin receptors were blocked in the in vitro studies.
The aim of this study was to examine if endogenous angiotensin II modifies the hypoglycemia-induced reflex increase in Epi release by an action in the central nervous system. Plasma concentrations of catecholamines, blood pressure, heart rate, and renin activity were measured during insulin-induced hypoglycemia in chronically instrumented, conscious rats pretreated with intracerebroventricular losartan (AT1-receptor blockade), PD-123319 (AT2-receptor blockade), combined AT1- and AT2-receptor blockade (losartan + PD-123319), or vehicle.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Materials
Male Sprague-Dawley rats (300 g) were purchased from Møllegården, Lille Skendsved, Denmark. Rats were housed individually at the Panum Institute animal care facility in rooms with constant humidity and temperature and a 12:12-h light-dark cycle. Animals had free access to tap water and a commercial standard rat diet (Altromin catalog no. C 1314, Altromin International, Lage, Germany). Experiments were performed in compliance with the ethical code for laboratory animal care issued by the Danish Ministry of Justice.Animal Preparation
Surgical procedures were performed during neurolept anesthesia induced by a subcutaneously injected mixture of (in mg/kg) 0.2 fentanyl, 6.7 fluanizone, and 3.4 midazolam. Permanent Tygon catheters were inserted into the abdominal aorta and into the inferior caval vein using aseptic techniques. Catheters were tunneled subcutaneously to the back of the neck, where they were fixed. To ensure long-term patency, catheters were filled with a solution containing 50% glucose added to 1,000 IU heparin /ml and 7,500 IU streptokinase/ml. After 24 h of recovery, a stainless steel cannula (Plastics One, Roanoke, VA) was inserted in the right lateral cerebral ventricle situated at the coordinates 0.9 mm posterior to bregma, 1.4 mm lateral to the midline, and 4.7 mm below the skull surface. At least 7 days of recovery were allowed before the experiment.Experimental Protocol
Rats were fasted overnight before the experiments, which were performed in a quiet laboratory environment. The rat was placed in the experimental cage and allowed an equilibration period of at least 30 min duration. Then the rats were randomized to intracerebroventricular pretreatment with either vehicle (isotonic saline 4 µl; n = 12), the AT1-receptor antagonist losartan (10 nmol in 2 µl + 2 µl vehicle; n = 12), the AT2-receptor antagonist PD-123319 (30 nmol in 2 µl + 2 µl vehicle; n = 12), or combined AT1- and AT2-receptor blockade (losartan, 10 nmol in 2 µl + PD-123319, 30 nmol in 2 µl; n = 12). After 20 min, a reference blood sample (time 0) was drawn to determine plasma concentrations of glucose, Epi, NE, and plasma renin activity (PRA). Then hypoglycemia was induced by intravenous administration of insulin, 4 IU/kg, and arterial blood samples were drawn every 7.5 min for the next 30 min, and at 45 and 60 min after insulin administration to determine plasma glucose, Epi, and NE. PRA was redetermined at time 45 min, when plasma catecholamine concentrations were near maximal. Blood samples (250 µl each) were drawn into chilled test tubes containing 1 mg EGTA and 0.7 mg reduced glutathione and kept on ice during handling. The blood was centrifuged at 4°C for 10 min, and plasma was stored at
20°C
until analysis. All blood samples were immediately replaced by
intravenous infusion of fresh donor blood obtained from littermates
that were pair fasted overnight. To verify accurate placement of the
intracerebroventricular cannula, each rat was sedated with intravenous
pentobarbital sodium at the end of the experiment. Five microliters of
black ink was injected intracerebroventricularly and allowed 15 min for
diffusion into the cerebrospinal fluid and adjacent brain tissue. Then
the rat was killed with an intravenous overdose of pentobarbital
sodium, and correct placement of the cannula was verified by staining of all ventricles and the base of the brain. On the basis of this test,
three rats were discarded due to uneven distribution of stain. To
determine the efficacy and confinement of intracerebroventricular administration of the AT1-receptor antagonist to brain
angiotensin receptors, six additional rats were prepared with
chronic catheters and intracerebroventricular cannulas. In these
animals, the blood pressure response to intracerebroventricular and
intravenous administered angiotensin II was determined before and after
intracerebroventricular administration of losartan.
Blood Pressure and Heart Rate Recording
Mean arterial pressure (MAP) was measured continuously with a pressure transducer (Statham P23 XL) and displayed on a Grass model 7D polygraph. Heart rate (HR) was recorded by a linear cardiotachometer (Grass model 7P4) triggered by the arterial pressure waveform. Analog signals were digitized using an AT-MIO-16XE-50 board (National Instruments) and sampled at 1,000 Hz using a data-acquisition program written in LabView (National Instruments), recorded and stored as described previously (35).Biochemical Analyses
Plasma glucose concentrations were determined on a model 6517 Glucose analyzer II (Beckman Instruments, Fullerton, CA). Determination of plasma catecholamine concentrations was done using high-pressure liquid chromatographic separation of radioenzymatically labeled catecholamines. Intra- and interassay coefficients of variation for Epi were 4 and 10%, and those for NE were 4 and 8%, respectively. PRA was determined as described previously (35). All analyses were done in duplicate.Drugs
Insulin (Novo Nordisk, Gentofte, Denmark), 4 IU/ml, was dissolved in isotonic saline with 1% human serum albumin added and stored at 5°C. Losartan (Du Pont Pharmaceuticals, Wilmington, DE) and PD-123319 (Parke-Davis, Ann Arbor, MI) were dissolved in isotonic saline to final concentrations of 5 and 15 nmol/µl, respectively. Angiotensin II (Sigma, St. Louis, MO) was dissolved in isotonic saline to final concentrations of 2 nmol/ml and 50 pmol/µl for intravenous and intracerebroventricular administration, respectively.Data Analysis
Hemodynamics.
Data on MAP and HR are average values during the last 60 s
preceding disconnection of the arterial catheter for blood sampling. Comparisons between groups were performed using two-way ANOVA for
repeated measurements. The HR response to the MAP increase differed
significantly between groups. Thus corresponding data pairs of MAP
and HR for each animal were plotted, and the slope of the
"baroreceptor" curves was obtained using linear regression. Then
the slopes of the regression lines were compared between selected
groups using one-way ANOVA.
Catecholamines. Time course evolution of plasma Epi and NE during the entire hypoglycemic period (time 0-60 min) were compared using two-way ANOVA for repeated measurements. The relationship between corresponding plasma glucose and plasma Epi concentrations during the period of increasing Epi (time 7.5-30 min) represented the gain of the reflex. With the least-square regression method, corresponding data pairs of glucose and Epi concentrations were fitted with the index function [Epi] = a × exp(k × [glucose]), equivalent to the linear expression: log[Epi] = log a + k × [glucose]. Then parameters log a and k of that function as well as area under the entire concentration vs. time curves (AUCs) were compared using one-way ANOVA. Statistical analysis was performed using the software package Statistica version 6.0 (Statsoft, Tulsa, OK). Plasma concentrations of Epi and NE were logarithmically transformed to obtain normal distribution of data before statistical analysis. A probability level of P < 0.05 was considered significant. Presented values are means ± SE.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Efficacy of Intracerebroventricular AT1-Receptor Blockade
Intracerebroventricular angiotensin II produced a marked blood pressure response (Fig. 1). The MAP response to intracerebroventricular angiotensin II was abolished after intracerebroventricular administration of losartan. AT1-receptor blockade was confined to the central nervous system, because the MAP response to intravenous angiotensin II was unaltered by intracerebroventricular losartan.
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Plasma Glucose
Intravenous administration of insulin, 4 IU/kg, produced a rapid, sustained, and similar hypoglycemic response in all groups (Fig. 2).
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Plasma Epi and NE
The catecholamine responses to hypoglycemia are shown in Fig. 2. During hypoglycemia, Epi increased 60-fold in vehicle-treated rats. This response and the corresponding AUCs were similar in all groups (P = 0.73). When the linear regression data were calculated, (Table 1), the goodness of fit (r2) was close to unity in all groups. The response was similar in all groups, however, because neither the slope (k) nor the intercept with the abscissa (log a) differed. Plasma NE increased about threefold in all groups, and this response was similar in all groups.
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Blood Pressure and HR
Baseline MAP was not significantly different among groups. However, baseline HR was significantly higher after losartan and PD-123319 compared with vehicle (P < 0.05, Table 2). The time course of changes in MAP and HR relative to baseline values during normoglycemia are shown in Fig. 3. During hypoglycemia, a significant but similar increase in MAP was observed in all groups, and this was associated with bradycardia in all groups. This response was significantly augmented in rats treated with PD-123319 either alone or in combination with losartan (PD-123319 vs. vehicle: P < 0.05; losartan + PD-123319 vs. vehicle: P < 0.01). However, calculating the regression curves forMAP
vs. HR and comparing it with the slope of the vehicle group showed
that the slope was markedly (61%) and significantly greater only in
the losartan + PD-123319 group (P < 0.05; Fig.
4, Table
3).
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PRA
As shown in Fig. 5, PRA values were similar in all groups both before insulin (time 0) and during maximal sympathoadrenal activation (time 45 min).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The key finding of this study is that brain AT1 and AT2 receptors are not essential for the reflex increase in adrenomedullary Epi release during hypoglycemia in conscious rats. Neither the overall measure of Epi release (AUC) nor the gain of the hypoglycemia-induced reflex increase of plasma Epi was affected by central angiotensin receptor blockade. Interestingly, however, simultaneous brain AT1 + AT2-receptor blockade appears to increase the gain of the baroreceptor-mediated bradycardia in this model.
We previously showed that the reflex increase in plasma Epi concentration (p-Epi) during hypoglycemia is unaltered during systemic AT1-receptor blockade in both rats and humans. However, systemic AT2-receptor blockade with PD-123319 attenuates this sympathoadrenal reflex response, and combined treatment with losartan and PD-123319 or angiotensin-converting enzyme inhibition attenuates Epi release more effectively than PD-123319 alone. These results indicate that the AT2 receptor plays an important role in the regulation of Epi release. However, the lack of effect of centrally administered AT1- and AT2-receptor blockade on p-Epi epinephrine concentrations suggests that angiotensin II facilitation of Epi release is mediated by an AT2 receptor-dependent effect outside the central nervous system.
The most likely site of action of peripheral AT2-receptor blockade on Epi release is at postsynaptic receptors in adrenal medullary chromaffin cells (15), which in both rats and humans are mainly of the AT2 subtype. This agrees with in vitro data from Belloni and coworkers (2) and with recent in vivo findings (16) supporting that adrenomedullary AT2 receptors play a dominant role in the regulation of Epi release.
Other putative sites of angiotensin II facilitation of Epi release may be at more caudal levels in the central nervous system. Thus angiotensin receptors were identified in the spinal cord (22). Moreover, the blood pressure response to intrathecal angiotensin II is blunted by both losartan and PD-123319 administered at the T9 level in rats (23), suggesting that functionally important AT2 receptors are located at that level. In the present study, we found that intracerebroventricular administration of dye into the right lateral ventricle reaches at least the T5 level within 1 h (data not shown). However, nuclei innervating the adrenal medulla are located at the T8-T11 level in the rat; therefore this study provides no evidence of effective blockade of spinal cord angiotensin receptors. Thus the significance of angiotensin receptors at that level in control of adrenal nerve activity remains unsettled.
The increase of NE release and MAP was similar and parallel in all
groups. Moreover, hypoglycemia-induced sympathoexcitation selectively
stimulates the adrenal medulla (6, 20). Thus the observed
blood pressure response was driven largely by adrenomedullary NE
release. Combined AT1 + AT2-receptor
blockade significantly increased the slope of the MAP-HR linear
regression curve, whereas the slope was similar to vehicle during
selective blockade of either AT1 receptors or
AT2 receptors alone. This suggests that simultaneous
blockade of central AT1 and AT2 receptors
increases the gain of the baroreflex control of HR (BRR) in this model. The mechanism of this finding is unclear at present. AT2
receptors have not been identified in nuclei traditionally perceived to participate in angiotensin II control of the baroreflex. Central angiotensin inhibits or resets the baroreflex by two mechanisms: 1) an increased sympathetic outflow via AT1
receptors in the rostral ventrolateral medulla (RVLM) and 2)
inhibition of parasympathetic activity and consequently withdrawal of
vagal inhibition of heart rate (27). Phillips
(25) proposed that neurons originating in the
paraventricular nucleus of the hypothalamus (PVH) terminate in the
nucleus of the solitary tract (NTS) and, through a presynaptic AT1 receptor-mediated mechanism, blunt parasympathetic
activity in the dorsal motor neuron of the vagus. Interestingly, PVH is one of only a few brain nuclei expressing a high density of
AT2 receptors (12). This leads us to speculate
whether these AT2 receptors are involved in the observed
response. The apparent involvement of both receptor subtypes might
explain why simultaneous blockade of AT1 and
AT2 receptors is required to counteract endogenous angiotensin II, i.e., increase the gain of the BRR. Several studies have shown an independent role of central AT1 receptors in
the BRR and renal sympathetic nerve activity (8, 27, 28).
Recently Matsumura and coworkers (18) demonstrated that
microinjection into NTS of an AT1-receptor blocker, but not
an AT2-receptor blocker, increased the sensitivity of BRR
in anesthetized rats (18). Against that finding, however,
Luoh and Chan (13), in a comparable model, demonstrated
that microinjection of PD-123319 as well as losartan into NTS produced
a 40-60% increased sensitivity of BRR. Those data agree with our
results in support of central AT2 receptor involvement in
regulation of BRR. Interestingly, the increased sensitivity of BRR was
quantitatively comparable between the two studies. However, proper
baroreflex studies are warranted to further elucidate the role of
AT2 receptors in the paraventricular hypothalamic nuclei.
Despite severe sympathoadrenal activation, PRA did not change during insulin-induced hypoglycemia. Because renal sympathetic nerve activity potently stimulates renin release, the present finding is consistent with earlier studies showing that neuroglucopenia increases adrenal sympathetic nerve activity without affecting renal sympathetic nerve activity (20).
The major limitation to this study is our inability to directly demonstrate that all relevant brain angiotensin II receptors were blocked. Generally, the conscious, unstressed animal approach limits the feasibility of directly targeting specific nuclei by microinjection of drugs. Thus precise knowledge of the concentrations of the applied receptor blockers in specific brain nuclei is not attainable using this model. Regarding AT1-receptor blockade, we demonstrated that 10 nmol losartan injected into the cerebral fluid effectively blocked the blood pressure response to intracerebroventricular angiotensin II (Fig. 1), a response thought to be mediated exclusively by AT1 receptors in nuclei of the forebrain and the lower brain stem. Regarding AT2-receptor blockade, the drinking response to intracerebroventricular angiotensin II is considered a paradigm of acute AT2 receptor-mediated function. However, the literature on that issue is not consistent (29, 31, 32), and, in our hands, neither losartan (10 nmol) nor PD-123319 (30 nmol) attenuated the drinking response to intracerebroventricular angiotensin II (unpublished observations). The applied PD-123319 was on a molar basis three times the concentration of losartan, which effectively blocked the AT1 receptor-mediated blood pressure response. Considering that the IC50 of losartan for the AT1 receptor and that of PD-123319 for the AT2 receptor are similar, i.e., 2-5 nM (11), it is highly probable that effective AT2-receptor blockade was obtained as well.
In summary, we found that blockade of brain AT1 and AT2 receptors either alone or in combination did not affect the reflex Epi release during insulin-induced hypoglycemia in conscious, chronically instrumented rats. This contrasts with the markedly attenuated Epi response observed during systemic AT1 + AT2-receptor blockade or ACE inhibition. Together, these results indicate that angiotensin II facilitates Epi release by an effect outside the central nervous system, most likely in the adrenal medulla. In addition, we found that simultaneous blockade of brain AT1 and AT2 receptors increased the gain of the BRR response in this model. These results support earlier findings that AT2 receptors play an important role in central BRR.
Perspectives
Because the hypoglycemia-induced increase of sympathetic activity is predominantly directed to the adrenal branch of the system, this model is primarily suitable for studies on Epi release. We found that central AT1 and AT2 receptors are not important in the regulation of this branch of the sympathetic system. However, the finding of brain AT1 + AT2 receptor involvement in the regulation of BRR points to an important role of AT2 receptors in sympathetic and/or parasympathetic pathways that function independently of the aforementioned part of the sympathetic system. Considering that high insulin levels per se may slightly increase sympathetic nerve activity (1, 21), thus complicating data interpretation, the present experimental model is not ideal for BRR studies, however. Rather, the well known pharmacological or physical means of manipulating blood pressure should be employed in future studies. By supporting earlier findings that central angiotensin II baroreceptor resetting is partly AT2 receptor dependent, this study adds another brick to the emerging concept of AT2 receptor involvement in cardiovascular regulation. This issue is important in a broader, clinical perspective, because converting enzyme inhibitors and selective AT1-receptor blockers, both widely used in hypertension, congestive heart failure, and diabetes mellitus, have opposite effects on AT2 receptor function, that is, decreased stimulation and increased stimulation, respectively. Thus uncovering AT2 receptor function might help explain clinical differences between these drugs.| |
ACKNOWLEDGEMENTS |
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The authors thank L. Christensen, I. Emanuel, and I. Krabbe; Biochemical Unit, Department of Clinical Physiology and Nuclear Medicine, KAS Glostrup, University Hospital of Copenhagen for excellent technical assistance.
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FOOTNOTES |
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Dr. R. Worck received a research fellowship from "Klinisk Forskningsfond," University of Copenhagen. The study was supported by grants from The Danish Heart Foundation, Diabetesforeningen, and the Eva and Robert Voss Hansens Foundation.
Address for reprint requests and other correspondence: R. H. Worck, Dept. of Pharmacology, The Panum Institute Bldg. 18.6, Univ. of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark (E-mail: worck{at}dadlnet.dk).
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.
Received 5 July 2000; accepted in final form 7 December 2000.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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P <0.001.
P < 0.01 vs. vehicle.
