Physiology & Behavior, Vol. 28, pp. 103-108. PergamonPress and BrainResearch Publ., 1982. Printedin the U.S.A.
Physiological and Behavioral Responses of New Zealand Hypertensive and Normotensive Rats to Stress' RICHARD McCARTY
D e p a r t m e n t o f Psychology, University o f Virginia, Charlottesville, VA 22901 R e c e i v e d 17 July 1981 McCARTY, R. Physiological and behavioral responses of New Zealand hypertensive and norrnotensive rats to stress. PHYSIOL. BEHAV. 28(1) 103-108, 1982.--A chronic catheter was inserted into the ventral tail artery of adult male New Zealand hypertensive (NZH) and normotensive (NZN) rats to allow for repeated sampling of blood and measurement of blood pressure and heart rate in conscious animals without handling. Two days after surgery, plasma levels of norepinephrine (NE) and epinephrine (EPI) were similar in NZH and NZN rats while resting and undisturbed in their home cages. Mean arterial blood pressure was significantly higher in NZH rats (166---9mm Hg) than in NZN rats (124___4mm Hg) but basal heart rates did not differ (345_+8 and 342_+14 beats/min, respectively). Increments in plasma levels of NE and EPI and in mean arterial blood pressure and heart rate were similar in NZH and NZN rats following transfer to a shock box and immediately and 10 minutes after exposure to 1 minute of intermittent footshock. Male rats of the two strains also did not differ in their behaviors during tests in an open field arena. These results indicated that NZH and NZN rats do not differ with respect to basal or stress-induced increments in sympathetic-adrenal medullary activity or in several behavioral measures. These results are in striking contrast to previous studies with the Okamoto strain of spontaneously hypertensive (SHR) rats and indicate that genetically determined increases in arterial blood pressure are not necessarily associated with sympathetic-adrenal medullary and behavioral hyperresponsivity to stress. Plasma catecholamines Open field behavior
T H E sympathetic nervous system plays a critical role in normal cardiovascular homeostasis . In addition, the findings of several studies suggest that abnormalities in the regulation of sympathetic nerve activity may be involved in the development and maintenance of spontaneous hypertension in animals [10, 11, 13, 24] and of essential hypertension in humans [7, 8, 9, 17]. To examine the relationship between sympathetic nerve activity and the development of elevated blood pressure, several studies have utilized the spontaneously hypertensive (SHR) rat. This strain and its Wistar-Kyoto normotensive (WKY) control were developed by Okamoto and his coworkers through selective inbreeding and represent a valuable animal model for human essential hypertension [30, 37, 42]. Previous studies from this laboratory have shown that SHR rats are more responsive than WKY rats to acute stress based upon several physiological and behavioral measures. For example, SHR rats had greater increments in plasma
Sympathetic nervous system
levels of norepinephrine (NE) and epinephrine (EPI) when stressed by exposure to intermittent footshock [2, 24, 25], anticipation of footshock , immobilization [18,28], or indirect measurement of blood pressure . In addition, SHR rats were more reactive behaviorally when placed in a novel environment , when tested in an open field arena [14, 29, 40], and when tested in an operant conditioning paradigm . Several explanations have been advanced to describe the relationship between behavioral and physiological responses of SHR rats and their genetically determined increases in arterial blood pressure. These include the following: (a) a common genetic etiology of hypertension and the behavioral or physiological characteristic, (b) a sequential dependence between the onset of high blood pressure and the appearance of the behavioral or physiological characteristic or vice versa and (c) random fixation of the various traits at the time of selective inbreeding for high blood pressure .
1This research was supported by U. S. Public Health Service Grant AG 01642, by National Science Foundation Grant SER 76-18457, and by a grant from the Scottish Rite Schizophrenia Research Program, NMJ, USA. I thank Ms. Debbie Mundie for her careful secretarial assistance. 2Requests for reprints should be addressed to Dr. Richard McCarty, Department of Psychology, Gilmer Hall, University of Virginia, Charlottesville, Virginia, 22901.
C o p y r i g h t © 1982 B r a i n R e s e a r c h P u b l i c a t i o n s Inc.--0031-9384/82/010103-06503.00/0
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In order to characterize further the relationship between genetically determined models of hypertension and behavioral and sympathetic-adrenal medullary hyperresponsiveness to acute stress, we have examined the behavioral and physiological responses of New Zealand hypertensive (NZH) and normotensive (NZN) rats to acute stress. The New Zealand strains were developed by Smirk and his colleagues by selective inbreeding of a colony of Wistar rats . Over the past 10 years, the mean systolic blood pressure of the hypertensive strain (>170 mmHg) has averaged 40-50 mmHg higher than the normotensive strain [34,35]. For this study, plasma levels of NE and EPI and mean arterial blood pressure and heart rate were measured in unrestrained N Z H and NZN rats during exposure to intermittent footshock. In addition, the behaviors of N Z H and N Z N rats were measured during testing in an open field arena. In both of these test conditions, SHR rats have been reliably different from normotensive W K Y controls. METHOD Animals Adult male New Zealand hypertensive (NZH) and normotensive (NZN) rats were obtained from Zivic-Miller Laboratories, Allison Park, PA. Rats were housed individually in Wahmann suspended cages and were allowed at least two weeks to acclimate to this laboratory prior to experimentation. Laboratory chow and water were available continuously and the vivarium was on a 12-hour light-dark photoperiod (lights on at 0600 hours) at a temperature of 21-23°C. Pro¢'edure Beginning at 10-12 weeks of age, N Z H and N Z N rats ( N = 10 per strain) were tested daily for 3 consecutive days in an open field arena. The open field was a square, open plywood box (120x 120x30 cm) that was painted flat black and divided by lines into 25 squares (24 cm on a side). Illumination was provided by overhead fluorescent lights. F o r each test, an individual rat was taken in its home cage to an adjacent room and placed into the center of the arena. Behaviors were then recorded for 5 minutes by a single observer and included the following: number of squares entered with the forepaws, number of rears, and number of fecal boli deposited. After each test, the open field was cleaned with a dilute soap solution and all tests were conducted between 1100-1500 hours. At least one week after the last open field test, N Z H and N Z N rats (310-410 g) were anesthetized with pentobarbital (35-40 mg/kg) and a PES0 catheter was inserted into the ventral caudal artery as described by Chiueh and Kopin . A 2 cm incision was made through the ventral tail sheath near the base of the tail and the artery was exposed and elevated. The catheter was inserted approximately 2 cm up into the artery and secured with two sutures (size 00). The tubing was then led under the tail sheath and skin to exit at the back of the neck. A 30 cm length of spring wire was placed over the tubing and secured to the rat with an adhesive tape collar. The tubing was filled with 0.9% saline that contained 300 IU heparin per ml and the end was occluded with a 1 ml disposable syringe. After surgery, rats were housed individually in plastic cages (25x25x 15 cm) and laboratory chow and water were available continuously. The spring wire was led out the top
of the cage and the rat was able to move freely to a~l parts ol the cage. Patency of the catheter was maintained with i n f u sions of 0.5 ml of the heparinized saline in the early morning and late afternoon. Two days after surgery, basal blood samples (0.5 ml) were collected from NZH and N Z N rats between 0900-1030 hours. Care was taken not to disturb the rats at any time during blood sampling. An equal volume of heparinized saline (100 IU/ml) was infused slowly into the catheter after each blood sample. Next, mean arterial blood pressure (MABP, mmHg) was measured by attaching the end of the catheter to a Statham pressure transducer (model P23ID) with tracings made on a Grass multichannel polygraph (model 78D). Heart rate (HR, beats/min) was measured with a Grass tachometer (model 7P44) that was triggered by fluctuations in arterial blood pressure. Each rat was then transferred to a shock box  and after 4 minutes a train of 10 scrambled footshocks (2.0 mA, 0.6 sec duration, every 6 sec) was delivered through the grid floor. Blood samples (0.5 ml) were obtained beginning l minute after transfer to the shock chamber and immediately and 10 minutes after the termination of footshock. Tracings of MABP and HR were made immediately after each blood sample was collected and the volume replaced with heparinized saline (usually 1-1.5 min). Assay o f Plasma Catecholamines Blood samples were collected in iced 10x75 mm glass tubes and centrifuged at 4000 x G at 4°C for 10 minutes and the plasma was removed and stored at -20°C. Within 3 weeks, plasma samples were assayed for amounts of NE and EPI by a radioenzymatic-thin layer chromatographic method [6, 3 l, 39]. After precipitation of proteins with 0.6 N HCIO4, 100/xl samples of plasma were incubated at 37°C for 90 minutes with partially purified rat liver catechol-O-methyl transferase and 3H-S-adenosylmethionine. The reaction was stopped by adding borate buffer (pH 8.0) and unlabeled metanephrine and normetanephrine. The O-methylated amines were extracted into toluene: isoamyl alcohol (3:2) and back extracted into 0.1 N acetic acid. After drying overnight in vacuo, the amines were dissolved in methanol and separated by thin layer chromatography. The areas corresponding to 3H-normetanephrine and 3H-metanephrine were visualized under ultraviolet light, scraped into 20 ml counting vials, oxidized to 3H vanillin by addition o f NalO,~ and quantified by liquid scintillation spectrometry. Included in each assay in quadruplicate were perchloric acid blanks and internal standards of pooled plasma samples with and without 500 pg of NE and of EPI. The sensitivity of the assays (values equal to twice the blank) was less than 8 pg for both amines. Statistical Analysis A two-tailed t-test for paired or unpaired samples as appropriate was used to evaluate the significance of differences between means. RESULTS As summarized in Fig. 1, N Z H and NZN rats did not differ in their levels of activity (squares entered) or frequency of rearing across the 3 open field tests. On test day 3, N Z H rats deposited fewer fecal boli than NZ rats (/9<0.05). Rats of both strains habituated to the test procedure, as evi-
HYPERTENSIVE RATS AND STRESS
TABLE 1 I
PLASMA LEVELS OF NOREPINEPHRINE (NE) AND EPINEPHRINE (EPI) AND MEASURES OF MEAN ARTERIAL BLOOD PRESSURE (MABP) AND HEART RATE (HR) IN CONSCIOUS UNDISTURBED NEW ZEALAND HYPERTENSIVE AND NORMOTENSIVE RATS
O" (/) 20
NE (pg/ml) EPI (pg/ml) MABP (mmHg) HR (beats/min)
370 - 38 163 -- 29 124-+ 4 342 -+ 14
366 143 166 345
- 30 --- 30 _+ 9* + 8
Values are means +__S.E. for groups of 11-13 rats. *p < 0.001 (two-tailed t -test).
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FIG. I. Behavioral responses of New Zealand hypertensive and normotensive rats during a 5 minute test in an open field arena on each of 3 consecutive days. Measures were taken of activity (number of squares entered), rearing and number of fecal boll deposited. Values are means for 10 rats per group and vertical bars denote one S.E.M.
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denced by d e c r e a s e s in activity and rearing with repeated testing (Fig. 1). Plasma levels o f N E and EPI did not differ b e t w e e n N Z H and N Z N rats w h e n blood samples were obtained from conscious, undisturbed animals while in their h o m e cages. The basal M A B P of N Z H rats was a p p r o x i m a t e l y 40 m m H g higher than N Z N rats (p<0.001) although basal H R ' s did not differ (Table 1). The mild stress of handling and transfer o f rats to the shock c h a m b e r was attended by significant increments a b o v e basal values in plasma N E and E P I for n o r m o t e n s i v e and h y p e r t e n s i v e rats (p<0.05). The strain difference in transfer-induced i n c r e m e n t s in plasma E P I a p p r o a c h e d but did not attain statistical significance (0.05
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101 POST FS
FIG. 2. Increments above basal values in plasma levels of norepinephrine (NE) and epinephrine (EPI) for New Zealand hypertensive and normotensive rats after transfer to a shock box (TRANSFER) and immediately (FS) and 10 minutes after exposure to one minute of intermittent footshock (101 POST FS). Values are in ng/ml and are means for 5-12 rats per group and vertical bars denote one S.E.M.
Me ( ' A R ] ~
As shown in Fig. 3, transfer from the home cage to the shock chamber resulted in significant increases in MABP for NZH rats (p<0.05) and in HR for rats of both strains (p's<0.001). The stress of footshock was attended by decreases in MABP for N Z H (p<0.05) and N Z N rats and increases in HR for rats of both strains that ranged from 120145 beats/min above resting levels (p's<0.001). Ten minutes after the termination of footshock, MABP's approached resting levels but H R ' s remained elevated (p's<0.01) (Fig. 3).
w HYPERTENSIVE V) (n uJ
8 m z ikl
The present findings indicate that the New Zealand strains of genetically hypertensive and normotensive rats are remarkedly similar in their behavioral and physiological responses to a variety of stressful stimuli. When tested in an open field arena, N Z H and N Z N rats did not differ in levels of activity or rearing during a 5 minute test on each of 3 consecutive days. In contrast, several studies have reported that levels of activity and rearing during open field testing are consistently higher in SHR rats compared to normotensive W K Y rats across a wide age range [14, 29, 40]. A second aspect of this study concerned the comparison of sympathetic-adrenal medullary activity and cardiovascular measures of N Z H and N Z N rats while resting and undisturbed and following exposure to mildly or intensely stressful stimuli. Levels of N E and EPI in plasma were measured to provide an accurate assessment of the functional state of the sympathetic nervous system and the adrenal medulla [5, 15, 19]. NE in plasma is derived primarily from sympathetic nerve endings while EPI enters the circulation almost exclusively from the adrenal medulla [16,27]. A recent study has shown that the half life of both catecholamines in blood is approximately 1 minute . Plasma levels of NE and EPI did not differ between N Z H and N Z N rats when blood samples were obtained from undisturbed rats in their home cages. This finding indicates that basal sympathetic-adrenal medullary activity is unchanged in adult male N Z H rats despite significant elevations in arterial blood pressure. Similar results have been obtained in this laboratory for SHR and W K Y rats [18,25]. Baseline values for heart rate were also similar in N Z H and N Z N rats. In at least one previous study , heart rates in adult N Z H rats were significantly higher than for N Z N rats. However, this strain difference and the higher values for heart rate (375-425 beats/min) may have been influenced by the stress associated with the measurement (i.e., light ether anesthesia, restraint, and heating). N Z H and N Z N rats also presented similar patterns of sympathetic-adrenal medullary responsiveness to the stress of transfer of the shock box and exposure to footshock. In addition, rats of the two strains had equal reductions in sympathetic-adrenal medullary activity following the train of footshocks, as indicated by similar plasma levels of N E and EPI 10 minutes after footshock. Again, these findings are in direct contrast to similar studies which have compared SHR and W K Y rats. In general, SHR rats have been reported to have excessive elevations in plasma catecholamines following exposure to a range of stressful stimuli [18, 23, 25, 28]. In addition, the hyperresponsivity of the sympathetic-adrenal medullary system of SHR rats has been implicated in the development and maintenance of high blood pressure [11,12]. The contribution of the sympathetic nervous system to the development and maintenance of high blood pressure in
p. tg X
j Im TRANSFER
10 POSl F S
FIG. 3. Increments (A) from basal values in mean arterial blood pressure and heart rate for New Zealand hypertensive and normotensive rats after transfer to a shock box (TRANSFER) and im~ mediately (FS) and 10 minutes after exposure to one minute of intermittent footshock (10 t POST FS). Values are means for 5-13 rats per group and vertical bars denote one S.E.M.
N Z H rats is unclear. Studies by Clark and his co-workers demonstrated that partial destruction of the sympathetic nervous system by neonatal injections of antisera to nerve growth factor  or of the catecholamine neurotoxin. 6-hydroxydopamine , attenuated the increase in systolic blood pressure of N Z H rats. Although these studies are suggestive of a role for the sympathetic nervous system in genetic hypertension, several methodological shortcomings must be considered. These include: (1) the blood pressures o f sympathectomized N Z N rats were also reduced below those of vehicle-injected controls, (2) immunosympathectomy with nerve growth factor antisera produced only a partial destruction of peripheral sympathetic nerves, and (3) peripheral injections of 6-hydroxydopamine to neonatal rats depleted the brain as well as peripheral tissues of catecholamines. The effects of central catecholamine depletion were not controlled and may have contributed to the observed decreases in blood pressure . Finally, Phelan  found no
RATS AND STRESS
differences in the t u r n o v e r rates o f a H - N E in several peripheral tissues o f N Z H and N Z N rats at 100 days o f age and c o n c l u d e d that the sympathetic n e r v o u s system was not a critical e l e m e n t in maintaining high blood pressure. In s u m m a r y , the present findings d e m o n s t r a t e that adult N e w Zealand h y p e r t e n s i v e and n o r m o t e n s i v e rats are quite
similar in their behavioral and sympathetic-adrenal medullary responses to stressful stimulation. T h e s e results are in direct contrast to similar studies of s p o n t a n e o u s l y hypertensive (SHR) rats and d e m o n s t r a t e that behavioral and sympathetic h y p e r r e s p o n s i v i t y to stress is not necessarily associated with genetically determined increases in blood pressure.
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Mc(?AR'IY 39. Weise, V. K. and 1. J. Kopin. Assay of catecholamines in human plasma: Study of a single isotope radioenzymatic procedure. Life Sci. 19: 1673-1686, 1976. 40. Wilson, L. M. Some developmental aspects of open-field behavior in the spontaneously hypertensive rat (SHR) and two normotensive strains. Paper presented to the International Society for Developmental Psychobiology, Toronto, Canada. 1976. 41. Yamaguchi, I. and I. J. Kopin. Plasma catecholamines and blood pressure responses to sympathetic stimulation in pithed rats. Am. J. Physiol. 237: H305-H310, 1979. 42. Yamori, Y. Pathogenesis of spontaneous hypertension as a model for essential hypertension..lap. Circul. J. 41: 259-266, 1977.