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Cross-fostering spontaneously hypertensive rat (SHR) pups to Wistar-Kyoto (WKY) normotensive mothers influenced physical development, resting mean arterial pressure and heart rate, open-field behavior, and sympathetic-adrenal medullary responses to stressors. In contrast, cross-fostering WKY pups to SHR mothers at birth did not affect these developmental processes.
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Binding sites for atrial natriuretic factor (ANF) were studied in kidneys and adrenal glands of 17 week old male spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) normotensive rats by quantitative autoradiography using 125I-ANF-28. In kidney, 125I-ANF-28 binding sites were found in high concentrations in glomeruli and in much lower concentrations in the renal papilla. In adrenal gland, 125I-ANF-28 binding sites were highly localized to the zona glomerulosa and were of moderate density in the inner cortical regions. ANF binding sites did not occur in the adrenal medulla. The maximum binding capacity (Bmax) of 125I-ANF-28 was reduced by 50% in the kidney glomeruli of SHRs compared to WKY controls. In contrast, the affinity constant (Ka) for 125I-ANF-28 was elevated by 100% in kidney glomeruli of SHRs. There were no significant strain differences in values for Bmax or Ka for 125I-ANF-28 binding in the adrenal zona glomerulosa. These findings suggest that the natriuretic and diuretic actions of ANF within kidney glomeruli may be compromised in adult SHR rats and these alterations may contribute to the development and maintenance of hypertension in rats of this strain.
Preweanling physical and behavioral development was studied in spontaneously hypertensive (SHR), borderline hypertensive (BHR), and Wistar-Kyoto normotensive (WKY) rat pups. Measures of physical development included body weight, onset of various morphological landmarks, and speed of surface righting. Behavioral tests assessed locomotor development, exploratory behavior, and cliff avoidance in pups of the 3 groups. On all measures employed, SHR pups exhibited a delay in physical maturation compared to age-matched BHR and WKY pups. Results from the locomotor development test revealed that young WKY pups (ages 1-7 days) spent more time locomoting than SHR pups, with BHR times being intermediate. In contrast, older SHR pups (ages 17-30 days) displayed greater activity in an exploratory maze than WKY pups, with BHR values again intermediate. Finally, SHR pups were more behaviorally reactive in the cliff avoidance task compared to BHR and WKY pups. These group differences may be useful in understanding the development of genetic hypertension and may serve as early behavioral markers of a predisposition to cardiovascular disease.
Maternal behavior of spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) normotensive rats was assessed over the preweanling period (days 1-21). Ten litters of each strain were observed during the dark phase of the light:dark cycle using a scan sampling technique. Cages were observed periodically throughout the day and the momentary behavior of the dam was recorded on a checklist of 9 different behaviors. These behaviors included: nursing entire litter, nursing part of litter, contact with entire litter, contact with part of litter, pup carrying/retrieval, licking pups, sniffing pups, nest building, and away from litter. A second set of ten litters per strain was observed in the same manner during the light phase of the light:dark cycle thus providing around the clock data throughout the entire preweanling period. For purposes of data analysis, the 21-day preweanling period was divided into 7 3-day blocks. The mean relative frequency with which each behavior was observed from SHR and WKY mothers was determined for each block and for each phase of the light:dark cycle separately. SHR mothers were with their pups and nursing them more frequently than WKY mothers during the light phase of the circadian cycle. Complimentary to this finding, WKY mothers were observed away from their pups more frequently than SHR mothers during both light and dark phases. Finally, SHR mothers were observed to lick their pups more often than WKY mothers during both phases of the light:dark cycle. These findings were consistent across the entire preweanling period.(ABSTRACT TRUNCATED AT 250 WORDS)
Functional development of the sympathetic nervous system was examined in inbred Dahl salt-sensitive (S/JR) and salt-resistant (R/JR) rats by assessing cardiac and adrenal medullary responses to insulin-induced hypoglycemia at 2, 4, 8, 12, and 16 days of age. Heart ornithine decarboxylase (ODC) activity and adrenal catecholamine content were measured in pups of the two strains 3 hours after administration of either saline or insulin. The centrally mediated increase in sympathetic outflow caused by insulin-induced hypoglycemia was attended by induction of heart ODC activity and depletion of adrenal epinephrine (EPI). No significant differences were found overall between R/JR and S/JR strains with regard to either heart ODC activity or adrenal epinephrine. This was true for basal values obtained from saline-injected pups as well as for measures from insulin-injected pups. Functional innervation of the heart was present in pups of both strains as early as 2 days of age, while in the adrenal medulla a significant response to stimulation was not detected until 8 days of age. While the susceptibility for hypertension in the salt-sensitive animals may well be linked to increased sympathetic tone, the present findings indicate that S/JR rats do not have an accelerated development or a hyperresponsiveness of sympathetic input to either the heart or the adrenal medulla during the pre-weanling period.
When individual rats were exposed to different intensities of a stressor, foot shock, plasma catecholamines were found to be sensitive and reliable indices of the stress. Plasma corticosterone did not perform as well. Similarly, levels of both plasma epinephrine and norepinephrine correlated highly significantly with a behavioral measure of the degree of stress--namely, the amount of movement about the cage seen during the 30 sec shock period. Importantly, this behavioral measure was as sensitive and reliable an index of stress as the catecholamines. However, use of either the catecholamines or this behavioral measure as a clinically useful measure of the level of stress was limited by the fact that their responses to the stressor were extremely short-lived. Nonetheless, because the catecholamines reliably and sensitively track the intensity of a stressor, they appear to be a good visceral measure of stress, perhaps the best currently available. But the behavioral concomitants of stress are quickly and easily quantifiable and present a wide range to study, starting with alerting, through a progression of more aroused motor activity, and ending with fight-flight. Because the behavioral concomitants of stress have not been as intensively studied as the endocrine ones, we believe that future efforts to find a clinically useful index of stress will be rewarded by a refocussing of attention away from the visceral respondent to the overt behavioral one.
Previous studies in conscious rats have examined the relationship between mean arterial pressure (MAP) and heart rate (HR) only during relatively small or unidirectional changes in blood pressure. We have now examined this relationship more fully in conscious Sprague-Dawley rats using graded bolus i.v. doses of phenylephrine and nitroprusside to alter MAP over a range of 60-160 mm Hg with a view to determining the contribution made by the vagus and sympathetic (after atenolol or methylatropine, respectively). In 25 rats the relationship of HR to MAP followed a sigmoidal rather than a linear function (P less than 0.001) with clear upper and lower HR plateaus. The HR range estimated from a logistic equation was 217 +/- 7 b/min while the average gain between the inflection points was 4.1 +/- 0.2 b/min/mm Hg (1.8 times greater than from a linear fit). The vagus makes a greater contribution to the HR range than the sympathetic (61 vs 39%, respectively) while the converse is the case for the gain (46% vagus, 63% sympathetic). In the presence of both blocking drugs, changes to HR were less than 7% of control. These results suggest that the baroreceptor-HR reflex in the conscious rat is best characterised by a sigmoid curve with approximately equal contributions from both the cardiac vagus and the sympathetic nerves.
Borderline hypertensive (BHR) rats are the first generation offspring of a cross of spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) normotensive rats. In adulthood, BHRs have systolic blood pressures in the 140-160 mm Hg range. If subjected to chronic stress paradigms, however, BHRs develop sustained and permanent elevations in systolic blood pressure (180-200 mm Hg). In the present study, we examined the functional development of cardiac and adrenal medullary responses to reflex activation of the sympathetic nervous system in preweanling BHR and WKY rats. Pups of the two groups were injected with insulin or saline at 4, 8, 12, or 16 days of age and sacrificed 3 h later. Insulin produces an acute lowering of blood glucose which is attended by a centrally mediated increase in sympathetic activity. The induction of ornithine decarboxylase (ODC) activity in heart and the depletion of epinephrine from the adrenal medulla were biochemical indicators of functional sympathetic neurotransmission. WKY and BHR pups had similar levels of cardiac ODC activity under basal conditions and following administration of insulin. In contrast, BHRs had higher amounts of adrenal norepinephrine and epinephrine from 4 to 16 days of age and greater depletion of adrenal epinephrine following insulin administration at 8, 12 and 16 days of age. These findings indicate that BHRs have a greater capacity for catecholamine biosynthesis, storage and release in the adrenal medulla during the preweanling period compared to age-matched normotensive WKY controls. This alteration in the adrenal medulla during the preweanling period may contribute to the susceptibility of adult BHR rats to stress-induced hypertension.
The development of functional sympathetic innervation to the heart and adrenal medulla was examined in Long-Evans and Sprague-Dawley rats during the preweanling period. Insulin-induced hypoglycemia was used to produce a centrally mediated activation of the sympathetic nervous system and the induction of ornithine decarboxylase activity in the heart and the depletion of adrenal epinephrine were used as indices of sympathetically mediated responses in these target organs. First, dose by time response curves were performed in 11-13 day old Sprague-Dawley pups to establish an insulin dose which would simultaneously produce stimulation of cardiac ornithine decarboxylase activity and depletion of adrenal medullary epinephrine at an appropriate time post-injection. This dose of insulin was then administered to pups of different postnatal ages to determine the onset of functional sympathetic innervation to these target organs. Significant increases in heart ornithine decarboxylase activity were seen by two postnatal days of age in both rat strains examined. In contrast, adrenal epinephrine depletions were not found until 8-12 postnatal days of age. These results indicate that functional sympathetic neurotransmission to the heart is present in the first few days after birth, and this precedes the onset of sympathetic control of adrenal epinephrine release, which matures near the end of the first postnatal week in laboratory rats.
Somatostatin has been localized in several hypothalamic and extrahypothalamic brain regions where it may function as a classical neurotransmitter or as a modulator of neural activity. In the present study, somatostatin binding sites were studied by incubation of coronal sections of rat forebrain with 125I-Tyr1-somatostatin, Ultrofilm autoradiography, computerized microdensitometry and comparison with 125I standards. Highest concentrations of somatostatin binding sites (fmol/mg protein) were found in the claustrum (151), basolateral nucleus of the amygdala (90), deep layers of the cerebral cortex (61), lateral olfactory nuclei (58), CA1 and CA2 areas of hippocampus (57), medial and lateral septal nuclei (54), and the medial habenula (44). Scatchard analysis of individual forebrain areas with high densities of somatostatin binding sites was also performed. Regulation of brain somatostatin binding sites may be studied as one approach to examining the involvement of central somatostatin pathways in various physiological and behavioral states.
The functional development of cardiac and adrenal medullary responses to reflex activation of the sympathetic nervous system was studied in preweanling spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) normotensive rats. Pups of the two strains received injections of insulin or saline at 2, 4, 8, 12, or 16 days of age and were sacrificed 3 h later. Insulin administration produces a significant decrease in circulating levels of glucose which in turn results in a centrally mediated increase in sympathetic outflow. The induction of ornithine decarboxylase (ODC) in heart and the depletion of epinephrine from the adrenal medulla served as tissue markers of functional sympathetic neurotransmission. WKY and SHR pups had comparable levels of ODC activity in heart under basal conditions. In contrast, levels of catecholamines in the adrenals were greater in SHR pups at 2 and 4 days of age. Following insulin administration, SHR pups exhibited a greater induction of cardiac ODC activity at 2, 4, and 8 days of age compared to age-matched WKY controls. However, there were no differences between SHR and WKY pups in the magnitude of the adrenal medullary response to insulin-induced hypoglycemia. These alterations in sympathetic-target tissue development during the first postnatal week of life may contribute in part to the higher arterial pressures maintained by SHRs throughout the lifespan.
The role of the maternal environment in the development of hypertension in spontaneously hypertensive (SHR) rats was evaluated using the technique of reciprocal cross fostering. Litters of SHR and Wistar-Kyoto (WKY) normotensive pups were either reared by their natural mothers, in fostered to mothers of the same strain, or cross fostered to mothers of the opposite strain shortly after birth. Litters were weaned at 21 days of age, at which time all pups were weighed. At 18-20 wk of age, resting mean arterial blood pressures (MAP) and heart rates were determined for male subjects from the six groups (2 strains X 3 rearing conditions) via an indwelling tail artery catheter. At weaning, SHR animals weighed less than WKY animals. SHRs fostered to WKY mothers were significantly heavier than control SHRs, and WKYs fostered to SHR mothers were significantly lighter than WKY controls at weaning. These body weight differences were also evident in adulthood. Cross fostering SHR pups to normotensive WKY mothers resulted in a dramatic reduction in resting MAP measured in adulthood. Conversely, cross fostering WKY pups to SHR mothers had no measurable effect on adult resting MAP. We propose that an interaction between characteristics of the SHR maternal environment and a genetic susceptibility in SHR pups is essential in triggering the full expression of the hypertensive phenotype in this animal model of human essential hypertension.
Binding sites for atrial natriuretic factor (ANF) were studied in kidneys and adrenal glands of 7- and 10-week-old male Dahl hypertension-sensitive (S/JR) and hypertension-resistant (R/JR) rats by quantitative autoradiography. Binding sites for 125I-ANF-28 in kidney were highly localized and of high density in the glomeruli; binding sites were less concentrated in the renal papilla. In adrenal gland, binding sites for 125I-ANF-28 were highly concentrated in the zona glomerulosa, but were of a very low density in the inner adrenal cortex. At 7 weeks of age, the maximum binding capacity (Bmax) for 125I-ANF-28 in kidney glomeruli was increased by 21% in S/JR rats compared with R/JR rats. From 7 to 10 weeks of age, decreases in Bmax for 125I-ANF-28 in glomeruli occurred, with no apparent difference between strains. Strain or age differences in the affinity constant (Ka) for 125I-ANF did not occur in the kidney. In adrenal zona glomerulosa, the Bmax for 125I-ANF-28 binding was similar for S/JR and R/JR rats at 7 weeks of age. At 10 weeks of age, however, Bmax for 125I-ANF-28 in adrenal zona glomerulosa was increased by 19% in S/JR rats compared with age-matched R/JR controls. These findings suggest that alterations may occur in ANF binding sites in kidney and adrenal gland of S/JR rats in response to the sharp increase in blood pressure that is characteristic of rats of this strain.
Dopamine occurs in the adrenal cortex and appears to provide maximum tonic inhibition of aldosterone secretion. In the present experiments, the effects of high or low sodium (Na+) intake on concentrations of dopamine in the adrenal cortex of adult male Sprague-Dawley rats were examined. In the first experiment, sham-operated and adrenal demedullated rats were provided with 1.5% NaCl or tap water for drinking for 5 days. In the second experiment, sham-operated and adrenal demedullated rats were fed regular laboratory chow (approximately 0.45% NaCl) or low Na+ chow (0.001-0.005% NaCl) for 5 days. High Na+ intake was attended by dramatic increases in fluid consumption, urine production and Na+ excretion. However, high Na+ intake did not affect levels of dopamine, norepinephrine or epinephrine in the adrenal glands. Approximately 45% of adrenal dopamine but less than 4% of either norepinephrine or epinephrine was localized in the adrenal cortex. In the second experiment, animals fed a diet low in Na+ had a significant reduction in Na+ excretion but levels of adrenal catecholamines were unaffected. Approximately 36% of adrenal dopamine but less than 5% of either norepinephrine or epinephrine was localized in the adrenal cortex. These findings suggest that adrenal cortical dopamine concentrations remain relatively constant in spite of presumed differences in turnover rates of this neurohormone.
Binding sites for atrial natriuretic factor (ANF-28) were analyzed in discrete brain areas of Brattleboro rats with hereditary diabetes insipidus and Long-Evans (LE) controls by quantitative autoradiography. The maximum binding capacity (Bmax) and affinity constant (Ka) for 125I-ANF-28 were elevated significantly in the subfornical organ of Brattleboro rats compared to matched LE controls. In contrast, values for Bmax and Ka for 125I-ANF-28 binding in choroid plexus and area postrema were similar for rats of the two strains. These findings are consistent with a selective upregulation of ANF-28 binding sites in the subfornical organ of Brattleboro rats which exhibit a profound disturbance in body fluid homeostasis. These alterations in ANF-28 binding sites in the subfornical organ may represent a compensatory response to the absence of vasopressin in the Brattleboro rat.
In mammals, aging is often viewed as a progressive decline in physiological competence with a corresponding inability to adapt to stressful stimulation. Several current theories of aging have implicated the sympathetic nervous system in many of the metabolic, cardiovascular and behavior changes which attend advancing age. To provide an empirical base for evaluating the role of the sympathetic nervous system in aging, I have studied the activity of the sympathetic nerves and the adrenal medulla of adult and aged Fischer 344 male rats before, during and after exposure to various stressful stimuli. Plasma levels of norepinephrine and epinephrine served as biochemical indices of the activity of the sympathetic nerves and the adrenal medulla, respectively. Under resting conditions, rats 4-24 months of age had similar plasma levels of both catecholamines. When stressed for a brief period of time (intermittent footshock for 1 min), 12- and 24-month-old rats exhibited a diminished sympathetic-adrenal medullary response compared to young adult rats (4 months old). With an increase in the intensity and duration of the stressor (cold water immersion for 10 min), the sympathetic-adrenal medullary responses of 6- and 22-month-old rats were comparable. However, the sympathetic nervous system remained in a heightened state of activity for a longer period of time following the stressful stimulus in aged rats. Finally, with prolonged exposure to an intense stressor (cellular glucoprivation following administration of 2-deoxy-D-glucose), 24-month-old rats exhibited an exaggerated adrenal medullary response and a greater mortality rate compared to 6-month-old rats. These findings suggest that homeostatic regulation of the sympathetic nervous system is impaired in aged rodents. Further, the nature of this impairment is dependent upon the intensity and duration of the activating stimulus. These apparent age-related alterations in regulation of the sympathetic nervous system may contribute to the increased morbidity and mortality of aged animals during prolonged exposure to stressful stimulation.
The functional development of cardiac and adrenal medullary responses to reflex activation of the sympathetic nervous system was studied in preweanling spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) normotensive rat pups. Pups from the two strains received injections of insulin or saline at 2, 4, 8, 12 or 16 days of age and were killed 3 h later. The induction of ornithine decarboxylase (ODC) in the heart and the depletion of epinephrine (EPI) from the adrenal medulla served as tissue markers of functional sympathetic neurotransmission. Compared with WKY pups, SHR pups showed a greater induction of ODC activity in the heart at 2, 4, and 8 days of age. There were no differences between SHR and WKY pups in the adrenal medullary response to insulin-induced hypoglycaemia. These altered patterns of sympathetic-target tissue development in early life may contribute to the higher arterial pressures maintained by SHR throughout life.