Richard McCarty

Relationship between plasma norepinephrine and sympathetic neural activity.

For circulating norepinephrine (NE) to reflect sympathetic activity validly, plasma NE should show an intensity-dependent increase during sympathetic stimulation and decrease during sympathetic inhibition, and circulating NE should correlate with more directly obtained measures of sympathetic activity. Review of published evidence indicates that NE in peripheral plasma satisfies these criteria. However, models used to explain the relationship between circulating NE and sympathetic activity must take into account processes intervening between the synaptic cleft and free NE in the circulation and, since sympathetic outflow is regionalized, the contributions of specific vascular beds to circulating NE. In this report a model is presented where removal processes for NE are viewed as acting in series to produce a gradient in NE concentrations from synapse to plasma, and where the relative contributions of specific vascular beds are calculated from the arteriovenous difference in plasma NE across those beds and the percentage of cardiac output distributed to them. In general, venous plasma NE provides a useful estimation of average sympathetic outflow.

Vagal and sympathetic components of the heart rate range and gain of the baroreceptor-heart rate reflex in conscious rats

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.

Effect of stressor intensity on habituation of the adrenocortical stress response

Although it is known that the number of presentations of a stressor can influence the adrenocortical stress response, relatively little information exists on how stressor intensity affects this process. To evaluate this, we repeatedly presented rats with stressors of 3 different intensities and sampled blood for corticosterone. The first major finding was that the rats initial adrenocortical responsiveness regardless of the stressor employed was a critical variable. Rats that showed a small corticosterone response showed no evidence of habituation or of differences due to stressor intensity. Rats that showed an initial robust response all showed partial habituation of their corticosterone response over time but the patterns varied with stressor intensity. Handled and prone restrained rats showed the same pattern but rats subjected to the more intense stressor of supine restraint showed delay in habituation and tonically elevated responses. These data indicate that individual differences in reactivity to stressors as well as stressor intensity can influence the pattern of the stress response over the course of repeated administration of the stressor.

Fluctuations in Brain Glucose Concentration during Behavioral Testing: Dissociations between Brain Areas and between Brain and Blood☆

Traditional beliefs about two aspects of glucose regulation in the brain have been challenged by recent findings. First, the absolute level of glucose in the brains extracellular fluid appears to be lower than previously thought. Second, the level of glucose in brain extracellular fluid is less stable than previously believed. In vivo brain microdialysis was used, according to the method of zero net flux, to determine the basal concentration of glucose in the extracellular fluid of the striatum in awake, freely moving rats for comparison with recent hippocampal measurements. In addition, extracellular glucose levels in both the hippocampus and the striatum were measured before, during, and after behavioral testing in a hippocampus-dependent spontaneous alternation task. In the striatum, the resting extracellular glucose level was 0.71 mM, approximately 70% of the concentration measured previously in the hippocampus. Consistent with past findings, the hippocampal extracellular glucose level decreased by up to 30 +/- 4% during testing; no decrease, and in fact a small increase (9 +/- 3%), was seen in the striatum. Blood glucose measurements obtained during the same testing procedure and following administration of systemic glucose at a dose known to enhance memory in this task revealed a dissociation in glucose level fluctuations between the blood and both striatal and hippocampal extracellular fluid. These findings suggest, first, that glucose is compartmentalized within the brain and, second, that one mechanism by which administration of glucose enhances memory performance is via provision of increased glucose supply from the blood specifically to those brain areas involved in mediating that performance.

Sympatho-adrenal medullary activity and behavior during exposure to footshock stress: A comparison of seven rat strains ☆

The effects of footshock stress on circulating levels of norepinephrine (NE) and epinephrine (EPI) and behavioral activation were examined in male rats of seven strains: spontaneously hypertensive (SHR), stroke-prone hypertensive (SP-SHR), Wistar-Kyoto (WKY), Sprague-Dawley (SD), Osborne-Mendel (OM), Brown Norway (BN), and Charles River Wistar (CRW). A catheter was inserted into the ventral caudal artery of each rat to allow for direct measurement of blood pressure and heart rate and for repeated sampling of blood in conscious, undisturbed animals. Two days after insertion of the catheter, resting levels of plasma NE and EPI were higher in SHRs than in CRWs; no other comparisons among strains were significant. No strain differences were noted in the increments in plasma NE and EPI following transfer of rats from the home cage to a shock chamber. There were, however, significant strain differences in the responses of rats to 5 min of footshock (2.5 mA, 0.4 sec duration every 5 sec). Shock-induced increments in plasma NE and EPI were greatest in SHRs and lowest in S-D, O-M, B-N and CRW strains. In addition, there was a significant positive relationship between activity and shock-induced increments in plasma NE (r=0.89, p<0.01) and EPI (r=0.93, p<0.01). These findings indicate an association between activity of the sympatho-adrenal medullary system and behavioral activation during footshock stress. In addition, responsivity to stress was greatest in those strains (SHR and SP-SHR) which are genetically predisposed to increases in blood pressure.

Alterations in plasma catecholamines and behavior during acute stress in spontaneously hypertensive and Wistar-Kyoto normotensive rats

Abstract The responsiveness of the sympathoadrenal system to stress was assessed in spontaneously hypertensive (SHR) and Wistar-Kyoto normotensive (WKY) rats at 6, 18, and 48 weeks of age. Two days after insertion of a tail arterial catheter, each rat was transferred from its home cage to a shock chamber, and after 5 min received 60 footshocks over a 5 min interval. Blood samples were taken from undisturbed rats when in the home cage, 3–5 min after transfer to the shock chamber, and at the end of shock. An additional group of naive SHR and WKY rats was exposed to footshock and behavioral responses were recorded. There were no strain differences in levels of norepinephrine (NE) or epinephrine (EPI) while rats were undisturbed in their home cages. Transfer to the shock chamber resulted in a greater increase in plasma levels of both catecholamines in SHRs of each age. A similar pattern was evident after footshock; SHR rats had significantly higher post-shock levels of plasma NE and EPI than age-matched WKY rats. During shock, SHR rats were more active and jumped and reared more frequently than WKYs. These results demonstrate that the sympathoadrenal system of SHR rats is more responsive than normotensive rats to stressful stimuli and that this hyper-responsitivity is independent of increases in blood pressure. The excessive discharge of NE and EPI into plasma during stress may contribute to the development and maintenance of high blood pressure in SHR rats.

Unilateral odor deprivation: effects on the development of olfactory bulb catecholamines and behavior.

The present studies began an examination of the process by which unilateral odor deprivation results in a 25% reduction in the size of the olfactory bulb. Rat pups had a single naris occluded on the day after the day of birth (Day 1) and were tested at several early postnatal ages. Dopamine (DA) levels were measured to gauge the effects of deprivation on a transmitter system which is intrinsic to the bulb, while norepinephrine (NE) concentrations were assessed to determine how deprivation affects inputs to the bulb from higher brain regions. A significant reduction in DA concentration (pg/mg protein) was observed on Day 8 and persisted until Day 30 although protein concentrations (pg/mg bulb) were not affected. In contrast, deprivation did not significantly alter NE concentration. Deprived and control pups did not differ on a series of behavioral and morphometric measures, suggesting that the surgical procedure did not seriously impair normal growth patterns. The results indicate that unilateral naris occlusion induces rapid and specific changes within the olfactory bulb.

Adrenal hormonal indices of stress in laboratory rats

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.

Gender differences in sympathoadrenal activity in rats at rest and in response to footshock stress

A comparison was made of the dynamics of sympathoadrenal activity in 11 age‐matched male and female rats, under basal conditions and after exposure to footshock. Rats were prepared with indwelling catheters in the tail artery 24 h before the experiment. Measurements were made of plasma corticosterone (COR), norepinephrine (NE), epinephrine (EPI), dihydroxyphenylalanine (DOPA), dihydroxyphenylglycol (DHPG) and dihydroxyphenylacetic acid (DOPAC) under resting conditions, after transfer to the shock box (novelty) and at various times after footshock. Under basal conditions, males have significantly higher blood pressure and plasma DHPG/NE ratios but lower plasma levels of COR, NE and DOPAC than females. Three min after exposure to the shock chamber (novelty stress) there were significant increases in COR, EPI, NE and DHPG in both sexes, while DOPA increased only in females and DOPAC remained unchanged in both sexes. Footshock produced a further increase in EPI, NE and DOPAC within 2 min, which lasted about 15 min. There were significant sex differences in the extent and duration of the response of COR, EPI and DHPG. The data show that the female sympathoadrenal system is more reactive than that of the male to the stresses of a novel environment and footshock. The smaller DHPG/NE ratios in females at rest and after stress suggest that neuronal uptake of NE is lower in females than in males. The finding that stress produces larger increments of plasma DOPA and DOPAC in female rats indicates that tyrosine hydroxylase in the sympathetic nerve terminals and adrenal medulla may also be higher than in males.

Autonomic nervous system control of heart rate during baroreceptor activation in conscious and anesthetized rats

Heart rate and blood pressure were recorded in conscious, freely behaving rats through a catheter in the tail artery during administration of nitroprusside or phenylephrine through a catheter in the jugular vein. The sympathetic and parasympathetic components were distinguished by treating the rats with atenolol or methyl-atropine. Reflex bradycardia induced by all doses of phenylephrine was almost totally blocked blocked following methyl-atropine treatment. Reflex tachycardia induced by small to moderate doses of nitroprusside was attenuated to an equal extent following atropine or atenolol treatment. A similar experimental schedule was followed with a separate group of rats to determine the effects of pentobarbital and urethane anesthesia on the baroreceptor reflex. Both pentobarbital and urethane equally attenuated the tachycardia response to a decrease in blood pressure. However, pentobarbital anesthesia resulted in a greater attenuation of the bradycardia response to an increase in blood pressure than did urethane anesthesia. These data support the conclusion that the parasympathetic nervous system is primarily responsible for baroreceptor reflex-induced bradycardia in conscious rats. The sympathetic and parasympathetic systems contribute equally to control baroreceptor reflex-induced tachycardia except in extreme acute hypotension when the tachycardia is predominantly due to the activation of sympathetic nerves. The findings of the second experiment indicate that pentobarbital and urethane affect sympathetic systems differently.