Photoperiod modulates the effects of norepinephrine on lymphocyte proliferation in Siberian hamsters

Siberian hamsters (Phodopus sungorus) rely on photoperiod to coordinate seasonally appropriate changes in physiology, including immune function. Immunity is regulated, in part, by the sympathetic nervous system (SNS), although the precise role of the SNS in regulating photoperiodic changes in immunity remains unspecified. The goal of the present study was to examine the contributions of norepinephrine (NE), the predominant neurotransmitter of the SNS, to photoperiodic changes in lymphocyte proliferation. In experiment 1, animals were maintained in long [16:8-h light-dark cycle (16:8 LD)] or short days (8:16 LD) for 10 wk, and splenic NE content was determined. In experiment 2, in vitro splenocyte proliferation in response to mitogenic stimulation (concanavalin A) was assessed in spleen cell suspensions taken from long- or short-day hamsters in which varying concentrations of NE were added to the cultures. In experiment 3, splenocyte proliferation was examined in the presence of NE and selective alpha- and beta-noradrenergic receptor antagonists (phenoxybenzamine and propranolol, respectively) in vitro. Short-day animals had increased splenic NE content compared with long-day animals. Long-day animals had higher proliferation compared with short-day animals independent of NE. NE (1 microM) further suppressed splenocyte proliferation in short but not long days. Last, NE-induced suppression of proliferation in short-day hamsters was blocked by propranolol but not phenoxybenzamine. The present results suggest that NE plays a role in photoperiodic changes in lymphocyte proliferation. Additionally, the data suggest that the effects of NE on proliferation are specific to activation of beta-adrenergic receptors located on splenic tissue. Collectively, these results provide further support that photoperiodic changes in immunity are influenced by changes in SNS activity.     

Modifications of arterial pressure and plasma renin: their effects on the norepinephrine content of hypothalamus and medulla oblongata.

The effects of the bilateral nephrectomy and acute hypotension caused by the cava vein ligature on the norepinephrine (NE) concentration in hypothalamus and medulla oblongata and on the plasma renin activity were studied in male rats. NE increased and plasma renin activity decreased in hypothalamus in 24 h nephrectomized rats with or without the ligatures of the cava vein. NE also decreased in medulla of groups with the ligatures only. The mean arterial pressure, did not correlate with the NE or plasma renin activity levels. The modifications of the NE in the central nervous system showed an inverse relationship with plasma renin activity and this, could be due to changes in the NE uptake and/or release caused by the plasma renin activity alterations. NE modifications do not seem to be caused directly through reflex of the arterial pressure.     

Increase in epinephrine-induced responsiveness during microgravity simulated by head-down bed rest in humans.

The epinephrine (Epi)-induced effects on the sympathetic nervous system (SNS) and metabolic functions were studied in men before and during a decrease in SNS activity achieved through simulated microgravity. Epi was infused at 3 graded rates (0.01, 0.02, and 0. 03 microg. kg(-1). min(-1) for 40 min each) before and on the fifth day of head-down bed rest (HDBR). The effects of Epi on the SNS (assessed by plasma norepinephrine levels and spectral analysis of systolic blood pressure and heart rate variability), on plasma levels of glycerol, nonesterified fatty acids (NEFA), glucose and insulin, and on energy expenditure were evaluated. HDBR decreased urinary norepinephrine excretion (28.1 +/- 4.2 vs. 51.5 +/- 9.1 microg/24 h) and spectral variability of systolic blood pressure in the midfrequency range (16.3 +/- 1.9 vs. 24.5 +/- 0.9 normalized units). Epi increased norepinephrine plasma levels (P < 0.01) and spectral variability of systolic blood pressure (P < 0.009) during, but not before, HDBR. No modification of Epi-induced changes in heart rate and systolic and diastolic blood pressures were observed during HDBR. Epi increased plasma glucose, insulin, and NEFA levels before and during HDBR. During HDBR, the Epi-induced increase in plasma glycerol and lactate levels was more pronounced than before HDBR (P < 0.005 and P < 0.001, respectively). Epi-induced energy expenditure was higher during HDBR (P < 0.02). Our data suggest that the increased effects of Epi during simulated microgravity could be related to both the increased SNS response to Epi infusion and/or to the beta-adrenergic receptor sensitization of end organs, particularly in adipose tissue and skeletal muscle.     

Sympathetic denervation does not prevent a reduction in fat pad size of rats or mice treated with peripherally administered leptin

Leptin increases sympathetic nervous system (SNS) activity in brown adipose tissue and renal nerves. Experiments described here tested whether SNS innervation is required for peripheral, physiological concentrations of leptin to reduce body fat. In experiment 1, one epididymal (EPI) fat pad was sympathectomized by local injection of 6-hydroxydopamine (6OHDA) in C57BL/6 mice that were then infused for 13 days with PBS or 10 microg leptin/day from an intraperitoneal miniosmotic pump. Surprisingly, EPI denervation increased total body fat of PBS-infused mice but leptin decreased the size of both injected and noninjected EPI pads in 6OHDA mice. Experiment 2 was identical except for the use of male Sprague-Dawley rats that were infused with 50 microg leptin/day. Leptin had little effect on EPI weight or norepinephrine (NE) content, but denervation of one EPI pad decreased the effect of leptin on intact EPI, inguinal and retroperitoneal (RP) fat and increased the size of the mesenteric fat pad. Experiment 3 included groups in which either one EPI or one RP pad was denervated. RP denervation reduced RP NE content but did not prevent a leptin-induced reduction in fat pad mass. Therefore, the SNS is not required for low doses of leptin to reduce body fat. EPI denervation significantly increased adipocyte number in contralateral EPI and RP fat pads and this was prevented by leptin. These changes in intact pads of rats with one denervated fat pad imply communication between fat depots and suggest that both leptin and the SNS regulate the size of individual depots.     

Effects of CL 115,347, (+/-)-15-deoxy-16-hydroxy-16-vinyl-PGE2 methyl ester, on cardiovascular responses and plasma catecholamines in pithed stroke-prone spontaneously hypertensive rats during sympathetic stimulation

The effect of CL 115,347, a topically active antihypertensive PGE2 analog, and PGE2 on changes in blood pressure (BP), heart rate (HR) response and plasma epinephrine (E) and norepinephrine (NE) levels induced by stimulation of the sympathetic spinal cord outflow were studied in pithed stroke-prone spontaneously hypertensive rats (SHRSP). Surgical pithing significantly reduced plasma E but not NE levels suggesting that the sympathoadrenal medullary system differentially affects E and NE release. Sympathetic stimulation of the spinal cord of pithed SHRSP increased HR, BP, plasma E and NE levels. Topically applied CL 115,347 (0.001-0.2 mg/kg) dose-dependently decreased BP, while intravenously infused PGE2 (30 micrograms/kg/min) did not alter BP except for a brief initial drop. Topical application of CL 115,347 (0.1 mg/kg) also inhibited BP responses to sympathetic stimulation without effects on HR or plasma E or NE levels. Intravenous infusion of PGE2 (30 micrograms/kg/min) inhibited both BP and HR responses to spinal cord stimulation but did not alter plasma catecholamine levels. These studies in SHRSP suggest that CL 115,347 and PGE2 modulate cardiovascular responses mainly via postjunctional effects, but act differently on the cardiovascular elements, viz. CL 115,347 acts primarily on blood vessels while PGE2 acts on blood vessels and heart.     

Parasympathetic inhibition of sympathetic neural activity to the pancreas

The present study tested the hypothesis that activation of the parasympathetic nervous system could attenuate sympathetic activation to the pancreas. To test this hypothesis, we measured pancreatic norepinephrine (NE) spillover (PNESO) in anesthetized dogs during bilateral thoracic sympathetic nerve stimulation (SNS; 8 Hz, 1 ms, 10 mA, 10 min) with and without (randomized design) simultaneous bilateral cervical vagal nerve stimulation (VNS; 8 Hz, 1 ms, 10 mA, 10 min). During SNS alone, PNESO increased from the baseline of 431 +/- 88 pg/min to an average of 5,137 +/- 1,075 pg/min (P < 0.05) over the stimulation period. Simultaneous SNS and VNS resulted in a significantly (P < 0.01) decreased PNESO response [from 411 +/- 61 to an average of 2,760 +/- 1,005 pg/min (P < 0.05) over the stimulation period], compared with SNS alone. Arterial NE levels increased during SNS alone from 130 +/- 11 to approximately 600 pg/ml (P < 0.05); simultaneous SNS and VNS produced a significantly (P < 0.05) smaller response (142 +/- 17 to 330 pg/ml). Muscarinic blockade could not prevent the effect of VNS from reducing the increase in PNESO or arterial NE in response to SNS. It is concluded that parasympathetic neural activity opposes sympathetic neural activity not only at the level of the islet but also at the level of the nerves. This neural inhibition is not mediated via muscarinic mechanisms.     

Effects of neonatal handling on sympathoadrenal activity and body composition in adult male rats

Neonatal handling permanently alters the hypothalamic-pituitary-adrenal (HPA) response to stress. Because the sympathetic nervous system (SNS) and adrenal medulla also participate in stress responses, the impact of daily handling between birth and weaning on SNS and adrenal medullary function was examined in adult rats using techniques of [(3)H]norepinephrine ([(3)H]NE) turnover and urinary catecholamine excretion. Handled animals exhibited a 23% reduction in [(3)H]NE turnover in heart and a 53% decrease in spleen. [(3)H]NE turnover in brown adipose tissue, stomach, and kidney did not differ between handled and nonhandled animals. In contrast, urinary epinephrine (Epi) excretion was significantly greater in handled rats in response to a 3-day fast than in nonhandled animals. Although body weight, weight gain in response to dietary enrichment with sucrose or lard, or body fat content did not differ in handled and nonhandled animals, handled rats displayed heavier abdominal fat depots than nonhandled animals, implying a difference in body fat distribution. Neonatal handling thus leads to decreased sympathetic activity within specific subdivisions of the SNS and, by contrast, to increased adrenal medullary responsiveness.     

Reactive oxygen species stimulate central and peripheral sympathetic nervous system activity

Recent studies have implicated reactive oxygen species (ROS) in the pathogenesis of hypertension and activation of the sympathetic nervous system (SNS). Because nitric oxide (NO) exerts a tonic inhibition of central SNS activity, increased production of ROS could enhance inactivation of NO and result in activation of the SNS. To test the hypothesis that ROS may modulate SNS activity, we infused Tempol (4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl), a superoxide dismutase mimetic, or vehicle either intravenously (250 microg x kg(-1) x min(-1)) or in the lateral ventricle (50 microg x kg body wt(-1) x min(-1)), and we determined the effects on blood pressure (BP), norepinephrine (NE) secretion from the posterior hypothalamus (PH) measured by the microdialysis technique, renal sympathetic nerve activity (RSNA) measured by direct microneurography, the abundance of neuronal NO synthase (nNOS)-mRNA in the PH, paraventricular nuclei (PVN), and locus coeruleus (LC) measured by RT-PCR, and the secretion of nitrate/nitrite (NO(x)) in the dialysate collected from the PH of Sprague-Dawley rats. Tempol reduced BP whether infused intravenously or intracerebroventricularly. Tempol reduced NE secretion from the PH and RSNA when infused intracerebroventricularly but raised NE secretion from the PH and RSNA when infused intravenously. The effects of intravenous Tempol on SNS activity were blunted or abolished by sinoaortic denervation. Tempol increased the abundance of nNOS in the PH, PVN, and LC when infused intracerebroventricularly, but it decreased the abundance of nNOS when infused intravenously. When given intracerebroventricularly, Tempol also reduced the concentration of NO(x) in the dialysate collected from the PH. Pretreatment with N(omega)-nitro-l-arginine methyl ester did not abolish the effects of intracerebral Tempol on BP, heart rate, NE secretion from the PH, and RSNA suggesting that the effects of Tempol on SNS activity may be in part dependent and in part independent of NO. In all, these studies support the notion that ROS may raise BP via activation of the SNS. This activation may be mediated in part by downregulation of nNOS and NO production, in part by mechanisms independent of NO. The discrepancy in results between intracerebroventricular and intravenous infusion of Tempol can be best explained by direct inhibitory actions on SNS activity when given intracerebral. By contrast, Tempol may exert direct vasodilation of the peripheral circulation and reflex activation of the SNS when given intravenously.     

Endothelium-dependent basilar and aortic vascular responses in normotensive and coarctation hypertensive rats

The responsiveness of acetylcholine (ACh), nitroglycerin (NG) and norepinephrine (NE) (aorta only) in both basilar arteries (BA) and thoracic aortic (TA) rings from coarctation hypertensive rats (CHR) were studied and compared to their sham-operated normotensive control rats (SNR). The effects of these agents were also evaluated in TA or BA with and without endothelium from naive normotensive rats (NNR). Blood pressure (BP) and plasma renin activity (PRA) of CHR were significantly higher than their time-matched SNR. Endothelium removal from TA of NNR significantly enhanced NE and NG sensitivity and reduced the maximum ACh relaxation. Removal of BA endothelium of NNR abolished ACh-induced relaxation but had no effect on NG-induced relaxation. In BA from CHR at any stage of hypertension studied, the sensitivity and maximum relaxation induced by ACh or NG were not significantly different than their respective time-matched SNR. ACh sensitivity of TA did not change in 1 Day CHR but decreased in 4 and 14 Day CHR. NG sensitivity increased, did not change and decreased in 1, 4 and 14 Day CHR, respectively. NE sensitivity increased in all stages of hypertension. These data suggest that in coarctation-induced hypertension there is a complex progression of events in TA which is modulated by different mechanisms as evidenced by the changes in the effects of NE, ACh and NG at various stages of hypertension. The results also suggest that the vascular endothelium of TA but not of BA may provide an acute protective mechanism to counteract the imbalance created by the increased sensitivity of smooth muscle cells to contractile agonists in the early stage of hypertension. However, persistent hypertension appears to override this mechanism.     

Pharmacologic tools for assessment of adrenergic nerve activity in human hypertension

Measurement of plasma norepinephrine concentration (plasma NE) has not resolved the role of the adrenergic system in the pathogenesis or maintenance of hypertension. A better picture is gained if plasma NE measurement is combined with the assessment of sympathetic drive and reactivity by the use of specific sympathetic antagonists and agonists. In mild hypertension, the decrease in heart rate and cardiac output after beta-adrenoceptor blockade correlates with the level of plasma NE. In established hypertension, the fall in blood pressure or peripheral vascular resistance after alpha-adrenoceptor blockade is related to plasma NE levels. Similarly, changes in forearm vascular resistance induced by local alpha-adrenoceptor blockage correlates with plasma NE in hypertension. Cardiovascular responsiveness to adrenergic agonists is altered in hypertension. The response to cardiac beta-receptor stimulation decreases during the course of the disease. To the contrary, vascular responses to exogenous NE increase with the progression of the hypertensive disease. Results with total autonomic blockade indicate that in some patients with early or borderline hypertension, increased sympathetic tone is involved in the maintenance of blood pressure. In established hypertension, there is no definite indication of increased sympathetic tone, but the sympathetic nervous system may nevertheless play a prominent role in the maintenance of the blood pressure. A vascular hyperreactivity to adrenergic stimulation is characteristically associated with established hypertension. The nature of this hyperreactivity has not been fully elucidated, but it is very likely that it reflects structural vascular changes in hypertension.     

Sympathetic activity and the heterogenous blood pressure response to exercise training in hypertensives.

To test whether changes in sympathetic nervous system (SNS) activity or insulin sensitivity contribute to the heterogeneous blood pressure response to aerobic exercise training, we used compartmental analysis of [3H]norepinephrine kinetics to determine the extravascular norepinephrine release rate (NE2) as an index of systemic SNS activity and determined the insulin sensitivity index (S(I)) by an intravenous glucose tolerance test, before and after 6 mo of aerobic exercise training, in 30 (63 +/- 7 yr) hypertensive subjects. Maximal O2 consumption increased from 18.4 +/- 0.7 to 20.8 +/- 0.7 ml x kg(-1) x min(-1) (P = 0.02). The average mean arterial blood pressure (MABP) did not change (114 +/- 2 vs. 114 +/- 2 mmHg); however, there was a wide range of responses (-19 to +17 mmHg). The average NE2 did not change significantly (2.11 +/- 0.15 vs. 1.99 +/- 0.13 microg x min(-1) x m(-2)), but there was a significant positive linear relationship between the change in NE2 and the change in MABP (r = 0.38, P = 0.04). S(I) increased from 2.81 +/- 0.37 to 3.71 +/- 0.42 microU x 10(-4) x min(-1) x ml(-1) (P = 0.004). The relationship between the change in S(I) and the change in MABP was not statistically significant (r = -0.03, P = 0.89). When the changes in maximal O2 consumption, percent body fat, NE2, and S(I) were considered as predictors of the change in MABP, only NE2 was a significant independent predictor. Thus suppression of SNS activity may play a role in the reduction in MABP and account for a portion of the heterogeneity of the MABP response to aerobic exercise training in older hypertensive subjects.     

Hyperinsulinemic yellow KK mice and norepinephrine turnover

To clarify whether hyperinsulinemia accelerates sympathetic nervous system (SNS) activity, norepinephrine (NE) turnover, a reliable indicator of SNS activity, was measured in the interscapular brown adipose tissue (IBAT) and heart of hyperinsulinemic yellow KK and normoinsulinemic C57BL control mice at 12 weeks of age. The yellow KK mice were more obese and had higher levels of plasma glucose (about 2.3 times) and of plasma insulin (about 24 times) than did the control mice. In IBAT, the rate of NE turnover following blockade of NE synthesis with alpha-methyl-p-tyrosine (alpha-MPT) was significantly slower in yellow KK mice than in C57BL mice, although in heart, no significant difference between both groups was observed in NE turnover. These results suggest that hyperinsulinemia dose not always increase NE turnover, and furthermore that the reduced NE turnover in IBAT of yellow KK mice may be one of the important factors in the development of obesity of this animal, as it is recognized that brown adipose tissue is a main effector of diet-induced thermogenesis and its defect or absence would predispose to obesity.     

Effect of preventive and regressive isosorbide 5-mononitrate treatment on catecholamine levels in plasma, platelets, adrenals, left ventricle and aorta in cyclosporin A-induced hypertensive rats

Increased vascular reactivity associated with cyclosporin A (CsA)-induced arterial hypertension might result from increased vasoconstriction and/or decreased vasodilatation. The administration of organic NO donors could have beneficial effects by the NO-cGMP reposition, but there is the risk of sympathetic nervous system worsening by neuro-hormonal counter-regulation. We evaluate the effect of preventive and regressive (curative) isosorbide 5-mononitrate (Is-5-Mn) treatment on blood pressures and on plasma, platelets, adrenals, left ventricle and aorta norepinephrine (NE) and epinephrine (E) contents, assessed by HPLC, in CsA-induced hypertensive rats. Five rat groups were tested: control (orange juice), CsA (5 mg/kg/day) and Is-5-Mn (150 mg/kg/day, bid) groups were treated for 7 weeks; preventive group (Is-5-Mn+CsA): Is-5-Mn during 2 weeks plus 7 weeks of Is-5-Mn+CsA; regressive group (CsA+Is-5-Mn): CsA during 7 weeks plus 5 weeks of CsA+Is-5-Mn. The increased BP in the CsA group was prevented, but was not reverted, by concomitant Is-5-Mn treatment. In the CsA-treated rats, there was a noticeable decrease in left ventricle NE and E contents and aorta NE levels and a moderate increase in circulating catecholamines, without significant effect in the adrenals values. When Is-5-Mn was preventively used, the CsA-induced effect on left ventricle and aorta was prevented. Concomitantly, however, the plasma-platelet catecholamine balance was disrupted, accumulating NE in plasma, whereas E increased in aorta, mimic the single Is-5-Mn-treated group. In opposition, in the group used as regressive Is-5-Mn therapy, the adrenals contents were higher compared with the CsA-group and, simultaneously, the CsA-evoked effects on circulating, left ventricle and aorta catecholamines were not reverted. In conclusion, regressive Is-5-Mn therapy was unable to attenuate CsA-induced catecholamine changes and BP values even worsened. On the contrary, preventive Is-5-Mn treatment prevented the catecholamine changes on left ventricle and aorta, but increased plasma NE and aorta E accumulation. Even though with those effects, hypertension development was totally prevented, suggesting that peripheral SNS per se cannot fully explain CsA-induced hypertension. Furthermore, Is-5-Mn might produce beneficial effects only if preventively employed but, considering the changes on peripheral catecholamine contents, a judicious evaluation of the nitrate therapy impact is recommended in order to avoid further deleterious effects.     

Effects of CL 115,347, (±)-15-deoxy-16-vinyl-PGE2 methyl ester, on cardiovascular responses and plasma catecholamines in pithed stroke-prone spontaneously hypertensive rats during sympathetic stimulation

The effect of CL 115,347, a topically active antihypertensive PGE₂ analog, and PGE₂ on changes in blood pressure (BP), heart rate (HR) response and plasma epinephrine (E) and norepinephrine (NE) levels induced by stimulation of the sympathetic spinal cord outflow were studied in pithed stroke-prone spontaneously hypertensive rats (SHRSP). Surgical pithing significantly reduced plasma E but not NE levels suggesting that the sympathoadrenal medullary system differentially affects E and NE release. Sympathetic stimulation of the spinal cord of pithed SHRSP increased HR, BP, plasma E and NE levels. Topically applied CL 115,347 (0.001–0.1 mg/kg) dose-dependently decreased BP, while intravenously infused PGE₂ (30 μg/kg/min) did not alter BP except for a brief initial drop. Topical application of CL 115,347 (0.1 mg/kg) also inhibited BP responses to sympathetic stimulation without effects on HR or plasma E or NE levels. Intravenous infusion of PGE₂ (30 μg/kg/min) inhibited both BP and HR responses to spinal cord stimulation but did not alter plasma catecholamine levels. These studies in SHRSP suggest that CL 115,347 and PGE₂ modulate cardiovascular responses mainly via postjunctional effects, but act differently on the cardiovascular elements, CL 115,347 acts primarily on blood vessels while PGE₂ acts on blood vessels and heart.     

Whole body norepinephrine kinetics in ANG II-salt hypertension in the rat

The purpose of this study was to investigate total body norepinephrine (NE) kinetics as an index of global sympathetic nervous system (SNS) outflow in a rat model of chronic ANG II-salt hypertension. Male Sprague-Dawley rats fed a 0.4% (normal salt, NS) or 2% (HS) NaCl diet were instrumented with arterial and venous catheters. After 5 days of recovery and a 3-day control period, ANG II (150 ng.kg(-1).min(-1)) was given subcutaneously by minipump for 14 days. Plasma NE levels and total body NE spillover and clearance were determined on control day 3 and ANG II infusion days 7 and 14 using radioisotope dilution principles. To perform this analysis, 3H-NE and NE were measured in arterial plasma after a 90-min infusion of tracer amounts of 3H-NE. Mean arterial pressure (MAP) was similar during the control period in NS and HS rats; however, MAP increased to a higher level in HS rats. During the control period, plasma NE tended to be lower in rats on HS, whereas NE clearance tended to be higher in HS rats. As a result NE spillover was similar in NS and HS rats during the control period. In NS rats, plasma NE, NE spillover, and NE clearance were unchanged by ANG II. In contrast, in rats on the HS diet, plasma NE and NE spillover increased during ANG II infusion, whereas NE clearance was unchanged. In conclusion, a HS diet alone or ANG II infusion in animals fed NS do not affect global sympathetic outflow. However, the additional hypertensive response to ANG II in animals fed HS is accompanied by SNS activation.     

Plasma catecholamine responses to exercise after training with beta-adrenergic blockade

Exercise training has been shown to decrease plasma norepinephrine (NE) and epinephrine (EPI) levels during absolute levels of submaximal exercise, which may reflect alterations in sympathetic tone as a result of training. To determine if beta-adrenergic blockade altered these changes in the plasma concentration of catecholamines with exercise conditioning, we studied the effects of beta-adrenergic blockade on NE and EPI at rest and during exercise in 24 healthy, male subjects after a 6-wk exercise training program. The subjects were randomized to placebo (P), atenolol 50 mg twice daily (A), and nadolol 40 mg twice daily (N). There were no changes in resting NE and EPI compared with pretraining values in any subject group. During the same absolute level of submaximal exercise NE decreased in P and A but was unchanged in N, whereas EPI decreased only in P. At maximal exercise all three groups developed significant increases in NE after training that paralleled increases in systolic blood pressure. EPI at maximal exercise increased after training with N but was unchanged with P or A. These training-induced changes in plasma catecholamine levels were masked or blunted when the A and N groups were studied while still on medication after training. Thus beta-adrenergic blockade has important effects on adaptations of the sympathetic nervous system to training, especially during submaximal exercise.     

Reduced sympathetic nervous system activity in rats with ventromedial hypothalamic lesions

To determine if alterations in sympathetic nervous system (SNS) activity occur in rats with ventromedial hypothalamic (VMH) lesions, norepinephrine (NE) turnover rates were examined in various tissues of lesioned and control, weanling rats. VMH-lesioned rats fed a high-carbohydrate diet ad libitum for 4 weeks following surgery were not hyperphagic, but they gained 50% more body energy than control rats. VMH lesions extended the half-life of ³H-NE in interscapular brown adipose tissue (BAT) by 42%, in abdominal white adipose tissue (WAT) by 201%, in heart by 61% and in pancreas by 85%, and reduced total NE turnover (ng/organ/hr) in BAT (38%), WAT (57%), heart (30%) and pancreas (53%). Reduced SNS activity in BAT is consistent with the decreased energy expenditure (heat production) and increased energy efficiency observed in VMH-lesioned rats. In WAT, decreased SNS activity coupled with hyperinsulinemia would facilitate energy storage as fat by reducing lipid mobilization. In the pancreas, reduced SNS activity would contribute to hyperinsulinemia. These results support the hypothesis that VMH lesions decrease SNS activity in several organs. This change in autonomic tone is very likely a major factor in the development of obesity in VMH-lesioned animals.     

Superior cervical ganglionectomy effects on median eminence and anterior and mediobasal hypothalamic taurine content in male rats: effects of hyperprolactinemia

The neuroendocrine sequelae of acute or chronic superior cervical ganglionectomy in control or pituitary-grafted rats were studied by analyzing both plasma prolactin, growth hormone (GH) and ACTH levels, and taurine (TAU) content in the hypophysiotropic area of the hypothalamus or the median eminence. As expected, after either acute or chronic ganglionectomy, norepinephrine (NE) content decreased in the brain areas studied, although the values remained higher in hyperprolactinemic rats. TAU content was differentially modified by acute vs. chronic surgeries, thus indicating the possible existence of hypothalamic interactions between TAU and NE to regulate pituitary hormone secretion. Indeed, associated differential changes in plasma prolactin, GH and ACTH levels may be due to the observed TAU changes. As expected, pituitary grafting increased plasma prolactin, GH and ACTH levels, so that the presence of a pituitary graft differentially interferes with the effects of either surgery not only on TAU content but also on the plasma levels of the hormone studied. Globally, ongoing studies confirm the differential effects of acute and chronic superior cervical ganglionectomy on plasma prolactin, GH and ACTH levels, and provide new evidence about its effects on TAU content in the hypophysiotropic area of the hypothalamus and the median eminence that may partially explain the changes observed in the pituitary hormones studied.     

Vascular escape from vasoconstriction and post-stimulatory hyperemia in the superior mesenteric artery of the cat

Vascular escape is seen as a partial recovery from initial vasoconstriction despite continued constrictor stimuli. Escape in the feline intestine (superior mesenteric artery) occurred for i.a. norepinephrine (NE) infusions (56% escape for low dose, 40% for high dose NE) and for sympathetic nerve stimulation (SNS) (65% for 1 Hz, 49% for 3 Hz, 44% for 9 Hz). Adenosine infusion or blockade of adenosine receptors (8-phenyltheophylline) did not alter the escape, showing that endogenous adenosine levels are unlikely to play any role in the mechanism of escape. Other aspects of escape were studied: equiconstrictor doses of NE given i.a. or i.v. lead to similar degrees of escape; propranolol and ouabain did not alter escape; the degree of escape was significantly greater for the low dose NE and the 1-Hz SNS than for higher intensities of stimulation, however, escape did not inversely correlate significantly with the initial degree of vasoconstriction when all data were pooled. Post-stimulatory hyperemia occurs upon cessation of vasoconstrictor stimuli, reaches a peak conductance within 1 min, and returns to baseline within about 3 min. Hyperemia was quantitated from the peak vasodilation and from the area under the flow-hyperemia curve. The hyperemias were not related to NE dose or SNS frequency nor did they correlate with initial vasoconstriction or extent of vascular escape. Contrary to the hypothesis that adenosine may mediate hyperemia, adenosine infusions reduced the response and adenosine receptor antagonism tended to elevate the response. Propranolol and ouabain did not produce significant effects on post-stimulatory hyperemia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison between effects of dantrolene and nifedipine on lipopolysaccharide-induced endotoxemia in the anesthetized rats

Intracellular calcium is an important mediator for regulating the cellular response in endotoxemia. In this study, we investigated the effects of dantrolene and nifedipine, two agents of reducing intracellular calcium levels, on bacterial endotoxin (lipopolysaccharide, LPS; 10 mg/kg i.v.)-induced production of tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) as well as hemodynamic changes in the anesthetized rat. Injection of LPS (i) induced biphasic changes of blood glucose and rectal temperature: an initial increased phase (<180 min after injection of LPS) followed by a decreased phase (at 240 or 360 min), (ii) caused a significant fall in mean arterial blood pressure from 119+/-3 mmHg (at time 0) to 73+/-67 mmHg (at 360 min) with a concomitant increase of heart rate, (iii) resulted in a substantial hyporeactivity to norepinephrine (NE) (1 microg/kg i.v.), (iv) increased plasma nitrate (an indicator of NO formation) in a time-dependent manner, and (v) induced bell-shape changes in plasma TNF-alpha levels which reached a peak at 60 min. Pretreatment of animals with dantrolene (1 mg/kg i.v. at 20 min prior to LPS) or nifedipine (20 microg/kg i.v. infusion for 20 min at 20 min prior to LPS) not only attenuated the delayed circulatory failure (e.g. delayed hypotension and vascular hyporeactivity to NE), but also prevented the overproduction of NO caused by LPS in the rat. However, the prevention of NO overproduction by dantrolene, but not by nifedipine, was associated with an inhibition of TNF-alpha production elicited by LPS. Thus, both dantrolene and nifedipine have beneficial hemodynamic effects, although through different mechanisms, in animals with endotoxic shock.