Search

A single bout of low-frequency electroacupuncture (EA) causing muscle contractions increases whole-body glucose uptake in insulin-resistant rats. We explored the underlying mechanism of this finding and whether it can be translated into clinical settings. Changes in glucose infusion rate (GIR) were measured by euglycemic-hyperinsulinemic clamp during and after 45 min of low-frequency EA in 21 overweight/obese women with polycystic ovary syndrome (PCOS) and 21 controls matched for age, weight, and body mass index (experiment 1) and in rats receiving autonomic receptor blockers (experiment 2). GIR was higher after EA in controls and women with PCOS. Plasma serotonin levels and homovanillic acid, markers of vagal activity, decreased in both controls and patients with PCOS. Adipose tissue expression of pro-nerve growth factor (NGF) decreased, and the mature NGF/proNGF ratio increased after EA in PCOS, but not in controls, suggesting increased sympathetic-driven adipose tissue metabolism. Administration of alpha-/beta-adrenergic receptor blockers in rats blocked the increase in GIR in response to EA. Muscarinic and dopamine receptor antagonist also blocked the response but with slower onset. In conclusion, a single bout of EA increases whole-body glucose uptake by activation of the sympathetic and partly the parasympathetic nervous systems, which could have important clinical implications for the treatment of insulin resistance.-Benrick, A., Kokosar, M., Hu, M., Larsson, M., Maliqueo, M., Marcondes, R. R., Soligo, M., Protto, V., Jerlhag, E., Sazonova, A., Behre, C. J., Hojlund, K., Thoren, P., Stener-Victorin, E. Autonomic nervous system activation mediates the increase in whole-body glucose uptake in response to electroacupuncture.

Congenital heart block develops in fetuses after placental transfer of Ro/SSA autoantibodies from rheumatic mothers. The condition is often fatal and the majority of live-born children require a pacemaker at an early age. The specific antibody that induces the heart block and the mechanism by which it mediates the pathogenic effect have not been elucidated. In this study, we define the cellular mechanism leading to the disease and show that maternal autoantibodies directed to a specific epitope within the leucine zipper amino acid sequence 200–239 (p200) of the Ro52 protein correlate with prolongation of fetal atrioventricular (AV) time and heart block. This finding was further confirmed experimentally in that pups born to rats immunized with p200 peptide developed AV block. p200-specific autoantibodies cloned from patients bound cultured cardiomyocytes and severely affected Ca2+ oscillations, leading to accumulating levels and overload of intracellular Ca2+ levels with subsequent loss of contractility and ultimately apoptosis. These findings suggest that passive transfer of maternal p200 autoantibodies causes congenital heart block by dysregulating Ca2+ homeostasis and inducing death in affected cells.

DeltaFosB is a transcription factor that accumulates in a region-specific manner in the brain after chronic perturbations. For example, repeated administration of drugs of abuse increases levels of DeltaFosB in the striatum. In the present study, we analyzed the effect of spontaneous wheel running, as a model for a natural rewarding behavior, on levels of DeltaFosB in striatal regions. Moreover, mice that inducibly overexpress DeltaFosB in specific subpopulations of striatal neurons were used to study the possible role of DeltaFosB on running behavior. Lewis rats given ad libitum access to running wheels for 30 d covered what would correspond to approximately 10 km/d and showed increased levels of DeltaFosB in the nucleus accumbens compared with rats exposed to locked running wheels. Mice that overexpress DeltaFosB selectively in striatal dynorphin-containing neurons increased their daily running compared with control littermates, whereas mice that overexpress DeltaFosB predominantly in striatal enkephalin-containing neurons ran considerably less than controls. Data from the present study demonstrate that like drugs of abuse, voluntary running increases levels of DeltaFosB in brain reward pathways. Furthermore, overexpression of DeltaFosB in a distinct striatal output neuronal population increases running behavior. Because previous work has shown that DeltaFosB overexpression within this same neuronal population increases the rewarding properties of drugs of abuse, results of the present study suggest that DeltaFosB may play a key role in controlling both natural and drug-induced reward.

To determine whether prenatal hypoxia increases the risk of developing cardiovascular disorders as an adult and, if so, the identity of the cell mechanisms involved in such dysfunction, we evaluated the sympathoadrenal system and central areas related to cardiovascular events during development and the cardiovascular parameters in adults. Pregnant rats were exposed to hypoxia (10% oxygen) from embryonic day (E) 5 to E20 and the offspring studied at 1, 3, 9 and 12 weeks of age for neurochemistry and at 12 weeks of age for cardiovascular analysis. In the 1-, 3- and 9-week-old offspring, the levels and utilization of catecholamines were reduced in sympathetic ganglia, in target organs, in adrenals and in the rostral part of the A2 cell group in the nucleus tractus solitarius, but were increased in the locus coeruleus. In the 12-week-old adult offspring, the lowered autonomic nervous activity was restricted to cardiac-related structures, i.e. the stellate ganglion, heart and adrenals. In adult rats, prenatal hypoxia did not affect the cardiac parameters under resting conditions but increased blood pressure and the variability of blood pressure and heart rate under stress conditions. The altered metabolic activity of the sympathoadrenal system and related central areas during development and at adulthood for most structures might be part of the potential mechanisms contributing to cardiovascular disorders in adults.

Septic shock, a major cause of death, is characterized by a pathophysiologic increased production of nitric oxide (NO), which leads to vasodilation and myocardial toxicity. Septic Escherichia coli frequently express proteinaceous curli fibers. In this study, curliated E. coli induced high levels of NO by directly inducing type 2 nitric oxide synthase (NOS2) both in vitro and in vivo. More severe hypotension and higher plasma nitrite/nitrate levels were seen in wild type mice systemically infected with curliated E. coli than in animals infected with E. coli mutants that lacked curli proteins. Blood pressure remained stable in NOS2-deficient mice with curliated bacteria. Increased heart rates, transient hypothermia, and loss of gross activity were seen in all mice, regardless of curli expression. Study results suggest that expression of curli fibers by E. coli activates the NO/NOS2 arm of the innate immune system, which leads to a significant fall in blood pressure.

The effects of somatic nerve stimulation on cholera toxin induced secretion was investigated in vivo in anaesthetised rats. Small intestinal secretion was induced with cholera toxin and measured by a gravimetric technique. Afferent stimulation (pulse frequency within train; 100 Hz; train duration: 50 ms; train frequency: 3 Hz) of the sciatic nerve over 30 min significantly reduced the net fluid secretion both during (P0.05) and after cessation of the stimulation (P0.01). The greatest effect was obtained immediately after the termination of the nerve stimulation when the secretion was reversed to net fluid absorption. The opioid receptor antagonist naloxone (10 mg kg(-1) i.v.) administrated during the stimulation, significantly inhibited the antisecretory effect seen after the stimulation, thus no significant difference was seen between the control period and the periods after cessation of the stimulation. The opioid receptor antagonist naloxone methiodide (10 mg kg(-1) i.v.), which does not cross the blood-brain barrier, partly inhibited the antisecretory effects but not with the same magnitude as naloxone, thus the net fluid secretion was still significantly inhibited after the stimulation (P0.05). We conclude that afferent stimulation of the sciatic nerve strongly inhibits the cholera toxin induced secretion in the small intestine. This inhibition involves primarily a central opioid mechanism and to a lesser extent peripheral opioid mechanism.

The effects of a neuropeptide Y (NPY) Y1-receptor antagonist (BIBP 3226) on mean arterial pressure (MAP) and heart rate were investigated in conscious unrestrained rats with chronic congestive heart failure. The rats were randomly assigned to 2 groups, and received either BIBP 3226 or its inactive enantiomer (BIBP 3435) as an intravenous infusion (6 mg/kg/h for 1.5 h, respectively). Before, during and after the infusion, rats were stressed with a jet of air and received a bolus injection of NPY (2 nmol/kg iv.). There was no difference between the 2 groups in resting MAP and heart rate before, during or after infusion (BIBP 3226 vs. BIBP 3435). The effects of exogenous NPY on MAP were significantly attenuated in BIBP 3226 group during and 1 h after the infusion (p0.05). The tissue NPY levels in heart, adrenal gland and kidney in heart failure rats were not different from those in sham-operated rats. The results suggest that Y1-receptor mechanisms are of minor importance in the short-term control of basal MAP and heart rate in conscious unrestrained rats with congestive heart failure.

To study possible effects of physical training on the expression of neurotrophic factors and their receptors in the brain, we used a rat strain (spontaneously hypertensive rat, SHR), known to spontaneously run up to 20 km/night. We show that such long-distance running affects the brain-derived neurotrophic factor (BDNF) and TrkB system in hippocampus, and in particular that abrupt deprivation of habitual running leads to long-lasting decreases of BDNF/TrkB expression in hippocampus. Quantitative in situ hybridization demonstrates that running increases the expression of mRNA coding for BDNF and its high affinity receptor TrkB in hippocampus in a running length dependent manner. In addition, we show that an abrupt interruption of prolonged spontaneous exercise decrease expression of mRNA encoding BDNF and TrkB in certain hippocampal areas and that this decrease lasts at least 10 days. This down-regulation was most prominent in medial cornu ammonis 3 (CA3M). Several other trophic factors and receptors were investigated, including NGF, NT3, GDNF, trkC and p75. For these other probes investigated, no robust changes in mRNA expression were noted. Areas examined included sensorimotor cortex and hippocampus. For RET, p75, NT3, TrkB and BDNF we also examined the spinal cord without detecting any robust changes. We conclude that spontaneous running as well as its abrupt termination, leads to area-specific and trophic factor-specific changes in hippocampus.

Central haemodynamics were studied in one group of morphine-dependent rats, and in a non-dependent control group, before and after administration of repeated bolus doses of naloxone. Dependence was induced by s.c. morphine pellet implantations. Mean arterial pressure (MAP), heart rate (HR), cardiac output (CO) and mean transit time (MTT) were measured in the conscious state, after induction of chloralose anaesthesia and after the administration of naloxone (0.005, 0.05, 0.5 and 5 mg kg-1 i.v.). Total peripheral resistance (TPR), stroke volume (SV) and central blood volume (CBV) were subsequently calculated. The haemodynamic variables did not differ significantly in the conscious state, except for a lower SV, when compared with the non-dependent control group. However, in response to anaesthesia the dependent rats exhibited a greater fall in MAP, mainly due to a TPR decrease. Naloxone elicited a marked increase in MAP in the morphine-dependent group, which was mainly caused by an increase in TPR. Naloxone induced no significant change compared with the control group in CO and CBV, while SV increased concomitantly with a lowered HR after naloxone in the morphine-dependent group. These results suggest that the withdrawal hypertension during morphine abstinence was mainly explained by an increase in TPR, reflecting an augmented tone of the resistance vessels. The minor changes in CBV indicate that the tone of the venous capacitance vessels was largely unaffected by naloxone-induced morphine abstinence.

A pharmaceutically acceptable microemulsion system composed of a medium-chain triglyceride (MCT), soybean phosphatidylcholine and poly(ethylene glycol)(660)-12-hydroxystearate (12-HSA-EO15) as amphiphiles, and poly(ethylene glycol) 400 (PEG 400) and ethanol as cosolvents is presented and characterized in terms of phase behavior, microstructure, solubilization capacity and in vivo effects after intravenous administration to conscious rats. At a total concentration of 11.9 wt % of soybean phosphatidylcholine and 12-HSA-EO15, a microemulsion region was formed over a wide range of alpha, where alpha is the weight fraction of MCT/(MCT + water + PEG 400 + ethanol). The microstructure of the microemulsion was of a bicontinuous nature even at high oil concentrations. The mean droplet diameter of the oil-in-water emulsion formed after dilution of microemulsions prepared at different alpha within the one-phase region was between 60 and 200 nm. It was concluded that it is possible to administer up to 0.5 mL/kg of the microemulsion (alpha = 0.5) without producing any significant effect on acid-base balance, blood gases, plasma electrolytes, mean arterial blood pressure (MAP), heart rate (HR), and PQ time (the time between depolarization of atrium and chamber). At a dose of 1.5 mL/kg, a temporary increase in MAP, a decrease in HR, and a prolongation of the PQ time were observed.

1,1-dimethylguanidine (DMG) is an endogenous nitric oxide (NO) synthesis inhibitor. This study investigates the effects of exogenous DMG administration, in anaesthetized spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Mean blood pressure (MBP), heart rate (HR) and renal sympathetic nerve activity (SNA) were recorded in 12- to 14-week old, anaesthetized SHR and WKY. Each rat received increasing bolus injections of DMG intravenously (1.03, 2.05, 6.39, 20.45 and 51.15 mg kg-1). In separate experiments, SHR received L-arginine or D-arginine in a dose of 300 mg kg-1 followed by DMG at 6.39 mg kg-1. Thirty minutes later they received the same doses of the respective arginines followed by DMG at 20.45 mg kg-1 DMG induced dose-dependant increases in MBP in SHR and WKY. In SHR, HR increased with increasing doses of DMG (except at the near-toxic doses of 51.15 mg kg-1), whereas in WKY HR decreased with increasing doses of DMG. The net change of renal SNA ranged from -5 +/- 3 to -55 +/- 12% in SHR and from -6 +/- 8 to -66 +/- 8% in WKY. Pre-treatment with L-arginine in SHR partly inhibited the pressor effect and attenuated the inhibition of renal SNA induced by DMG, but had little effect on HR. Thus the administration of NO inhibitor DMG could alter cardiovascular function and sympathetic nerve activity, and subsequently resulted in tachycardia in SHR and bradycardia in WKY.

We have studied the effect of chronic intracerebroventricular (i.c.v.) infusion of different opioid peptides on natural killer (NK) cell mediated cytotoxicity in vivo in the spontaneously hypertensive rat (SHR). The in vivo NK cell activity was measured as the clearance of 51Cr-labelled YAC-l lymphoma cells from the lung tissues. Further, the phenotype of lymphocytes in spleen and peripheral blood was analysed by flow cytometry (FACS). All opioid drugs were administered i.c.v. for 6 days with osmotic minipumps releasing 1.0 microliter/h. beta-Endorphin (10 or 20 micrograms/rat per day) significantly increased NK cell cytotoxicity in vivo. The opioid receptor antagonist naloxone (10 mg/kg, i.p.) given immediately before the injection of YAC-lymphoma cells, completely abolished the effects of i.c.v. administered beta-endorphin. Corresponding doses of beta-endorphin administered subcutaneously (s.c.) with minipumps for 6 days did not significantly affect NK cell cytotoxicity. Neither Leu- or Met-enkephalin (20 micrograms/rat per day) nor dynorphin (20 micrograms/rat per day) administered i.c.v. had any significant effects on NK cell activity. In beta-endorphin treated SHR, the percentage of cells with NK cell phenotype (OX52+/CD5-) in peripheral blood was not significantly different from that of controls, while the percentage of cells with T cell phenotype (CD5+/OX52-) was significantly decreased. The percentage of splenic NK cells (OX52+/CD5-) and T cells (CD5+/OX52-) was also unchanged by beta-endorphin treatment i.c.v. These results suggest that of the opioid peptides administered i.c.v., only beta-endorphin augments in vivo NK cell mediated cytotoxicity. We thus conclude that these effects most probably are centrally and opioid receptor mediated effects, since beta-endorphin in the same dose administered peripherally does not influence in vivo NK cell cytotoxicity.

Hypertonic solutions act in the central nervous system (CNS) to increase mean arterial blood pressure (MAP) by activation of the sympathoadrenal axis. However, adrenal nerve activity (pre- and postganglionic nerve fibers) has not been determined during central osmotic stimulation. Therefore, these experiments evaluated adrenal (AdSNA) and renal (RSNA) sympathetic nerve activity, MAP, and heart rate (HR) following CNS administration of isotonic, hypertonic, and hypotonic sodium chloride solutions in chloralose-anesthetized rats. Injection of isotonic saline (5 microliters) did not alter MAP, HR, RSNA, or AdSNA. However, injection of hypertonic saline (5 microliters of 0.5 M) into the anteroventral portion of the third cerebral ventricle increased MAP (12 +/- 2 mmHg) and decreased HR (16 +/- 6 bpm). In addition, hypertonic saline significantly decreased RSNA (58 +/- 5% control), whereas AdSNA increased (158 +/- 10% control). Injection of hypotonic (5 microliters of 0.05 M) NaCl produced the opposite responses in RSNA (119 +/- 7% control) and AdSNA (86 +/- 5% control) and had no significant effect on MAP or HR. Furthermore, pre- and postganglionic adrenal nerve fibers responded similarly to changes in CNS osmolality. These results demonstrate that osmotic stimulation produces differential responses in RSNA and AdSNA, but not in pre- and postganglionic adrenal nerve fibers.

Recently emerging evidence has indicated that efferent renal sympathetic nerve activity (RSNA) is increased in congestive heart failure (CHF). In the present study the cyclic activity of the renal nerve in the normal and CHF rat was studied. An ischaemic myocardial lesion resulting in CHF was induced by left coronary artery ligation. Sham-operated rats subjected to thoracotomy served as normal controls. Renal sympathetic nerve activity was recorded under chloralose anaesthesia. The neural cycle activity was significantly higher in CHF (47 +/- 3%) compared with sham-operated rats (34 +/- 3%, P < 0.005). Baroreceptor control of RSNA was significantly attenuated in CHF compared with normal control rats (P < 0.005). In response to noxious thermal stimulation by 48 degrees C water immersion of the tail tip, the increase of RSNA was significantly higher in CHF compared with sham-operated rats. A stepwise 15% blood volume expansion over 5 min which induced no alterations of blood pressure or heart rate (HR) resulted in a gradual decrease of RSNA in control rats by approximately 25% at the end of the volume expansion procedure. In CHF rats however, there was no significant change in RSNA during volume expansion. It is concluded that in CHF rats: (1) efferent RSNA is increased; (2) baroreceptor control of RSNA is decreased; (3) RSNA in response to cutaneous thermal noxious stimulation is exaggerated; and (4) RSNA inhibition by cardiopulmonary receptors is blunted.

The activity in cerebrospinal fluid (CSF) of dynorphin-converting enzyme (DCE) has been studied after voluntary exercise in the spontaneously hypertensive (SH) rat. The exercise consisted of spontaneous running in wheels for 4–5 weeks and the average running distance during the last two weeks was 4.0 km/24h. CSF samples were obtained under anaesthesia from the cisterna magna after penetration of the atlanto-occipital membrane. DCE transforms the members of the dynorphin family of opioid peptides into Leu-enkephalin-Arg6. In the present investigation a radioimmunoassay was used for quantitation of Leu-enkephalin-Arg6 release from dynorphin A1–17 and dynorphin B1–13. The rats that were running had a DCE activity (vs. both substrates) in CSF that was approximately 6–12 times higher than in animals not given the running opportunity. A statistically significant correlation between the two prodynorphin-derived substrate peptides was found in terms of DCE activity. We therefore propose that a single enzyme activity may be responsible for the hydrolysis of dynorphin B1–13 and dynorphin A1–17. Furthermore, a significant correlation was also found between running activity and DCE activity 12–14 h before the CSF was withdrawn. Besides measurement of DCE activity by radioimmunoassay, the formation of Leu-enkephalin-Arg6 was identified by reversed-phase micro-column liquid chromatography and plasma desorption mass spectrometry. The experiment shows that voluntary exercise affects opioid peptidergic mechanisms.

The aim of the study was to compare pre-ganglionic adrenal nerve activity (pre-aSNA) to post-ganglionic adrenal nerve activity (post-aSNA) in rats after administration of 2-deoxy-d-glucose (2-DG, 500 mg kg-1, i.v.), which mimicks a central hypoglycaemia or to the response in pre-aSNA and post-aSNA to hypoglycaemia after injection of insulin (5U). Renal postganglionic sympathetic nerve recordings (rSNA) in a separate group was used as a reference. Adrenal or renal multifibre nerve activity was recorded in chloralose-anaesthetized Wistar-rats. Trimethaphan, a short-lasting ganglionic blocker, was administered i.v. (10 mg kg-1) in order to test for pre- or post-aSNA in the adrenal nerves. The adrenal nerves was considered to contain predominantly post or preganglionic fibres, respectively if the nerve activity in the adrenal nerve decreased (post-aSNA) or increased (pre-aSNA). In contrast, all renal nerves showed almost a pure postganglionic activity. Post-aSNA responded with a tendency to increase after the 2-DG injection. The highest value (percentage change from control) 5 min after injection was 12 ± 9%. The pre-aSNA increased with values of 99 ± 52% at 3 min and 86 ± 31% at 5 min (percentage change from control). The activity in the rSNA was only slightly decreased after the injection of 2-DG when compared to pre-drug control activity. There was a significant difference between the pre-aSNA vs. post-aSNA at 1 min (P < 0.05), 3 min (P < 0.01) and 5 min (P < 0.05). Insulin caused an increase in post-aSNA with the maximum level of 154 ± 8% reached at 40 min compared to pre-aSNA, which increased substantially and reached a peak value of 349 ± 43% at 50 min. RSNA was also increased with a maximum level, 160 ± 29% at 50 min (P < 0.01). There was a significant difference in the main effect in pre-aSNA vs. post-aSNA. Thus, this study gives further evidence that the adrenal gland is innervated by both post- and pre-ganglionic fibres with different characteristics.

The aim of this study was to examine and characterize the post-ganglionic innervation of the adrenal gland, using a neurophysiological nerve recording technique. Adrenal multifibre nerve activity was recorded in chloralose-anaesthetized Wistar rats. To test for post-ganglionic nerve activity, trimethaphan, a ganglionic blocker, was given intravenously. About 60% of the adrenal nerve preparations tested responded with a marked decrease in nerve activity (to 52 +/- 11% of pre-trimethaphan activity, P less than 0.01), while other nerves responded with an increase in activity (to 152 +/- 29% of pre-trimethaphan activity, P less than 0.01). Based on these responses, the nerves were considered to contain predominantly post- or preganglionic fibres respectively, and the difference in response to an intravenous injection of trimethaphan between the two groups was significant (P less than 0.01). It was also demonstrated that the post-ganglionic adrenal nerve activity had a greater variability in firing pattern than preganglionic adrenal nerve activity. We also examined whether there was any cardiac rhythmicity in the investigated nerves. There was a weak cardiac rhythmicity in six out of 12 post-ganglionic adrenal nerves, but there was no cardiac rhythmicity in the remaining six post-ganglionic nerves, and we observed no cardiac rhythmicity in preganglionic nerves. In contrast, renal sympathetic nerves showed a profound cardiac rhythmicity. Our results might explain recent histological findings of a direct post-ganglionic innervation of the adrenal cortex. We speculate that this nerve population is involved in steroid synthesis indirectly via regulation of the cortical blood flow or directly via a direct innervation of parenchymal cells in the adrenal cortex.

In a previous study, prolonged low-frequency muscle stimulation, inducing dynamic contractions in the hind leg of unanaesthetized rats, was shown to give rise to a hypoalgesia. The increase in pain threshold, measured as squeak threshold to noxious electric pulses, lasted 3 h. In the present study, the involvement of the endogenous opioid system in the post-stimulatory analgesia was investigated using selective opioid receptor antagonists. The post-stimulatory analgesia was completely reversed back to prestimulatory control levels by naloxone, 1 mg kg-1. ICI 154, 129 and MR 2266 BS, selective δ- and ±-receptor antagonists respectively, did not significantly influence the post-stimulatory analgesia, although ICI 154, 129 had a minor pain threshold-lowering effect. Rats pretreated with β-funaltrexamine, a μ-preceptor antagonist, did not exhibit any post-stimulatory analgesia. These results suggest that opioid systems are involved in the increase in pain threshold after muscle stimulation and that the analgesic response is both elicited and maintained by the μ-preceptor.

In a previous study prolonged low-frequency muscle stimulation in the hind leg of the spontaneously hypertensive rat (SHR) was shown to induce a reduction in blood pressure (about 15 mmHg) that lasted for many hours. We showed in that study that endorphin and serotonin systems were involved. In the present study drugs with selective affinity for the serotonin (5-HT) receptors were used to analyse further the involvement of different serotonin systems. In one group of SHR, a prestimulatory dose of metitepine maleate (a 5-HT1 and 5-HT2 receptor antagonist) completely abolished the post-stimulatory depressor response. The long-lasting depressor response was still present, although less pronounced, after a bolus dose of the 5-HT2 blocking agent ritanserin (R 55667) at the start of stimulation. The 5-HT3 receptor antagonist ICS 205–930 did not influence the response at all, nor did the selective 5-HT1a receptor agonist 8-OH-DPAT enhance the depressor response. These results indicate that the reduction in blood pressure after muscle stimulation is mainly mediated by the 5-HT1 receptor.

The effect of voluntary exercise on cerebrospinal fluid (CSF) levels of immunoreactive beta-endorphin has been studied in the spontaneously hypertensive rat (SHR). The exercise consisted of 5-6 weeks of spontaneous running in wheels and the average running distance was 3.5 +/- 0.4 km/24 h. CSF samples were obtained under anaesthesia from the cisterna magna. Five experimental groups were examined, four groups of runners and one group of sedentary controls. The runners were sampled either (a) shortly (0-3 h) after termination of exercise, or after the wheel had been locked for (b) 24, (c) 48 or (d) 96 h. The runners in group a had significantly higher immunoreactive beta-endorphin levels than the controls. The levels remained increased as compared with controls after 24 and 48 h of enforced abstinence but had returned to control after 96 h. The data indicate that voluntary exercise induces adaptive changes in central beta-endorphin systems.

In a previous study, prolonged low-frequency muscle stimulation in the hind leg of the fully conscious spontaneously hypertensive rat (SHR) was shown to induce a long-lasting reduction of blood pressure. It was also shown that opioid and serotonergic (5-HT) systems were involved. More recently, we have shown that the 5-HT1 receptors are involved in the post-stimulatory decrease in blood pressure. In the present study, the influence of this type of muscle stimulation on the pain threshold was investigated. Pain perception was measured as the squeak threshold to noxious electric pulses. After cessation of the stimulation, an analgesic response was elicited within 60 min and peak analgesia developed after 120 min, being 139 +/- 10% (P less than 0.01) of the prestimulatory control value. The increased pain threshold lasted for another 2 h. One group of SHR was pretreated with PCPA, a serotonin synthesis blocker, which completely abolished the post-stimulatory analgesia. To analyse further the involvement of different serotonin systems, drugs with selective affinity for 5-HT receptors were used. In one group a prestimulatory dose of metitepine maleate (a 5-HT1&2 receptor antagonist) abolished the post-stimulatory elevation of the pain threshold. The prolonged analgesic response was still present after prestimulatory treatment with ritanserin or ICS 205-930 (5-HT2 and 5-HT3 blocking agents respectively). In another group of experiments, the serotonin receptor antagonists were administered post-stimulation to animals with fully elicited analgesia. None of the antagonists used could reverse the elevation of pain threshold towards prestimulatory levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Wheel running performed by rats is reinforcing, rewarding and possibly addictive. In this study we analyzed if wheel running could affect ethanol preference. Lewis rats, known to be both addiction-prone and to develop an excessive wheel running behavior, were given access to ethanol in a two-bottle free-choice paradigm. The animals reached a high and stable ethanol intake after 5 weeks. In the next phase, rats were subjected to ethanol withdrawal for 1, 2 or 4 weeks with or without access to running wheels. Finally animals were again given access to ethanol in the same two-bottle free-choice paradigm, combined with access to running wheels. The rats that ran in running wheels during 1 or 2, but not 4, weeks of ethanol withdrawal increased both ethanol intake and preference as compared with the control group that did not have access to the wheels. Previous studies have demonstrated that low doses of morphine increases ethanol preference. Here we show that also running potentiates ethanol intake and preference. Thus, running which shares many of the reinforcing properties with addictive drugs appears to potentiate rats to an increased preference for ethanol. Our results describe a behavioral interaction where running increases ethanol consumption.

Administration to anaesthetized rats of N-methyl-D-aspartate (NMDA 30 nmol ICV) induced a profound derangement of stimulation evoked potential (f-SEP) and also autonomic excitation with an increase in arterial blood pressure and heart rate. These effects were antagonised by pretreatment with dizocilpine (0.5 mg/kg IV). Pretreatment with chlormethiazole (20 mg/kg IV 26 min before NMDA) also markedly diminished the derangement of f-SEP. At the end of the registration period 2 h after NMDA the SEP had recovered to 72.7 +/- 3.4 (% of control; mean +/- SEM) in saline-treated rats as compared to 96.1 +/- 5.6% in chlormethiazole treated animals (P0.01). In contrast to dizocilpine, chlormethiazole alone had no effect on heart rate or blood pressure and did not alter the autonomic effects of ICV NMDA. These results demonstrate that chlormethiazole can antagonise some NMDA-receptor mediated functions, even though there is no evidence that it is an NMDA antagonist.

Chronic voluntary exercise in wheels for 5 weeks in spontaneously hypertensive rats (SHR) augments in vivo natural killer (NK) cell cytotoxicity. Endogenous beta-endorphin is increased in cerebrospinal fluid after voluntary exercise in rats and we have recently shown that beta-endorphin administered i.c.v. augments NK cell mediated cytotoxicity in vivo in a similar way as chronic voluntary exercise. We have now further investigated the involvement of central opioid systems in the exercise-induced augmentation in natural immunity. Exercise consisted of voluntary running in wheels for 5 weeks. In vivo cytotoxicity was measured as clearance of injected 51Cr-labeled YAC-1 lymphoma cells from the lungs. The clearance of YAC-1 cells in vivo was significantly increased in runners as compared to sedentary controls. Selective delta, kappa, or mu-opioid receptor antagonists were administered i.c.v. with osmotic minipumps during the last 6 days of the 5 weeks of running. The delta-receptor antagonist naltrindole (40-50 microg/day) significantly but not completely inhibited the enhanced NK-cell cytotoxicity seen after 5 weeks of exercise. Neither the kappa-receptor antagonist nor-BNI or the mu-receptor antagonist beta-FNA influenced the augmentation in NK cell cytotoxicity. Nor-BNI per se significantly augments in vivo cytotoxicity, indicating some inhibiting effect on natural immunity that could be mediated through the kappa-opioid receptor. Our data suggest the involvement of central delta-opioid receptors in the enhancement of natural cytotoxicity seen after chronic voluntary exercise.

We have examined the effects of chronic voluntary running for 30 d on the levels of nerve growth factor inducilble-B (NGFI-B) and neuron-derived orphan receptor 1 (NOR1) mRNAs in Fischer and Lewis rats. The aim was to compare the addiction-prone Lewis rat strain to the Fischer strain in a plausible model for natural reward. The Lewis strain ran markedly more than the Fischer strain, as indicated by the length of running per day when given free access to running wheels. Both strains progressively increased their amount of daily running. By day 14, Lewis rats had reached a maximal level corresponding to 10 km/d, which slowly decreased to approximately 8 km/d. Fischer rats ran considerably less, averaging approximately 1. 5 km/d by day 30. After 30 d of running, levels of mRNA encoding NGFI-B and Nor1 were decreased in cerebral cortex in Lewis but not Fischer rats. The downregulation of NGFI-B mRNA in Lewis rats could not be attenuated by the opioid receptor antagonist naloxone. Instead, naloxone by itself downregulated NGFI-B in striatum and cerebral cortex in both strains. In contrast, naloxone had no effect on Nor1 mRNA levels, although the running-induced downregulation of Nor1 was, in most cases, attenuated by naloxone. Data from the present study suggest that the same genetic factors contributing to the drug addiction-prone behavior of Lewis rats also control the excessive running behavior and that this coincides with downregulation of transcription factors of the NGFI-B family.

Previous investigations indicate that the spontaneously hypertensive rat (SHR) has elevated sympathetic tone at rest. The present study aimed to determine whether SHR has exaggerated sympatho-adrenal activation in response to various sympathetic stimuli. The mean blood pressure (MBP), heart rate (HR) and preganglionic adrenal sympathetic nerve activity (SNA) were recorded from conscious, unrestrained SHR and from its normotensive control, the Wistar-Kyoto rat (WKY) (n=7, respectively).Ganglionic blockade (trimethaphan, 5 mg/kg) reduced MBP identically in both groups of rats. It did not change HR in SHR, but increased HR significantly in WKY (P

We have recently shown that in vivo natural cytotoxicity is enhanced after chronic exercise in spontaneously hypertensive rats (SHRs). In the present report, we have studied the duration of this augmentation and some possible mechanisms involved. Exercise consisted of voluntary running for 4-5 weeks, with the running distance ranging from 2.7-15.6 km day(-1) during the last week of running. In vivo cytotoxicity was measured as clearance of injected 51Cr-labelled YAC-1 lymphoma cells from the lungs. The in vivo natural cytotoxicity was increased in running SHRs, and also in SHRs that had their running wheel locked for 24 and 48 h prior to the experiment, and was still present after 96 h. The enhancement of in vivo cytotoxicity after 5 weeks of exercise was abolished after an acute injection of the beta-adrenergic receptor antagonist timolol (0.5 mg kg(-1) i.v.), indicating that catecholamines are involved in this augmentation. Interestingly, 24 h after the last exercise bout, the increased natural cytotoxicity could be blocked by timolol. The opioid receptor antagonist naloxone given subcutaneously for 7 days by osmotic pumps (6 mg kg(-1) h(-1)) could not reverse the increased in vivo cytotoxicity seen in the running SHRs, suggesting that opioid receptor mechanisms are not involved, or at least not the naloxone-sensitive mu-receptor. Natural immunity was not influenced by the histamine H2 receptor antagonist ranitidine, either in controls or in runners, indicating that the natural killer cell-regulatory effect of histamine is not present in SHRs and does not seem to be involved in the exercise-induced changes in natural immune function. We conclude that the augmentation of in vivo natural cytotoxicity after voluntary chronic exercise in rats is long-lasting and that the augmentation is partly mediated by beta-adrenergic receptors.

We have previously shown that voluntary running for 4–5 weeks in the spontaneously hypertensive rat (SHR) significantly increased in natural cytotoxic mechanism in vivo, measured as clearance of 51Cr YAC-1 lymphoma cells from the lungs. In the present study, we have studied the possible role of the spleen and the splenic nerves in this augmentation. The SHR were randomly allocated to either a voluntary exercise group or a sedentary control group. After four weeks of exercise the runners and sedentary control SHR were further assigned to one of four groups: 1) no surgery, 2) sham operation, 3) splenic nerve section and 4) splenectomy. Splenectomy drastically reduced in vivo cytotoxicity in both runners and sedentary controls, but in vivo cytotoxicity of splenectomized voluntary runners was significantly higher than that of splenectomized sedentary control animals. Selective denervation of the spleen did not affect the in vivo cytotoxicity. These results indicate that the enhanced in vivo natural cytotoxic mechanism following voluntary chronic exercise in SHR is partly dependent on intact splenic function. However, this enhancement does not seem to be mediated by the splenic sympathetic nerves.

The brain regional dopamine (DA) and serotonin (5-HT) levels and turnover were studied in the spontaneously hypertensive rat (SHR), following voluntary, long-lasting (7 weeks) wheel-running exercise. Groups of rats were sacrificed 1-2 h, 23-24 h or 47-48 h after termination of the last running session, and the cerebral tissue levels of 5-HT, 5-HIAA, DA and DOPAC were determined and compared to corresponding levels obtained in sedentary controls. In the exercised animals, there was a selective decrease in the limbic forebrain levels of DOPAC in the immediate post-exercise period (1-2 h), while the DA turnover (DOPAC/DA ratio) was not altered. In addition, the 5-HT and 5-HIAA levels in the serotoninergic nerve terminal limbic forebrain and the 5-HT turnover (5-HIAA/5-HT ratio) in the cell body-containing brain stem areas were decreased in the immediate post-exercise period. No significant changes in the DA, DOPAC, 5-HT or 5-HIAA levels, nor in the DA and 5-HT turnover, were obtained in the remainder of the brain regions analyzed, regardless of time after termination of running. Taken together, the present study indicates that voluntary exercise in the SHR gives rise to differentiated regional effects on brain DA and 5-HT levels and turnover, thus supporting the view that changes in central monoaminergic activity are involved in the functional effects of long-term exercise. Interestingly, the psychomotor-associated limbic forebrain areas appeared particularly susceptible.

The aim of this study was to investigate the blood flow in the adrenal cortex of the rat. Relative changes in the adrenal cortical blood flow were continuously measured by Laser Doppler flowmetry in 33 chloralose-anaesthetized artificially ventilated rats during electrical stimulation (1 ms, 5 V) of the left great splanchnic nerve (LGSN), which conveys both pre- and post-ganglionic nerve fibres to the adrenal gland. Laser Doppler flux (LDF) was decreased and regional resistance (RR) was increased by augmenting nerve stimulation at increasingly higher frequencies (2, 4, 8, 20 and 40 Hz). The decrease in LDF, when compared to pre-drug stimulations at 4 Hz was partially or totally inhibited by the adrenergic blocking agents trimethaphan (TRIM), guanethidine (GUA) and alpha 1-blockade with prazosin (PRAZ). Furthermore, both the decrease in LDF and the increase in RR were either completely or partially blocked by stimulation at 40 Hz after TRIM-treatment and GUA-treatment. It is concluded that the adrenal cortex in the rat is innervated by post-ganglionic adrenergic nerve fibres, which are involved in the regulation of blood flow in the adrenal cortex.

Carlsson, S., Skarphedinsson, J. O., Delle, M., Hoffman, P. & Thoren, P. 1992. Reflex changes in post- and preganglionic sympathetic nerve activity and postganglionic sympathetic renal nerve activity upon arterial baroreceptor activation and during severe haemorrhage in the rat. Acta Physiol Scand144, 317–323. Received 19 August 1991, accepted 18 November 1991. ISSN 0001–6772. Department of Physiology, University of Goteborg, Sweden and Department of Physiology, University of Iceland, Reykjavik, Iceland. The aim of the study was to compare pre- (pre-aSNA) and postganglionic adrenal sympathetic nerve activity (post-aSNA) and postganglionic renal sympathetic nerve activity (rSNA) in rats during arterial baroreceptor activation and haemorrhage. Adrenal multifibre nerve activity was recorded in chloralose-anaesthetized Wistar rats. To test for pre-aSNA or post-aSNA in adrenal nerves, a ganglionic blocker, trimethaphan (10 mg kg-1), was administered i.v. If the nerve activity in the adrenal nerve decreased or increased the nerve was considered to contain predominantly post-or preganglionic fibres, respectively. In contrast, the renal nerves exhibit an almost pure postganglionic activity. Baroreceptor activity was tested by activation of baroreceptors, with an a-receptor agonist, phenylephrine, which was slowly infused (0.5–2 mUg kg-1 min-l), and to deactivate the baroreceptors the rats were bled down to 50 mmHg for 8 min. The experiments showed that all tested nerve types were baroreceptor dependent. There were no significant differences between the slopes relating nerve activity inhibition to increase in blood pressure (infusion of phenylephrine). During maximal inhibition there was a difference between the rSNA and pre-aSNA, 87 ± 4%, n=6, and 68±6%, n = 10 (P < 0.01) of the control value, respectively. The maximal inhibition of post-aSNA was 80 ± 3%, n=7, of the control value. During haemorrhage there was a difference between the nerve populations. Pre-aSNA responded with a marked increase within 1.5 rnin (159 ± 29% of control, n= 7) and was then maintained at that level until retransfusion. Post-aSNA responded with i transient increase, reaching 158 ± 19% of control after 1.5min but then decreased slowly during the next 3 min, reaching a value of 89 8 76 at 7.5 rnin of haemorrhage. Finally, rSNA (n = 7) responded with an initial increase (peak value 1.5 min 138 ± 16%) followed by an inhibition to a minimum of 74±12% of control. Our conclusion is that the postganglionic adrenal nerves respond in a similar way to postganglionic renal nerves during baroreceptor activation and also show the same pattern of response during haemorrhage. This might indicate that postganglionic fibres to the adrenal gland and postganglionic renal fibres to the kidney have the same target structures, i.e. blood vessels. and postganglionic adrenal fibres might therefore be of importance in adrenal blood flow regulation.

We have previously shown that prolonged low-frequency muscle stimulation, inducing contractions of the gastrocnemius muscle, in conscious spontaneously hypertensive rats leads to an opioid-mediated post-stimulatory reduction in blood pressure and analgesia. In the present study we investigated whether muscle stimulation would also induce a post-stimulatory reduction in behavioural activity in the spontaneously hypertensive rats. Selective opioid receptor antagonists were used to analyse the involvement of endogenous opioids. Muscle stimulation, lasting 60 min, induced a post-stimulatory sedation that outlasted the stimulation for hours. Sniffing, locomotor activity and total behavioural activity were significantly reduced. The post-stimulatory reduction in activity was reversed back to control levels by a high dose of naloxone (15 mg kg-1 i.v.). The selective mu-receptor antagonist beta-funaltrexamine, given intracerebroventricularly before stimulation, did not influence the development of the post-stimulatory drop in activity. The delta-receptor antagonist ICI 154,129 had no effect at all on the already developed sedation, whereas MR 2266 BS, a kappa-receptor antagonist (3 mg kg-1 i.v.), completely reversed the drop in activity. These results show that muscle stimulation gives rise to an opioid-mediated post-stimulatory reduction in activity in spontaneously hypertensive rats. The results also indicate the involvement of the opioid kappa-receptor in the behavioural response.

In a previous study, electrically induced contractions of the gastrocnemius muscle in conscious spontaneously hypertensive rats were shown to induce a blood pressure reduction of 15-20 mmHg lasting several hours. We showed in that study that endogenous opioid systems were involved. In this study, drugs with selective affinity for different opioid receptors were used to analyse further the involvement of endogenous opioid systems in the post-stimulatory drop in blood pressure in spontaneously hypertensive rats. Prestimulatory intracerebroventricular administration of beta-FNA (a mu-receptor antagonist) did not significantly influence the response at all, nor did a lower intravenous dose of naloxone reverse the post-stimulatory drop in blood pressure. High-dose naloxone (15 mg kg-1) increased post-stimulatory blood pressure by around 10 mmHg. About 50% of the drop thus remained after this treatment. A similar, partial reversal of the decreased blood pressure was seen after intravenous administration of a delta-receptor antagonist, ICI 154,129. However, the depressor response was completely reversed by a low intravenous dose of MR 2266 BS (a kappa-receptor antagonist). These results suggest that the reduction in blood pressure after muscle stimulation is mainly mediated by the opioid kappa-receptor. A certain involvement of the delta-receptor is also indicated.

Summary: Infusion of felodipine and verapamil in increasing doses to anesthetized spontaneously hypertensive rats induced a progressive fall in arterial blood pressure (BP). To estimate the cardiac action of the different drugs, we also measured changes in cardiac output (CO) and velocity of flow (dF/dT) by a Doppler flow probe placed on the ascending aorta. Infusion of verapamil induced a parallel decrease in mean arterial BP, CO, and cardiac inotropy (as estimated by max. dF/dT). In contrast, upon felodipine administration, the decrease in arterial BP was accompanied by an initial small rise in dF/dT. A decrease in dF/dT was observed only after high doses of felodipine, which cause pronounced levels of hypotension.

The silicon used in the present study was Bisico S4i, which consists of dual chamber tubes filled with two components. Silicon S4i is loaded in a dispenser and its outlet is connected to a nozzle and a small tip (these all come from Bisico, Germany). When the dispenser is triggered, the two components flow into the nozzle, mix there, and then go out through the tip. The mixed silicon hardens in room temperature within a few minutes. Spontaneously hypertensive rats (SHR) (260 ? 9 g) were from Mollegaard Breeding Centre (Skensved, Denmark). They were given standard rat pellets and tap water ad libitum and housed in the animal unit of the department for at least 1 week (22” C, 60% humidity and 12:12 of light-dark cycle). The experiments were approved by the Animal Ethical Committee at Karolinska Institute, Stockholm, Sweden. The rats were anesthetised with methohexital (Brietal) 60 mg/kg i.p.. Body temperature was kept at about

We studied the effect of the dihydropyridine calcium antagonists felodipine nimodipine on perfusion of the cerebral cortex in the spontaneously hypertensive rat (SHR). Nimodipine and felodipine were infused in equipotent doses in chloralose-anaesthetized SHR. During the infusion of a low and an intermediate dose of felodipine, mean arterial blood pressure was lowered to 90.5 +/- 1.5 and 67.1 +/- 2.9% of the control level. The nimodipine infusion lowered mean arterial pressure to 85.7 +/- 2.0 and 59.7 +/- 2.4% of the control level. At these pressures, cortical perfusion as measured by a laser Doppler flow technique increased to 123.5 +/- 6.9 and 130 +/- 5.4% of the control level during the felodipine infusion and to 114.0 +/- 1.6 and 122.3 +/- 3.2% of the control level during the nimodipine infusion. When these results were compared by covariance analysis of variance, felodipine induced a significantly greater change in cortical perfusion. At the highest dose of felodipine and nimodipine there was no significant difference in cortical perfusion between the two drugs. The administration of felodipine induced a decrease in cerebrovascular autoregulation. However, this impairment of cerebrovascular autoregulation is not likely to trigger cerebral hypoperfusion. Thus, for a mean arterial pressure of 55 mmHg, the laser Doppler-measured cortical flow was, if anything, elevated after felodipine administration.

The present study was undertaken to study the changes in efferent renal sympathetic nerve activity (RSNA) and heart rate (HR) during the acute fall in blood pressure after surgical reversal of two-kidney, one-clip renovascular hypertension in rats, and to explore if cardiopulmonary vagal afferents can influence sympathetic outflow in this situation. In 14 rats with a MAP of 199 ± 6 mmHg the renal artery clip was surgically removed and after 90 min MAP had decreased to 109 ± 7 mmHg. The HR had then decreased by 26 ± 15 beats min-1 (P < 0.05) and RSNA did not increase as expected, but was somewhat reduced (84 ± 8 % of control). In contrast, lowering pressure with nitroprusside to the same extent produced large and significant increases in HR and RSNA in seven other renal hypertensive rats. Acute bilateral vagotomy was performed in seven of the declipped rats, which induced an immediate increase in MAP (+ 35 ± 10 mmHg, P < 0.05), HR + 28 ± 10 beats min-1, P < 0.05) and RSNA (+ 51 ± 19%, P < 0.05). A few minutes afterwards the vagotomy pressure again started to fall and was, after another 90 min 107 ± 10 mmHg together with slight reductions in HR and RSNA. Another group of six rats were initially exposed to bilateral vagotomy. In these vagotomized rats declipping also induced hypotension (204 ± 10 to 95 ± 7 mmHg, P < 0.001), together with tendencies of decreases in HR (425 ± 17 to 397 ± 17 beats min-1) and in RSNA (-4 ± 6%). In conclusion, this study shows that the response pattern induced by removing a renal artery obstruction is characterized by a slight reduction in heart rate and renal sympathetic nerve activity despite a rapid fall in blood pressure. This suppression of the expected baroreceptor reflex may at least partly be elicited by an activation of caridiopulmonary vagal afferens, since acute bilateral vagotomy induces an immdiate rise in RSNA and HR. However, other unknown mechanisms also contribute.

The effect of chronic voluntary exercise on resting blood pressure and heart rate was measured in two different age groups of spontaneously hypertensive rats (SHR). In the younger group, left ventricular dimensions were also measured. The younger group was 9 weeks old at the start of the experiment and was in a period of rapid blood-pressure rise. The older group, 13 weeks old at the start of the experiment, already had established hypertension. During a period of 6 weeks, the animals ran spontaneously in wheels mounted in their cages and reached a maximum of 6-7 km per 24 h. Age-matched, sedentary SHR were used as controls. Both groups of runners showed a decrease in body weight in comparison to controls. The younger runners exhibited a delayed onset of hypertension. They also showed a significantly increased left ventricular (LV) end-diastolic volume for every measured end-diastolic pressure between 7.5 mmHg and 20 mmHg (P less than 0.05). This suggests the development of a structural growth-dependent increase of the internal LV radius while LV weight and wall-to-lumen ratio were largely unaltered in younger runners compared with controls. In SHR with established hypertension, physical training did not reduce arterial blood pressure but heart rate was significantly lower than in the controls. These results thus indicate that an early onset of physical exercise in SHR may delay the development of hypertension. In addition, a more favourable cardiac design could also be seen.

The purpose of this study was to examine the effects of naloxone on signs of relative cerebral ischaemia induced by hypotensive haemorrhage. Mean arterial blood pressure (MAP), heart rate (HR), renal sympathetic nerve activity (rSNA) and somatosensory evoked potentials (SEP) were recorded in chloralose-anaesthetized spontaneously hypertensive rats exposed to graded bleeding. Hypotensive haemorrhage resulted, after a very brief sympathetic excitation, in marked sympathetic inhibition and bradycardia and a considerable reduction of SEP, indicating relative cerebral ischaemia. However, after 25-30 min this sympatho-inhibitory response was reversed to pronounced sympathetic excitation and tachycardia, which was accompanied by a further attenuation of SEP. A single bolus of naloxone (10 mg kg-1) caused transient sympathetic inhibition and bradycardia, which was accompanied by an improvement of SEP. A bolus injection (5-10 mg kg-1) followed by a 30 min infusion of naloxone (25-35 mg kg-1 h-1) caused a sustained SEP improvement despite the fact that MAP was kept constant during naloxone administration. We conclude that naloxone can have beneficial effects on brain function during cerebral ischaemia, effects that are probably due to blockade of opioid receptors. Our model of relative cerebral ischaemia might be useful for evaluating the mechanisms behind the naloxone effects during this condition.

1 Mean arterial pressure (MAP), heart rate (HR) and renal sympathetic nerve activity (RSNA) were recorded in conscious spontaneously hypertensive rats (SHR). 2 Infusion of metoprolol (4 mumol kg-1 h-1) or propranolol (1.5 mumol kg-1 h-1) reduced HR and significantly increased RSNA. 3 Administration of metoprolol caused a sustained decrease of MAP starting in the third hour of infusion. In contrast, administration of propranolol induced a biphasic response in MAP. It is suggested that the increase of RSNA after both beta-adrenoceptor blocking drugs is due to a decrease in arterial baroreceptor activity.

Brain monoamine metabolism in rats was studied during spontaneous, long-term running in a microprocessor-controlled wheel cage. Immediately after heavy spontaneous exercise, DOPA accumulation was decreased in dopamine-rich brain regions such as the limbic forebrain and corpus striatum, indicating a decreased rate of synthesis of dopamine in brain. In contrast, DOPA accumulation was increased in the noradrenaline-predominated region of the brain stem, indicating an increased synthesis of noradrenaline in this region. Alterations in brain monoamine metabolism were normalized in exercising animals analysed 24 h after the last running period. Changes in brain monoamine metabolism may be involved in the mechanisms underlying the clinically observed psychological effects of physical exercise.

Characteristics of left atrial receptors were studied in normotensive control (Wistar) and spontaneously hypertensive rats. The left atrial pressure was chronically elevated in spontaneously hypertensive rats and at the end of the expiratory phase was 10.3 mm Hg as compared with 4.6 mm Hg in normotensive control rats. The thresholds of the receptor endings were twice as high in the hypertensive as in the normotensive rats (10.2 and 4.6 mm Hg, respectively). In other experiments the reflex inhibition of renal sympathetic outflow was studied during plasma infusion in baroreceptor denervated normotensive and hypertensive rats and was inhibited at a lower left atrial pressure in the former. These differences are attributed to decreased distensibility of the left atrium in spontaneously hypertensive rats. The reflex splanchnic nerve inhibition with volume load also was recorded in awake rats. At a 10 percent increase in blood volume, splanchnic outflow was more significantly decreased in spontaneously hypertensive than in normotensive rats. The mechanism underlying such a hyperreactive volume receptor response is unknown, but a less distensible venous system, centrally or peripherally, might be a contributing factor.

Isolated hearts from adult spontaneously hypertensive rats (SHR; Okamoto 1969), with established hypertension, were investigated in an antegrade perfusion apparatus where preload and afterload could be varied independently. Frank-Starling curves were constructed at constant afterloads ranging from 50 mmHg to 150 mmHg. As earlier reported, the SHR hearts exhibited a rightward shift of their Frank-Startling relationships compared to those from the normotensive control hearts, though visible only at afterloads up to about 100 mmHg. At higher afterloads the SHR hearts performed significantly better then the NCR ones as their maximal stroke volume was significantly greater compared to that of controls. Thus, left ventricular hypertrophy obviously increases the work capacity of the heart, though at the cost of an altered Frank-Startling relation dependent on the reduced diastolic compliance. For such reasons the myocardial hypertrophy in established SHR hypertension must be considered a physiologic adaptation and not a degenerative phenomenon, though naturally degenerative processes may later become superimposed.

Cerebral blood flow (CBF, by laser Doppler flowmetry) and extracellular cortical concentrations (by microdialysis) of adenosine, inosine, xanthine, hypoxanthine, and lactate were measured together with somatosensory evoked potentials (SEP) in chloralose-anaesthetized spontaneously hypertensive rats (SHR) during relative cerebral ischemia induced by hypotensive hemorrhage. Reduction of mean arterial blood pressure (MABP) to 40–50 mm Hg, which decreased SEP to about 50% of prebleeding control level, decreased CBF only to about 75% of control due to cerebrovascular “autoregulation.” A secondary, marked rise in cerebrovascular resistance (CVR) occurred after about 15 min in parallel with a striking increase in heart rate (after initial bradycardia). This late rise in heart rate is probably elicited by relative ischemia in medullary centers. The increase in CVR might indicate increased sympathetic nerve activity to the circle of Willis and large cerebral arteries. Cortical lactate increased initially but started to decline after about 30 min, and after 2 h it was not significantly higher than control. Cortical adenosine, inosine, hypoxanthine, and xanthine increased slowly and were significantly elevated after 50 min of hemorrhage. After 80 min, adenosine and inosine had returned to initial levels, while hypoxanthine and xanthine were further elevated. Despite the apparent partial recovery of metabolic disturbances during late hemorrhage, and with a blood flow maintained at 75% of resting control, SEP did not improve. It is suggested that the depression of SEP is not primarily caused by circulatory-metabolic derangements, but instead by activation of specific inhibitory systems.

The aim of this study was to determine the mechanism of action of norepinephrine (NE) on arterial baroreceptors (BRs), with the focus on regularly discharging, presumably myelinated fibers. With the use of an in vitro aortic arch/aortic nerve preparation from rats, BR single-fiber discharge was recorded simultaneously with aortic pressure and diameter. At constant suprathreshold pressure, NE had two dose-dependent effects. Inhibition was produced at low concentrations (10(-10)-10(-7) M), whereas excitation was produced at high concentrations (10(-6)-10(-5) M). Inhibition was attributed to BR unloading since the response was consistent with the fall in diameter, was mimicked by angiotensin II (10(-10)-10(-6) M), and was prevented by pretreatment with the smooth muscle relaxant sodium nitroprusside (10(-6) M) or the selective alpha 1-adrenergic antagonist, prazosin (10(-6) M). Excitation was attributed to direct activation of the BR endings since this response was independent of changes in diameter, was not mimicked by angiotensin II, and was not prevented by sodium nitroprusside but was blocked by prazosin. These results indicate that NE has two modes of action, one mediated by contraction of local vascular smooth muscle and the other due to direct excitation of the nerve endings. It was also found that BR discharge at given diameters decreased more when pressure was lowered (smooth muscle passive) than when the aorta constricted (smooth muscle active). Furthermore, if diameter was held constant during smooth muscle contraction, discharge increased, as opposed to decreasing at constant pressure. These later results suggest that BR responses to vasoactive agents reflect not only changes in wall dimension but perhaps changes in wall tension and/or the coupling relation between BR and smooth muscle structures.

The characteristics of 22 atrial receptors in 15 normotensive adult male Wistar rats were investigated. All the receptor afferents were included in the C-fibre group with conduction velocities from 0.4 to 1.2 m/sec. No atrial medullated receptors or ventricular C-fibre endings were found. Two receptors were located in right atrium and 2 receptors throughout left atrium. Upon elevation of the left atrial pressure the receptor discharge was markedly elevated with thresholds from 2.5 to 9 mmHg in mean left atrial pressure. Ten of the atrial receptors displayed a clear cardiac rhythmicity upon activation and the discharge correlated with the v-wave, indicating distension as the cause of receptor activation. The maximal firing rate in most receptors was very high (up to 70 Hz), but 8 receptors had maximal firing rates below 25 Hz. These low frequency receptors had higher threshold and showed a more irregular firing. Thus, there is a substantial population of atrial receptors with vagal non-medullated afferents in the rat heart and the thresholds for many of these receptors are so low that they are likely to be active during normal conditions.

In the present study we have recorded spontaneous variations in mean arterial blood pressure (MAP), heart rate (HR) and mean rectified splanchnic nerve activity (SNA) in conscious undisturbed normotensive Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). The variability in blood pressure was not significantly different but HR variability tended to be lower in SHR. The variability in SNA expressed as % change from mean value was not significantly different between SHR and WKY. By computer techniques the correlation between HR, MAP and SNA could be calculated during spontaneous variations of these parameters. The slope of the regression line correlating HR and SNA was significantly steeper in SHR than in WKY (0.73, 0.47 resp.). Thus a certain change in HR was associated by a greater change in SNA in SHR compared with WKY. Spontaneous changes in SNA could be divided in principally two different patterns. One typical pattern was a rise in SNA in parallel with a drop in MAP. This pattern was most likely triggered by the arterial baroreceptors and was called a "baroreceptor-pattern". Marked spontaneous excitations in SNA and HR was also observed during natural behaviours such as eating, drinking and explorative behaviour, a so called "centrally mediated pattern".

The characteristics of 11 left atrial receptors in 9 adult male spontaneously hypertensive rats (SHR) were investigated. All the receptor afferents were non-medullated with conduction velocities from 0.5 to 1.5 m/s. Elevation of left atrial pressure during graded aortic occlusion always induced a marked increase in receptor discharge with maximal frequencies ranging from 29 to 70 Hz. The threshold for activation was from 7.5 to 13 mmHg in mean left atrial pressure (mean +/- S.E., 10.2 +/- 0.6 mmHg). Upon atrial distension all the receptors displayed a clear rhythmicity and the discharge correlated mainly with the v-wave, indicating distension as the cause of receptor activation. The relationship between the mean left atrial pressure and the frequency of discharge was constructed for all the receptors and compared with similar data obtained from normotensive control rats (NCR) (Thorén et al. 1979). It was then obvious that the left atrial receptors are reset in SHR probably secondarily to a decreased distensibility of the left atrium.

In 7-week-old male, spontaneously hypertensive rats (SHR) and matched normotensive control rats, Wistar Kyoto Rats (WKY), a bilateral renal denervation was performed. In two additional groups of rats a sham denervation was done (SHRS, WKYS). The animals were then kept in metabolic cages during a 10-day period during which sodium intake, urine volume, urinary sodium excretion, fecal sodium excretion, urinary aldosterone excretion and plasma renin activity were determined. Fractional urinary excretion of sodium was higher in the denervated SHR (p < 0.1) and WKY (p < 0.05) during the first 3 days after denervation, but during the following 3-day periods no difference between denervated and sham-operated groups was noted. The difference in fractional urinary excretion of sodium initially was due to a diminished urinary sodium excretion in the sham-operated groups since both SHRS and WKYS exhibited a significant increase between the first and the last 3-day period. Urine volume increased significantly in both SHR and WKY after denervation. Urinary aldosterone excretion on the 7th day after denervation was significantly lower in SHR compared to WKY, but there was no significant difference between the denervated and sham-operated groups. PRA was also significantly lower in SHR but no significant decrease was seen after denervation.