Acta Physiologica Hungarica, Volume 92 (3–4), pp. 237–324 (2005)

Angiotensinerg regulation of salt hunger in the zona incerta of rat brain Bagi É, Tóth K, Truta-Feles K, Lénárd L Institute of Physiology and Neurophysiology, Research Group of the Hungarian Academy of Sciences, Medical School, University of Pécs, Pécs, Hungary

The zona incerta (ZI) and the renin-angiotensin system in the brain plays a definitive role in the regulation of fluid balance, thirst and hunger for salt. In the present experiments AII and AIII microinjections into the ZI of rats have been studied on drinking salt solution in two-bottle test procedures during the consequent 60-min-dailydrinking period. The volume consumed were determined in every 5 min all along the experiments. The dipsogen and salt hunger inducing power of the two angiotesins were compared to vehicle treated rats. After, angiotensin receptor antagonists on AII or AIII induced fluid intake were also tested. Before drug injection, preoperatively and postoperatively, animals were habituated to the two-bottle test paradigm. Neither neophobia nor preference was experienced for the first time of introduction of the salt solution. From day two of habituation, animals prefered water to sodium solution all the time, when not treated. In the first experiment AII increased animals’ preference to salt solution compared to water insomuch, that water intake of AII treated rats dropped to 50% compared to the vehicle treated animals. In the second experiment AIII also increased sodium intake, but not to the expence of water intake. Considering the antagonist pre-treatments in the third and fourth experiments, animals were injected by Losartan (Los), an AT1 antagonist or PD 123319 (PD), an AT2 antagonist, respectively. The effect of AII could be blocked both by Los and PD. On the other hand, the effect of AIII could not be blocked by Los, but by the PD. In the sixth experiment, salt hunger was previously induced by an overnight per os treatment of the natriorexigen amiloride. Salt ingestion of the animals was significantly increased next day. AII microinjection could even more facilitate the already elevated hunger for salt, but AIII could not. The effects of AII, AIII, Los, PD on salt hunger have not been tested in the ZI. The finding that salt intake increased after AII or AIII injections and it could be blocked differently by the antagonists in two-bottle tests suggests that AT1 and AT2 receptors play partially different roles in the regulation of salt and water intake in the zona incerta. Supported by the HAS, OTKA T034489 and Losartan by the Merck & Co.

0231–424X/$ 20.00 © 2005 Akadémiai Kiadó, Budapest


LXIXth Annual Meeting of the Hungarian Physiological Society

Role of PECAM-1 mediating NO-dependent dilation of arterioles to wall shear stress Bagi Zs1,2, Frangos JA4, Yeh JC4, White CR4, Kaley G1, Koller A1,3 2Department

1Department of Physiology, New York Medical College, Valhalla, NY, USA of Clinical Physiology, Institute of Cardiology, University of Debrecen, Debrecen, Hungary 3Department of Pathophysiology, Semmelweis University, Budapest, Hungary 4La Jolla Bioengineering Institute, La Jolla, CA, USA

Changes in wall shear stress via endothelial mediation have been established as an important regulator of arteriolar tone. Among others, increases in shear stress activate endothelial nitric oxide synthase (eNOS) although the exact coupling mechanisms are not known. Recent studies of endothelial cells in culture indicated that platelet endothelial cell adhesion molecule-1 (PECAM-1) is specifically involved in sensing high temporal gradients of fluid shear stress, which than activates eNOS. However, whether or not this PECAM-1 dependent pathway exists in intact vessels and leads to mechanical coupling i.e. changes in diameter, has not yet been proven. We hypothesized that dilations of isolated skeletal muscle arterioles from wild type (WT) and PECAM-1 knockout mice (PECAM-KO) will be reduced to rapid increases in wall shear stress elicited by increases in perfusate flow. Both small and large step increases in flow/shear stress resulted in substantial dilations in arterioles of WT mice (45±4%), but they were markedly reduced in arterioles of PECAM-KO mice (22±5%). The initial slope of dilations, when shear stress increased rapidly, was greater in vessels of WT than those of PECAM-KO mice (slopes: 0.378 and 0.094, respectively), whereas the second phase of dilations, when flow/shear stress was steady, was similar in the two groups (slopes: 0.085 and 0.094, respectively). Inhibition of eNOS with Nω-nitro-Larginine-methyl-ester significantly reduced the initial phase of dilations in arterioles from WT, but not from PECAM-KO mice. The calcium ionophore, A23187 elicited similar, L-NAME sensitive, dilation in both WT and PECAM-KO mice (33±2 and 35±6%, respectively). Collectively, these findings suggest that in skeletal muscle arterioles of PECAM-KO mice activation of eNOS and consequent dilation by agonists is maintained, but the dilations to high temporal gradients of shear stress are reduced. Thus, PECAM-1 seems to play an important role in the endothelium’s ability to sense high temporal gradients of shear stress, which is then coupled with NO-mediated vasodilatation. Supported by USA NIH HL-43023, HL-46813 and Hungarian Scientific Research Fund, OTKA M045186, 048376, F-048837.

Acta Physiologica Hungarica 92, 2005



The actions of selective µ-opioid receptor antagonists on rat striatal dopamine release increased by endomorphins Bagosi Zs1, Jászberényi M1, Bujdosó E2, Telegdy G2 1Department 2Neurohumoral

of Pathophysiology, University of Szeged, Szeged, Hungary Research Group of the Hungarian Academy of Sciences, Szeged, Hungary

Endomorphins (EMs) are endogenous ligands for µ-opioid receptors with neurotransmitter role in mammals. Besides their antinociceptive and vasodilatator actions, endomorphin-1 (EM1: Tyr-Pro-Trp-Phe-NH2) and endomorphin-2 (EM2: TyrPro-Phe-Phe-NH2) cause locomotor activation. Previously our in vitro superfusion studies demonstrated that both neuropeptides increase striatal dopamine (DA) release induced by electric stimulation in rats. The effect of EM1 is mediated by nitric oxid (NO) from the endothelium and the effect of EM2 is inhibited by dipeptidyl-aminopeptidase IV (DPPIV) found in synaptic membranes. Furthermore in vitro superfusion system was used to investigate the involvement of µ-opioid receptors in these processes. Rat striatal slices incubated with tritium labelled dopamine (3H-DA) were pretreated with β-funaltrexamine, a selective µ-opioid antagonist and naloxonazine, a µ1 selective antagonist, then EM1 or EM2 were superfused. Before the administration of EM2 slices were pretreated with DDPIV enzyme inhibitor diprotin A. β-funaltrexamine antagonized the striatal 3H-DA release induced by electric stimulation and increased by EM1 and EM2. Naloxononazine did not inhibit the effect of EM1 considerably but reduced the effect of EM2 significantly. These results might suggest that locomotor activation caused by EMs and demonstrated by the increase in striatal DA release in vitro is mediated by µ-opioid receptors. The DA stimulating action of EM1 is elicited through µ2- and that of EM2 through µ1-receptor activation. Supported by grants from OTKA (T-037224), ETT (123-04), NKFP 1/027/2001 and RET-08-2004.

Effects of neuropeptide Y antagonists on food intake in rats: differences with cold-adaptation Balaskó M1, Pétervári E1, Uzsoki B2, Székely M1 2Department

1Department of Pathophysiology, Medical School, of Zoology and Neurobiology, Faculty of Science, University of Pécs, Pécs, Hungary

Neuropeptide Y (NPY) is known to be one of the most important central orexigenic peptides that upon central administration also influences thermoregulation by Acta Physiologica Hungarica 92, 2005


LXIXth Annual Meeting of the Hungarian Physiological Society

suppressing the enhancement of metabolic rate in cold environments (2). After being produced primarily in the arcuate nucleus, via nerve projections it reaches different hypothalamic regions such as the ventromedial, dorsomedial, paraventricular, perifornical nuclei or the lateral hypothalamus. Its role is clearly defined in the development of adaptive hyperphagia induced by food deprivation (5). A possible role for elevated central NPY levels may be hypothesized in cold-adapted (CA) animals, which also react with enhanced food intake to their chronic cold-exposure (a state with negative energy balance) although its hypothermic effect would be disadvantageous for cold-exposed animals. In our present study we investigated the effects of NPY antagonists on hyperphagia induced by centrally administered exogenous NPY or fasting in CA and non-adapted (NA) rats. Female Wistar rats of 220–260 g body weight served as our subjects. Thermal adaptation lasted for at least 4 weeks at an ambient temperature of 3–5 °C for CA and 23–26 °C for NA animals. After the adaptation period a metal guide cannula was surgically implanted into a lateral cerebral ventricle (ICV) for central injections of 2, 10 µg NPY, 10 µg D-Tyr27,36, D-Thr32-NPY (27–36) (a non-selective receptor antagonist) (3), 20 µg D-myo-inositol-1,2,6-trisphosphate (α-trinositol, a functional NPY antagonist) (1) or pyrogen-free saline (PFS). All substances were dissolved in PFS and given in a volume of 5 µl. Food deprivation (CA: 24-h, NA: 48-h) resulted in a similar rate of weight loss in the CA and NA groups. Following fasting or central drug administration food intake was measured directly at the end of the 3-h feeding period and also assessed indirectly by measuring body weight every 30 minutes for 3 hours. All results are expressed as mean values ± S.E.M. For statistical analysis of the data one-way ANOVA and Bonferroni’s post hoc test were used. In CA rats the exogenous NPY-induced hyperphagia was more pronounced than in NA animals. Both NPY antagonists were effective in attenuating NPY-induced food intake in the CA and NA groups. In CA animals this suppressive effect was even stronger and it practically abolished food intake. The re-feeding hyperphagia was significantly suppressed by both NPY antagonists in NA rats, but they failed to affect fasting-induced enhancement of food intake in the CA group. It is concluded that the enhanced sensitivity of CA rats previously described for certain central mediators such as PGE or NPY (4) can also be observed in case of different NPY antagonists. However, according to the present data endogenous NPY cannot play an exclusive role in the development of cold-adaptation associated hyperphagia, the contribution of other mediators has to be considered and investigated. Supported by Hungarian Scientific Research Fund, OTKA T049321.

Acta Physiologica Hungarica 92, 2005



REFERENCES 1. Heilig M, Edvinsson L, Wahlestedt C: Effects of intracerebroventricular D-myo-inositol-1,2,6trisphosphate (PP56), a proposed neuropeptide Y (NPY) antagonist, on locomotor activity, food intake, central effects of NPY and NPY-receptor binding. Eur. J. Pharmacol. 209, 27–32 (1991) 2. Jolicoeur FB, Bouali SM, Fournier A, St-Pierre S: Mapping of hypothalamic sites involved in the effects of NPY on body temperature and food intake. Brain Res. Bull. 36, 125–129 (1995) 3. Myers RD, Wooten MH, Ames CD, Nyce JW: Anorexic action of a new potential neuropeptide Y antagonist [D-Tyr27,36,D-Thr32]-NPY(27-36) infused into the hypothalamus of the rat. Brain Res. Bull. 37, 237–245 (1995) 4. Uzsoki B, Fekete Á, Pétervári E, Balaskó M, Székely M: Enhanced responsiveness to central prostaglandin E or neuropeptide Y in cold-adapted rats. J. Therm. Biol. 26, 499–504 (2001) 5. Williams G, Bing C, Cai XJ, Harrold JA, King PJ, Liu XH: The hypothalamus and the control of energy homeostasis. Different circuits, different purposes. Physiol. Behav. 74, 683–701 (2001)

Activation of mitochondrial ATP-sensitive K+ channels impedes post-ischemic injury in the brain Bari F1, Domoki F1, Kis B2, Lenzsér G2, Busija DW2 1Department 2Department

of Physiology, Faculty of Medicine, University of Szeged, Szeged, Hungary of Physiology/Pharmacology, Wake Forest University Health Sciences, Winston-Salem, NC

Diazoxide (DIAZ) a mitochondrial ATP-sensitive potassium (mitoKATP) channel opener protects the neuronal-vascular coupling in the brain against ischemic stress. Direct effect of the mitoKATP channel agonist on the ischemia-sensitive endothelial and vascular smooth functions has not been examined. It is also unknown if ischemic damage of the blood-brain barrier (BBB) could be prevented by DIAZ treatment. In piglets we tested if DIAZ preserves endothelium-dependent (CO2) or -independent (iloprost, ILO) cerebrovascular dilator responses following ischemia/reperfusion (I/R), and whether the effect of DIAZ is specific (5HD). To confirm the direct effect of DIAZ on mitochondria, mitochondrial membrane potential in piglet cerebrovascular endothelial cells was monitored. Hypercapnia resulted in dose-dependent pial arteriolar vasodilation, which was attenuated by ~70% after I/R in the controls. DIAZ and 5HD treatment did not affect the CO2 response. DIAZ significantly preserved vasodilation to hypercapnia after I/R but not to ILO. DIAZ depolarized mitochondria in cerebrovascular endothelial cells, and 5HD completely abolished the protective effect of DIAZ, both indicating a role for mitoKATP. We also provide evidence that high dose of DIAZ given prior to ischemia in rats restores the BBB damage. In summary, preservation of cerebral arterial and capillary function by DIAZ may contribute to neuroprotective action of the drug.

Acta Physiologica Hungarica 92, 2005


LXIXth Annual Meeting of the Hungarian Physiological Society

The breath-hold time and the exercise capacity of the eighty-year-old people Barnai M1, Domjan A1, Varga J2, Somfay A2, Jeney K1, Sarga N1, Verebely B1, Horvath G1,3 1Department

of Physiotherapy, Faculty of Health Sciences, 2Department of Pulmonology, 3Department of Physiology, Faculty of Medicine, University of Szeged, Szeged, Hungary

Goal. To investigate the effect of an 8-weeks exercise training on the physical capacity in healthy eighty year-old people, and the correlation between the voluntary breath-hold time and the endurance capacity. The objective and subjective parameters were investigated which reflected the effect of the training program. Methods. Nine healthy subjects aged 80 yr (76–83 yr) with a normal range of lung function participated in a cycle ergometer training program, three times per week, for 8 wk. The breath-hold time, the lung function, the peak exercise capacity on an ergospirometer, the range of a subjective dyspnoea and legs fatique were measured before and after the training program. Statistical analysis: Student-t-test, and Pearson correlation analysis were used for the evaluation of the data. Results. Six persons performed the total program. Significant increases were found in the oxygen uptake at the anaerobic threshold and at the maximal load (p

LXIXth Annual Meeting of the Hungarian Physiological Society.

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