Masked excitatory action of noradrenaline on rat islet β-cells via activation of phospholipase C

The effect of noradrenaline (NE) on rat islet -cells was examined. NE reduced insulin secretion from rat islets exposed to extracellular solutions containing glucose at 5.5 or 16.6 mM. In islets treated with pertussis toxin (PTX), however, NE increased insulin secretion. The NE-induced augmentation of insulin secretion was inhibited by prazosin. In intact islets, NE increased phospholipase C (PLC) activity, an effect that was prevented by treatment of islets with U-73122. NE elevated intracellular [Ca²⁺] ([Ca²⁺]_i) in isolated -cells independently of PTX. Although this NE effect was inhibited by prazosin, phenylephrine did not mimic it. The [Ca²⁺]_i response to NE was also prevented by the treatment of cells with U-73122. NE produced depolarization of -cells followed by nifedipine-sensitive action potentials. NE reduced the whole-cell membrane currents through ATP-sensitive K⁺ channels (K_ATP), responsible for the depolarization. This NE effect was prevented by treatment of -cells with U-73122 or BAPTA/AM. Although at least some of our results imply the presence of ₁-adrenoceptors, -cells were not stained by a polyclonal IgG antibody recognizing all adrenergic ₁-receptor subtypes so far identified. These results suggest that an interaction of NE with an unknown type of receptor activates rat islet -cells via a PLC-dependent signal pathway. This effect is, however, masked by the inhibitory action via a PTX-sensitive pathway also activated by NE.     

Pressor effects of the injection of noradrenaline into different cerebroventricular spaces in unanesthetized rats

Injection of noradrenaline (NA) into the lateral cerebral ventricle (i.c.v.) was reported to cause blood pressure increase in unanesthetized rats, blocked by i.v. injection of vasopressin antagonists. We report similar responses to NA injection into the III or IV ventricles, suggesting multiple sites of action for i.c.v. NA. These responses were blocked by i.v. pretreatment with vasopressin antagonist, suggesting a common mediation by vasopressin release into circulation. Selected ventricular spaces were occluded with Nivea^® cream plugs to identify ventricular areas responding to i.c.v. NA. III ventricle or aqueduct occlusions markedly reduced pressor responses to i.c.v. NA. Microinjection of NA into the periaqueductal gray matter (PAG) caused pressor responses that were similar to those of i.c.v. NA, reinforcing the idea of a site of action in the aqueduct. IV ventricle occlusion only partially blocked the response to i.c.v. NA. The results suggest at least two sites of action for i.c.v. NA in unanesthetized rats. A primary site located in the PAG and another on the IV ventricle wall.     

Plasma testosterone and catecholamine responses to physical exercise of different intensities in men

Summary Plasma testosterone, noradrenaline, and adrenaline concentrations during three bicycle ergometer tests of the same total work output (2160 J·kg^–1) but different intensity and duration were measured in healthy male subjects. Tests A and B consisted of three consecutive exercise bouts, lasting 6 min each, of either increasing (1.5, 2.0, 2.5 W·kg^–1) or constant (2.0, 2.0, 2.0 W·kg^–1) work loads, respectively. In test C the subjects performed two exercise bouts each lasting 4.5 min, with work loads of 4.0 W·kg^–1. All the exercise bouts were separated by 1-min periods of rest.Exercise B of constant low intensity resulted only in a small increase in plasma noradrenaline concentration. Exercise A of graded intensity caused an increase in both catecholamine levels, whereas, during the most intensive exercise C, significant elevations in plasma noradrenaline, adrenaline and testosterone concentrations occurred. A significant positive correlation was obtained between the mean value of plasma testosterone and that of adrenaline as well as noradrenaline during exercise.It is concluded that both plasma testosterone and catecholamine responses to physical effort depend more on work intensity than on work duration or total work output.This work was performed within the Scientific Exchange Programme between the Institute of Experimental Endocrinology, Slovak Academy of Sciences in Bratislava and Medical Research Centre, Polish Academy of Sciences, Warsaw/Project 10.4/     

Dorsal bundle extinction effect: Motivation or attention?

Male albino Wistar rats were injected bilaterally with 4 micrograms of 6-hydroxydopamine into the dorsal noradrenergic bundle to deplete forebrain noradrenaline to less than 5% of control values. Acquisition learning of a fixed interval schedule or a continuously reinforced schedule was not altered but resistance to extinction was seen after food reinforced training on either schedule but not after water reinforced training. A possible increase in food motivation was tested by the use of preloading with free food prior to a fixed interval session but both control and lesioned rats reacted similarly to this manipulation thus appearing to exclude an increase in food motivation. An attentional explanation is proposed and tested by the demonstration that resistance to extinction does not occur after a partially (variable ratio 4), as opposed to a continuously, reinforced schedule. Further evidence in favour of an attentional mechanism comes from the finding that on both a fixed interval and a continuously reinforced schedule the lesion has to be present during the acquisition phase to result in subsequent resistance to extinction. Intact animals trained on either schedule and subsequently subjected to the lesion failed to show an increased resistance to extinction.     

Active and inactive renin after exercise

Summary The effects of graded exercise on plasma concentrations of active and inactive renin were studied in seven healthy men. Exercise was performed on a cycle ergometer at four different exercise intensities (corresponding to 30%, 50%, 80% and 87% of ) for 10 min each. Concentrations of active renin and total renin after activation by trypsin were measured by direct immunoradiometric assay. Non-trypsin-activated renin concentration (inactive) was obtained by subtraction. Active renin concentrations at 30%, 50%, 80% and 87% of were 1.2, 1.9, 3.1 and 4.6 times higher than the control concentration, respectively. Similar increases in plasma renin concentration, determined by conventional enzymatic assay, were observed at every stage. In contrast, changes in inactive renin concentration were not significant at any stage. Significant increases in noradrenaline concentration were found at every exercise stage, but adrenaline, aldosterone and lactate concentrations were significantly elevated only after exercise at 50%, 80% and 87% of . The similarity between the changes in concentration of active renin and noradrenaline would suggest that sympathetic nerve activity may have been responsible either for the release of active renin or for the conversion of inactive renin to its active form in the kidney.     

内毒素休克时大鼠肠系膜微血管对去甲肾上腺素反应性的变化

本文应用微循环显微也视录象技术,研究内毒素休克大鼠在休克不同时期肠系膜微血管对去甲肾上腺素(NA)反应性的变化。发现局部滴用由低至高浓度NA使微血管口径呈剂量依赖性缩小,对照组在相当于休克相应时间三次观察收缩反应曲线无明显差异(P>0.05),而休克早期微血管对NA的缩血管反应明显,晚期收缩反应减弱(均P<0.01);同时,休克早期浓度—反应曲线右移,EC_(50)减小,反应阈值降低;休克晚期浓度—反应曲线左移,EC_(50)增大,反应阈值增高;但对照组三次观察无明显变化。提示内毒素休克早期微血管对NA的反应性增高,晚期反应性降低,一、二级细动脉的变化尤为显著。可能是休克早期的代偿与晚期的失代偿机理之一。     

Thermogenesis due to noradrenaline in muscles under different rates of perfusion

Vascularly isolated hind legs of cold acclimated rats were perfused with arterial blood either without noradrenaline (NA) or with a constant concentration of NA (10 ng·ml^–1) at different perfusion rates ranging from 2 to 14l·g^–1·min^–1. The oxygen consumption of the leg during perfusion both with or without NA was linearly related to the perfusion rate. The linear increase of leg oxygen consumption with respect to the perfusion was steeper after NA, which indicates that the same arterial concentration of NA may produce a greater thermogenic effect at higher blood flow rates (the difference between resting metabolic rate and the thermogenesis stimulated by NA, was 8.20 l O₂·g^–1·h^–1 at a blood flow of 3l·g^–1·min^–1, compared with 45.02 l O₂·g^–1·h^–1 at a blood flow of 14 l·g^–1·min^–1). These data confirm the important role of the extravascular influx rate of NA in the control of thermogenesis due to NA in muscles.     

Changes in cyclic nucleotides during the calcium paradox in the isolated rat heart

Reperfusion of hearts with a Ca²⁺-containing medium after a perfusion period in Ca²⁺-free medium results in irreversible cell damage (calcium paradox). In this investigation we have studied coronary flow and cyclic AMP and cyclic GMP levels after several periods of Ca²⁺-free perfusion in isolated rat hearts. We also investigated the effects of papaverine (Pap), noradrenaline (NA), acetylcholine (ACh) and absence of inorganic phosphate during Ca²⁺-free perfusion on coronary flow (CF) and cyclic nucleotide levels. Inability of the heart to recover contractile activity with development of contracture during the reperfusion period was accepted as indicative of the calcium paradox. Ca²⁺-free perfusion alone and NA and absence of inorganic phosphate during the Ca²⁺-free perfusion period increased CF, whereas Pap and ACh decreased it. However, only Ca²⁺-free perfusion and NA elevated cyclic AMP. On the other hand, Pap and ACh increased cyclic GMP (with a transient rise of cyclic AMP in Pap infusion), and absence of inorganic phosphate decreased both cyclic AMP and cyclic GMP. Pap, ACh and absence of phosphate prevented the calcium paradox. Our study suggests that increased cyclic AMP during the Ca²⁺-free perfusion may contribute, with the other factors, to the occurrence of the calcium paradox.     

Are the blood pressure and endocrine responses of healthy subjects exposed to cold stress altered by an acutely increased sodium intake?

In the study reported here, we examined blood pressure and endocrine responses in cold conditions during salt load in young healthy subjects who had previously shown increased resting blood pressure during acutely increased sodium intake. Subjects (n=53) added 121 mmol sodium into their normal diet for 1 week. If their mean arterial pressure had increased by a minimum of 5 mmHg compared to the previous measure they were selected for subsequent experiments. The subjects (n=8) were given 121 mmol supplemental sodium · day⁻¹ for 14 days. They were then put into a wind tunnel for 15 min (temperature −15 °C, wind speed 3.5 · ms⁻¹). Their blood pressure increased (P < 0.05) during the cold exposure, independent of the sodium intake. Their mean (SEM) plasma noradrenaline increased from 3.58 (0.62) nmol · l⁻¹ to 5.61 (0.79) nmol · l⁻¹ (P < 0.05) when the subjects were given a normal diet, and from 2.45 (0.57) nmol · l⁻¹ to 5.06 (0.56) nmol · l⁻¹ (P < 0.05) when the subjects were given an elevated sodium diet. The starting concentrations and the endpoint concentrations were statistically similar. The plasma levels of the N-terminal fragment of pro-atrial natriuretic peptide decreased during the whole-body cold exposure: with the sodium load the change was from 256.6 (25.5) nmol · l⁻¹ to 208.0 (25.3) nmol · l⁻¹, and with the normal diet, from 205.8 (16.4) nmol · l⁻¹ to 175.1 (16.1) nmol · l⁻¹. The haematocrit and red blood cell count increased (P < 0.05) with normal and elevated sodium diet in cold conditions, but haemoglobin increased (P < 0.05) only with high salt in cold conditions. To conclude, acutely increased sodium intake does not change the blood pressure response or hormonal responses to exposure to acute cold stress in healthy subjects. Accepted: 28 September 2000     

Ro 11-2465 (cyan-imipramine), citalopram and their N-desmethyl metabolites: Effects on the uptake of 5-hydroxytryptamine and noradrenaline in vivo and related pharmacological activities

Ro 11-2465 (cianopramine, cyan-imipramine) and citalopram (CIT), putative antidepressant drugs, are very potent and selective 5-hydroxytryptamine (5-HT) uptake inhibitors in vitro. This study investigated the effects of these drugs and their desmethyl metabolites, Ro 12-5419 (desmethylcianopramine, cyan-desipramine) and desmethylcitalopram (DCIT), respectively, on the uptake of 5-HT and noradrenaline (NA) in vivo [protection against H 77/77 (4, alpha-dimethyl-metatyramine)-induced displacement of 5-HT and NA] and on related pharmacological activities. All the investigated drugs antagonized H 77/77-induced displacement of 5-HT in the rat brain, though the effects of the metabolites were considerably weaker than those of the parent compounds. The H 77/77-induced displacement of brain NA in rats and mice was antagonized only by Ro 12-5419 and Ro 11-2465. All the drugs potentiated the pressor response to 5-HT in pithed rats; however, Ro 12-5419 and particularly Ro 11-2465 could also block the response when used in higher doses (0.1 mg/kg). Only Ro 12-5419 and Ro 11-2465 were able to potentiate the pressor response to NA. Ro 12-5419 also potentiated thyrotropin releasing hormone (TRH) hyperthermia and antagonized reserpine hypothermia in mice; Ro 11-2465 potentiated the TRH hyperthermia only. CIT and DCIT were inactive in both these tests. Of all the four drugs only CIT and Ro 12-5419 considerably stimulated the hind limb flexor reflex in spinal rats. However, whereas the stimulatory effect of CIT was inhibited by the 5-HT antagonists metergoline and cyproheptadine, that of Ro 12-5419 was counteracted by the NA antagonist phenoxybenzamine only. Ro 11-2465, when used in low doses (ca. 1 mg/kg), slightly potentiated the flexor reflex, whereas in higher doses (4–16 mg/kg) it had no effect itself but antagonized the stimulatory action of the 5-HT agonists fenfluramine, quipazine and LSD. The results obtained indicate that Ro 11-2465 and CIT, as well as their desmethyl metabolites, are also potent 5-HT uptake inhibitors in vivo. However, only CIT and DCIT are concurrently devoid of effect on uptake of NA. In contrast, Ro 11-2465 and particularly Ro 12-5419 appear to also inhibit the uptake of NA. Moreover, Ro 11-2465 appears to block central and peripheral 5-HT receptors.The results were presented at the 14th CINP Congress, Florence, June 19–23, 1984