Involvement of platelet-activating factor in the modulation of vascular tone in the isolated perfused rabbit kidney

The hypothesis that platelet-activating factor (PAF) plays a role in the modulation of the vasomotor tone and blood pressure was put forward by our group in previous in vivo studies in anaesthetised rabbits. The present study was undertaken to investigate the putative role of this lipid mediator in the vascular reactivity of the renal circulation, using the experimental model of the isolated perfused rabbit kidney. Dose-response curves to noradrenaline-induced vasoconstriction were performed before and after continuous infusions of two different PAF-receptor antagonists (WEB 2086 and yangambin) and of the phospholipase A₂ inhibitor mepacrine. The increases in renal perfusion pressure elicited by noradrenaline were potentiated by all the above-mentioned treatments in a dose-dependent manner. Moreover, prostaglandin F_2α-induced vasoconstriction was also potentiated by the administration of the PAF receptor antagonists and mepacrine. Furthermore, the administration of PAF into the renal circulation induced dose-related and long-lasting vasodilator responses, which were blocked by the PAF receptor antagonists. Nevertheless, PAF-induced renal vasodilation was also abolished by a pretreatment with mepacrine or with the cyclooxygenase inhibitor indomethacin, suggesting that it enhances the secondary formation of vasodilator arachidonic acid metabolites. The data indicate that PAF is involved in the modulation of the vasomotor tone in the renal circulation, through the release of cyclooxygenase products, constituting an additional mechanism of modulation of smooth muscle cell contractility to the ones exerted by well-known vasoactive substances of endothelial origin such as nitric oxide. Received: 20 April 1998 / Accepted: 5 March 1999     

Analysis of the action of idazoxan calls into question the reliability of the rat isolated small mesenteric artery assay as a predictor for α1-adrenoceptor-mediated pressor activity

We have studied the effects of idazoxan in rat aorta and small mesenteric artery. In the aorta, idazoxan behaved as a partial agonist (pK_A=6.30). Prazosin produced rightward shift (pA₂=9.88) and steepening of the idazoxan curve. In contrast, idazoxan had no effect of basal tension in the mesenteric artery, but shifted the noradrenaline curve to the right in a parallel manner (pA₂=6.12). The selective al-adrenoceptor agonist, indanidine, also behaved as a partial agonist in the aorta and produced no significant contractions of the small mesenteric artery. Since idazoxan and indanidine have been reported to raise blood pressure in the pithed rat via an action at vascular ₁-adrenoceptors, these results call into question the reliability of the small mesenteric artery assay as a predictor for ₁-adrenoceptor-mediated pressor activity in vivo.     

Mianserin markedly and selectively increases extracellular dopamine in the prefrontal cortex as compared to the nucleus accumbens of the rat

The atypical antidepressant mianserin, administered at doses of 1, 5 and 10 mg/kg SC, dose-dependently increased up to about 6 times extracellular dopamine in the medial prefrontal cortex of the rat, as estimated by vertical concentric microdialysis probes. Mianserin failed to modify extracellular dopamine in the nucleus accumbens. Mianserin also dose-dependently increased extracellular noradrenaline in the prefrontal cortex. Yohimbine, an ₂ antagonist, increased extracellular dopamine in the prefrontal cortex but the maximal increase was lower than that elicited by mianserin. Yohimbine also increased extracellular noradrenaline in the prefrontal cortex, but to a lesser extent than dopamine. Clonidine, an ₂ agonist, decreased extracellular dopamine and noradrenaline in the prefrontal cortex but failed to affect extracellular dopamine in the nucleus accumbens. Ritanserin, a 5HT₂ antagonist, at doses of 1.0 mg/kg, failed to increase extracellular dopamine in the prefrontal cortex, but significantly potentiated the increase in extracellular noradrenaline due to yohimbine. Ritanserin failed to potentiate the increase in extracellular noradrenaline elicited by yohimbine in the prefrontal cortex. The results are interpreted to indicate that mianserin increases extracellular DA as a result of the concurrent blockade of ₂ and 5HT₂ receptors. Failure to affect extracellular dopamine in the nucleus accumbens is explained as due to the lack of a significant effect of ₂ and 5HT₂ tone on DA release in the nucleus accumbens as compared to the prefrontal cortex. The results are consistent with the postulated relationship between antidepressant drug action and the ability to increase extracellular dopamine in the prefrontal cortex.     

Spike conduction properties of T-shaped C neurons in the rabbit nodose ganglion

Noradrenaline (NA) and angiotensin II (A II) were infused intravenously in conscious dogs without (series I) and with (series II) additional infusions of sodium nitroprusside at doses re-establishing normal levels of mean arterial pressure (MAP). In series I, NA infusion (1.6 g/min per kg for 30 min) initially elevated MAP by some 25 mm Hg and lowered heart rate by some 30 beats/min. Plasma concentrations of arginine vasopressin (AVP) remained constant, while those of A II and atrial natriuretic factor were slightly, but significantly, increased. Infusion of A II (10 or 20 ng/min per kg for 30 min) induced similar rises in MAP and slight reductions of heart rate and increased plasma AVP by 70% and atrial natriuretic factor by 60%. In series II, sodium nitroprusside (1–4 g/min per kg) was added for 30 min to infusions of NE (1.6 g/min per kg) and A II (20 ng/min per kg) in order to maintain MAP at its control level. This resulted in an 11-fold increase in plasma AVP during NA infusion and a 19-fold increase during A II infusion. Infusing sodium nitroprusside (4 g/min per kg) alone lowered MAP to clearly hypotensive levels, but the resulting rises in plasma AVP were less than, rather than equal to, those seen at normotensive MAP levels during the combined infusions of sodium nitroprusside with A II or NA, respectively. It is concluded that both NA and A II exert strong stimulatory actions on AVP release which are, however, counteracted by inhibitory influences arising from the hypertensive effects of NA and A II.     

Noradrenaline transport by rat heart sympathetic nerves: A re-examination of the role of sodium ions

Summary The effect of sodium ion on ³H-(–)-noradrenaline (0.0875 to 0.5 M) transport by rat heart atrial hemi-appendages incubated in vitro has been studied, and the following observations made: a) When sodium was omitted (choline and lithium substitution) there was no evidence for active noradrenaline transport, and only a component that did not show saturation kinetics up to 1 M noradrenaline, remained. b) Omission of sodium or addition of 4×10^–5 M desipramine inhibited noradrenaline transport to exactly the same extent, and their effects were not additive. Alprenolol did not reduce this sodium-independent transport, but tropolone lowered it somewhat. c) No evidence for corticosterone-sensitive noradrenaline transport (uptake-2) was found in this preparation at the low amine concentrations used. d) In control medium, the kinetic parameters of transport were: K _m: 0.59 ± 0.063 M and V _max: 2.44 ± 0.43 (pmoles/mg protein/min). With 26 mM sodium and the rest substituted by choline, K _m:2.26 ± 0.70 M (P0.001) and V _max: 2.74 ± 0.43 (pmoles/mg protein/min) (not significant). Also with 26 mM sodium, but with sucrose substitution, K _m: 0.76 ± 0.13 M (N.S.) and V _max: 1.06 ± 0.13 (pmol/mg/min) (P<0.05). Such results indicate that sodium only modifies the affinity of the transport system for noradrenaline, without changing V _max, and that changes in the latter are only a consequence of a reduction of the ionic strength. e) When noradrenaline transport was studied at different concentrations of external sodium, at constant ionic strength and with precautions to minimize the noradrenaline-releasing effect of low sodium, it was found that the data could be best represented by two hyperbolas placed in series. This suggests that the noradrenaline carrier has two sites for sodium, that do not interact with each other. When the same experiments were repeated in the absence of chloride, it was found that the noradrenaline transport system had lost virtually all its affinity for sodium. f) The effect of prolonged tissue incubation in the absence of sodium was found to produce a relatively small inactivation of noradrenaline transport. Such phenomenon was enhanced by raising the calcium concentration to 2 mM.     

Impaired dopamine function and muscular rigidity induced by 6-aminonicotinamide in rats

Summary In corpus striatum, 6-aminonicotinamide (6-AN), 10 mg/kg i.p., lowered the concentration of dopamine and markedly reduced the disappearance of dopamine after synthesis inhibition with -methyl-p-tyrosine. In the dopamine-rich part of the limbic system, the formation of DOPA after decarboxylase inhibition with 3-hydroxybenzylhydrazine was decreased.In diencephalon, 6-AN altered neither the steadystate level nor the utilization of noradrenaline.The data suggest that the muscular rigidity induced by 6-AN may be associated with disruption of dopaminergic transmission.     

The effects of a permanent and selective depletion of brain catecholamines on the antinociceptive action of morphine

Summary 6-Hydroxydopamine was given to newborn mice. After 60 days their brains were deficient in noradrenaline and dopamine while morphine's antinociceptive action was reduced. 6-Hydroxydopa was administered to adult mice. This depleted brain noradrenaline and reduced morphine's antinociceptive action. Newborn rats received 6-hydroxydopa. After 60 days morphine's antinociceptive action was potentiated, brain noradrenaline was reduced while dopamine had increased. Adult rats were treated with 6-hydroxydopa. This reduced brain noradrenaline but did not affect morphine's antinociceptive action. Guanethidine, which depletes noradrenaline in the peripheral nervous system, was given to newborn animals of both species. It had no effect on morphine's antinociceptive action. It is concluded that in the mouse the antinociceptive action of morphine relies in part on normal brain noradrenaline function and dopamine is not directly involved. In the rat morphine's action is affected by neurotoxic drugs which alter brain dopamine function.     

Mechanism of the enhancement in transmitter release from central and peripheral noradrenergic nerve terminals induced by the purified scorpion venom,tityustoxin

Summary In the isolated nerve-muscle preparation of the cat nictitating membrane exposure to 0.04 M of the scorpion venom tityustoxin (TsTX) increased significantly the overflow of ³H-noradrenaline and the responses elicited by postganglionic nerve stimulation (1200 pulses, 0.5 ms duration, supramaximal voltage). Concentration effect curves to exogenous (-)-noradrenaline were not affected in the presence of this concentration of TsTX.The enhanced release of ³H-noradrenaline obtained during nerve stimulation as well as the increase of the postsynaptic responses observed during exposure to TsTX were more pronounced at 4 Hz than at 20 Hz. The increase in the overflow of noradrenaline observed with the toxin was selective for nerve stimulation since the release evoked by tyramine was not affected by TsTX.TsTX did not increase further the enhancement of ³H-noradrenaline release obtained in the presence of 18 mM tetraethylammonium (TEA). On the other hand, both TsTX and TEA were able to increase further the overflow of ³H-noradrenaline after block of the presynaptic alpha-adrenoceptors with phenoxybenzamine 0.29 or 2.9 M.In slices of rat cerebral cortex, TsTX 0.04 M increased ³H-noradrenaline release induced by 10 mM and by 20 mM KCl. The increased release evoked by the toxin was more pronounced for the lower concentration of K⁺.An increased release of ³H-noradrenaline in the presence of the toxin was also observed in rat hypothalamic slices stimulated with 20 mM K⁺. The K⁺ stimulated induced release of ³H-noradrenaline was also increased by 1.8 mM TEA. As shown for the peripheral nervous, system the simultaneous addition of TEA and TsTX did not result in additive effects when compared with the effects of the two agents added separately. Tityustoxin did not modify the metabolic pattern of the neurotransmitter released by K⁺ from rat hypothalamic slices.It is concluded that TsTX increases the stimulation-induced release of ³H-noradrenaline from both peripheral and central noradrenergic nerve terminals. Tityustoxin appears to act on the nerve terminal by a mechanism similar to that of TEA, an agent known to enhance the amount of noradrenaline released by nerve stimulation by increasing the duration of the action potentials.     

Effects of LSD and BOL on the catecholamine synthesis and turnover in various brain regions

In the rat, lysergic acid diethylamide (LSD) 0.5 mg/kg and 2-bromo lysergic acid diethylamide (BOL) 0.5 mg/kg increased the rate of the striatal in vivo tyrosine hydroxylation as measured by the DOPA accumulation after decarboxylase inhibition. Neither LSD nor BOL significantly changed the DOPA accumulation in the olfactory tubercle, a dopamine-rich part of the limbic system. LSD but not BOL increased the DOPA accumulation in the cerebral cortex and in the brain stem. LSD and BOL appeared not to alter the rate of -MT-induced disappearance of DA or of NA in the whole brain, nor did they change the rate of the -MT-induced disappearance of DA in the striatum. It is suggested that in the striatum LSD and BOL block autoreceptors (presynaptic receptors) regulating the tyrosine hydroxylation. These receptors may be DA receptors, but may also be 5-HT- or LSD-sensitive receptors.The regional differences observed between LSD and BOL suggest that LSD in the cerebral cortex and in the brain stem increases the DOPA accumulation by mechanism other than that functioning in the striatum. One possible explanation is that LSD and BOL may differ in their effects on 5-hydroxytryptaminergic systems in the cerebral cortex and in the brain stem.     

Noradrenergic influences on catalepsy

Widespread depletion of forebrain noradrenaline, produced by the intracerebral injection of 4 g of 6-hydroxydopamine into the fibres of the dorsal noradrenergic bundle, potentiated the catalepsy induced by 20 mg/kg of morphine and severely attenuated the catalepsy induced by two separate cholinergic agonists, arecoline and pilocarpine. It did not, however, affect haloperidol catalepsy at any of the four doses tested. These results suggest that cholinergic catalepsy may be critically dependent on an intact noradrenergic substrate, perhaps through cholinergic receptors located either presynaptically on noradrenergic terminals or on the cell bodies of origin in the locus coeruleus. Noradrenaline appears to play a modulatory role in morphine catalepsy, although other sites of action must also be involved. Ascending noradrenergic systems do not appear to influence haloperidol catalepsy.