Assessment of the role of glutathione conjugation in the protection afforded by anethol dithiolthione against hexachloro-1,3-butadiene-induced nephrotoxicity

Arachidonic acid and oleoylacetylglycerol enhance depolarization-evoked glutamate release from hippocampal mossy fiber nerve endings. It was proposed this is a Ca(2+)-dependent effect and that protein kinase C is involved. Here we report that arachidonic acid and oleoylacetylglycerol synergistically potentiate the glutamate release induced by the Ca2+ ionophore ionomycin. The Ca2+ dependence of this effect was established, as removal of Ca2+ eliminated evoked release and the lipid-dependent potentiation. Also, Ca2+ channel blockers attenuated ionomycin- and KCl-evoked exocytosis, as well as the facilitating effects of the lipid mediators. Although facilitation required Ca2+, it may not involve an enhancement of evoked Ca2+ accumulation, because ionomycin-dependent glutamate release was potentiated under conditions that did not increase ionomycin-induced Ca2+ accumulation. Also, the facilitation may not depend on inhibition of K+ efflux, because enhanced release was observed in the presence of increasing concentrations of 4-aminopyridine and diazoxide did not reduce the lipid-dependent potentiation of exocytosis. In contrast, disruption of cytoskeleton organization with cytochalasin D occluded the lipid-dependent facilitations of both KCl- and ionomycin-evoked glutamate release. In addition, arachidonic acid plus glutamatergic or cholinergic agonists enhanced glutamate release, whereas a role for protein kinase C in the potentiation of exocytosis was substantiated using kinase inhibitors. It appears that the lipid-dependent facilitation of glutamate release from mossy fiber nerve endings requires Ca2+ and involves multiple presynaptic effects, some of which depend on protein kinase C.     

NMDA and non-NMDA ionotropic glutamate receptors modulate striatal acetylcholine release via pre- and postsynaptic mechanisms

The effects of NMDA and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) on endogenous acetylcholine release from rat striatal slices and synaptosomes were investigated. Both agonists (1-300 microM) facilitated acetylcholine release from slices in a dose-dependent manner. NMDA (100-300 microM) and AMPA (30-300 microM), however, subsequently inhibited acetylcholine release. NMDA (100 microM)-induced facilitation was antagonized by 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) and dizocilpine (both 1-10 microM), whereas the 10 microM AMPA effect was antagonized by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 1-30 microM). NMDA (100 microM)-induced inhibition was counteracted by CPP, but not dizocilpine, and by the nitric oxide synthase inhibitor L-nitroarginine (1-100 microM). Tetrodotoxin (0.5 microM) prevented the facilitatory effect of 3 microM NMDA and AMPA, but left unchanged that of 30 microM NMDA and 100 microM AMPA. Acetylcholine release from synaptosomes was stimulated by KCl (7.5-100 mM) in a dose-dependent manner. NMDA and AMPA maximally potentiated the 20 mM KCl effect at 1 microM and 0.01 microM, but were ineffective at 100 microM and 10 microM, respectively. Inhibition of acetylcholine release was never found in synaptosomes. The effects of 1 microM NMDA and 0.01 microM AMPA were antagonized by CPP (0.0001-1 microM) or dizocilpine (0.0001-10 microM) and by CNQX (0.001-1 microM), respectively. These data suggest that glutamatergic control of striatal acetylcholine release is mediated via both pre- and postsynaptic NMDA and non-NMDA ionotropic receptors.     

Involvement of alpha1B-adrenoceptors in the positive inotropic effect of endogenous noradrenaline in rabbit myocardium

We studied the alpha1-adrenoceptor subtypes mediating the positive inotropic effects of phenylephrine and noradrenaline as well as endogenous noradrenaline released by tyramine in rabbit papillary muscle. In the presence of propranolol, both phenylephrine and tyramine produced a positive inotropic effect in a concentration-dependent manner. WB4101 (N-[2-(2,6-dimethoxyphenoxy]ethyl]-2,3-dihydro-1,4-benzodioxin+ ++-2-methanamine) and chlorethylclonidine each antagonized the positive inotropic effect of phenylephrine. On the other hand, only chlorethylclonidine significantly blocked the positive inotropic effect of tyramine. However, the presence of both antagonists was needed to block the positive inotropic effect elicited by the exogenous addition of the low concentration of noradrenaline. These data suggest that after extensive blockade of beta-adrenoceptors the positive inotropic effects of phenylephrine and exogenous noradrenaline result from stimulation of the alpha1A- and alpha1B-adrenoceptor subtypes, whereas that of endogenous noradrenaline is mediated via the alpha1B-adrenoceptor subtype. This could be explained by assuming that the alpha1B-adrenoceptor subtype population may be located on a space confronting more closely to the sympathetic nerve endings than the alpha1A-adrenoceptor subtype population.     

Safety of long-term levodopa therapy in malignant melanoma

Levodopa therapy is contraindicated in malignant melanoma because of its apparent carcinogenic effects reported by physicians in the early 1970s. We discuss the case of a 74-year-old man with Parkinson's disease who was treated with levodopa and whose malignant melanoma was later diagnosed. Before development of malignant melanoma, the patient received an estimated 5.7 kg levodopa over 6 years. Therapy with levodopa was continued for > 10 years, with a total dose of approximately 4.3 kg levodopa (together with carbidopa.) Recurrence of the melanoma was not observed. Based on our experience with this patient and an extensive literature review, we conclude that the natural history of malignant melanoma is not adversely influenced by concurrent levodopa therapy. Levodopa therapy should not be withheld for fear of accelerating malignant melanoma in parkinsonian patients.     

Levodopa improves motor function without impairing cognition in mild non-demented Parkinson's disease patients. Parkinson Study Group

OBJECTIVE: The objective of the study was to determine the effects of short-term levodopa administration on motor, cognitive, and psychiatric aspects of Parkinson's disease (PD). BACKGROUND: The effects of levodopa on mental processes in PD are controversial. Opinions range from the claim that levodopa improves cognition to the opposite view that levodopa causes or exacerbates dementia, delusions, and hallucinations. Of the 800 idiopathic PD patients enrolled in the original DATATOP study, 387 reached the end point of functional disabilities sufficiently severe to require levodopa treatment. There were 263 men and 124 women who were comparable with regard to age, symptom duration of PD, and measures of PD severity. We compared test scores on motor performance, cognitive function, and psychiatric status before levodopa and again within 6 months after initiation of levodopa therapy. RESULTS: Levodopa administration improved all motor functions significantly. The improvement was significantly greater in women than in men. Levodopa administration did not worsen scores on any cognitive tests, and there were quantitatively small but significant improvements in tests of frontal lobe function. Levodopa exerted only minor effects on psychiatric measures. There were small but significant decreases in scores for depression, and increases in vivid dreams and hallucinations. CONCLUSIONS: Levodopa administration for up to 6 months in dosages sufficient to improve motor function has only small effects on cognitive function and psychiatric status in mild to moderate PD patients. We conclude that motor symptoms in early PD, which result from dopamine depletion, are dissociable from cognitive functions and psychiatric status, which may be more dependent on nondopaminergic mechanisms.     

P2 purinoceptors modulating noradrenaline release from sympathetic neurons in culture

ATP (1 mM) inhibited, whereas 2-methylthio-ATP (30 microM), a P2Y-selective purinoceptor agonist, increased electrically evoked release of [3H]noradrenaline from chick sympathetic neurons. The P2X-selective purinoceptor agonist alpha,beta-methylene-ATP (30 microM) had no effect. The ATP-induced inhibition of release as well as the facilitation caused by 2-methylthio-ATP was not affected by the selective adenosine (P1) receptor antagonist 8-(p-sulfophenyl)-theophylline (8-PST; 100 microM), but completely prevented by the non-selective P2 antagonist suramin (300 microM). The present data reveal a dual regulation of noradrenaline release from sympathetic neurons. Facilitation seems to be mediated by a P2Y purinoceptor, whereas inhibition is caused by a P2 purinoceptor which needs further subtype characterization.     

Dopamine receptors and dopaminergic nerves in the vas deferens of the rat

Phentolamine antagonized competitively the effects of noradrenaline (pA2 = 7.1), dopamine (pA2 = 8.0) and tyramine (pA2 = 8.2). Haloperidol had a pA2 value of 7.3 against dopamine and 6.5 against noradrenaline. Apomorphine antagonized competitively dopamine (pA 2 = 4.8) and tyramine (pA2 = 5.1) and noncompetitively antagonized noradrenaline (pD'2 = 3.6). From these data it is concluded that these antagonists interact with dopamine receptors and alpha-adrenergic receptors. Apomorphine (10-4 M) attenuated the maximal response to dopamine and field stimulation, whereas the same concentration of apomorphine potentiated the maximal response to noradrenaline. Assuming that tyramine and field stimulation release the naturally occurring neurohumoral transmitter from adrenergic nerve endings, it is concluded that dopamine is the physiologically functional neurohumoral transmitter in the rat vas deferens which, when released, stimulates specific dopamine receptors.     

Evidence for participation of nitric oxide in excitatory neurotransmission in rat vas deferens

A depression of the fast, non-adrenergic, and also of the slow, adrenergic, components of muscle contraction in response to intramural nerve stimulation was induced by the blocker of nitric oxide synthase NG-nitro-L-arginine methyl ester (L-NAME), in rat vas deferens. Effects of exogenous noradrenaline or ATP were not reduced by L-NAME. However, L-arginine also caused an inhibition of electrically induced effects in most of the preparations, contrary to the expectations for a precursor of nitric oxide synthesis. In spite of these difficulties L-arginine antagonized the action of L-NAME. These results indicate that nitric oxide is involved in excitatory nerve-muscle transmission in vas deferens.     

Muscarinic M1 receptor mediated inhibition of GABA release from rat cerebral cortex

Presynaptic modulation of [3H]GABA release was examined using rat cerebral cortical slices. In vitro addition of carbachol, a muscarinic receptor agonist, resulted in a significant suppression of the release of [3H]GABA evoked by high potassium (50 mM) stimulation in a dose dependent manner, while noradrenaline, isoproterenol, dopamine, 5-hydroxytryptamine, histamine and glutamic acid had no significant effect on the evoked release of [3H]GABA. This suppressive effect of carbachol was antagonized invariably by atropine. Furthermore, it was found that the suppressive action of carbachol could be antagonized by pirenzepine, a selective M1 muscarinic receptor antagonist, but not by AF-DX 116 and 4-DAMP, M2 and M3 receptor antagonists, respectively. These results suggest that the release of GABA from cerebral cortical GABA neurons may be modulated by presynaptic M1 muscarinic receptor.     

Measurement possibilities using an electronic portal imaging device

The effects of hexachlorocyclohexane (HCH) isomers and some GABAergic compounds on [3H]noradrenaline (NA) release from rat hippocampal slices prelabelled with 80 nM [3H]NA were determined. The convulsant gamma-HCH isomer facilitated (EC50 = 21 microM) and the depressant delta-HCH isomer reduced (EC50 = 48 microM) the Ca(2+)-dependent K(+)-evoked release of [3H]NA, whereas alpha- and beta-HCH isomers did not show any effect. Moreover, alpha- and delta-HCH isomers antagonized the facilitation of evoked [3H]NA release induced by the gamma-HCH isomer. The GABAergic convulsant drugs, bicuculline, picrotoxin and pentylenetetrazol, did not cause any modification of the evoked [3H]NA release even at high concentrations. Neither bicuculline nor picrotoxin blocked the effects of HCH isomers on K(+)-evoked release of [3H]NA. Exposure of slices to diazepam reduced the K(+)-evoked release of [3H]NA (EC50 = 33 microM) in a manner similar to that of the delta-HCH isomer. In addition, diazepam (50 microM) blocked the gamma-HCH effect and caused an additive inhibitory response with the delta-HCH isomer. On the other hand, diazepam and delta-HCH induced a time-dependent Ca(2+)-independent enhancement of basal [3H]NA release. The results suggest that modulation of [3H]NA release in the hippocampus by HCH isomers may be involved in the central actions of these compounds, and that sites other than the classic GABAA receptor may underlie their presynaptic mechanisms of action.     

Mechanisms of the hypoglycemic effects of the alpha2-adrenoceptor antagonists SL84.0418 and deriglidole

The effects of the alpha2-adrenoceptor antagonist SL84.0418 and its two enantiomers, (+) deriglidole and (-)SL86.0714 on glucose and insulin levels were examined in mice and in neonatal streptozotocin-induced diabetic rats. It was recently demonstrated in mouse pancreatic beta-cells that both deriglidole and SL86.0714 inhibit ATP-sensitive K+ channel with similar potency whereas alpha2-adrenoceptors are blocked only by deriglidole. In the present study, we showed, in vivo in mice, that SL84.0418 and deriglidole potently reduced glycemia and antagonized diazoxide-induced hyperglycemia, whereas SL86.0714 and tolbutamide were markedly less potent. In diabetic rats, SL84.0418 and deriglidole (10 mg/kg i.p.) fully normalized glucose tolerance whereas SL86.0714 and tolbutamide only slightly improved it. Five min after deriglidole administration in mice a marked and short lasting rise in insulin levels was observed, followed by a progressive reduction of glycemia. In diabetic rats, insulin and norepinephrine levels rose 15 min after deriglidole administration. Sympathetic outflow blockade by chlorisondamine, beta-adrenoceptor blockade by propranolol or their combination markedly reduced deriglidole-induced rise in insulin levels in a similar manner. Furthermore, in chlorisondamine-treated animals norepinephrine levels were strongly lowered and not modified by deriglidole and propranolol administration. However, in spite of sympathetic outflow and beta-adrenoceptor blockade, a moderate rise in insulinemia was still observed after deriglidole administration. Taken together these data demonstrate that deriglidole is the enantiomer that mediates the antihyperglycemic and insulin secretory effects of SL84.0418. Our study suggests that the major part of deriglidole effects is the consequence of the blockade of prejunctional alpha2-adrenoceptors that have reinforced the release of catecholamines in adrenergic nerve endings and indirectly activated postjunctional beta-adrenoceptors to further potentiate insulin secretion. However, it is also suggested that another undefined mechanism is involved in deriglidole potentiation of insulin secretion.     

Estradiol coupling to endothelial nitric oxide stimulates gonadotropin-releasing hormone release from rat median eminence via a membrane receptor

The median eminence (ME), which is the common termination field for adenohypophysiotropic systems, has been shown to produce nitric oxide (NO), a signaling molecule involved in neuroendocrine secretion. Using an ex vivo technique, 17beta-estradiol exposure to ME fragments, including vascular tissues, stimulated NO release within seconds in a concentration-dependent manner, whereas 17alpha-estradiol or testosterone had no effect. 17Beta-estradiol conjugated to BSA (E2-BSA) also stimulated NO release, suggesting mediation by a membrane surface receptor. Tamoxifen, an estrogen receptor inhibitor, antagonized the action of both 17beta-estradiol and E2-BSA. Furthermore, estradiol-stimulated NO stimulates GnRH release. This was demonstrated by hemoglobin (a NO scavenger), N(omega)-nitro-L-arginine methyl ester, and L-N5-(1-iminoethyl)ornithine (nitric oxide synthase inhibitors) inhibition of estradiol stimulated NO and GnRH release. In this regard, L-N5-(1-iminoethyl)ornithine, specific for endotheliol constitutive nitric oxide synthase, was significantly more potent, suggesting that the estradiol-stimulated NO release arose from vascular endothelial cells. Additionally, the NO-stimulated GnRH release occurs via guanylyl cyclase activation in GnRH nerve terminals, as ODQ, a potent and selective inhibitor of NO-sensitive guanylyl cyclase, abolished the estradiol-stimulated GnRH release. The results suggest that at physiological concentrations, 17beta-estradiol may have immediate actions on ME endothelial cells via nongenomic signaling pathways leading to NO-stimulated GnRH release.     

Effects of histamine on rat isolated atria

The effects of histamine were studied in atria obtained from untreated and reserpine-pretreated rats. At high doses, histamine caused a positive chronotropic response that was not antagonized by either promethazine or cimetidine. In the presence of propranolol or in atria from reserpine-pretreated rats histamine caused an atropine-sensitive negative chronotropic response. Large doses of histamine also caused a positive inotropic response in left atria that were antagonized by the beta adrenoceptor antagonist propranolol. Reserpine pretreatment abolished the inotropic response of histamine in the rat heart. The results indicate that in large doses histamine causes an indirect stimulation of beta adrenoceptors (right and left atrium) by releasing endogenous noradrenaline and of muscarinic receptors (right atrium) by releasing acetylcholine.     

The relative importance of dopamine and noradrenaline receptor stimulation for the restoration of motor activity in reserpine or alpha-methyl-p-tyrosine pre-treated mice

Two animal models of Parkinsonism have been employed to investigate the role of noradrenaline in the motor effects of levodopa. Pretreatment with reserpine or alpha-methyl-p-tyrosine (AMPT) causes cerebral amine depletion and reduction of motor activity, which can be reversed by levodopa. The effect of inhibitors of noradrenaline (NA) synthesis and antagonists of NA and dopamine (DA) receptors on the action of levodopa have been studied. For comparison, the effects of such treatments on apomorphine action has been investigated. Reversal of reserpine (10 mg/kg) induced akinesia in mice by levodopa (200 mg/kg) plus the peripheral decarboxylase inhibitor MK 486 (L-alpha-methyl-dopahydrazine; 25 mg/kg) was inhibited by prior administration of phenoxybenzamine (20 mg/kg), haloperidol (1 mg/kg), pimozide (1 mg/kg) or the dopamine-beta-hydroxylase inhibitor FLA-63 (bis [4-methyl-l-homopiperazinylthiocarbonyl] disulphide; 15 or 25 mg/kg). Apomorphine (2 mg/kg) reversal of reserpine akinesia was similarly inhibited by haloperidol (1 mg/kg) and pimozide (2 mg/kg) but not by phenoxybenzamine (20 mg/kg) or FLA-63 (25 mg/kg). Apomorphine (5 mg/kg) reversal of reserpine akinesia was enhanced by simultaneous administration of the noradrenergic agonist clonidine (1 mg/kg) and this effect was not significantly altered by prior administration of FLA-63. Clonidine, however, reversed the FLA-63 induced inhibition of the levodopa effect on reserpine akinesia. Levodopa reversal of akinesia induced by AMPT (200 mg/kg) was also inhibited by FLA-63, pimozide and haloperidol. Phenoxybenzamine, however, was without effect, but produced a different pattern of behaviour. Similarly, pimozide and haloperidol blocked apomorphine reversal of AMPT induced akinesia; FLA-63 was without effect but phenoxybenzamine produced marked inhibition. The results suggest that full restoration of motor activity in reserpine or AMPT pretreated animals requires stimulation of both DA and NA receptors.     

Handwriting and speech changes across the levodopa cycle in Parkinson's disease

Levodopa treatment is used to reduce rigidity and bradykinesia in Parkinson's disease (PD). This study tracked the handwriting and speech performance of 10 PD patients at 30-minute intervals across one levodopa drug cycle to evaluate levodopa-related changes in temporal and spatial measures that are assumed to correspond to changes in rigidity and bradykinesia. The handwriting measures included l and e upstroke duration and size. The speech measures included duration of the vowels /i/, /u/, /ae/, and /[symbol: see text]/ and the quadrilateral area produced by these vowels, and the slope of the diphthong /aI/. Levodopa significantly improved handwriting upstroke duration but not upstroke size. Speech measures did not show a significant trend across the levodopa cycle. The results suggest that upstroke duration is sensitive to the presumed effects of levodopa and that handwriting analysis may hold promise in helping to estimate an optimum levodopa regimen for PD patients.     

Differential effects of levodopa on dopaminergic function in early and advanced Parkinson's disease

The effect of levodopa on L-[11C]DOPA influx rate was evaluated in patients with early and advanced Parkinson's disease (PD) by using positron emission tomography (PET). The patients were scanned both drug-free and after a subsequent therapeutic levodopa infusion. Regional analysis of striatal L-[11C]DOPA influx rate showed a correlation to the degenerative loss of nerve terminals reported at postmortem analysis in PD. Levodopa induced markedly differential effects on the striatal L-[11C]DOPA influx rate in early and advanced patients. In patients with mild PD, levodopa infusion decreased L-[11C]DOPA influx, whereas in patients with advanced PD, levodopa induced significant upregulation of L-[11C]DOPA influx. These changes were confined to the putamen and were, in both patient categories, most prominent in the dorsal part of the region. The present investigation demonstrates a marked shift in the modulatory action of levodopa with the advancement of PD and suggests the induction of positive feedback in advanced PD. These findings could help explain the less graded clinical response to levodopa in advanced PD and would thus have importance for the understanding of the pathogenesis underlying motor fluctuations.     

The serotonin receptor agonist 5-methoxy-N,N-dimethyltryptamine facilitates noradrenaline release from rat spinal cord slices and inhibits monoamine oxidase activity

1. The influences of the purported serotonergic agonist 5-methoxy-N,N-dimethyltryptamine (MeODMT) on noradrenaline release and metabolism were investigated in a rat spinal cord release model and a monoamine oxidase (MAO) assay. 2. MeODMT inhibited the basal outflow of tritium from rat spinal cord slices preincubated with [3H]noradrenaline and enhanced the electrically-evoked overflow. 3. Effects on basal outflow were not observed, when monoamine oxidase (MAO) was inhibited by pargyline. Effects on the evoked overflow were not observed in the presence of metitepine or phentolamine. 4. Preferential inhibition by MeODMT of MAO A-type enzyme activity was found in a direct assay. 5. The results provide evidence for two different effects by which MeODMT reinforces noradrenergic neurotransmission in the rat spinal cord: facilitation of stimulation-evoked noradrenaline release and inhibition of noradrenaline metabolism by MAO inhibition.     

Anti-B-50 (GAP-43) antibodies decrease exocytosis of glutamate in permeated synaptosomes

The involvement of the protein kinase C substrate, B-50 (GAP-43), in the release of glutamate from small clear-cored vesicles in streptolysin-O-permeated synaptosomes was studied by using anti-B-50 antibodies. Glutamate release was induced from endogenous as well as 3H-labelled pools in a [Ca(2+)]-dependent manner. This Ca(2+)-induced release was partially ATP dependent and blocked by the light-chain fragment of tetanus toxin, demonstrating its vesicular nature. Comparison of the effects of anti-B-50 antibodies on glutamate and noradrenaline release from permeated synaptosomes revealed two major differences. Firstly, Ca(2+)-induced glutamate release was decreased only partially by anti-B-50 antibodies, whereas Ca(2+)-induced noradrenaline release was inhibited almost completely. Secondly, anti-B-50 antibodies significantly reduced basal glutamate release, but did not affect basal noradrenaline release. In view of the differences in exocytotic mechanisms of small clear-cored vesicles and large dense-cored vesicles, these data indicate that B-50 is important in the regulation of exocytosis of both types of neurotransmitters, probably at stages of vesicle recycling and/or vesicle recruitment, rather than in the Ca(2+)-induced fusion step.     

Staurosporine and its derivatives enhance f-Met-Leu-Phe-induced superoxide production via phospholipase D activation in human polymorphonuclear leukocytes

Staurosporine (STAR) is one of the most potent inhibitors of protein kinase C (PKC). It is known that in human polymorphonuclear leukocytes (PMNs), the phorbol ester-induced generation of superoxide anion (respiratory burst) is effectively inhibited by STAR in a dose-dependent manner, whereas superoxide generation induced by chemoattractants, e.g. n-formyl-methionyl-leucyl-phenylalanine (FMLP) or PAF, is regulated biphasically by STAR. We compared the effects of STAR and K252a on FMLP-induced superoxide production from PMNs and examined the effects of propranolol, a inhibitor of phosphatidic acid (PA) phosphohydrolase, on the potentiation of the production by STAR. We also examined the effects of some derivatives of STAR and K252a on the production and the alteration of the effects induced by propranolol pretreatment. When PMNs were stimulated with FMLP, STAR potentiated superoxide production by 240.5 +/- 30.9% at a low concentration (100 nmol/l). Propranolol pretreatment specifically inhibited the potentiation. When phorbol-12-myristate-13-acetate (PMA) was used as a stimulant, STAR inhibited superoxide production dose-dependently and did not enhance the production. K252a inhibited PMA or FMLP-induced superoxide production dose-dependently and did not enhance FMLP-induced superoxide production. STAR derivatives showed potentiation of FMLP-induced superoxide production similar to that of STAR at concentrations ranging from 10-100 nmol/l, and propranolol (200 mumol/l) effectively inhibited it. K252a derivative NA332 did not show any potentiative effect on the production. PMA-induced superoxide production was inhibited by all compounds dose-dependently.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hemodynamic actions of systemically injected pituitary adenylate cyclase activating polypeptide-27 in the rat

The aims of this study were (1) to characterize the hemodynamic mechanisms underlying the hypotensive effects of pituitary adenylate cyclase activating polypeptide-27 (PACAP-27 0.1-2.0 nmol/kg, i.v.) in pentobarbital-anesthetized rats, and (2) to determine the roles of the autonomic nervous system, adrenal catecholamines and endothelium-derived nitric oxide (NO) in the expression of PACAP-27-mediated effects on hemodynamic function. PACAP-27 produced dose-dependent decreases in mean arterial blood pressure and hindquarter and mesenteric vascular resistances in saline-treated rats. PACAP-27 also produced pronounced falls in mean arterial blood pressure in rats treated with the ganglion blocker, chlorisondamine (5 mg/kg, i.v.). The hypotensive and vasodilator actions of PACAP-27 were not attenuated by the beta-adrenoceptor antagonist, propranolol (1 mg/kg, i.v.), or the NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME 50 micromol/kg, i.v.). PACAP-27 produced dose-dependent increases in heart rate whereas the hypotensive response produced by the nitrovasodilator, sodium nitroprusside (10 microg/kg, i.v.), was associated with a minimal tachycardia. The PACAP-27-induced tachycardia was unaffected by chlorisondamine, but was virtually abolished by propranolol. These results suggest that the vasodilator effects of PACAP-27 are due to actions in the microcirculation rather than to the release of adrenal catecholamines and that this vasodilation may not involve the release of endothelium-derived NO. These results also suggest that PACAP-27 produces tachycardia by directly releasing norepinephrine from cardiac sympathetic nerve terminals rather than by direct or baroreceptor reflex-mediated increases in sympathetic nerve activity.