Biomedical subjects

D T Beattie

Publications and source records attributed to D T Beattie.

At least 19 recordsLinked to original sources

PubMed2006

The 5-HT2B antagonist and 5-HT4 agonist activities of tegaserod in the anaesthetized rat.

The 5-HT4 receptor agonist and gastroprokinetic, tegaserod, possesses 5-HT2B receptor antagonist activity. However, the relevance of such activity is unclear. In this study, the 5-HT2B receptor antagonist and 5-HT4 agonist activities of tegaserod were investigated. Two piezoelectric crystals were implanted on the stomach fundus or oesophagus of anaesthetized Sprague-Dawley rats. Measurement of the transmission time of ultrasonic pulses between the implanted crystals provided a continuous record of inter-crystal distance, and thus of muscle length. In the stomach fundus, tegaserod (1 and 3 mg kg(-1)), administered subcutaneously (s.c.), inhibited the contractile response evoked by the 5-HT2B receptor agonist, BW 723C86 (0.01-1 mg kg(-1) intravenously (i.v.)). SB 206553 (1 mg kg(-1) s.c.), a selective 5-HT2B/2C receptor antagonist, also inhibited the BW 723C86-mediated responses. In the rat oesophagus, tegaserod (0.001-0.3 mg kg(-1) i.v. or 0.003-3 mg kg(-1) s.c.) increased inter-crystal distance, consistent with smooth muscle relaxation; the responses were inhibited by the 5-HT4 antagonist, piboserod (0.1 mg kg(-1) s.c.). Data from this in vivo rat study are consistent with tegaserod-induced 5-HT4 receptor-mediated oesophageal relaxation, and antagonism of 5-HT2B receptor-mediated stomach fundus contraction. The clinical relevance of the 5-HT2B receptor antagonism of tegaserod remains to be determined.

Animals↗

PubMed2004

The 5-HT4 receptor agonist, tegaserod, is a potent 5-HT2B receptor antagonist in vitro and in vivo.

1 Tegaserod (Zelnorm) is a potent 5-hydroxytryptamine4 (5-HT4) receptor agonist with clinical efficacy in disorders associated with reduced gastrointestinal motility and transit. The present study investigated the interaction of tegaserod with 5-HT2 receptors, and compared its potency in this respect to its 5-HT4 receptor agonist activity. 2 Tegaserod had significant binding affinity for human recombinant 5-HT2A, 5-HT2B and 5-HT2C receptors (pKi=7.5, 8.4 and 7.0, respectively). The 5-HT2B receptor-binding affinity of tegaserod was identical to that at human recombinant 5-HT4(c) receptors (mean pKi=8.4) in human embryonic kidney-293 (HEK-293) cells stably transfected with the human 5-HT4(c) receptor. 3 Tegaserod (0.1-3 microm) inhibited 5-HT-mediated contraction of the rat isolated stomach fundus potently (pA2=8.3), consistent with 5-HT(2B) receptor antagonist activity. Tegaserod produced, with similar potency, an elevation of adenosine 3',5' cyclic monophosphate in HEK-293 cells stably transfected with the human 5-HT4(c) receptor (mean pEC50=8.6), as well as 5-HT4) receptor-mediated relaxation of the rat isolated oesophagus (mean pEC50=8.2) and contraction of the guinea-pig isolated colon (mean pEC50=8.3). 4 Following subcutaneous administration, tegaserod (0.3 or 1 mg kg(-1)) inhibited contractions of the stomach fundus in anaesthetized rats in response to intravenous dosing of alpha-methyl 5-HT (0.03 mg kg(-1)) and BW 723C86 (0.3 mg kg(-1)), selective 5-HT2B receptor agonists. At similar doses, tegaserod (1 and 3 mg kg(-1) subcutaneously) evoked a 5-HT4 receptor-mediated increase in colonic transit in conscious guinea-pigs. 5 The data from this study indicate that tegaserod antagonizes 5-HT2B receptors at concentrations similar to those that activate 5-HT4 receptors. It remains to be determined whether this 5-HT2B receptor antagonist activity of tegaserod contributes to its clinical profile.

Animals↗

PubMed2000

Vaccine-induced antibodies inhibit CETP activity in vivo and reduce aortic lesions in a rabbit model of atherosclerosis.

Using a vaccine approach, we immunized New Zealand White rabbits with a peptide containing a region of cholesteryl ester transfer protein (CETP) known to be required for neutral lipid transfer function. These rabbits had significantly reduced plasma CETP activity and an altered lipoprotein profile. In a cholesterol-fed rabbit model of atherosclerosis, the fraction of plasma cholesterol in HDL was 42% higher and the fraction of plasma cholesterol in LDL was 24% lower in the CETP-vaccinated group than in the control-vaccinated group. Moreover, the percentage of the aorta surface exhibiting atherosclerotic lesion was 39.6% smaller in the CETP-vaccinated rabbits than in controls. The data reported here demonstrate that CETP activity can be reduced in vivo by vaccination with a peptide derived from CETP and support the concept that inhibition of CETP activity in vivo can be antiatherogenic. In addition, these studies suggest that vaccination against a self-antigen is a viable therapeutic strategy for disease management.

Animals↗

PubMed1998

Identification of novel staphylococcal virulence genes by in vivo expression technology.

We have applied in vivo expression technology (IVET) to the study of staphylococcal virulence. Using a promoter trap that relies on genetic recombination as a reporter of gene expression, we identified 45 staphylococcal genes that are induced during infection in a murine renal abscess model. Of these, only six were known previously; 11 others have homology to known non-staphylococcal genes. The known staphylococcal genes include agrA, part of a key locus regulating numerous virulence products, and a glycerol ester hydrolase, which may enhance staphylococcal survival in abscesses. We constructed 11 strains containing mutations in previously unknown ivi genes. Of these strains, seven were significantly attenuated in virulence compared with the wild-type parent. The mutagenized ivi genes may encode novel staphylococcal virulence factors.

Abscess↗

PubMed1997

Attenuation of Fos-like immunoreactivity in the trigeminal nucleus caudalis following trigeminovascular activation in the anaesthetised guinea-pig.

The present study has examined the involvement of sensory neurotransmitters in activating neurones in the trigeminal nucleus caudalis following stimulation of the trigeminovascular system in anaesthetised guinea-pigs. Electrical stimulation of the right trigeminal ganglion produced a unilateral expression of Fos-like immunoreactivity (Fos-LI) in the trigeminal nucleus caudalis. The tachykinin NK1 receptor antagonist, GR205171 (100 micrograms/kg i.v.) and the N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 (1 mg/kg i.v.) each inhibited expression of Fos-LI following electrical stimulation. The calcitonin gene-related peptide (CGRP) receptor antagonist, CGRP8-37 (1.3 mg/kg i.v.), administered following rostral intracarotid infusion of mannitol to disrupt the blood-brain barrier, tended to reduce Fos-LI evoked by electrical stimulation, although this failed to reach statistical significance. Capsaicin (10 nmol in 0.1 ml), administered intracisternally, produced a bilateral expression of Fos-LI in the trigeminal nucleus caudalis. This expression was unaffected by the peripherally acting NK1 receptor antagonist, GR82334 (0.2 mg/kg i.v.) or CGRP8-37 (1.3 mg/kg i.v.). The centrally penetrant NK1 receptor antagonist, GR205171 (100 micrograms/kg i.v.), inhibited significantly Fos-LI evoked by intracisternal capsaicin administration. It is concluded that the sensory neurotransmitters, substance P and glutamate are released centrally following activation of the trigeminovascular system and that each may be involved in activation of cells in the trigeminal nucleus caudalis.

Animals↗

PubMed1997

The activity of GR205171, a potent non-peptide tachykinin NK1 receptor antagonist, in the trigeminovascular system.

The in vivo activity of GR205171, a novel, highly potent non-peptide tachykinin NK1 receptor antagonist, has been investigated in the trigeminovascular system in order to assess its potential as an acute therapy for migraine headache. In anaesthetised rabbits, GR205171 attenuated reductions in carotid arterial vascular resistance evoked by the tachykinin NK1 receptor agonist, substance P methyl ester (SPOMe), injected via the lingual artery (DR30 (i.e., the dose producing a dose-ratio of 30) = 0.4 microgram/kg, i.v.). In anaesthetised rats, GR205171 (0.1 and 1 mg/kg, i.v.) produced a dose-dependent inhibition of plasma protein extravasation (PPE) in dura mater, conjunctiva, eyelid and lip in response to electrical stimulation of the trigeminal ganglion. In anaesthetised guinea-pigs, GR205171 (1.10 and 100 micrograms/kg, i.v.) inhibited, by up to approximately 60%, expression of c-fos in the trigeminal nucleus caudalis in response to electrical stimulation of the trigeminal ganglion. It is concluded that GR205171 is a potent antagonist of NK1 receptor-mediated cranial vasodilatation, dural PPE and expression of c-fos in the trigeminal nucleus caudalis. Such a profile of action suggests that GR205171 may have potential as a novel therapeutic agent in the treatment of migraine headache.

Animals↗

PubMed1997

Baclofen: reduction of presynaptic calcium influx in the cat spinal cord in vivo.

In the ventral horn of the lumbar spinal cord of cats anaesthetised with pentobarbitone sodium, micro-electrophoretically administered (-)-baclofen, but not (+)-baclofen, reversibly reduced the duration of the orthodromic action potential of muscle group Ia afferent terminations, but not those of muscle group I afferent myelinated fibres. The presumably submicromolar concentrations are already known to reversibly reduce excitatory transmitter release from muscle group Ia afferent terminations. Action potential durations were estimated from threshold recovery curves after an orthodromic impulse using an extracellular microstimulation technique. Both of these presynaptic effects of (-)-baclofen were blocked by baclofen antagonists, and neither appeared to be reduced by the potassium channel blocking agents tetraethylammonium and 4-aminopyridine. Tetraethylammonium and 4-aminopyridine also did not significantly modify the reduction by (-)-baclofen of monosynaptic field potentials in the lumbar cord of rats anaesthetised with pentobarbitone sodium. In the cat the maximum reduction by (-)-baclofen of termination action potentials was considerably less than that produced by cadmium ions, which, unlike (-)-baclofen, also reduced the action potential duration of group I myelinated fibres. These findings are consistent with a reduction by (-)-baclofen of the influx of calcium through voltage-activated channels in the membrane of group Ia terminations, a proposal which also accounts for the reduction by (-)-baclofen of the release of GABA at axo-axonic depolarizing synapses on these terminations. The results are discussed in relation to the mode of action of (-)-baclofen and the different sensitivities of transmitter release at various central synapses.

Animals↗

PubMed1997

Naratriptan: biological profile in animal models relevant to migraine.

The biological profile of naratriptan (N-methyl-3-(1-methyl-4-piperidinyl)-1H-indole-5-ethane-sulphonamide), a novel 5HT1B/1D receptor agonist, was investigated in a variety of experimental models of relevance to migraine. Naratriptan has high affinity for human recombinant 5HT1B and 5HT1D receptors (pKi = 8.7 +/- 0.03 and 8.3 +/- 0.1, respectively) and causes contractions of dog isolated basilar and middle cerebral artery (EC50 values of 0.11 and 0.07 microM, respectively). Naratriptan causes small contractions of human isolated coronary arteries (EC50 value of 0.17 microM; maximum contraction equivalent to 33% of 5HT maximum). In anaesthetized dogs, naratriptan causes selective vasoconstriction of the carotid arterial bed (CD50 dose = 19 +/- 3 micrograms kg-1) and, in anaesthetized rats, naratriptan selectively inhibits neurogenic plasma protein extravasation in the dura (ID50 = 4.1 micrograms kg-1). In a variety of antinociceptive tests, naratriptan has no effect even at high doses. In conscious rats and dogs, naratriptan has high oral bioavailability (71% and 95%, respectively). The data show that naratriptan is a selective agonist at 5HT1B/1D receptors, with a pharmacological profile very similar to that of sumatriptan, albeit 2-3 fold more potent. These observations, coupled with high oral bioavailability in animals, suggest that naratriptan has the profile of an orally effective anti-migraine drug.

Animals↗

PubMed1996

GR205171: a novel antagonist with high affinity for the tachykinin NK1 receptor, and potent broad-spectrum anti-emetic activity.

It has been demonstrated recently that antagonists of the tachykinin NK1 receptor, specifically CP-99,994 and GR203040, possess anti-emetic activity in a range of species. To optimise this activity, a series of analogues based around the structure of GR203040 have been synthesised and their affinity at the human tachykinin NK1 receptor determined. In addition, the potency of these analogues to inhibit emesis induced in the ferret by whole-body X-irradiation has been examined. A range of substitution at the C-1 position of the tetrazole moiety in GR203040 were explored in vitro and in vivo. The trifluoromethyl compound, GR205171, was the most potent antagonist with regard to the ability to inhibit emesis induced by X-irradiation. This compound was demonstrated to have a broad spectrum of anti-emetic activity, inhibiting emesis in the ferret induced by cisplatin, cyclophosphamide, morphine, ipecacuanha and copper sulphate. Furthermore, emesis was also inhibited in the house-musk shrew, Suncus murinus, when induced by either motion or cisplatin, and in the dog when induced by ipecacuanha. GR205171 has the most potent anti-emetic activity of any tachykinin NK1 receptor antagonist described to date. The compound is orally active in the ferret and dog, long-lasting, and warrants further investigation as a potential broad-spectrum anti-emetic agent.

Administration, Oral↗

PubMed1996

GR127935: a potent and selective 5-HT1D receptor antagonist.

GR127935 is the most potent 5-HT1D receptor antagonist yet described, possessing nanomolar affinity at human 5-HT1D receptors. Sumatriptan-induced contractions of the dog isolated basilar artery and saphenous vein are antagonised by GR127935 in an insurmountable manner indicative of its slow dissociation from the 5-HT1D receptor. 5-HT1D receptor-mediated hypothermia and rotational behaviour in guinea-pigs are antagonised potently, and with long duration, by GR127935, administered by a variety of routes. GR127935 also blocks central 5-HT1D autoreceptors in vitro and in vivo. GR127935 has much lower affinity at other 5-HT, and non-5-HT, receptors. In functional studies, GR127935 fails to affect 5-HT2 receptor-mediated 'wet dog shakes' in guinea-pigs and 5-HT1A receptor-mediated inhibition of 5-HT release in rat dorsal raphé nucleus. The compound has a good safety profile in all species tested. It is concluded that GR127935 is a useful pharmacological tool to characterise 5-HT1D receptor function.

Animals↗

PubMed1996

NK1 and CGRP receptor-mediated dilatation of the carotid arterial bed of the anaesthetized rabbit.

The present study has investigated the effects of alpha and beta calcitonin gene-related peptide (CGRP), and the tachykinin neurokinin1 (NK1) receptor agonist, substance P methyl ester (SPOMe), on carotid vascular resistance, following their injection into the carotid artery bed of the anaesthetized rabbit. The involvement of CGRP and NK1 receptors in nicotine-induced alterations in carotid vascular resistance has also been characterized. alpha-or beta CGRP (1 and 10 pmolkg-1 i.a.) and SPOMe (0.01 and 0.1 pmolkg-1 i.a.) caused dose-related increases in carotid arterial blood flow associated with decreases in carotid arterial vascular resistance with little effect on arterial blood pressure. The selective CGRP receptor antagonist, CGRP8-37 (0.34 mumolkg-1 i.v.), caused a rightward displacement of the dose-response curves to both alpha- and beta CGRP; mean dose-ratios, 5 min after antagonist administration, were 14 and 24 respectively. The selective NK1 receptor antagonist, CP99 994 (0.23 mumolkg-1 i.v.), caused a rightward shift in the dose-response curve to SPOMe; mean dose-ratios, 15 and 75 min after antagonist administration, were 42 and 16 respectively. CGRP8-37 (0.34 mumolkg-1) had no effect on decreases in carotid arterial vascular resistance produced by SPOMe, and CP99 994 (0.23 mumolkg-1 i.v.) had no effect on vasodilator responses produced by either alpha- or beta CGRP. Intracarotid injection of nicotine (0.002-2 mumolkg-1) caused dose-dependent transient, followed by a more prolonged, increase in carotid blood flow and reduction in arterial vascular resistance. The prolonged carotid vasodilator response produced by nicotine (0.2 mumolkg-1) was markedly attenuated by CGRP8-37 (0.34 mumolkg-1 i.v.) but unaffected by CP99 994 (1.15 mumolkg-1 i.v.) suggesting a role for CGRP, and not substance P, in this vasodilation. Neither receptor antagonist affected the transient response produced by nicotine. This study has demonstrated that intracarotid injection of NK1 and CGRP receptor agonists to the anaesthetized rabbit results in an increase in carotid blood flow and a reduction in vascular resistance, indicative of vasodilatation of this artery bed. CGRP mediates the nicotine-induced dilatation of the carotid vascular bed, consistent with its release from sensory nerves. This model should prove useful for the in vivo characterization of NK1 or CGRP receptor agonist and antagonist activities, and in the study of neurogenically induced vasodilation.

Anesthesia↗

PubMed1995

The activity of 5-HT1D receptor ligands at cloned human 5-HT1D alpha and 5-HT1D beta receptors.

The present study has examined the functional activity of the 5-HT1D receptor agonist, sumatriptan, and antagonists, GR127935 (2'-methyl-4'-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxyl ic acid [4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-amide), GR55562 (3-[3-(dimethylamino)propyl]-4-hydroxy-N-[4-(4-pyridinyl)phenyl] benzamide), metergoline and methiothepin in HeLa cells, stably transfected with either 5-HT1D alpha or 5-HT1D beta receptor subtypes. Sumatriptan, GR127935 and metergoline (each 0.01-1 microM) behaved as agonists, producing a concentration-dependent inhibition of forskolin-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) production at both 5-HT1D alpha and 5-HT1D beta receptor subtypes (mean pIC50 values of 8.4 and 8.3 for sumatriptan, 7.9 and 8.0 for GR127935, and 7.9 and 8.3 for metergoline, respectively). In contrast, GR55562 and methiothepin behaved as competitive 5-HT1D receptor antagonists and were devoid of any agonist activity. GR55562 (10 microM) caused a rightward displacement of the GR127935 and metergoline concentration-response curves. The agonist activity of GR127935 and metergoline, observed in the present study, contrasts with their recognised 5-HT1D receptor antagonist profiles in animal isolated tissue and behavioural models. Unlike GR127935, GR55562 behaved as a silent antagonist at the cloned human 5-HT1D alpha and 5-HT1D beta receptors in the study.

Cyclic AMP↗

PubMed1995

The modulation of the increase in rat facial skin blood flow observed after trigeminal ganglion stimulation.

Electrical stimulation of the trigeminal ganglion causes an increase in facial skin blood flow in the anaesthetised rat, as measured by laser Doppler flowmetry. We investigated the modulation of this neurogenic vasodilator response using selective receptor agonists for putative prejunctional inhibitory receptors, as well as other pharmacological agents to further characterise this response. [D-Ala2,Me-Phe4,Gly5-ol]enkephalin (DAGO, a mu-opioid receptor agonist) inhibited the vasodilator response in a dose-related (0.058-5.8 mumol/kg i.v.) and naloxone-sensitive manner. A similar inhibitory response was observed with the local anaesthetic lignocaine (2% w/v, s.c. 20 microliters). In contrast, the histamine H3-receptor agonist alpha-methylhistamine (15 or 35 mumol/kg, i.v.) and the 5-HT1D receptor agonists sumatriptan (0.24 or 2.4 mumol/kg, i.v.) and CP 122,288 (0.0003-3 mumol/kg, i.v.) had no effect on these responses. Similarly, atropine (1.5 mumol/kg, i.v.) and indomethacin (28 mumol/kg, i.v.) did not alter the vasodilatation observed in this model. In conclusion, only mu-opioid receptor activation and local anaesthetic had any inhibitory action on the neurogenic vasodilatation observed in this model.

Animals↗

PubMed1995

Safety, immunogenicity, and efficacy of live attenuated Vibrio cholerae O139 vaccine prototype.

New vaccines are needed to prevent cholera caused by Vibrio cholerae O139. Attenuated V cholerae O139 vaccines were made by deleting multiple copies of the cholera-toxin genetic element from two virulent strains of the organism, MO10 and AI4456. The deletion mutants were further modified by insertion of a construct that encoded the B subunit of cholera toxin, thus generating strains Bengal-3 and VRI-16. A stable spontaneous non-motile derivative of Bengal-3 was isolated and designated Bengal-15; VRI-16 is naturally non-motile. Bengal-3, Bengal-15, and VRI-16 were evaluated as oral single-dose cholera vaccine candidates in 4 volunteers each, and MO10 was given to 3 volunteers. 1 of 4 volunteers who received Bengal-3 and all 3 who received MO10 had diarrhoea. VRI-16 caused no significant symptoms but was not immunogenic. Bengal-15 produced few symptoms and was nearly as immunogenic as MO10. Subsequently, Bengal-15 was given to 10 volunteers at a dose of 10(8) colony-forming units. No volunteers had diarrhoea, and other subjective symptoms were as common in vaccinees as in 3 buffer recipients. 1 month after vaccination, 7 vaccinees, the 3 buffer recipients, and 3 unimmunised subjects were challenged with 5 x 10(6) colony-forming units of V cholerae O139. 5 of 6 controls had cholera-like diarrhoea. By contrast, 1 of 7 vaccinees had diarrhoea, which was mild and had a long incubation period. Vaccine protective efficacy was 83%. Our results indicate the Bengal-15 is a safe live attenuated vaccine candidate for cholera caused by the O139 serogroup.

Administration, Oral↗

PubMed1995

The pre- and postjunctional activity of CP-122,288, a conformationally restricted analogue of sumatriptan.

The present study investigated the pre- and postjunctional of CP-122,288 (5-methyl-aminosulphonylmethyl-3-(N-methylpyrrolidin-2R-yl-m ethyl)-1H-indole), an analogue of the vascular 5-HT1 receptor agonist, sumatriptan. CP-122,288 inhibited neurogenic plasma protein extravasation in rat dura with a potency approximately 40,000-fold greater than sumatriptan (ID50 values of 0.3 pmol/kg and 13.9 nmol/kg i.v. respectively). However, CP-122,288 was only approximately 2-fold more potent than sumatriptan at inhibiting neurogenically mediated contractions of the dog saphenous vein. CP-122,288 contracted the dog saphenous vein and basilar artery with a potency approximately 2-fold greater than that of sumatriptan. Both compounds possessed similar affinities at either human 5-HT1D alpha or 5-HT1D beta receptors. It is concluded that CP-122,288 exhibits a prejunctional selectivity in the meninges to inhibit dural plasma protein extravasation independent of 5-HT1D alpha and 5-HT1D beta receptor activation.

Animals↗

PubMed1995

Trigeminal ganglion stimulation increases facial skin blood flow in the rat: a major role for calcitonin gene-related peptide.

Activation of the trigeminovascular system leads to neurogenic inflammation within the dura mater and cerebral vasodilatation. These processes have been implicated in the pathogenesis of migraine headache. Neurogenic vasodilator responses to trigeminal ganglion stimulation were investigated in rat facial skin, an area innervated by the trigeminal nerve. Microvascular blood flow changes in the facial skin were measured in anaesthetised rats, using laser Doppler flowmetry. Electrical stimulation of the trigeminal ganglion caused an ipsilateral increase in facial skin blood flow which was found to be frequency dependent (0.5-10 Hz). The role of several neuropeptides in these blood flow responses was studied using selective receptor antagonists. The calcitonin gene-related peptide antagonist, CGRP8-37 (400 nmol.kg-1, i.v.) had no effect on resting levels of facial skin blood flow, but markedly inhibited responses induced by trigeminal ganglion stimulation (5 Hz, 10 V, 1 ms for 30 s). However, neither the neurokinin-1 (NK1) receptor antagonist, RP67580 (0.23 or 2.3 mumol.kg-1, i.v.) nor the vasoactive intestinal peptide (VIP) antagonist, [p-Cl-D-Phe6,Leu17]-VIP (15 or 30 nmol.kg-1, i.v.) had any effect on these responses. These results suggest that CGRP is the major neuropeptide involved in the vasodilator response to trigeminal ganglion stimulation in rat facial skin. Clarification of the mechanisms involved in this neurogenic vasodilator response may aid the development of drugs that target the trigeminovascular system during migraine headache.

Animals↗

PubMed1995

An in vivo electrophysiological investigation of group Ia afferent fibres and ventral horn terminations in the cat spinal cord.

An extracellular microstimulation technique has been used to investigate and compare the properties of group I primary afferent myelinated fibres in the dorsal column and group Ia unmyelinated terminations in the lumbar spinal cord of cats anaesthetised with pentobarbitone sodium. Fibres were distinguished from terminations on the basis of location, anodic blocking factor and sensitivity to GABAA mimetics. The recovery curves of threshold following an orthodromic impulse provided an estimate of both action potential duration and rate of repolarization. The action potentials of group Ia terminations were of briefer duration (by a factor of approximately 2) with more rapid rates of repolarization (factor of approximately 3) than those of the myelinated fibres. The prolongation of termination but not fibre action potentials by microelectrophoretic tetraethylammonium and 4-aminopyridine indicated the presence of voltage-activated potassium channels in the termination membrane. Differences in the effects on Ia termination action potentials of depolarizations (reductions in threshold) associated with a preceding action potential, synaptically released GABA, microelectrophoretic piperidine-4-sulphonic acid or DL-homocysteic acid suggest that an increase in termination membrane conductance is the major factor in the reduction of transmitter release during the activation of presynaptic GABAA receptors.

4-Aminopyridine↗

PubMed1995

The involvement of calcitonin gene-related peptide (CGRP) and substance P in feline pial artery diameter responses evoked by capsaicin.

The effects of capsaicin and selective neuropeptide antagonists on pial artery diameter were measured using an on-line image analyser in anaesthetised cats, in order to monitor the effects of mediators released in response to activation of trigeminal nerves. Perivascular injection of CGRP (10(-8) M) and the neurokinin-1 (NK1) receptor agonist substance P methyl ester, SPOMe (10(-6) M) produced an increase in pial artery diameter. The vasodilatory action of these agonists was significantly and selectively inhibited using the CGRP receptor antagonist, CGRP8-37 (10(-6) M), and the NK1 receptor antagonist, CP99994 (10(-6) M) respectively. Capsaicin (10(-8)-10(-5) M) produced a biphasic response upon perivascular injection that was concentration dependent. At 10(-6) M capsaicin an initial transient vasoconstriction was observed followed by a longer-lasting vasodilatation. The vasodilator component was significantly reduced by CGRP8-37 (10(-6) M) or CP99994 (10(-6) M). These results show that chemical (capsaicin) activation of trigeminal nerves leads to vasodilatation of feline arteries in situ. This vasodilatation is mediated via the activation of CGRP and NK1 receptors probably via the efferent release of CGRP and a substance P-like peptide.

Anesthetics↗