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PubMed1999

Temperature coefficient of membrane currents induced by noxious heat in sensory neurones in the rat.

1. Membrane currents induced by noxious heat (Iheat) were studied in cultured dorsal root ganglion (DRG) neurones from newborn rats using ramps of increasing temperature of superfusing solutions. 2. Iheat was observed in about 70 % of small (< 25 microm) DRG neurones. At -60 mV, Iheat exhibited a threshold at about 43 C and reached its maximum, sometimes exceeding 1 nA, at 52 C (716 +/- 121 pA; n = 39). 3. Iheat exhibited a strong temperature sensitivity (temperature coefficient over a 10 C temperature range (Q10) = 17.8 +/- 2.1, mean +/- s.d., in the range 47-51 C; n = 41), distinguishing it from the currents induced by capsaicin (1 microM), bradykinin (5 microM) and weak acid (pH 6.1 or 6.3), which exhibited Q10 values of 1.6-2.8 over the whole temperature range (23-52 C). Repeated heat ramps resulted in a decrease of the maximum Iheat and the current was evoked at lower temperatures. 4. A single ramp exceeding 57 C resulted in an irreversible change in Iheat. In a subsequent trial, maximum Iheat was decreased to less than 50 %, its threshold was lowered to a temperature just above that in the bath and its maximum Q10 was markedly lower (5.6 +/- 0.8; n = 8). 5. DRG neurones that exhibited Iheat were sensitive to capsaicin. However, four capsaicin-sensitive neurones out of 41 were insensitive to noxious heat. There was no correlation between the amplitude of capsaicin-induced responses and Iheat. 6. In the absence of extracellular Ca2+, Q10 for Iheat was lowered from 25.3 +/- 7.5 to 4. 2 +/- 0.4 (n = 7) in the range 41-50 C. The tachyphylaxis, however, was still observed. 7. A high Q10 of Iheat suggests a profound, rapid and reversible change in a protein structure in the plasma membrane of heat-sensitive nociceptors. It is hypothesized that this protein complex possesses a high net free energy of stabilization (possibly due to ionic bonds) and undergoes disassembly when exposed to noxious heat. The liberated components activate distinct cationic channels to generate Iheat. Their affinity to form the complex at low temperatures irreversibly decreases after one exposure to excessive heat.

Animals↗
PubMed2000

Responses of nerve fibres of the rat saphenous nerve neuroma to mechanical and chemical stimulation: an in vitro study.

The response of neuroma nerve endings to different stimuli was studied in a saphenous nerve neuroma preparation in vitro. Electrical activity was recorded from 141 single fibres dissected of saphenous nerve. One-third (27 %) displayed spontaneous activity. Based on their response to mechanical and chemical stimuli, neuroma nerve fibres were classified as mechanosensory fibres (47.5 %), mechanically insensitive chemosensory fibres (17.0 %), polymodal nociceptor fibres (28.4 %) and unresponsive fibres (7.1 %). Mechanosensory and polymodal neuroma endings responded to von Frey hair stimulation either with a few impulses (phasic units) or a sustained discharge (tonic units). Polymodal units were additionally activated by at least one of the following stimuli: acidic solutions; a combination of bradykinin, prostaglandin E2, serotonin, substance P and histamine (all at 1 microM) plus 7 mM KCl (inflammatory soup); 600 mM NaCl and capsaicin. Low pH solutions increased the firing discharge of polymodal endings proportionally to the proton concentration. The 'inflammatory soup' evoked a firing response characterized by the absence of tachyphylaxis, which appeared when its components were applied separately. Both stimuli sensitized polymodal fibres to mechanical stimulation. Hypertonic NaCl (600 mM) and capsaicin (3.3 mM) induced a prolonged discharge that outlasted the stimulus duration. Mechanically insensitive chemosensory neuroma fibres exhibited responses to chemical stimuli analogous to polymodal fibres. They became mechanically sensitive after chemical stimulation. These findings show that neuroma nerve endings in the rat saphenous nerve neuroma in vitro are functionally heterogeneous and exhibit properties reminiscent of those in intact mechanosensory, polymodal and 'silent' nociceptor sensory afferents, including their sensitization by algesic chemicals.

Animals↗
PubMed2001

Sustained sensitization and recruitment of rat cutaneous nociceptors by bradykinin and a novel theory of its excitatory action.

Excitation and sensitization to heat of nociceptors by bradykinin (BK) were examined using an isolated rat skin-saphenous nerve preparation. A total of 52 C-fibres was tested: 42 were mechano-heat sensitive (CMH) and 40% of them were excited and sensitized to heat by BK superfusion (10-5 M, 5 min) of their receptive fields; heat responses were augmented by more than five times and heat thresholds dropped to 36.4 degrees C, on average. Sixty per cent of the CMH did not respond to BK itself, but 3/4 of these units showed an increase in their heat responses by more than 100% following BK exposure. Ten high-threshold mechanosensitive C-fibres did not discharge upon BK application but following this five of them responded to heat in a well-graded manner. In all fibres, the sensitizing effect of BK was abolished within 9 min or less of wash-out, and it could be reproduced several times at equal magnitude, whereas the excitatory effect of BK regularly showed profound tachyphylaxis. Sustained superfusion (20 min) of BK induced a desensitizing excitatory response while superimposed heat responses showed constant degrees of sensitization. The large extent and high prevalence of BK-induced sensitization (almost 80% of all fibres tested) and de novo recruitment of heat sensitivity suggest a prominent role of BK not only in hyperalgesia but also in sustained inflammatory pain which may be driven by body or even lower local temperatures acting on sensitized nociceptors. Based on the latter assumption, a hypothesis is put forward that excludes a direct excitatory effect of BK on nociceptors, but assumes a temperature-controlled activation as a result of rapid and profound sensitization.

Action Potentials↗
PubMed1961

Assay of substance P on the fowl rectal caecum.

The optimum conditions for the assay of substance P on fowl rectal caecum have been studied. Effective concentrations vary from 0.01 to 0.5 u./ml.; it is remarkably insensitive to other polypeptides, such as bradykinin. The test can be made more specific by using a bath fluid containing antagonists for known interfering substances. A suitable antagonist for acetylcholine is atropine or hyoscine, for 5-hydroxytryptamine, methysergide and for catecholamines, ephedrine. The effects of histamine and adenosine compounds can be abolished by specific tachyphylaxis, in which the bath fluid contains an excess of the active substance itself. The assay is reasonably accurate. Woolf's index of precision (L) was estimated as 15.5 with a range (9) of 9.2 to 29.4. Simplified methods of calculating L, and the fiducial range, are described.

Acetylcholine↗
PubMed1969

Role of catecholamines in centrogenic cardiac arrhythmia induced by aconitine.

1. Injection of 20 mug of aconitine into the lateral ventricle of dogs anaesthetized with pentobarbitone regularly induced cardiac irregularities and hypertension. The cardiovascular changes appeared within 5 min and lasted for about 90 min. Tachyphylaxis to the aconitine-induced cardiovascular effects was observed.2. The aconitine-induced arrhythmia and hypertension were centrogenic, for they were abolished or prevented by spinal transection (C(2)) or ganglionic blockade.3. Bilateral vagotomy as well as bilateral stellate ganglionectomy merely raised the threshold for arrhythmia without affecting the blood pressure response. The neural supply to the heart, therefore, does not seem to be the major pathway concerned in the genesis of the centrogenic cardiovascular effects of aconitine.4. The centrally evoked release of endogenous catecholamines from the adrenal glands was responsible for the aconitine-induced arrhythmia, since the arrhythmia could be blocked or prevented by prior reserpinization, bilateral adrenalectomy or thoracic splanchnic nerve section.5. alpha- and beta-adrenoceptive receptor blocking agents prevented or abolished the aconitine-induced arrhythmia in a manner similar to the catecholamine-induced arrhythmia.

Aconitum↗
PubMed1970

Evidence that adenosine triphosphate or a related nucleotide is the transmitter substance released by non-adrenergic inhibitory nerves in the gut.

1. Stimulation of the vagal non-adrenergic inhibitory innervation caused the release of adenosine and inosine into vascular perfusates from the stomachs of guinea-pigs and toads.2. Stimulation of portions of Auerbach's plexus isolated from turkey gizzard caused the release of adenosine triphosphate (ATP), adenosine diphosphate (ADP) and adenosine monophosphate (AMP).3. ATP, added to solutions perfused through the toad stomach vasculature, was broken down to adenosine, inosine and adenine.4. Of a series of purine and pyrimidine derivatives tested for inhibitory activity on the guinea-pig isolated taenia coli, ATP and ADP were the most potent.5. ATP caused inhibition of twelve other gut preparations previously shown to contain non-adrenergic inhibitory nerves. The inhibitory action of ATP was not prevented by tetrodotoxin.6. Quinidine antagonized relaxations of the guinea-pig taenia coli caused by catecholamines or adrenergic nerve stimulation. Higher concentrations of quinidine antagonized relaxations caused by ATP or non-adrenergic inhibitory nerve stimulation.7. When tachyphylaxis to ATP had been produced in the rabbit ileum, there was a consistent depression of the responses to non-adrenergic inhibitory nerve stimulation but not of responses to adrenergic nerve stimulation.8. It is suggested that ATP or a related nucleotide is the transmitter substance released by the non-adrenergic inhibitory innervation of the gut.

Adenine↗
PubMed1971

Actions of acetylcholine and carbachol on the chick biventer cervicis muscle.

1. The possibility that carbachol may act on the chick biventer cervicis muscle by releasing acetylcholine was investigated.2. Log dose-response curves for acetylcholine and carbachol were constructed in the presence of triethylcholine, tubocurarine and physostigmine, in both innervated and denervated chick biventer cervicis muscles.3. The log dose-response curve for acetylcholine was shallower than that for carbachol and was moved to the left by triethylcholine, indicating potentiation. In the presence of physostigmine, the curve was as steep as that for carbachol, and like that for carbachol was moved to the right by triethylcholine, indicating antagonism. In the presence of tubocurrine, the log dose-response curves for both acetylcholine and carbachol were moved to the right.4. The log dose-response curves for both acetylcholine and carbachol were moved to the left by chronic denervation, indicating increased sensitivity to these drugs. Both curves were moved similar distances to the right by excess magnesium ion concentration. No tachyphylaxis developed to repeated administration of carbachol in the presence of triethylcholine or tubocurarine, either in innervated or denervated muscles.5. It was concluded that the main action of triethylcholine in the chick biventer cervicis muscle is a tubocurarine-like action, which, in the presence of acetylcholine, is masked by a weak anticholinesterase action. It was also concluded that the diminished response to carbachol in the presence of triethylcholine is due to the postjunctional blocking action of triethylcholine, and that carbachol owes none of its activity to an ability to release acetylcholine from the nerve terminals.

Acetylcholine↗
PubMed1972

Pharmacological studies on the hypogastric ganglion of the rat and guinea-pig.

1. Preparations were developed whereby the hypogastric ganglion of the rat or guinea-pig was perfused through its vasculature with saline solutions. Drugs were injected into the perfusion stream, and their effects were indicated by contractions of the vas deferens. The base of this organ could be ligated to prevent the drugs reaching the smooth muscle via the blood vessels. For comparison, experiments were also performed on fully isolated preparations of the rat and guinea-pig hypogastric nerve-vas deferens, where the vas deferens was held in an inner bath, so that drugs added to the outer bath could act only on the ganglion. Attempts were made to demonstrate non-nicotinic receptors in these preparations.2. It was shown that the perfused hypogastric ganglion of the guinea-pig would respond repeatedly to several nicotinic stimulants, though autodesensitization eventually occurred. The fully isolated preparation behaved similarly, but desensitized much more rapidly. In contrast, the rat ganglion, either perfused or fully isolated, was remarkably insensitive to nicotinic stimulant drugs.3. Neither species responded well to non-nicotinic stimulants; that from the guinea-pig gave small contractions to methacholine in about 33% of cases, but did not respond to (4-m-chlorophenyl-carbamoyloxy)-2-butynyl trimethylammonium chloride (McN-A-343). With the rat, the situation was opposite.4. The guinea-pig ganglion did not become more sensitive to non-nicotinic stimulants after some treatments known to sensitize the cat superior cervical ganglion. These include preganglionic tetanization, chronic decentralization, and removal of all potassium. Sensitization did occur, however, in the presence of physostigmine, after tachyphylaxis to dimethyl phenyl piperazinium iodide (DMPP) had developed, and when the preparation was perfused with a suspension of washed erythrocytes.5. It is concluded that the responses of sympathetic ganglia vary from one species to another, and according to whether the organs are perfused or fully isolated.

Animals↗
PubMed1972

In vitro effect of 6-hydroxydopamine on isolated rat atria.

In vitro treatment with 6-hydroxydopamine (6-OHDA), but not with oxidized 6-hydroxydopamine, caused transient, positive inotropic and chronotropic responses in the isolated rat atria. In the presence of rat blood plasma, the excitatory effect of 6-hydroxydopamine persisted unless the drug was washed out by fresh medium. 6-Hydroxydopamine failed to elicit the excitative response in the atria obtained from reserpinized rats or rats treated with 6-hydroxydopamine in vivo. In vitro treatment with 6-hydroxydopamine did not cause the development of supersensitivity to noradrenaline. Cocaine and desipramine, but not bretylium, inhibited the excitative action of 6-hydroxydopamine. No tachyphylaxis developed after repeated exposure to 6-hydroxydopamine in vitro. Propranolol, but not phentolamine, blocked the excitatory effect of 6-hydroxydopamine. It is thus concluded that in vitro treatment with 6-hydroxydopamine may cause atrial stimulation by an indirect action involving the release of catecholamines as a result of its displacement at the nerve ending.

Animals↗
PubMed1974

Effects of Gymnodinium breve toxin on the smooth muscle preparation of guinea-pig ileum.

1 The effects of Gymnodinium breve neurotoxin (GT) on smooth muscles were studied using the guinea-pig isolated ileum.2 The toxin caused strong spasmogenic effects at 1-4 mug/ml, characterized by prolonged tonic contraction with superimposed pronounced pendular movements. Tachyphylaxis was observed upon administration of successive doses.3 Atropine blocked the contractile response elicited by GT, whereas mepyramine and hexamethonium failed to do so. These findings tentatively suggested a cholinergic involvement at a post-ganglionic site of action.4 In the presence of tetrodotoxin the effects of GT were abolished, excluding direct action of the toxin on the smooth muscle.5 It is concluded that GT exerts its spasmogenic effects through stimulation of the post-ganglionic cholinergic nerve fibres.

Acetylcholine↗
PubMed1974

Effects of Gymnodinium breve toxin on the smooth muscle preparation of guinea-pig ileum.

1 The effects of Gymnodinium breve neurotoxin (GT) on smooth muscles were studied using the guinea-pig isolated ileum.2 The toxin caused strong spasmogenic effects at 1-4 mug/ml, characterized by prolonged tonic contraction with superimposed pronounced pendular movements. Tachyphylaxis was observed upon administration of successive doses.3 Atropine blocked the contractile response elicited by GT, whereas mepyramine and hexamethonium failed to do so. These findings tentatively suggested a cholinergic involvement at a post-ganglionic site of action.4 In the presence of tetrodotoxin the effects of GT were abolished, excluding direct action of the toxin on the smooth muscle.5 It is concluded that GT exerts its spasmogenic effects through stimulation of the post-ganglionic cholinergic nerve fibres.

Acetylcholine↗
PubMed1976

Stereospecific actions of 2,5-dimethoxy-4-methylamphetamine (DOM) on colonic temperature in the rat at various ambient temperatures.

The R(-) and S(+)-isomers of 2,5-dimethoxy-4-methylamphetamine (DOM) produce a dose-dependent hypothermia in rats kept in the cold (6 degrees C). 2 This hypothermia was linearly dependent upon ambient temperature and the R(-)-isomer was considerably more potent than the S(+)-isomer. 3 A statistically significant tachyphylaxis was observed when R(-)-DOM was administered on two successive days. The response seven days after the second injection was similar to that on the first day of injection. 4 The hypothermia induced by R(-) and S(+)-DOM was antagonized by methysergide but not by p-chlorophenylalanine (PCPA) or pimozide. Methysergide, PCPA or pimozide alone did not elicit hypothermia at the doses used. The results indicate that R(-) and S(+)-DOM act at post-synaptic 5-hydroxytryptamine receptors.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1980

Pharmacological analysis of salivary and blood flow responses to histamine of the submandibular gland of the dog.

1 The submandibular gland in situ was perfused with blood through the glandular artery at constant pressure in anaesthetized dogs. Drugs were administered intra-arterially. 2 Histamine produced both salivation and an increase in blood flow, each response having an early and a late component. 3 Marked tachyphylaxis to histamine developed in both of the salivary responses but only in the late blood flow response to histamine. 4 The early and late salivary responses were abolished and the late blood flow response was diminished by infusion of tetrodotoxin in doses that abolished the salivary and blood flow responses to electrical stimulation of the chorda-lingual nerve. 5 The whole salivary response to histamine was abolished by infusion of (--)-hyoscyamine in doses that greatly antagonized the salivary and blood flow responses to acetylcholine, whereas the blood flow responses to histamine were scarcely modified. These doses of (--)-hyoscyamine abolished the salivary response to chorda-lingual nerve stimulation but left the blood flow response to it unaffected. 6 The salivary and blood flow responses to histamine were unaffected by infusion of hexamethonium in doses that almost abolished the salivary and blood flow responses to chorda-lingual nerve stimulation. 7 The whole salivary response to histamine was abolished and the late blood response to histamine was partially inhibited by the histamine H1-receptor antagonist, mepyramine, but not by the histamine H2-receptor antagonist, metiamide. 8 The early blood flow response to histamine was antagonized by both mepyramine and metiamide but mepyramine was far more effective than metiamide. 9 These results led to the following conclusions: (1) the whole salivary response and a part of the late blood flow response to histamine are due entirely to excitation of parasympathetic postganglionic neurones; (2) neuronal histamine receptors involved are exclusively of the H1-type; (3) histamine has no direct stimulant action on the glandular cells; (4) the early blood flow response and the remaining part of the late blood flow response to histamine result from the direct action on vascular smooth muscle in the glandular vascular bed; (5) vascular histamine receptors consist of H1- and H2-receptors.

Animals↗
PubMed1988

Effects of neuropeptides and capsaicin on the canine tracheal vasculature in vivo.

1. The nonadrenergic, noncholinergic nervous system may control the airway vasculature via various neuropeptides. We have perfused the cranial tracheal arteries of the anaesthetized dog and investigated the effects of neuropeptides and capsaicin (which is supposed to release neuropeptides from sensory nerve endings) on the tracheal vasculature by injecting them locally into the perfusion system. 2. Neurokinin A (NKA, 0.02-20 pmol), calcitonin gene-related peptide (CGRP, 2-200 pmol) and peptide histidine isoleucine (PHI, 0.02-2 nmol) dose-dependently decreased tracheal vascular resistance (Rtv). NKA was 10 and 100 times more potent than CGRP and PHI, respectively. The duration of the response to CGRP was greatly prolonged with larger doses. Galanin (0.2-2 nmol) had no appreciable effect on Rtv. 3. Neuropeptide Y (NPY 0.02-2 nmol) and bombesin (0.02-10 nmol) dose-dependently increased Rtv. However, the dose-response curve for bombesin was bell-shaped suggesting the development of tachyphylaxis with larger doses. In smaller doses, bombesin was twice as potent as NPY. The duration of the response to NPY was prolonged with larger doses. 4. With the exception of PHI no neuropeptide altered tracheal smooth muscle tone; PHI (1 and 2 nmol) caused small dilatations of the trachea. 5. The effects of capsaicin (2-100 nmol) were complex. Usually, the vascular response had two dose-dependent phases: a rapid vasoconstriction followed by a small, longer-lasting vasodilatation. The tracheal smooth muscle response was usually biphasic, a contraction followed by a relaxation. 6. According to previous and present data, the order of potency of the neuropeptides on the canine tracheal vasculature is for the vasodilators : NKA > vasoactive intestinal peptide (VIP) > CGRP > substance P > PHI, and for the vasoconstrictors: bombesin > NPY. The longer-acting neuropeptides (VIP, CGRP and NPY) may be more important than the shorter-acting neuropeptides (substance P, NKA, PHI and bombesin) as regulators of the airway wall blood flow.

Animals↗
PubMed1992

The role of nitric oxide in the regional vasodilator effects of endothelin-1 in the rat.

1. The role of nitic oxide (NO) derived from L-arginine in the regional vasodilator effects of endothelin-1 has been investigated in anaesthetized, spontaneously hypertensive (SH) rats in which autonomic reflexes were abolished by ganglion blockade. The experimental design incorporated animals infused with phenylephrine to mimic the peripheral vasconstrictor effects of the NO biosynthesis inhibitors and a single dose per animal paradigm to obviate problems of tachyphylaxis to the vasodilator effects of endothelin-1. 2. Infusion of the inhibitor of NO synthase, N-monomethyl-L-arginine (L-NMMA) at a dose (5 mg kg-1 min-1) which maximally raised blood pressure did not influence either the fall in blood pressure or the vasodilator responses induced in the hindquarters and carotid vascular beds by endothelin-1 (1 nmol kg-1, i.v.) The duration (but not the initial magnitude) of the vasodepressor response to endothelin-1 was however significantly attenuated (by 49%) during infusion of the more potent inhibitor of NO synthase, NG-nitro-L-arginine methyl ester (L-NAME), 2 mg kg-1 min-1. 3. Increasing the dose of L-NAME to 10 and 25 mg kg-1min-1 significantly attenuated, but did not abolish, the falls in blood pressure and hindquarters vasodilator responses to acetylcholine, 1 microgram kg-1, and endothelin-1, 1 nmol kg-1 min-1. The effects were selective in that vasodepressor responses to the endothelium-independent vasodilator, sodium nitroprusside, 1-10 micrograms kg-1 min-1, were unaltered. The effects were selective in that vasodepressor responses to the endothelium-independent vasodilator, sodium nitroprusside, 1-l0mg kg min , were unaltered.4. The data indicate that NO generated de novo from L-arginine mediates a significant component of the vasodilator effect of endothelin-1 in the anaesthetized, ganglion-blocked SH rat. However, a major component of the vasodepressor effects of both endothelin-1 and acetylcholine may occur independently of this mechanism.

Animals↗
PubMed1992

Evidence for multiple endothelin receptors in the guinea-pig pulmonary artery and trachea.

1. The responses of the three peptides, endothelin 1 (ET-1), endothelin 2 (ET-2) and endothelin 3 (ET-3) were analysed on isolated circular segments of pulmonary arteries and trachea from the guinea-pig. 2. In the pulmonary artery, the vasomotor responses to the endothelins, expressed as the maximum contraction (Emax%), had the order ET-1 greater than ET-2 greater than ET-3 while the order of potency (pD2) was ET-1 = ET-2 greater than ET-3. ET-1 and ET-2 caused cross-desensitization, but did not affect the responses to ET-3. ET-3 did not cause cross-desensitization to ET-1 or ET-2 although it induced homologous desensitization. Finally, the effects of ET-1 and ET-2 were additive to those of ET-3. The additive effect of ET-3 to those of ET-1 or ET-2 was more difficult to demonstrate, given the profound contraction produced by ET-1 and to a lesser extent by ET-2. 3. In the trachea, the rank order of potency, additivity and desensitization were different from the pulmonary artery. Basically, all three peptides were equipotent but less potent than ET-1 in the artery. There was no evidence for additivity and only a slight tendency to tachyphylaxis was seen. 4. The guinea-pig pulmonary artery appears to be endowed with one receptor type which is sensitive to ET-1/ET-2 and with another receptor type which responds preferentially to ET-3. In the trachea, neither of these receptors appears to be present since all three peptides apparently act on a homogeneous population of receptors with characteristics different from those of the two arterial receptors. This suggests a third non-isopeptide selective type of endothelin receptor.

Animals↗
PubMed1993

Effects of interactions of naturally-occurring neuropeptides on blood flow in the rat knee joint.

1. Changes of blood flow in the rat knee joint, measured by laser Doppler flowmetry, were produced by topical application of naturally-occurring neuropeptides to the joint capsule. 2. Substance P (SP), neurokinin A (NKA), and neurokinin B (NKB) all produced dose-dependent transient vasodilatation of the rat knee joint microvasculature. NKB showed significantly smaller vasodilator responses compared to SP and NKA which were similar in their potencies. 3. Calcitonin gene-related peptide (CGRP) produced dose-dependent vasodilatation which was more pronounced than that produced by the neurokinins. The rank order of potency was: CGRP > SP = NKA > NKB. The vasodilator effect of CGRP was also more prolonged and this extended phase was abolished by co-administration of SP. 4. Cross-tachyphylaxis was not observed with the different neurokinins, but SP and NKA showed novel antagonistic effects on NKB-induced vasodilatation. 5. Co-administration of 1 nmol of the specific NK1 receptor antagonist, CP-96345, with 1 nmol of each of the neurokinins produced significant inhibition of the vasodilator response to SP but did not affect vasodilator responses to NKA and NKB. Co-administration of CP-96345 with the neurokinins plus superfusion of the rat knee joint with a solution containing 0.1 mM CP-96345 further reduced the vasodilator responses to SP but again the vasodilator responses to NKA and NKB were not significantly altered. 6. The results suggest that multiple neurokinin receptor types may be present in the rat knee joint which could mediate the vasodilator responses of the different neurokinins. Co-release of neuropeptides from sensory nerve endings in the rat knee joint may have inter-regulatory actions on their individual responses on the microvasculature.

Animals↗
PubMed1993

Endothelin (16-21): biphasic effect and no desensitization on the guinea-pig isolated ileum.

1. In the guinea-pig ileum the C-terminal hexapeptide of the endothelins, endothelin (16-21), induced a biphasic effect (relaxation followed by contraction) qualitatively similar to that seen in the responses to endothelins 1 and 3. Both components of the response were concentration-dependent in the range studied (2-100 microM). 2. The response induced by endothelin (16-21) was inhibited in low-sodium (80 mM) medium. 3. Repeated administration of endothelin (16-21) induced no desensitization of the preparation, contrasting with the tachyphylaxis induced by endothelin-1 and endothelin-3 in the guinea-pig ileum. 4. Tissues rendered tachyphylatic to endothelin-1 or endothelin-3 responded normally to endothelin (16-21). 5. The results suggest that the C-terminal tail of the endothelins contains the message for the biphasic response, whereas the N-terminal domain may be responsible for the strong binding to the receptor and for the tachyphylactic properties of endothelin-1 and endothelin-3, in the guinea-pig isolated ileum. However, the possibility that endothelin (16-21) may be acting on a site other than the endothelin receptor cannot be ruled out.

Amino Acid Sequence↗