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PubMed1983

Bradykinin contracts the pupillary sphincter and evokes ocular inflammation through release of neuronal substance P.

Bradykinin contracts the isolated rabbit sphincter pupillae muscle. The contraction produced by 10(-8) M bradykinin was resistant to atropine but not to tetrodotoxin, suggesting a non-cholinergic nervous mechanism. The contraction was blocked by specific substance P (SP) antagonists, suggesting the involvement of SP. The SP antagonists tested were [D-Pro2,D-Trp7,9]SP-(1-11) and [Arg5,D-Trp7,9]SP-(5-11). The bradykinin-induced contraction exhibited marked tachyphylaxis in contrast to that induced by SP. It appears that the tachyphylaxis reflects the depletion of a bradykinin-sensitive neuronal pool of SP. Injection of bradykinin into the vitreous chamber of the rabbit eye caused miosis and disruption of the blood-aqueous barrier (manifested as aqueous flare). A second administration of bradykinin a few hours after the first injection evoked a reduced response; the response to SP upon repeated administration was unchanged. Atropine was without effect on the response to bradykinin whereas tetrodotoxin and the SP antagonists reduced the response. The results suggest that bradykinin causes miosis and aqueous flare at least partly through local release of neuronal SP.

Animals↗
PubMed1984

Prostacyclin modulates the responses to leukotrienes C4 and D4 of guinea-pig airway smooth muscle.

Superfusion of lung parenchymal strips or tracheal strips from the guinea-pig with effluent from perfused isolated lungs reduced the contractions elicited by leukotriene C4 (LTC4) and leukotriene D4 (LTD4) but not those elicited by acetylcholine (ACh). Incubation of the lung perfusate for 15 min at 37 degrees C removed the inhibitory effect, as did treatment of the lungs with indomethacin (0.5 microgram ml-1) suggesting that a labile cyclo-oxygenase product was causing the inhibition. Addition of prostacyclin (0.8-5.0 ng ml-1) to the fluid superfusing tracheal and parenchymal strips produced a dose-related decrease in leukotriene-induced contractions, whereas 6-oxo-PGF1 alpha and PGE2 were inactive. Contractions of tracheal strips induced by LTC4 were significantly enhanced by infusion of PGF2 alpha. Parenchymal strips usually developed tachyphylaxis to repeated doses of LTC4. This tachyphylaxis has less evident in the presence of indomethacin (2 micrograms ml-1). Contractions of parenchymal and tracheal strips to histamine, acetylcholine and the stable thromboxane mimetic U-46619 were unaffected by infusion of prostacyclin (5 ng ml-1). These results indicate that prostacyclin selectively antagonises airway smooth muscle reactivity to LTC4 and LTD4 by a mechanism which remains to be elucidated.

Acetylcholine↗
PubMed1985

Comparison of angiotensin receptors in isolated smooth muscle tissues by photoaffinity labelling.

The isolated rat uterus and rabbit aorta were photolabelled with [Azidobenzoic acid 1, isoleucine8]angiotensin II ([AB', Ile8]ANG II) and dose-response curves to angiotensins II and III were determined before and after the irreversible labelling procedure. The data obtained were used to calculate affinities, efficacies and 'spare' receptors for angiotensins II and III. In the rat uterus angiotension II was the higher affinity ligand, whereas in the rabbit aorta angiotensins II and III had similar affinities. 'Spare' receptors were present for both ligands in both tissues. In the rat uterus ANG II and ANG III had similar efficacies, whereas in the rabbit aorta ANG II was the more efficacious ligand. Angiotensin receptors in the rabbit aorta, rat uterus, and rat portal vein appear to be substantially different from one another, and point to the possibility of different functional roles for angiotensins II and III in different smooth muscle tissues. For the vascular tissues, tachyphylaxis to angiotensin was more marked after irreversible labelling than before, suggesting that the mechanism of angiotensin tachyphylaxis is receptor deactivation.

Affinity Labels↗
PubMed1991

Effects of repeated administration of the preferential dopamine autoreceptor antagonist, (+)-AJ76, on locomotor activity and brain DA metabolism in the rat.

AJ76, the cis-(+)-(1S,2R) enantiomer of 5-methoxy-1-methyl-2-(n-propyl-amino) tetralin is a dopamine autoreceptor antagonist which has shown locomotor stimulatory properties, especially in habituated rats. AJ76 was given repeatedly to male rats at different time intervals and different doses to investigate if tachyphylaxis/tolerance would develop. Tolerance did not occur if AJ76 (300 mumol/kg p.o.) was administered once daily for 7 days, (regarding both stimulation of locomotor activity and increase in brain DOPAC levels). Tolerance occurred after a single dose of 52 mumol/kg s.c. given in the morning followed by the same challenge dose 4 but not 24 h later. When the first dose was decreased to 13 mumol/kg s.c. no tachyphylaxis could be demonstrated regarding stimulation of locomotor activity. It is concluded that AJ76 induces a dose-dependent and short lasting tachyphylaxis, while no tolerance is observed after one week repeated administration. The possible mechanism behind these effects are discussed.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Effects of endothelin-3 on the isolated guinea-pig ileum: role of Na+ ions and endothelin receptor subtypes.

Endothelin-3 induced a relaxation followed by contraction in the isolated guinea-pig ileum. The contractile but not the relaxant component of the response was concentration-dependent in the dose range studied. Neuronal mechanisms, cyclic GMP and ATP-dependent K+ channels are not involved in the relaxing effect since this component was not affected by either tetrodotoxin, methylene blue or glibenclamide. Endothelin-3 induced tachyphylaxis (homologous desensitization) that was not fully reversed after a 3-h resting period. The responses were inhibited in low-Na+ medium or after treatment with ouabain. Verapamil affected both the relaxant and the contractile components of the response, and phorbol-12,13-dibutyrate affected mainly the contractile component. Cross-tachyphylaxis studies between endothelin-1 and endothelin-3 suggest the existence of at least two endothelin receptor subtypes (or different ligand-receptor complexes) in the guinea-pig ileum.

Animals↗
PubMed1993

Effects of haemoglobin and N-nitro-L-arginine on constrictor and dilator responses of aortic rings from streptozotocin diabetic rats.

This study investigated the effects of N-nitro-L-arginine and haemoglobin on responses of aortic rings (10 g resting tension) from 2-week streptozotocin-diabetic and control rats. N-Nitro-L-arginine (0.1 mM) or haemoglobin (10 microM) potentiated constrictor responses of aortae from both groups of rats to 5-hydroxytryptamine (5-HT) or noradrenaline. They also overcame the tachyphylaxis which occurred on the second exposure to 5-HT. Following constriction of aortae with 5-HT or noradrenaline, acetylcholine produced concentration-dependent relaxation. At concentrations of acetylcholine of 0.1 microM to 0.1 mM for 5-HT-constricted rings, and 0.1 microM for noradrenaline-constricted rings, the specific component of relaxation attributable to acetylcholine was significantly less for aortae from diabetic rats than for those from controls. For aortae from both groups, N-nitro-L-arginine (or haemoglobin) inhibited relaxation in the presence of acetylcholine (noradrenaline or 5-HT-constricted rings), and N-nitro-L-arginine (or N-nitro-L-arginine with haemoglobin) partially inhibited spontaneous relaxation of 5-HT-constricted rings. These results suggest that NO may play a role in tachyphylaxis to 5-HT, and that acetylcholine-induced output of endothelium-derived relaxing factor/nitric oxide (EDRF/NO) (or responsiveness to EDRF/NO) may be reduced in noradrenaline- and 5-HT-constricted aortic rings from 2-week diabetic rats.

Acetylcholine↗
PubMed1983

Hemodynamic characterization of porcine hemorrhagic pancreatitis ascites fluid.

The hemodynamic reactions of hemorrhagic pancreatitis ascites fluid (HAF) were observed after intravascular injection in the pig. The HAF vascular reactions were compared to the reactions of known vasoactive agents in hopes of identifying the vasoactive agent(s) in HAF. Pancreatitis was induced in five pigs with pancreatic ductal injection of a bile/trypsin mixture. HAF from these pigs was injected into the portal vein of five anesthetized pigs which were monitored for changes in femoral artery pressure (FAP), cardiac output (CO), and portal pressure (PoVP). Trypsin was also tested in the same way in five additional pigs. HAF elevated PoVP, then lowered VAP, depressed CO, and exhibited tachyphylaxis. Trypsin did not cause tachyphylaxis. The effects observed after infusion of HAF are similar to the reported effects observed after injecting histamine, an agent previously implicated in hemorrhagic pancreatitis.

Acute Disease↗
PubMed1988

Effects of intraperitoneal administration of apomorphine and the isomers of 3-(1-propyl-3-piperidinyl)phenol on the firing activity of substantia nigra dopamine neurons: comparison of agonist efficacies and development of acute tolerance.

The effects of intraperitoneal administration of apomorphine, (+)-3-PPP, and (-)-3-PPP on slow-(less than 4 spikes/sec) and fast-(greater than 4 spikes/sec) firing dopaminergic neurons in the substantia nigra zona compacta of rats anesthetized with chloral hydrate were assessed. All compounds completely inhibited slow-firing dopaminergic neurons. When a dose-response was determined by administering each dose in a single bolus injection, apomorphine and (+)-3-PPP produced dose-related inhibitions of fast-firing dopaminergic neurons, with the largest dose of each compound completely inhibiting nearly all cells tested. In contrast, (-)-3-PPP only partially inhibited (50%) fast-firing dopaminergic neurons. Thus, on fast-firing neurons, (-)-3-PPP had the profile of a partial agonist, while apomorphine and (+)-3-PPP demonstrated greater efficacy than (-)-3-PPP. Pretreatment while doses of apomorphine, (+)-3-PPP, or (-)-3-PPP that partially inhibited the activity of dopaminergic neurons antagonized the complete inhibitory effects of a dose of apomorphine that normally produced complete inhibition of neuronal firing. In addition, pretreatment with doses of (+)-3-PPP that partially inhibited the activity of cells antagonized the complete inhibitory effects of a dose of (+)-3-PPP that, normally produced complete inhibition of neuronal firing. From the antagonism studies alone, it was not clear if tachyphylaxis or partial agonist activity accounted for the observed antagonisms. However, since apomorphine and (+)-3-PPP completely inhibited the activity of fast-firing DA neurons, it is proposed that they antagonize by inducing a dose- and time-dependent tachyphylaxis. In contrast, (-)-3-PPP is proposed to antagonize by virtue of its partial agonist activity.

Action Potentials↗
PubMed1977

Hormonal stimulation of arachidonate release from isolated perfused organs. Relationship to prostaglandin biosynthesis.

The lipids of isolated Krebs perfused rabbit kidneys and hearts were labelled with [14C]arachidonic acid. Subsequent hormonal stimulation (e.g. bradykinin, ATP) of the pre-labelled tissue resulted in dose-dependent release of [14C]prostaglandins; little or no release of the precursor [14C]arachidonic acid was observed. When fatty acid-free bovine serum albumin was added to the perfusion medium as a trap for fatty acids substantial release of [14C]arachidonic acid was detected following hormonal stimulation. The release of [14C]arachidonic acid was dose-dependent and greater than 3 fold that of [14C]prostaglandin release. Indomethacin by inhibiting the cyclo-oxygenase, completely inhibited release of [14C]prostaglandins and only slightly inhibited release of [14C]arachidonic acid. These results demonstrate that in both rabbit kidney and heart much more substrate is released by hormonal stimulation than is converted to prostaglandins. This suggests that either the deacylation reaction is not tightly coupled to the prostaglandin synthetase system or that there are two deacylation mechanisms, one which is coupled to prostaglandin synthesis while the other is non-specific. It has previously been shown that prostaglandin release due to hormones such as bradykinin is transient despite continued presence of the hormone (tachyphylaxis). By utilizing albumin to trap released fatty acid, it was found that hormone-stimulated release of arachidonic acid is also transient. This directly demonstrates that tachyphylaxis occurs at a step prior to the cyclo-oxygenase.

Adenosine Triphosphate↗
PubMed1981

Role of prostaglandins in the regulation of intestinal electrolyte transport.

The E prostaglandins (and to a lesser extent PGE2 alpha) stimulate active electrolyte secretion in mammalian small intestine and colon. They do so by stimulating intestinal mucosal adenylate cyclase and thereby increasing cAMP concentration. The diarrheagenic action of the prostaglandins is seen as a side effect of their therapeutic use, in certain hormone-secreting tumors, and in inflammatory lesions of the bowel in which leukocyte infiltrates are the probable sources of prostaglandin excess. Prostaglandins are also normally synthesized by intestinal epithelial cells and appear to play an important role in the physiologic regulation of intestinal fluid transport. In recent in vitro studies, we have shown that addition of arachidonic acid (K 1/2 congruent to 10(-6) M) also stimulates secretion, cAMP accumulation, and PGE2 production in rabbit ileal mucosa. In the continued presence of arachidonate, tachyphylaxis develops: both secretory and cAMP responses have a half-life of about twenty minutes and subsequent additions of arachidonate produce little or no further response. In contrast, PGE2 production continues undiminished. Similar tachyphylaxis develops when PGE2 itself is added. Resensitization following removal of PGE2 is rapid, 50% of the initial sensitivity being restored in 6-7 min. Prostaglandin desensitization has been noted in other cell systems and appears to be exerted on adenylate cyclase.

Adenylyl Cyclases↗
PubMed1987

Beta-adrenergic agonists reduce spontaneous motor activity through either beta 1 or beta 2 receptors.

In mice, the clenbuterol-induced decrease in spontaneous motor activity was antagonized by IPS-339 (beta 2 antagonist) but not by betaxolol (beta 1 antagonist), whereas the isoproterenol-induced decrease in spontaneous motor activity was completely antagonized by betaxolol and only partially by IPS-339. It can be concluded that the clenbuterol-induced decrease in spontaneous motor activity is of the beta 2-type, whereas that induced by isoproterenol is essentially of the beta 1 type. In addition, chronic treatment with clenbuterol induced a tachyphylaxis to the effect of clenbuterol but not of isoproterenol. After chronic administration of tricyclic antidepressants (imipramine and desipramine) the number of cortical beta 1 adrenergic receptors decreased without impairing the clenbuterol-induced decrease in spontaneous motor activity. We conclude that beta 2 adrenergic receptors mediate the clenbuterol-induced decrease in spontaneous motor activity and the tachyphylaxis to this effect after chronic treatment.

Adrenergic beta-Agonists↗
PubMed1990

Evaluation of tremor and efficacy of oral procaterol in adult patients with asthma.

Tremor, the most common side effect of ordinary doses of beta 2-agonists, was evaluated in a quantitative manner and compared to improvement in pulmonary function in respect to time of onset, duration, peak effect, and tachyphylaxis with procaterol in adults. Forty-five adult patients with reversible obstructive airway disease were studied during administration of three different dosages of procaterol, 25 micrograms escalating to 100 micrograms, and 100 micrograms twice daily. Tremor was quantitatively evaluated with a Grass model accelerometer. The patients were evaluated during 8 hours approximately every 2 weeks for 8 weeks. Daily diaries of symptoms and side effects were also maintained. The study demonstrated no direct relationship between tremor and pulmonary function as far as time of onset, peak effect, or duration. Although tachyphylaxis was demonstrated, much of the tolerance developed to the tremor was explained by an increase in baseline tremor. Procaterol was demonstrated to be an effective bronchodilator, and tolerance to tremor was demonstrated to develop with time but is highly variable. There was not a direct relationship between tremor and pulmonary function, indicating possible differences between lung and peripheral muscle beta 2-receptors. It appeared that the best way to minimize the problem of tremor is to begin with a lower dose and increase the dose gradually during a period of weeks.

Administration, Oral↗
PubMed1985

Presynaptic modulation by noradrenaline and an opioid of the substance P-induced release of [3H]acetylcholine from the myenteric plexus.

Substance P (7.5-750 nM) applied in superfusion dose-dependently released 3H from isolated strips of myenteric plexus-longitudinal muscle of the guinea-pig ileum loaded with [3H]choline. Separation of the [3H]acetylcholine and [3H]choline components of the released radioactivity revealed that in response to substance P (SP) administration only the release of [3H]acetylcholine increased above resting level. A slowly developing tachyphylaxis to the effect of SP was observed. Evidence has been obtained that the slow tachyphylaxis developed to the acetylcholine-releasing effect of SP was not due to the exhaustion of releasable acetylcholine pool. Release of acetylcholine by 150 nM SP was completely prevented by tetrodotoxin or in a Ca2+-free medium and greatly reduced in the presence of noradrenaline or the opioid receptor agonist (D-Met2,Pro5)-enkephalinamide. The effect of noradrenaline and the opioid peptide was apparently prevented by yohimbine and naloxone, respectively.

Acetylcholine↗
PubMedDate not supplied

The effects of pancreatic polypeptides and neuropeptide Y on the rat vas deferens.

In order to study the physiological significance of the coexistence of pancreatic polypeptide and norepinephrine (NE) in peripheral noradrenergic nerves, the effects of pancreatic polypeptides of several species were tested on the isolated rat vas deferens. Neuropeptide Y (NPY) was also studied because of its sequence homology to the pancreatic polypeptides. The contractile responses, which were mediated predominantly by activation of noradrenergic nerves following electrical stimulation, were inhibited by bovine pancreatic polypeptide (BPP), human pancreatic polypeptide (HPP), avian pancreatic polypeptide (APP) and NPY in a dose-dependent manner using a constant flow bath. The decreasing order of the inhibitory responses was as follows: BPP = HPP greater than NPY greater than APP. The inhibitory responses produced by BPP and HPP lasted more than 1 hr and displayed a marked tachyphylaxis. In contrast, the inhibitory effects induced by NPY and APP usually returned to the control level after 20-30 min and had minimal tachyphylaxis. The inhibitory action of NPY was still present during alpha-adrenergic blockade. Contractions produced by a single submaximal dose of exogenous NE or serotonin (5-HT) in unstimulated preparations were not affected by pretreatment with NPY. The amplitude of contractions was partially reduced 1 min after pretreatment with BPP or HPP; recovery occurred about 15 min after peptide pretreatment in a constant flow bath. These results suggest that an NPY receptor exists presynaptically in the rat vas deferens and that stimulation of the receptor by NPY inhibits the release of NE from noradrenergic nerves.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic Fibers↗
PubMedDate not supplied

Neuropeptide Y is an inhibitor of neural function in the myenteric plexus of the guinea-pig ileum.

Neuropeptide Y (NPY) reduced the resting tension of the myenteric plexus-longitudinal muscle preparation (MP-LM) of the guinea-pig ileum (GPI). NPY in a dose-dependent manner also reduced the neurally-mediated excitatory effect of cholecystokinin octapeptide (CCK8) sulfated form on this preparation. However, NPY, at the concentration used in the study, did not modify the effect of exogenous acetylcholine (ACh). All these features were also shared by other inhibitory peptides, like somatostatin (SOM) and the enkephalin derivative FK 33-824. The preparation developed a degree of tachyphylaxis to the inhibitory effect of NPY more rapidly than it did to SOM. Moreover, the inhibitory effect of neuropeptide Y was of longer duration than the one seen for somatostatin. A faster metabolic rate might account for the lower development of tachyphylaxis to somatostatin. The presence of the opioid antagonist naloxone did not alter the inhibitory features of NPY or SOM. Therefore, the involvement of any endogenous opioid in the action of these two inhibitory peptides can be disregarded.

Animals↗
PubMedDate not supplied

Vasoconstrictor and dilator responses to neurokinin A in isolated guinea pig heart.

Effects of neurokinin A (NKA) and substance P (SP) on coronary resistance vessels were studied in isolated guinea pig hearts perfused with isotonic buffer containing 20 mM KCl. Injections of NKA and SP caused dose-dependent reductions in perfusion pressure with ED50 values of 14.0 and 0.326 pmol, respectively. Blockade of nitric oxide synthesis or removal of the endothelium inhibited vasodilator responses to neurokinins. Infusions of NKA or SP caused tachyphylaxis and cross-desensitization to the other neurokinin but not to acetylcholine. Injections of 2.5 nmol NKA increased perfusion pressure by 31 +/- 8% when given after tachyphylaxis developed to infused SP (2.5 nmol/100 microliters/min). It was concluded that 1) neurokinins cause an endothelium-dependent relaxation of coronary resistance vessels by stimulating NK-1 receptors on endothelial cells, and 2) desensitization of the receptor mediating vasodilation unmasks a vasoconstrictor response to NKA.

Animals↗
PubMed1983

A comparison of the cardiovascular and orofacial blood flow changes resulting from hypotension induced by sodium nitroprusside and adenosine triphosphate in the rat.

These experiments compared the cardiovascular effects and the alterations in orofacial blood flow resulting from hypotension induced with sodium nitroprusside and adenosine triphosphate infusions in 30 male rats. The authors found that sodium nitroprusside did not significantly change heart rate or cardiac output, while adenosine triphosphate caused a significant decrease in heart rate associated with a small increase in cardiac output. Both hypotensive agents produced similar profound decreases in total peripheral resistance. Blood flows to orofacial structures were qualitatively similar with both agents. Both adenosine triphosphate and sodium nitroprusside caused decreased flows to the maxilla and mandible. Sodium nitroprusside increased flows to masseter and suprahyoid muscles. Adenosine triphosphate caused increased flows to suprahyoid muscles but masseter muscle flows were not significantly changed. Tongue flows responded similarly to both agents, initially decreasing, then returning to normotensive levels. Finally, sodium nitroprusside-induced hypotension was associated with the development of tachyphylaxis in some animals, whereas no similar problem was observed with use of adenosine triphosphate. The demonstration of reduced blood flows to orofacial bony structures and the absence of resistance or tachyphylaxis during adenosine triphosphate-induced hypotension support its usefulness as a hypotensive agent during orthognathic and other surgery.

Adenosine Triphosphate↗
PubMed1992

Activation of normal and inflamed fine articular afferent units by serotonin.

In cats anesthetized with alpha-chloralose, extracellular recordings were made from fine afferent units belonging to the medial articular nerve (MAN) of the knee joint. The excitatory and sensitizing effects on articular afferents of serotonin (5-HT) applied intra-arterially close to the joint were examined. The joints were either normal or an experimental arthritis had been induced some hours before the recording session. Bolus injections of 1.35-135 micrograms 5-HT excited about 43% of group III (CV: 2.5-20 m/sec) and 73% of group IV units (CV: less than 2.5 m/sec) from normal joints. The latency was usually between 10 and 30 sec, and the duration and size of the responses were dose-dependent. Fast group III units (CV: greater than 16 m/sec) and group II units (CV: greater than 20 m/sec) were never excited by 5-HT. Repetitive administration led to pronounced tachyphylaxis of the 5-HT response. Inflammation induced an enhanced sensitivity of group III articular afferent units to close intra-arterial application of 5-HT. In particular the total duration of each response was considerably prolonged (4-10 min against 1-2 min under normal conditions). At the same time the tachyphylaxis seen under normal conditions was greatly reduced. In contrast, group IV articular afferent units did not become sensitized to 5-HT in the course of inflammation. In normal joints 5-HT did not sensitize fine afferent units for movement-induced responses. However, after inflammation, a distinct sensitization to such movements by 5-HT application could be observed both in group III and group IV fiber ranges. The sensitization had a short time course not exceeding 7 min. The tonic component of the movement-induced response was more enhanced than the phasic one. The bolus application of 5-HT led to temporary vasoconstriction of the knee joint vessels. This vasoconstriction was especially pronounced in inflamed joints and impeded the access of subsequently applied substances to the terminal regions of the afferent units under observation. It is concluded that the present results support the notion that 5-HT may participate in the mediation of pain from inflamed tissue such as an arthritic joint by exciting and sensitizing fine afferent units. During inflammation group III units are particularly sensitive to 5-HT and, thus, may carry the bulk of the 5-HT-induced nociceptive messages.

Animals↗