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PubMed2001

Gastrin-releasing peptide is a potent vasodilator in humans.

OBJECTIVES: Our objective was to characterize the local vascular effects of gastrin-releasing peptide in forearm resistance vessels as a biomarker to aid the clinical development of broad-spectrum neuropeptide antagonists as anticancer agents. METHODS: On different occasions, 7 healthy male volunteers received brachial artery infusions of gastrin-releasing peptide, and forearm blood flow was measured by venous occlusion plethysmography. Dose-finding studies identified a range of pharmacologically active doses of gastrin-releasing peptide (3 to 450 pmol/min) for use in dose response and tachyphylaxis studies. The nitric oxide clamp method was used for the assessment of the contribution of nitric oxide to the vasodilatory effect shown. RESULTS AND CONCLUSIONS: Gastrin-releasing peptide proved to be a potent, dose-dependent arteriolar vasodilator. The time to onset and offset of effect was rapid, within minutes, and marked tachyphylaxis was shown, with recovery by approximately 20 minutes. The contribution of nitric oxide to this vasodilatation was minimal. Forearm blood flow studies with the use of gastrin-releasing peptide may be usefully incorporated into the further clinical development of broad-spectrum neuropeptide growth factor antagonists.

Adult↗
PubMed1983

Long-term succinylcholine infusion during isoflurane anesthesia.

The characteristics of the neuromuscular blockade produced by prolonged succinylcholine infusion were compared in 40 patients anesthetized with either nitrous-oxide-isoflurane (0.75-1.50% inspired) or nitrous-oxide-fentanyl. Neuromuscular transmission was monitored using train-of-four stimulation and the infusion rate was adjusted to keep the first twitch at 10-15% of its control value. Initially, all patients exhibited a depolarizing-type block, and the infusion rates were similar in the isoflurane (61 micrograms . kg-1 . min-1) and fentanyl (57 micrograms . kg-1 . min-1) groups. Tachyphylaxis developed in both groups and correlated well with the onset of non-depolarizing (phase II) block. Both occurred sooner and at a lower cumulative dose in the isoflurane groups. After 90 min, infusion rates were similar in both groups (isoflurane: 107 micrograms . kg-1 . min-1, fentanyl;: 93 micrograms. kg-1 . min-1). After the infusion was stopped, the recovery of the train-of-four ratio was inversely related to the dose and duration of exposure to succinylcholine, and was slower with nitrous-oxide-isoflurane anesthesia. After 10 min of recovery, patients receiving isoflurane exhibited train-of-four ratios of 0.5 or less after 8.5 mg/kg succinylcholine and 103 min. Corresponding figures for fentanyl patients were 13 mg/kg and 171 min. The block in all 13 patients (eight with isoflurane, five with fentanyl) who did not recover spontaneously was antagonized successfully with atropine and neostigmine. It was concluded that with succinylcholine infusion of 90 min or less, isoflurane accelerates the onset of tachyphylaxis and phase II neuromuscular block without affecting succinylcholine requirements. These results, with isoflurane, were similar to those reported previously with enflurane or halothane.

Adult↗
PubMed2002

Changes in the effect of isoflurane on N-methyl-D-aspartic acid-gated currents in cultured cerebral cortical neurons with time in culture: evidence for subunit specificity.

BACKGROUND: Developmental changes in NR1 splice variants and NR2 subunits of the N-methyl-D-aspartate (NMDA) receptor have been associated with changes in the sensitivity of NMDA receptors to agonists, antagonists, and pharmacologic modulators. The authors have investigated changes in the effect of isoflurane on NMDA-gated currents from cultured cortical neurons with time in culture and related these changes to the subunit composition of the NMDA receptors. METHODS: N-methyl-D-aspartate-gated currents were measured using whole-cell voltage clamp recording in cortical neurons cultured for 1-4 weeks and HEK 293 cells transiently expressing NR1-1a + NR2A or NR1-1a + NR2B subunit-containing receptors. NMDA alone or NMDA with treatment agents (isoflurane or ifenprodil) was applied to cells using a U tube. RESULTS: The effect of isoflurane and the NR2B selective antagonist ifenprodil on NMDA-gated currents from cortical neurons decreased significantly with time in culture. NMDA-gated currents mediated by NR2A-containing receptors were less sensitive to isoflurane than those mediated by NR2B-containing receptors. Tachyphylaxis to repeated application of isoflurane was found in cortical neurons and HEK 293 cells with recombinant NMDA receptors. Hooked tail currents were induced by isoflurane in cultured cortical neurons and HEK 293 cells with expressed NMDA receptors. CONCLUSIONS: Isoflurane inhibits NMDA-gated currents at concentrations well below 1 minimum alveolar concentration (MAC). This effect of isoflurane was subunit dependent with the NR2B-containing receptors more sensitive to isoflurane than the NR2A-containing receptors. A potent tachyphylaxis occurred after brief exposure to isoflurane.

Anesthetics, Inhalation↗
PubMed1991

Differential pharmacological profile of endothelin-1 and its precursor, big endothelin.

In pentobarbital-anesthetized rats endothelin-1 (ET-1), endothelin-2 (ET-2), endothelin-3 (ET-3), and mouse ET-2 (mET-2), in contrast to human big ET-1 (h-big ET), administered as i.v. bolus injections (0.25 nmol/kg i.v.) produced rapidly appearing and short-lasting blood pressure decreases. This effect was markedly inhibited (80-100%) after an 8-min i.v. infusion (0.1 nmol/kg/min over 10 min) of any of the ET studied, but not by h-big ET, the precursor of ET-1. Similarly, in pithed rats given a 10 min i.v. infusion of an equipressor dose (0.1 nmol/kg/min) of ET-1 or h-big ET, the hypotensive effects of ET-1 were entirely blocked only in the group of animals pretreated with ET-1. In pithed rats, ET-1 (0.25 nmol/kg i.v.) and h-big ET (0.5 nmol/kg i.v.) produced equivalent maximal pressor responses and the same pattern of increase in systemic, hindquarter, and renal vascular resistance. However, ET-1 was three times more potent than h-big ET as a vasoconstrictor of the mesenteric bed. Also the pressor response to h-big ET, but not ET-1 (0.25 nmol/kg i.v.), was markedly inhibited by the metalloprotease inhibitor phosphoramidon (5 mg/kg i.v.). These results indicate that the hypotensive effects of ET isopeptides have a common mechanism because they elicit cross tachyphylaxis, although h-big ET did not inhibit the decrease in blood pressure produced by ET-1. A possible explanation for this finding is that h-big ET has intrinsic pressor activity but does not have affinity for receptors mediating the vasodepressor effects of ET isoforms. Alternatively, h-big ET is converted into ET-1 too slowly to yield biophase concentrations of ET-1 necessary for lowering blood pressure and developing tachyphylaxis to ET-isoform-induced hypotension. Finally, if the pressor effects of h-big ET are mediated by ET-1 formation, phosphoramidon can be considered as an inhibitor of the endothelin-converting enzyme.

Animals↗
PubMed1993

Why big endothelin-1 lacks a vasodilator response.

The biphasic arterial blood pressure response to endothelin-1 (ET-1) results from a transient decrease, followed by a longer-lasting increase, in systemic vascular resistance. In contrast to ET-1, big endothelin-1 (bET-1) produces monophasic increases in systemic vascular resistance and arterial blood pressure. This is somewhat surprising, because bET-1 activity is reportedly due to ET-1, bET-1 being converted to ET-1 by a putative converting enzyme. In this study we tested two hypotheses that could explain the singular effect of bET-1 on the arterial vasculature: that bET-1 vasoconstriction, mediated by ETA receptors at the level of the smooth muscle, masks the release of endothelial derived vasodilators, and/or that the endothelium develops tachyphylaxis owing to prolonged activation of endothelial ETB receptors. In anesthetized rats, blockade of the vasoconstrictor activity of bET-1 with BQ-123, an ETA-receptor antagonist, did not reveal a masked bET-1 vasodilator component in the rat hindquarter. Furthermore, in the presence of bET-1 (after 3.0 nmol/kg bET-1 i.v.), low doses of ET-1 (0.03-0.3 nmol/kg) produced dose-dependent hindquarter vasodilation, indicating activation of endothelial ETB and therefore no tachyphylaxis. Collectively, these experiments suggest that i.v. administration of bET-1 results in little or no activation of endothelial ETB receptors and therefore lacks a vasodilator response.

Animals↗
PubMed1997

Comparative vasoconstrictor effects of angiotensin II, III, and IV in human isolated saphenous vein.

Elevated levels of angiotensin (Ang II) and its degradation products angiotensin III (Ang III) and angiotensin IV (Ang IV) may contribute to the regulation of vascular tone under various clinical circumstances. We investigated the contractile effects of Ang III and Ang IV in endothelium-denuded human saphenous vein (SV) preparations and compared them with those of Ang II. The veins were suspended in organ chambers, and changes in isometric force were recorded. Ang II (0.1-100 nM), Ang III (1 nM-3 microM), and Ang IV (0.3 microM-0.1 mM) caused concentration-dependent contractions with comparable maximal responses (Emax). Ang III was 16 times less active than Ang II, whereas Ang IV was approximately 2,700-fold less potent than Ang II. In the presence of the aminopeptidase-A and -M inhibitor amastatin (10 microM), the potencies of Ang III and Ang IV were increased by approximately 16 and 12 times, respectively, although no changes of Ang II potency were observed. The AT1-selective Ang II receptor antagonist losartan (10 and 100 nM) but not the AT2-selective antagonist PD123177 (1 microM), shifted the concentration-response curves (CRC) for the angiotensin peptides to the right in a parallel manner. Preincubation with indomethacin (10 microM), a cyclooxygenase inhibitor, did not influence the CRCs for any of the angiotensin peptides studied. Tachyphylaxis was investigated by constructing a second series of CRCs for the angiotensin peptides after an interval of 60 min. Ang II showed strong tachyphylaxis (the Emax value of the second Ang II CRC was approximately 50% of the first), whereas Ang III and Ang IV did not. Our results indicate that in endothelium-denuded human SV, both Ang III and Ang IV are less potent but similarly efficacious vasoconstrictor agents compared with Ang II. Endogenous aminopeptidase activity may counteract the effects of the angiotensin peptides. The contractile responses to all three peptides are mediated via AT1-receptors but not AT2-receptors.

Aged↗
PubMed2005

Vasodilator actions of the endothelium-derived relaxing factor L-S-nitrosocysteine in anaesthetized rats are markedly diminished by peroxynitrite.

The aim of the present study was to assess the effects of the potent oxidant and nitrating agent peroxynitrite on the haemodynamic actions of the endothelium-derived S-nitrosothiol L-S-nitrosocysteine. The haemodynamic actions of L-S-nitrosocysteine (12.5-100 nmol/kg, i.v.) were determined in pentobarbital-anaesthetized rats before and after the induction of tachyphylaxis to peroxynitrite achieved by giving 10 intravenous injections of a 10 micromol/kg dose. L-S-Nitrosocysteine elicited dose-dependent reductions in mean arterial blood pressure and in hindquarter and mesenteric vascular resistance. The L-S-nitrosocysteine-induced responses were substantially attenuated after administration of peroxynitrite. We have reported previously that nitric oxide-mediated vasodilation is not diminished after the induction of tachyphylaxis to peroxynitrite. Taken together, these findings support the concept that peroxynitrite reduces the vasodilator actions of L-S-nitrosocysteine via oxidation and/or nitration of putative membrane-bound S-nitrosothiol recognition sites.

Anesthesia↗
PubMed1968

The actions of caerulein on the smooth muscle of the gastrointestinal tract and the gall bladder.

1. In the intact conscious dog, caerulein causes emesis and evacuation of the bowel. The mean effective dose by the intravenous route is 0.4-0.5 mug/kg, and by the subcutaneous route 3-4 mug/kg.2. The gall bladder in situ or as an isolated preparation is highly sensitive to caerulein. A few ng/kg injected intravenously are sufficient to stimulate the gall bladder in situ and less than 1 ng/kg per min is effective when infused intravenously. The isolated gall bladder is contracted by caerulein in concentrations as low as 0.03-2 ng/ml. Krebs solution. There is no tachyphylaxis but, generally, a good dose-response relationship. Hence the gall bladder, especially that of the guinea-pig, appears to be very suitable for the bioassay of caerulein and related peptides.3. In situ, the musculature of the gastrointestinal tract is also highly sensitive to caerulein. Doses as low as 1-5 ng/kg, administered intravenously, have a spasmogenic action on jejunal loops of the dog, and slightly larger doses contract the small intestine of the cat. The stomach and the large intestine seem to be somewhat less sensitive to the polypeptide. Caerulein has a considerable spasmogenic action on the rat pylorus but relaxes the sphincter of Oddi of the guinea-pig.4. Isolated preparations of the gastrointestinal tract are relatively insensitive to caerulein and tachyphylaxis occurs readily.5. Blockade with atropine produces different effects in different intestinal segments and in different animal species. The spasmogenic action of caerulein on the gall bladder is atropine-resistant.6. The effects of caerulein are similar to those of cholecystokinin-pancreozymin in the organs tested in situ or as isolated preparations. Caerulein, however, is always more potent than cholecystokinin-pancreozymin, even on a molar basis. Compared with caerulein, human gastrin I has negligible activity.7. The possible use of caerulein in cholecystography is discussed.

Animals↗
PubMed1969

The action of eledoisin on the peristaltic reflex of guinea-pig isolated ileum.

1. Low concentrations of eledoisin, acting from the serosal surface of the guinea-pig isolated ileum, had no effect on the peristaltic reflex, whereas in high concentrations it depressed or sometimes abolished this reflex.2. Eledoisin stimulated the peristaltic activity of the guinea-pig ileum subjected to continuously raised intraluminal pressure. This stimulatory effect could be produced regularly when the interval between additions of eledoisin was at least 20 min. When added at shorter intervals, tachyphylaxis to eledoisin developed, but its ability to promote peristaltic activity was restored by the addition of an anticholinesterase to the bath fluid. During tachyphylaxis to eledoisin, nicotine and dimethylphenylpiperazinium were unable to restore peristalsis.3. When the peristaltic reflex had been abolished by ganglion-blocking agents, morphine and morphine-like substances, or adrenaline, eledoisin restored the reflex. Eledoisin was much more effective in overcoming the blocking effect of hexamethonium, tetraethylammonium and azamethonium than that of nicotine or dimethylphenylpiperazinium.4. Eledoisin did not antagonize the inhibitory effects of atropine, hyoscine and hyoscine butylbromide.5. It is suggested that the stimulant effect of eledoisin may be due to a direct action on the smooth muscle and a release of acetylcholine from postganglionic nerve endings, but an effect on the intestinal ganglion cells cannot be excluded.

Animals↗
PubMed1970

Hyposensitivity to drugs induced by morphine and some related substances in the cat.

1. Hyposensitivity to noradrenaline occurred concomitantly with morphine tachyphylaxis in the absence of any obvious depressant effect on the heart or peripheral circulation.2. The actions of adrenaline, noradrenaline and angiotensin and, occasionally, other drugs were tested before and after repeated injections of morphine or one of ten related substances in various preparations of the spinal cat.3. Tachyphylaxis in response to morphine could be related to a simultaneous decrease in the tissue responses to adrenaline, noradrenaline and angiotensin but such a parallelism has not been shown for the substances related to morphine.

Angiotensin II↗
PubMed1972

Atropine resistant excitation of the urinary bladder: the possibility of transmission via nerves releasing a purine nucleotide.

1. The possibility that a purine nucleotide is involved in excitatory transmission to the urinary bladder has been tested. All the purine compounds tested which contained a pyrophosphate bond produced contraction, adenosine triphosphate (ATP) being the most potent. Adenosine and adenosine monophosphate caused relaxation.2. The response to ATP closely mimicked the nerve-mediated contraction, both being characterized by a rapid contraction which was not maintained. A lack of sensitivity to ATP was noted in some preparations of the rat urinary bladder.3. Both nerve-mediated contractions and contractions caused by ATP were blocked by quinidine, while the response to acetylcholine persisted.4. Nerve-mediated responses were depressed during tachyphylaxis produced by high concentrations of ATP. Tachyphylaxis did not occur when low concentrations were used. Possible explanations for these results are discussed.5. The results are consistent with the hypothesis that non-cholinergic excitatory nerves to the guinea-pig bladder release a purine nucleotide, but do not provide critical evidence for it.

Adenosine↗
PubMed1973

Acetylcholine release from guinea-pig ileum by parasympathetic ganglion stimulants and gastrin-like polypeptides.

1. The release of acetylcholine by parasympathetic ganglion stimulants from the nerve terminals of the guinea-pig longitudinal muscle strip was studied. The acetylcholine released was collected in the presence of physostigmine sulphate.2. Nicotine and 1,1-dimethyl-4'-phenylpiperazinium iodide (DMPP) released acetylcholine. Tetrodotoxin (50 ng/ml) and hexamethonium completely prevented their action on acetylcholine release, indicating that their effect is on nicotinic receptors of cell bodies. Noradrenaline (1 mug/ml), excess magnesium, and calcium withdrawal inhibited the acetylcholine release induced by nicotine or by DMPP.3. There was rapid tachyphylaxis to the acetylcholine releasing action of both nicotine and DMPP.4. The octapeptide amide of cholecystokinin and caerulein (10(-9)M) enhanced the acetylcholine release without producing tachyphylaxis. Tetrodotoxin completely inhibited acetylcholine release. However, hexamethonium or desensitization with 5-hydroxytryptamine did not prevent their action. In the early phase of nicotine action the polypeptides studied failed to increase acetylcholine release. However, a few minutes later the tissue became sensitive to polypeptides despite the fact that the tissue was still exposed to nicotine. These data suggest the presence in the parasympathetic ganglion cells of separate gastrointestinal hormone-sensitive receptors.5. Noradrenaline inhibited the acetylcholine releasing action of polypeptides. This effect was mediated via alpha-adrenoceptors since phentolamine prevented its action.6. Excess magnesium (9.3 mM) also reduced the acetylcholine release in response to the polypeptides.

Acetylcholine↗
PubMed1976

Effect of indomethacin and prostaglandin on the smooth muscle contracting activity of angiotensin and other agonists.

Indomethacin had an equal inhibitory effect on the response of the guinea-pig isolated ileum to angiotensin II (angiotensin), bradykinin, histamine and acetylcholine. This effect did not seem to result from inhibition of prostaglandin synthesis, as it did not depend on the time of treatment with indomethacin. Prostaglandin E2 (prostaglandin) potentiated the responses of the guinea-pig ileum to angiotensin, bradykinin, histamine and acetylcholine without significant differences in the effects observed. In the rabbit isolated mesenteric and coeliac arteries, indomethacin had an equal potentiating effect on the responses to angiotensin and to adrenaline. In these organs pre-incubation with indomethacin was necessary for the effect to be observed, and this effect lasted for 2 h or more after that drug was removed from the medium. No cross-tachyphylaxis between angiotensin and adrenaline was observed in the rabbit mesenteric and coeliac arteries. It is concluded that the effects of indomethacin and prostaglandin on the response of the guinea-pig ileum to the four agonists result from an action on the smooth muscle contractile mechanism per se rather than from an inhibitory action on the release of endogenous prostaglandin produced by the four agonists. The results with the rabbit isolated arteries indicate that tachyphylaxis to angiotensin in these organs is not caused by prostaglandin release.

Acetylcholine↗
PubMed1983

Pharmacological characterization of the inhibitory effects of neurotensin on the rabbit ileum myenteric plexus preparation.

Neurotensin in picomolar concentrations caused a concentration-related inhibition of the spontaneous contractile activity of the longitudinal muscle from the rabbit isolated ileum. Neurotensin was approximately 100 times more potent than adrenaline and about 10000 times as active as adenosine triphosphate (ATP) in producing similar relaxations. The neurotensin-induced inhibitory effect did not follow activation of adrenoceptors or P1-purinoceptors since the effect of the neuropeptide was not antagonized by a combination of phentolamine plus (-)-propranolol, nor by pretreatment with theophylline. Tetrodotoxin did not reduce the potency of neurotensin in relaxing the rabbit ileum, suggesting that the neurotensin-induced inhibition is not neuronally mediated. The inhibitory responses of neurotensin were blocked non-competitively by apamin. The inhibitory effect of neurotensin was short-lived with the subsequent development of tachyphylaxis, which was not crossed to the inhibitory action of adrenaline or ATP. Similarly, when tachyphylaxis to adrenaline or to ATP was established, the inhibitory action of neurotensin was unaffected. Desensitization was characterized by a gradual shift of the neuropeptide concentration-response curve to the right and downwards. Preincubation of rabbit ileum strips with 10 nM dynorphin (1-13) significantly increased the inhibitory action of neurotensin.

Adenosine Triphosphate↗
PubMed1988

Possible mechanism of acetaldehyde-induced noradrenaline release from sympathetic nerve terminals in isolated blood vessels.

1. Vasoconstrictor responses to acetaldehyde were investigated in isolated and perfused canine intermediate auricular (ear) arteries. 2. Single injections of small doses of acetaldehyde (1-3 mumol) induced vasoconstriction in a dose-related manner and showed no tachyphylaxis. On the other hand, large doses of acetaldehyde (10-30 mumol) frequently caused tachyphylaxis when injected at 10 min intervals. 3. After tyramine treatment, constrictions induced by a large dose of acetaldehyde were consistently restored temporarily. 4. The acetaldehyde-induced vasoconstriction was inhibited by bunazosin, a potent alpha 1-adrenoceptor antagonist. 5. A small dose of imipramine blocked tyramine-induced vasoconstriction, but had no significant influence on noradrenaline (NA)-induced constrictions, and caused slight potentiation of acetaldehyde-induced constrictions. 6. Hydrocortisone treatment did not modify tyramine-induced vasoconstrictions and slightly suppressed NA- and acetaldehyde-induced constrictions but not significantly. 7. It is suggested that acetaldehyde causes a release of NA from a NA store of the sympathetic nerve terminals which is different from the tyramine-sensitive NA store, and that the acetaldehyde-sensitive NA store may be readily filled up with NA from the tyramine-sensitive store.

Acetaldehyde↗
PubMed1977

Actions of neurotensin and (Gln4)-neurotensin on isolated tissues.

The actions of neurotensin and (Gln4)-neurotensin have been investigated on a number of isolated tissues. They were ineffective in contracting the guinea pig vas deferens, the rabbit aortic strip or the frog rectus abdominis muscle in concentrations up to 0.24 micron. Neurotensin and (Gln4)-neurotensin relaxed the rat duodenum at fairly high concentrations (24 nM). The guinea pig ileum contracted in response to increasing doses, although the maximum response were only one half that caused by histamine. Tachyphylaxis was observed at dose intervals of less than 12 minutes, but this tachyphylaxis did not inhibit responses to acetylcholine, histamine, 5-HT or to DMPP, suggesting that the neurotensins may act at specific receptor sites. They contracted the rat fundus strip at concentrations of 0.24 nM and higher. The neurotensins and 5-HT were approximately equipotent on this tissue, although the maximum responses was about 80% of that to 5-HT. The contractions of the rat fundus strip could not be blocked by atropine, hexamethonium, methysergide, morphine or by 7-OH-THC. These data indicate that neurotensin and (Gln4)-neurotensin are equipotent as far as smooth muscle stimulating activity is concerned. Of those organs tested, the rat fundus strip seems to be the most suitable one for studies concerning structure-activity relationships.

Acetylcholine↗
PubMed1984

The effects of chronic inhalation of salbutamol on the acute airway responsiveness to salbutamol and ipratropium bromide in the conscious and the anaesthetized guinea-pig.

The effects of chronic exposure to a nebulized mist of salbutamol on the capacity of systemic salbutamol to prolong the time taken for inhaled histamine to produce bronchospasm in guinea-pigs have been examined. Initially a reproducible cough time to inhalation of histamine acid phosphate (0.5 ml ml-1) in 100% O2 was established. Antagonism of this response by intraperitoneal salbutamol or ipratropium Br was assessed to establish submaximal responses to these drugs. A fresh group of animals was then exposed to a persistent mist of nebulized water for 16 days, before and during which each animal was tested by exposure to histamine mist either alone or shortly after salbutamol (10 micrograms kg-1 i.p.) or ipratropium Br (5 micrograms kg-1 i.p.). The nebulized water had no effect on the response to the drugs. The same animals were rested for 7 days and then exposed to nebulized salbutamol solution (5 mg ml-1) for 15 days, during which time tachyphylaxis developed to salbutamol (i.p.) but not to ipratropium Br. At the end of the 15 days the animals were anaesthetized and total lung resistance (RL) measured. At this time, the protective effect of intravenous salbutamol was also diminished by comparison with untreated guinea-pigs while the response to ipratropium Br was unaffected. A separate group exposed to 1 mg ml-1 of nebulized salbutamol for 20 days developed selective tachyphylaxis to intraperitoneal salbutamol. The animals were then allowed to breathe room air and the response to intraperitoneal salbutamol after 13 days returned to normal as did the effects of intravenous salbutamol on the RL response to histamine.

Aerosols↗
PubMed1990

The excitatory effect of dopamine on isolated canine tracheal smooth muscle.

The effect of exogenous dopamine on canine tracheal smooth muscle has been studied in-vitro. Dopamine at concentrations over 10(-5)M induced contractions of tracheal muscle strips and repeated exposures resulted in desensitization (tachyphylaxis) of the muscle. The sensitivity of the response varied dramatically among muscle strips. At lower concentrations, dopamine caused neither muscle relaxation nor inhibition of contractions evoked by 10(-6)M acetylcholine. Both a dopaminergic antagonist, haloperidol (10(-5) and 10(-4)M), and an alpha-adrenoceptor antagonist, phentolamine (10(-7) to 10(-5)M), attenuated the contraction to 10(-3)M dopamine. The beta-adrenoceptor antagonist, propranolol (10(-8) to 10(-6)M), enhanced the contraction. However, the contraction could only be abolished by phentolamine at 10(-4) M. Thus, in canine tracheal smooth muscle, the contractile response to dopamine is predominantly through the activity of alpha-adrenoceptors and the role of dopaminergic receptors is vague. It is suggested that the weakness of the dopamine-induced contraction results from an antagonism between alpha- and beta-adrenoceptor effects and the dopamine tachyphylaxis may reflect a gradually decreased activation of the alpha-adrenoceptor mechanism in comparison with the beta-adrenoceptor mechanism.

Animals↗