Pharmacological responses of human and porcine lung parenchyma, bronchus and pulmonary artery

1 Responses of preparations of human and porcine isolated bronchus and pulmonary artery to carbachol (CCh), methacholine, histamine, 5-hydroxytryptamine (5-HT), (-)-noradrenaline (NA), (-)adrenaline (Adr) and (+/-)-isoprenaline (Iso) were compared with responses to the same agonists in isolated lung parenchyma strips. 2 All preparations from both human and porcine lung contracted in response to histamine and all, except preparations of porcine pulmonary artery, contracted in response to CCh. Human and porcine pulmonary artery and parenchyma strip contracted in response to NA while bronchial preparations invariably relaxed. Iso caused relaxation of human and porcine bronchus and parenchyma strip. Although 5-HT was completely inactive in tissues isolated from pig lung, this amine was a powerful spasmogen in human pulmonary artery, relaxed human bronchus and caused variable responses in human parenchyma. 3 Results indicate that the pharmacological characteristics of human and porcine parenchyma strips may be explained in terms of responses of vascular or airways smooth muscle.     

Characterization of the anatomical structures involved in the contractile response of the rat lung periphery.

1. When lung parenchymal strips are challenged with different smooth muscle agonists, the tensile and viscoelastic properties change. It is not clear, however, which of the different anatomical elements present in the parenchymal strip, i.e., small vessel, small airway or alveolar wall, contribute to the response. 2. Parenchymal lung strips from Sprague Dawley rats were suspended in an organ bath filled with Krebs solution (37 degrees C, pH = 7.4) bubbled with 95%O2/5%CO2. Resting tension (T) was set at 1.1 g and sinusoidal oscillations of 2.5% resting length (L0) at a frequency of 1 Hz were applied. Following 1 h of stress adaptation, measurements of length (L) and T were recorded under baseline conditions and after challenge with a variety of pharmacological agents, i.e., acetylcholine (ACh), noradrenaline (NA) and angiotensin II (AII). Elastance (E) and resistance (R) were calculated by fitting changes in T, L and delta L/ delta t to the equation of motion. Hysteresivity (eta, the ratio of the energy dissipated to that conserved) was obtained from the equation eta = (R/E)2 pi f. 3. In order to determine whether small airways or small vessels accounted for the responses to the different pharmacologic agents, further studies were carried out in lung explants. Excised lungs from Sprague Dawley rats were inflated with agarose. Transverse slices of lung (0.5-1.0 mm thick) were cultured overnight. By use of an inverted microscope and video camera, airway and vascular lumen area were measured with an image analysis system. 4. NA, ACh and AII constricted the parenchymal strips. Airways constricted after all agonists, vessels constricted only after All. Atropine (Atr) pre-incubation decreased the explanted airway and vessel response to AII, but no difference was found in the parenchymal strip response. 5. Preincubation with the arginine analogue N omega-nitro-L-arginine (L-NOARG) did not modify the response to ACh but mildly increased the oscillatory response to NA after co-preincubation with propranolol (Prop). 6. These results suggest that during ACh and NA challenge, small vessels do not contribute substantially to the parenchymal strip response. The discrepancy between results in airways, vessels and strips when Atr was administered prior to AII implicates a direct contractile response in the parenchymal strip.     

Carbamylcholine- and 5-hydroxytryptamine-induced contraction in rat isolated airways: inhibition by calcitonin gene-related peptide.

1. The effects of rat and human alpha-calcitonin gene-related peptide (alpha-CGRP) were investigated in isolated smooth muscle preparations obtained from three levels of the rat respiratory tract. 2. Neither peptide (10(-10)-10(-6) M) had any effect on resting tension or on carbamylcholine (10(-6) M)-induced tone of trachea or main bronchus. In contrast, CGRP sometimes reduced spontaneous or carbamylcholine-induced tone of lung parenchymal strips. 3. CGRP produced a significant rightward shift of the log concentration-response curves to carbamylcholine and 5-hydroxytryptamine (5-HT) in the main bronchus. A rightward shift was also seen in trachea and parenchymal strips but this did not achieve the level of significance. The maximal response to 5-HT was reduced in the main bronchus and lung parenchyma whereas the maximal contraction to carbamylcholine was decreased in parenchymal strip only. 4. In all three airway preparations, CGRP caused concentration-dependent inhibition of responses elicited by challenges with 10(-7) M carbamylcholine or 5 x 10(-7) M 5-HT. The inhibitory effect of the peptide was inversely related to the size of the airways: the smaller the calibre, the greater the inhibition. 5. The inhibitory action of CGRP was not modified by pretreatment with tetrodotoxin (10(-6) M), propranolol (10(-6) M) or indomethacin (10(-6) M). 6. The results strongly suggest that (a) CGRP has a nonspecific inhibitory action on airway smooth muscle cells, (b) CGRP may act as a potent inhibitor of responses elicited by bronchoconstrictor substances and (c) its inhibitory activity may be most powerfully expressed in peripheral regions of the respiratory tract.     

The cat lung strip as an in vitro preparation of peripheral airways: a comparison of beta-adrenoceptor agonists, autacoids and anaphylactic challenge on the lung strip and trachea.

1 A new in vitro preparation, the isolated lung strip of the cat, is described for investigating the direct effect of drugs on the smooth muscle of the peripheral airways of the lung. The preparation comprises a thin strip of lung parenchyma which can be mounted in a conventional organ bath for isometric tension recording. Its pharmacological responses have been characterized and compared with the isolated tracheal preparation of the cat. 2 The lung strip exhibited an intrinsic tone which was relaxed by catecholamines, aminophylline and flufenamate. It was contracted strongly by histamine, prostaglandin F2alpha, acetylcholine, compound 48/80, potassium depolarizing solution and alternating current field stimulation. In contrast, the cat trachea was unresponsive to histamine and prostaglandin F2alpha and did not exhibit an intrinsic tone. 3 (-)-Isoprenaline and (-)-adrenaline were much more potent in relaxing the lung strip than the trachea. The potency order of relaxation responses to isoprenaline, adrenaline and (+/-)-noradrenaline in the lung strip was isoprenaline greater than adrenaline greater than noradrenaline but in the trachea was isoprenaline greater than noradrenaline greater than or equal to adrenaline. 4 beta2-Adrenoceptor selective agonists salbutamol and terbutaline were more potent in the lung strip than the trachea, suggesting beta2-adrenoceptors predominated in the lung strip. Propranolol was equipotent in inhibiting isoprenaline relexations of the lung strip and trachea, whereas practolol was much less effective in inhibiting lung strip than trachea, further supporting a predominance of beta2-adrenoceptors in lung strip and beta1-adrenoceptors in trachea. 5 Strong Schultz-Dale type contractions were elicited in both lung strips and trachea by Ascaris lumbricoides antigen in actively sensitized cats. The initial phase of the contractile response of the lung strip following challenge was shown to be due to histamine release and was absent in the trachea. The delayed phase of the contraction which took several minutes to develop in both the mepyramine-treated lung strip and trachea was not due to prostaglandins E1, F2alpha or bradykinin, the probable mediator being slow reacting substance of anaphylaxis (SRS-A). 6 It is concluded that the isolated lung strip of the cat is useful as an in vitro model for investigating the effect of drugs on the smooth muscle of the peripheral airways of the lungs.     

Reactivity of isolated trachea, bronchus and lung strip of cats of carbachol, 5-hydroxytryptamine and histamine: evidence for the existence of methysergide-sensitive receptors.

1 The reactivity was investigated of cat isolated tracheal chains, bronchial spirals and lung parenchymal strips to carbachol, 5-hydroxytryptamine (5-HT) and histamine. 2 Carbachol and 5-HT produced concentration-dependent contractions of all three tissues, responses to the former drug being selectively blocked by atropine and to the latter by methysergide. 3 Histamine failed to elicit a contractile response from the tracheal or bronchial muscle. However, it induced dose-related concentrations of the lung strips, that were selectively blocked by mepyramine. 4 It is concluded that lung parenchymal strips of cats possess mepyramine-sensitive histamine H1-receptors. Receptors for 5-HT, susceptible to methysergide, occur in the tracheobronchial smooth muscles as well as in lung strips of cats.     

Modifications of responses to adrenergic drugs in arterial strip by treatment in vivo with ephedrine and reserpine.

The aim of the present experiment was to investigate effects of ephedrine and reserpine, administered in vivo, on responses of dog isolated arterial strips to adrenergic drugs, and to study a possible mechanism involved in the reversal of blood pressure responses to dopamine. Dose-dependent contractile responses to adrenaline (A), dopamine (DA) and ephedrine (ED) were depressed in the femoral strips isolated from the ED-treated dogs as compared with those isolated from the untreated dogs. Those to noradrenaline (NA) were potentiated in low concentration and in hibited in high concentration, though those to tyramine (TY) were not altered. Relaxing and contractile responses to isoprenaline (IP) were inhibited. DA did not induce a relaxing effect but a contractile one even in the strips brought to a state of moderate tone with ED or phelypressin. In the strips isolated from the reserpine-treated dogs, contractile responses were to some extent potentiated by NA, A and DA, and significantly by ED, while those to TY were inhibited. Relaxing responses to IP were reduced and contractile responses potentiated. In the strips extirpated from the reserpine and ED-treated dogs, contractile responses to NA and A were potentiated in low concentration and tended to be potentiated in high concentration whereas those to DA and ED were not affected. Dose-dependent relaxing effects of DA in the dog renal and mesenteric strips contracted previously by KCl after phenoxybenzamine were attenuated by treatment with ephedrine in vivo. The results suggested that the dopamine reversal in the blood pressure may be mainly due to actions other than its peripheral effect on the blood vessels.     

HISTAMINE AND CARBACHOL CONTRACTILE RESPONSES IN PROXIMAL AND DISTAL AIRWAYS OF THE RABBIT

Airway preparations from the trachea, main bronchi, subsegmental bronchi and the parenchyma of rabbits were studied. The proximal airways, the trachea and main bronchi, were less sensitive to histamine than the distal airways of the subsegmental bronchi and lung parenchymal strip. The proximal airways were more sensitive to carbachol than the distal airways. These results may assist in the interpretation of airway responses in vivo.     

5-Hydroxytryptamine induces relaxation of goat pulmonary veins: evidence for the noninvolvement of M and D-tryptamine receptors.

1 Reactivity of goat isolated pulmonary arteries and veins to a variety of vasoactive agents was investigated. 2 Bradykinin (Bk), acetylcholine (ACh), noradrenaline (NA), prostaglandin A1 (PGA1), PGE2, PGF2 alpha and histamine induced dose-dependent contractile responses on veins; 5-hydroxytryptamine (5-HT) induced veno-relaxation. Angiotensin was virtually inactive. 3 Angiotensin, NA, Bk, histamine and 5-HT produced concentration-dependent contractile responses on the arterial strips; these arteries failed to respond to ACh, PGA1, PGE2 or PGF2 alpha. 4 The pulmonary veno-relaxant response to 5-HT was found to be resistant to propranolol, indomethacin, metiamide, cimetidine, methysergide, atropine and morphine. These findings appear to exclude the involvement of adrenergic mechanisms and prostaglandin generation as well as activation of classical M and D-tryptamine receptors by 5-HT in the goat pulmonary veins. This response may be mediated via a presynaptic inhibitory 5-HT receptor. 5 5-HT-induced arterial contractile responses were antagonized by methysergide, showing the occurrence of classical D receptors in the goat pulmonary artery. 6 It is concluded that differential reactivity of pulmonary arteries and veins to vasoactive agents may play differential role(s) in the pathophysiology of pulmonary disease. 5-HT may exert an antiinflammatory activity in goat pulmonary veins.     

Effect of 5-hydroxytryptamine on the membrane potential of endothelial and smooth muscle cells in the pig coronary artery.

1. Many endothelium-dependent vasodilators hyperpolarize the endothelial cells in blood vessels. It is not known whether these hyperpolarizations are linked to nitric oxide synthesis or to an endothelium-derived hyperpolarizing phenomenon, since most of the vasodilators release both factors. In this context, we first verified that the endothelium-dependent relaxations induced by 5-hydroxytryptamine (5-HT) on pig coronary arteries are due only to the activation of the nitric oxide pathway. Then we studied the effects of 5-HT on membrane potential of endothelial and smooth muscle cells. 2. In the absence of endothelium, 5-HT caused a concentration-dependent contraction of coronary artery strips. No change of the smooth muscle cell membrane potential was observed during contraction to 1 microM 5-HT. 3. In the presence of 1 microM ketanserin to suppress the contractile effect of 5-HT, 5-HT induced concentration-dependent relaxation of endothelium-intact strips precontracted by 10 microM prostaglandin F2 alpha (PGF2 alpha). These relaxations were suppressed by 1 microM NG-nitro-L-arginine, an inhibitor of nitric oxide synthesis, showing that they were produced predominantly by nitric oxide. 4. In the presence of 1 microM ketanserin, 1 microM 5-HT did not change the smooth muscle cell membrane potential of strips precontracted by either 10 microM PGF2 alpha or by 10 microM acetylcholine (ACh). In the same conditions, 1 microM 5-HT caused a weak 2.6 +/- 0.4 mV hyperpolarization, of the endothelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)     

Isolated lung strips of guinea pigs: responses to beta-adrenergic agonists and antagonists.

Isolated lung strips of guinea pigs were examined as an in vitro model for assessing the direct effect of beta-adrenergic drugs at the level of peripheral airways. Changes in intrinsic tone of thin strips of lung parenchyma were measured with an isometric force transducer. Isoproterenol, a nonselective beta-adrenergic agonist, and several beta-adrenergic agonists, soterenol, salbutamol, metaproterenol and ritodrine elicited a dose-related relaxation of lung strip. Responses to isoproterenol were antagonized by propranolol and the selective beta blocking agents butoxamine (beta2) and practolol (beta1). These results were compared to data obtained with the same compounds on isolated guinea pig atria. All agonists except ritodrine were full agonists in the lung strip whereas isoproterenol and metaproterenol were the only full agonists in the atrial preparation. In the atria, practolol was a more effective blocker of isoproterenol responses than butoxamine, and the reverse was true for the lung strip.     

A comparative study of beta-adrenoceptors in human and porcine lung parenchyma strip

1. Responses to (+/-)-isoprenaline (Iso), (-)-adrenaline (Adr) and (-)-noradrenaline (NA) were compared in isolated preparations of human and porcine lung parenchyma strip. 2. The order of relaxant potencies of these catecholamines in both human and porcine lung parenchyma was Iso greater than Adr greater than NA (1:0.24:0.01, human; 1:0.21:0.01.pig). These results suggest that beta 2-adrenoceptors predominate in both types of lung parenchyma strip. 3. pA2 values for the beta-adrenoceptor antagonist, propranolol (non-selective), with Iso as the agonist, in human and porcine lung strips were 7.84 and 7.83 respectively and for atenolol were 6.50 and 5.35 respectively. Taken as a whole results indicate the existence of an apparently homogeneous population of beta 2-adrenoceptors in porcine parenchyma strip, while both beta 1 and beta 2-adrenoceptors were revealed in human lung parenchyma.     

The inhibitory action of two thrombin inhibitors (TI-189 and TI-233) on the contractile responses to 5-hydroxytryptamine and prostaglandin endoperoxide analogue (U-44069) in isolated vascular strips.

1. Two arginine derivatives that were developed as thrombin inhibitors (TI-189 and TI-233) selectively inhibited the 5-hydroxytryptamine (5-HT)-induced contraction of rabbit aortic strips in a competitive manner. The PA2 values of TI-189 and TI-233 were 5.24 +/- 0.21 and 6.23 +/- 0.32 respectively. 2. Even at 10(-4) M they had no inhibitory effect on the contractile response to noradrenaline (NA), histamine, prostaglandin E2 (PGE2), PGF2 alpha, arachidonic acid or potassium in rabbit aortic strips. 3. In dog basilar and coronary arterial strips and also in rat fundus, both agents inhibited the 5-HT response in a non-competitive manner. 4. At 10(-5) M, TI-233 but not TI-189 antagonized effects of NA and KCl in the dog basilar and coronary arteries. 5. These arginine derivatives decreased the contractile responses induced by a prostaglandin endoperoxide analogue (U-44069) in rabbit aorta and in dog basilar and coronary arteries but there was no evidence for competitive antagonism. 6. These results indicate that the arginine derivatives are competitive antagonists selective for 5-HT receptors in rabbit aorta.     

The effect of catecholamines on the in vivo and in vitro responses of the cat lung during anaphylaxis.

1. Anaphylaxis in the lung of cats actively sensitized to Ascaris antigen has been investigated in vivo and in vitro. 2. In vivo there was a 100% increase in airways resistance and a 50% decrease in dynamic lung compliance following intravenous challenge with Ascaris antigen. Prostaglandin F2alpha induced similar changes but with histamine only dynamic lung compliance was affected. (-)-Isoprenaline prevented these prostaglandin F2alpha- and histamine-induced changes and caused a delay of about 2 min in the onset of the mechanical changes following anaphylactic challenge. 3. In vitro the isolated lung strip contracted within seconds of challenge whereas there was a delay of 2 to 3 min in the onset of the tracheal anaphylactic response. (-)-Isoprenaline, (-)-adrenaline and (+/-)-noradrenaline reduced the magnitude of anaphylactic contractions of the isolated trachea but did not significantly affect those of the isolated lung strip. This indicated lack of inhibition of mediator release from the lung parenchyma. 4. Histamine was released from sensitized lung fragments following challenge with the Ascaris extract. This release constituted 6.3% of the total tissue histamine and was not inhibited by (-)-isoprenaline (1 micrometer). 5. (-)-Isoprenaline abolished 5-hydroxytryptamine (5-HT)-induced contractions of the isolated trachea but not those elicited in response to acetylcholine. The isolated lung strip responses to histamine, prostaglandin F2alpha and 5-HT were highly resistant to inhibition by (-)-isoprenaline.     

INTERACTIONS BETWEEN 5-HYDROXYTRYPTAMINE, NORADRENALINE AND THE THROMBOXANE-A2 MIMETIC U44069 IN THE MARMOSET ISOLATED AORTA

1. The effects of 5-hydroxytryptamine (5-HT) in the absence and presence of noradrenaline (NA) or the thromboxane-A₂ mimetic, U44069, were investigated in ring preparations of marmoset aorta. 2. 5-HT (0.001-10 μmol/L) produced little or no contractile response in preparations at basal tone. When the tone was elevated to 50% of maximum with NA the predominant response to 5-HT was relaxation. The 5-HT₂ receptor antagonist LY53857 (0.1 μmol/L) unmasked a contractile response to low concentrations of 5-HT (0.01 - 1.0 μmol/L) and reduced relaxation to high concentrations of 5-HT (1.0-10 μmol/L) in vessels precontracted with NA. 3. In U44069-contracted vessels, 5-HT was contractile in the range 0.01-1 μmol/L and relaxant in concentrations of 6.0-10.0 μmol/L. Ketanserin (1.0 μmol/L) had no effect on the contraction or relaxation to 5-HT. 4. The relaxant response to 5-HT was not significantly diminished in endothelium-impaired arteries. 5. In conclusion, 5-HT exerts complex inhibitory and excitatory actions on the marmoset aorta. The inhibitory actions are not endothelium-dependent and the excitatory actions do not appear to involve the 5-HT₂ receptor.     

Mechanism of vanadate-induced contraction of airways smooth muscle of the guinea-pig.

The characteristics of vanadate-induced contraction of airways smooth muscle are described in isolated preparations of guinea-pig central and peripheral airways. Vanadate (1-1000 microM) induced sustained contractions of trachea and lung parenchymal strips within 1 min of challenge. It was more potent (P less than 0.001) on the lung strip (EC50 = 63 microM) than on the trachea (EC50 = 123 microM). The lung strip also developed greater maximum isometric tension (P less than 0.001) than the trachea. The efficacy on the lung strip was 2 and the trachea 0.6, relative to the response to acetylcholine (efficacy = 1). Vanadate-induced contractions of the trachea were not inhibited by atropine, mepyramine, phentolamine or indomethacin, nor after mast cell depletion by compound 48/80, showing that contractions were not mediated via specific receptors or by release of endogenous mediators of tone. Inorganic phosphate specifically inhibited vanadate responses in a dose-dependent and reversible manner, suggesting a common site of action. Contractions could be elicited in depolarized muscle and after treatment with ouabain plus propranolol, showing that membrane depolarization and inhibition of the Na, K-ATPase system were not involved in the contractile action of vanadate. Pretreatment of tracheal smooth muscle with verapamil had no influence on contractions elicited by vanadate. After removal of extracellular calcium, vanadate-induced contractions declined slowly with time, indicating that influx of extracellular calcium was not giving rise to contractions elicited by vanadate. Vanadate markedly increased the rate of calcium efflux from trachealis muscle loaded with 45Ca into both Ca2+-free and normal Krebs solutions; this is compatible with vanadate mobilizing an intracellular store of Ca2+. Such a store involving sites with Ca-ATPase activity would be consistent with the action of vanadate in isolated membrane preparations. Membrane-skinned tracheal fibres contracted by micromolar Ca2+ were relaxed by vanadate in a reversible dose-related manner, indicating that the contractile action of vanadate was not related to its interaction with proteins at the cross-bridge level.     

Receptor mechanisms for 5-hydroxytryptamine in rabbit arteries

1 Previous investigations into the vascular actions of biogenic amines implicated in migraine have shown that the contractile effects of both 5-hydroxytryptamine (5-HT) and noradrenaline (NA) in the rabbit ear artery are mediated by a direct sympathomimetic action at alpha-adrenoceptors, while in the rabbit aorta, 5-HT and NA act on pharmacologically distinct receptors. The purpose of the present investigation was to determine whether the absence of 5-HT receptors in rabbit ear arteries is characteristic of distributing arteries in general, or is confined to particular regional circulations.2 Agonist-antagonist interactions were studied in various rabbit vascular preparations (common carotid, external carotid and femoral arterial strips, and perfused ear arteries) by determining pA(2) values for pizotifen and phentolamine against 5-HT- and NA-induced contractile responses.3 In common carotid and femoral arteries, pizotifen was a potent competitive antagonist of 5-HT, but weak against NA. The converse applied to phentolamine. In external carotid and ear arteries, pizotifen was a weak competitive antagonist of both 5-HT and NA, whereas phentolamine was a potent competitive antagonist of both. Cocaine did not influence pA(2) values against NA.4 5-HT and NA were of similar potency in common carotid and femoral arteries, but 5-HT was much less potent than NA in external carotid and ear arteries.5 The results indicate that rabbit common carotid and femoral arteries contain both D-type 5-HT receptors and alpha-adrenoceptors, as does the aorta. However, external carotid arteries, like ear arteries, do not contain specific 5-HT receptors. The action of 5-HT in the external carotid artery is mediated by alpha-adrenoceptors; this is a direct sympathomimetic action since it was not inhibited by cocaine or reserpine-pretreatment.6 The absence of 5-HT receptors in the rabbit extracranial circulation may limit the usefulness of this species as a model for research relating to migraine.     

Diminution of contractile response of the aorta from endotoxin-injected rats

The contractility of a helical strip of the thoracic aorta was studied in rats injected intraperitoneally with endotoxin. The contractile response to any of the agonistic agents, KCl, norepinephrine or 5-hydroxytryptamine was time dependently diminished in the endotoxin-injected rats compared to the controls. This diminution preceded the depression of blood pressure. When the external calcium concentration was increased from 2.5 to 7.5 mM after the KCl (80 mM)-induced contractile response reached a plateau, the diminished contractile response was reversed in the endotoxin-injected group. The strips from the endotoxin-injected rats showed a higher 45CaCl2 uptake into the vascular tissue with the KCl-stimulated contraction. These findings suggest that the blood pressure depression during endotoxic shock may be attributed partially to the diminished contractility of the blood vessels and that this diminution is induced by a disorder of calcium utilization within vascular smooth muscle during vascular contraction.     

Comparative studies with 5-hydroxytryptamine and its derivatives in isolated, blood-perfused small intestine and ileum strip of the rat

The mode of actions of 5-hydroxytryptamine (5-HT) and its derivatives, tryptophan (TP), 5-hydroxytryptophan (5-HTP) and 5-hydroxyindole acetic acid (5-HIAA) was studied on the isolated, blood-perfused small intestine and isolated ileum strip of rats. In the isolated, blood-perfused intestinal preparations, 5-HT and 5-HTP injected into the superior mesenteric artery caused a monophasic fast contraction, while TP and 5-HIAA had no effects on the intestine. The contractile responses to 5-HT and 5-HTP were abolished by tetrodotoxin (TTX), hexamethonium (C6) and morphine, but were resistant to blockade of either atropine, methysergide or phentolamine. On the other hand, in the ileum strip preparations, 5-HT contracted the ileum, but its derivatives had no effects on the ileum. TTX, C6, morphine and atropine failed to prevent the contractile response to 5-HT, whereas methysergide effectively antagonized the response. The present results indicate that 5-HT acts by exciting intramural neuronal elements or by directly contracting the smooth muscle of the intestine. 5-HTP seems to act in the same manner as 5-HT.     

Correlation between blood eosinophilia and airways hyper-responsiveness in rats

The injection of Sephadex particles intravenously into rats produced a specific blood eosinophilia and an hyper-responsiveness of the airways to 5-hydroxytryptamine (5-HT). The rats given Sephadex had an hyper-sensitivity to the respiratory effects of 5-HT in vivo with a shift to the left of the intravenous dose response curve. In vitro lung strips from rats given Sephadex were hyper-reactive to 5-HT in that the strips from these rats and control rats responded over the same dose range of 5-HT but the slope of the dose response curve and the maximum response were greater in the strips from the Sephadex treated rats. The levels of hyper-sensitivity in vivo and of hyper-reactivity in vitro both correlated with the numbers of blood eosinophils.     

5-Hydroxytryptamine is a possible neurotransmitter of the non-cholinergic excitatory nerves in the longitudinal muscle of rainbow trout stomach (Salmo gairdneri).

1. The neurotransmitter of the non-cholinergic excitatory nerves in the rainbow trout stomach was identified on the basis of the pharmacological properties of the contractile responses to transmural stimulation (TMS) and nicotine. 2. TMS caused tetrodotoxin-sensitive contractions of rainbow trout stomach strips in a frequency-dependent manner (0.5-50 Hz). Atropine (1 microM) significantly decreased the contractile response to low-frequency stimulation (0.5-2 Hz), but did not affect that to high-frequency stimulation (3-20 Hz). 3. The atropine-resistant contractile response to TMS (20 Hz) was unaffected by hexamethonium (100 microM), phentolamine (5.4 microM), pyrilamine (1 microM), naloxone (1 microM) or substance P-induced desensitization. 4. 5-Hydroxytryptamine (5-HT, 3 nM-3 microM) caused atropine-resistant contractions in a concentration-dependent manner. In the presence of atropine, methysergide (1 microM) decreased the contractile responses to TMS and 5-HT. 5. Nicotine (3 microM-500 microM) induced atropine-resistant contractions that were completely abolished by tetrodotoxin or hexamethonium. Also methysergide inhibited the contractile responses to nicotine. 6. An acid extract of rainbow trout stomach exhibited atropine-resistant contractions that were decreased by methysergide, in both rainbow trout stomach and guinea-pig ileum longitudinal smooth muscle preparations. 7. The present results indicate that, in longitudinal muscle strips of the rainbow trout stomach, 5-HT is one of the mediators (neurotransmitters) of the non-cholinergic excitatory contractions induced by TMS and nicotine.