Different Effects of the K+ Channel Blockers 4-Aminopyridine and Charybdotoxin on Sensory Nerves in Guinea-pig Lung

Abstract: In the isolated guinea-pig bronchus, the potassium channel blocking agent 4-aminopyridine (10^-4 M) caused a contraction which was abolished by capsaicin tachyphylaxis, suggesting involvement of sensory neuropeptides. Charybdotoxin (10^-8, 5 × 10^-8 M), which is a potent blocker of the high-conductance Ca²⁺-activated K⁺ channel in smooth muscle, caused slowly developing and long lasting bronchoconstriction, which was resistant to capsaicin tachyphylaxis. Neither 4-aminopyridine (10^-3, 10^-4 M) nor charybdotoxin (10^-8, 5 × 10^-8 M) had any significant effect on the bronchoconstriction induced by electrical field stimulation. Furthermore, charybdotoxin had no significant influence on the inhibitory effect of the α₂-adrenoceptor agonist SKF 35886 (5 × 10^-7 M) on the bronchoconstriction induced by electrical field stimulation. In the isolated perfused guinea-pig lung, 4-aminopyridine (3 × 10^-5- 10^-3 M) caused bronchoconstriction and enhanced both basal and (at 3 × 10^-5 M) vagal nerve stimulation-evoked calcitonin gene-related peptide outflow from pulmonary sensory nerves. In conclusion, 4-aminopyridine stimulated capsaicin-sensitive sensory neurons and enhanced the sensory activation induced by vagal nerve stimulation in guinea-pig lung. Charybdotoxin, on the other hand, caused bronchial contraction independently of capsaicin-sensitive nerves.     

The effects of PGE1 on responses to cardiac vagus nerve stimulation and acetylcholine release

PGE₁, 2.5 × 10^?9 to 5 × 10^?9 g/ml, reduced the negative chronotropic responses to vagal stimulation and to acetylcholine in isolated guinea-pig atria. Neither ganglionic transmission nor axonal impulse conduction were depressed by the compound in anaesthetized cats. PGE₁ did not affect acetylcholine release from the parasympathetic nerve terminals of the guinea-pig ileum. These findings are in disagreement with the view that PGE₁ modulates parasympathetic transmission by reducing the release of the cholinergic transmitter. It reduces vagal bradycardia by antagonizing the effect of acetylcholine on the atrial cells. This ‘anticholinergic’ action may be related to the cyclic AMP system.     

Indole Alkaloids from Sickingia williamsii Reduce the In-vitro Effects of Morphine Withdrawal in the Guinea-pig

The effect of indole alkaloids from Sickingia williamsii Standi. (Rubiaceae) on the effects of morphine withdrawal have been examined in-vitro. All the indole alkaloids isolated from S. williamsii (10^?4, 5 ×10^?5 and 10^?5 m ) significantly and in a concentration-dependent manner reduced the effects of morphine withdrawal on the guinea-pig ileum. The results suggest that these alkaloids might be potential anti-addictive agents.     

Pharmacology of B-HT 920 in some Isolated Smooth Muscles of the Guinea-pig

Abstract: The effects of B-HT 920 were investigated on four isolated preparations from the guinea-pig, namely the aorta, trachea, ileum and vas deferens. The latter three preparations were studied during electrical field stimulation, which induced contractions by activating cholinergic neurones (trachea and ileum) or adrenergic neurones (vas deferens), respectively. Comparative studies were also made with clonidine and noradrenaline. In ileum and trachea B-HT 920 was almost equipotent with noradrenaline to inhibit the electrically induced contractions. In these tissues, B-HT 920 also displayed almost the same maximal effect as noradrenaline. Clonidine also inhibited the contractions in ileum and trachea; the drug was slightly more potent than noradrenaline. However, in contrast to the intrinsic activity of B-HT 920 that of clonidine was only submaximal. In vas deferens both B-HT 920 and clonidine induced inhibition of contractions on electrical field stimulation at low concentrations. In this organ, both drugs were capable of inducing complete inhibition of the contractile response. In aorta B-HT 920 as well as clonidine were only weak agonists in comparison to noradrenaline. The α₂-blocker, yohimbine, completely blocked the effect of B-HT 920 in ileum at low concentrations (1 × 10^?7 M). Remarkably, however, the inhibitory action of B-HT 920 in trachea was only marginally affected even by high concentrations of yohimbine (1 × 10^?6 M). It is suggested from the present results that B-HT 920 can induce inhibition of both cholinergic and adrenergic neurotransmission presumably by inducing selective stimulation of prejunctional α₂-receptors. In fact, the selectivity of B-HT 920 seems to be comparable to that of clonidine for the α₂-receptor. However, the mode of action of B-HT 920 in trachea may be somewhat uncertain since its effect was not inhibited by yohimbine.     

Interaction between clonidine and histamine on the guinea-pig isolated trachea

In experiments on guinea-pig isolated tracheal spirals, clonidine, in concentrations of 10^?6 to 3 times 10^?4 M. had a contracting effect which was strongly inhibited by prazosin but not significantly modified by yohimbine. Moreover, clonidine (3 times 10^?5 to 3 times 10^?4 M) potentiated histamine-induced contractions; this latter effect was inhibited specifically by α₁-adrenoceptor antagonists (e.g. prazosin, AR-C 239) but unmodified by yohimbine, nicardipine or agents acting on the arachidonic acid cascade. It would therefore appear that clonidine in high concentrations contracts the guinea-pig trachea by stimulating α₁-adrenoceptors and that, contrary to what has been reported with other animal species, notably the dog, the guinea-pig trachea is devoid of α₂-adrenoceptors that mediate contractions.     

Centrally acting drugs alter in vitro β-endorphin processing in the rat

Strychnine (10^?5-3×10^?4M) increased the amplitude and duration of the spontaneous electrical and mechanical activity of the rat isolated portal vein. Similar effects were seen with tetraethylammonium and 4-aminopyridine. This stimulant action of strychnine was unaffected by tetrodotoxin (3×10^?7M) or prazosin (5×10^?8M) but was significantly reduced by verapamil (3×10^?8M). On the isolated aorta, only inhibitory actions of strychnine were observed, yet tetraethylammonium and 4-aminopyridine had excitatory actions. It is suggested that the stimulant actions of strychnine on the portal vein are likely to be due to a reduction in potassium conductance and/or an increase in calcium conductance of the smooth muscle cell membrane.     

GABA-RELATED ACTIVITIES OF AMINO PHOSPHONIC ACIDS ON GUINEA-PIG ILEUM LONGITUDINAL MUSCLE

• 1 The effects of phosphonic analogues of GABA, β-alanine and glycine on guinea-pig ileum longitudinal muscle were measured.
• 2 Aminomethylphosphonic acid (AMPh) and 2-aminoethylphosphonic acid (2-AEPh) were devoid of any effect both in non-stimulated preparations and in electrically-stimulated preparations.
• 3 The phosphonic analogue of GABA, 3-aminopropylphosphonic acid (3-APPh) possessed a GABA_B agonistic effect (relaxation and inhibition of twitch response) at doses of 10^?3 M. No agonistic effect on GABA_a receptors was observed.
• 4 3-APPh at doses tested (2 × 10^?4 M and 10^?3 M) also displayed antagonistic action on the effects of GABA_B agonists producing a parallel shift of the log dose-effect curves of GABA- and (-)-baclofeninhibition of twitch responses. In contrast 3-APPh did not antagonize the inhibitory effect of morphine and noradrenaline.
• 5 The contractile effect of GABA, mediated via GABA_A receptors, was unaffected by 3-APPh (10^?3 M).
• 6 It is concluded that 3-APPh is a partial agonist at the GABA_B site in guinea-pig ileum.

     

Effects of new 4-aminopyridine derivatives on neuromuscular transmission and on smooth muscle contractility

The effects of new 4-aminopyridine (4-AP) derivatives were investigated in the isolated mouse phrenic nerve-hemidiaphragm preparation under single impulse stimulation and tetanic conditions. The basic 4-AP structure was modified in position 3 on the pyridine nucleus by introducing different substituents. Results were compared to those obtained with 4-AP and 3,4-diaminopyridine. The compounds were tested for their antagonistic effect against calcium antagonists and botulinum toxin A. The effect on smooth muscle was investigated on the isolated guinea-pig ileum. Physico-chemical parameters of the test compounds were determined by the partition coefficient and ionization constant. Finally structure-activity relationship analysis revealed that the activity was highly related to lipophilicity and the steric volume. So far 4-AP itself provided the most advantageous molecular structure.     

A comparison of the binding constant (Kd) of 125I-labelled 3-(4-iodophenoxy)-1-isopropylamino-propan-2-ol obtained on β-adrenoceptors in guinea-pig myocardial membranes,with its dissociation constants (Kb) obtained on guinea-pig isolated atria and trachea

The dissociation constant of binding (K_D) of ¹²⁵I-labelled 3-(4-iodophenoxy)-1-isopropyl-aminopropan-2-ol (IIP) to guinea-pig myocardial membrane preparations was 2·2 × 10^?8m. In pharmacological experiments with the non-labelled material and 60 min contact time, IIP produced a parallel shift in the orciprenaline concentration-response line on guinea-pig isolated tracheal and atrial preparations. The dissociation constant (Kb ) of IIP was 2·9 × 10^?8m on atria (pA₂ 7·54) and 3·3 × 10^?8m on trachea (pA₂ 7·48). These values indicate that IIP is not a selective β-adrenoceptor blocking drug. In addition, agreement was found between the affinity constant of this antagonist for β-adrenoceptors as determined by a direct binding study and an indirect pharmacological study.     

Studies on the action and mechanism of action of oxyfedrine on isolated tracheal chains

Oxyfedrine, a β-sympathomimetic drug, did not affect isolated rat and rabbit trachea in concentration from 2.86 × 10^?8 to 2.86 × 10^?4 M, but on the guinea-pig trachea, it caused a dose dependent relaxation of natural tone in lower concentrations (1.79 × 10^?7 to 2.86 × 10^?6 M. In higher concentrations (1.14 × 10^?5 to 2.86 × 10^?4 M), however, a contraction was observed, which was also dose dependent. This contraction was not affected by atropine, lysergic acid diethylamide or by pretreatment with reserpine but was blocked by antihistaminics (isothipendyl and clemastine). Adrenaline, noradrenaline, phenylephrine and isoprenaline did not contract the guinea-pig trachea, whereas contractions were observed after high concentrations of norephedrine, amphetamine, ephedrine and tyramine. These contractions were also unaffected by reserpine pretreatment.It is concluded that the contraction of the guinea-pig trachea by oxyfedrine is related to its structural relationship to the phenylethylamines and might be due to histamine release, an action on histamine receptors or a histamine-like action.     

Inotropic and Chronotropic Effects of 4-(4′-n-Butylaniline)-7,8-dimethoxy-5H-pyrimido[5,4–b]indole in Guinea-pig Atria

Cardiotonic effect of 4-(4′-n-butylaniline)-7,8-dimethoxy-5H-pyrimido[5,4-b)]indole (B₁₁) was investigated in isolated cardiac tissue preparations. The action of this agent on force of contraction, beating frequency and cyclic nucleotide phosphodiesterase (PDE) activity was studied. Amrinone was used for comparison. B₁₁ produced concentration-dependent (5 × 10^?6-1 × 10^?4m) positive inotropic and positive chronotropic responses in guinea-pig atrial tissues. The potency of B₁₁ was greater than that of amrinone. The cardiotonic effects of B₁₁ were not modified by β-adrenoceptor blockade. Carbachol inhibited the positive inotropic effect of B₁₁. The activity of B₁₁ was increased in desensitized left atrial tissues. B₁₁ inhibited the activities of PDE isoenzymes (type I, II, IV and V) from dog heart ventricle and PDE type IV from guinea-pig heart ventricle nonselectively. It is concluded that B₁₁ possesses potent positive inotropic activity in guinea-pig atria, and the effect is probably mediated by a non-selective inhibition of PDE activity.     

Effect of venoms from Conidae on skeletal,cardiac and smooth muscles

J. Kobayashi, H. Nakamura, Y. Hirata and Y. Ohizumi. Effect of venoms from Conidae on skeletal, cardiac and smooth muscles. Toxicon20, 823–830, 1982.—The effects of the venoms of 29 species of Conidae were studied on the mouse isolated diaphragm, the guinea-pig isolated left atria and ileum, and the rabbit isolated aorta. When the directly stimulated mouse diaphragm was exposed to the venom (10^?4 g/ml) of C. geographus, there occurred a marked decline in twitch tension. The venoms of C. magus (3 × 10^?6 g/ml) and C. striatus (10^?3 g/ml) also caused complete loss of contractile response to electrical stimulation. This was followed by a gradual rise in the baseline.The venoms (10^?6?3 × 10^?5 g/ml) of C. magus and C. striatus caused dose-dependent increases in the contractile force of the electrically driven guinea-pig left atria. The venoms (10^?5?10^?4 g/ml) of C. eburneus and C. tessulatus also elicited long-lasting positive inotropic actions on the atria. The inotropic actions induced by the venoms of C. magus and C. striatus were abolished by tetrodotoxin (TTX, 10^?6 M), but were not affected by verapamil (3 × 10^?7 M), whereas those induced by the venoms of C. eburneus and C. tessulatus were completely inhibited by verapamil (3 × 10^?7 M), but were not modified by TTX (10^?6 M). These results suggest that the inotropic actions of the venoms of C. magus and C. striatus may be due to an increase in Na⁺ permeability of the cardiac cell membrane, while those of venoms of C. eburneus and C. tessulatus may be due to an increase in Ca²⁺ permeability.The venoms (10^?6 g/ml) of C. magus and C. striatus elicited rhythmic, transient contractions of the guinea-pig ileum followed by relaxations, which were blocked by TTX (10^?6 M). This suggests that these biphasic responses were caused by increasing Na⁺ permeability of the nerve cell membrane. On the other hand, the venoms (10^?4 g/ml) of C. eburneus and C. tessulatus caused transient contractions of the ileum followed by relaxations.The venoms (10^?4 g/ml) of C. tessulatus and C. eburneus caused marked, long-lasting contractions of the rabbit aorta which were abolished by verapamil (10^?6 M), but were not affected by TTX (5 × 10^?7 M) or phentolamine (10^?6 M). It is suggested that these venoms increase the verapamil-sensitive Ca²⁺ influx across the smooth muscle membrane of the aorta, resulting in contractions.The active principles in the venoms of C. geographus, C. textile and C. imperialis were stable at 100°C for 15 min and passed through PM 10 filters, suggesting molecular weights lower than 10,000. On the other hand, the active principles in the venoms of C. magus, C. striatus, C. tessulatus and C. eburneus were partially destroyed with heating and were kept in the retentate of the PM 10 filters.     

Comparison of the pharmacological actions of some new 4-aminopyridine derivatives

The pharmacological actions of 2,4-diaminopyridine (2,4-DAP) and 3-[(dimethylamino)-carbonyl] amino 4-aminopyridine (LF-14) were examined and compared with those of 4-aminopyridine (4-AP) in anaesthetized rats and on isolated rat and guinea-pig tissues. Both compounds were more potent than 4-AP in reversing the neuromuscular block caused by pancuronium bromide. The ED₅₀s of LF-14, 2,4-DAP and 4-AP were 100 μg/kg, 140 μg/kg and 450 μg/kg, respectively. LF-14 and 2,4-DAP were also more potent in their in vitro actions on the neuroeffector junctions in the ileum and the isolated heart. 2,4-DAP and LF-14 either did not facilitate or only slightly facilitated the recovery time from xylazine/ketamine anaesthesia which was used as a test for their central action; 4-AP significantly reduced the recovery time. We therefore conclude that both 2,4-DAP and LF-14 are stronger peripherally acting compounds with less central action, and that they may be possible replacements for 4-AP as antagonists of non-depolarizing muscle relaxants.     

Possible differences in α-adrenoceptors in rabbit ileum and spleen

In isolated tissues from reserpinized rabbits (5 mg kg^?1, i.m. 20 h before experiment) and in the presence of cocaine (3 × 10^?5 m ), corticosterone (2·8 × 10^?5 m ), tropolone (3 × 10^?5m ), propranolol (4 × 10^?6m ) and disodium EDTA (3 × 10^?5m ), the potency ratios (relative to (—)-noradrenaline) of (—)adrenaline, (—)-phenylephrine and (±)-methoxamine were (m ± s.e.) 203 ±0·13, 0·045 ± 0·003 and 0·0062 ± 0·0018 respectively in splenic strips and 1·77 ± 0·41, 0·093 ± 0·018 and 0·029 ± 0·004 respectively in isolated ileum. Although the pA₂ values for phentolamine and thymoxamine against (—)-noradrenaline in the two tissues were very similar there was a statistically significant difference when using yohimbine as the α-adrenoceptor blocking agent (pA₂ = 6·80 ± 0·30 in spleen; 5·60 ± 0·12 in ileum). These differences suggest that the α-adrenoceptor in the two tissues is not identical. The pA₂ value of phentolamine in rabbit ileum was not significantly different whether (—)-noradrenaline or (±)-methoxamine was used as agonist (7·91 ± 0·07 and 7·97 ± 0·06 respectively) while that of yohimbine was 5·56 ± 0·10 using (—)-noradrenaline and 6·19 ± 0·12 using (±)-methoxamine. In the light of this latter result and, considering the scatter of the experimentally determined values, there may be two α-adrenoceptors in rabbit ileum and either or both may not be identical in all respects to the α-adrenoceptor found in rabbit spleen.     

Effects of vanadate on mechanical responses and Na-K pump in vascular smooth muscle

The effects of vanadate on tension and on the Na-K pump in isolated guinea-pig aorta were investigated. Vanadates (NH₄VO₃ or Na₃VO₄ · nH₂O) (10^?3 M) produced a sustained contraction (about 0.5 g) which was not influenced by phentolamine (10^?6 M). In the absence of external Ca, vanadate and norepinephrine (2 × 10^?6 M) induced a small contraction, although high K (45.4 mM) did not. In a Ca-depleted, high K (142.2 mM) solution, vanadate and norepinephrine still caused muscle contraction. D600 (10^?6 M) slightly inhibited the contractions induced by vanadate and norepinephrine, while this agent completely inhibited the contraction induced by high K. Sodium nitroprusside (10^?5 M) strongly inhibited the contractions induced by vanadate and norepinephrine but not the contraction induced by high K. Vanadate produced a contraction in K-free solution with ouabain (10^?4 M). The tissue K content did not change during a 2 h treatment of the muscle with vanadate. Reaccumulation of K following a 3 h treatment of the muscle with K-free solution was inhibited by ouabain but not by vanadate. These results indicate a similarity between the contractions induced by vanadate and by norepinephrine and suggest that the vanadate-induced contraction is not due to an inhibition of the Na-K pump.     

Fourth international symposium on quantitative mass spectrometry in life sciences

The compound 4(5)-[2-(4-azido-2-nitroanilino)ethyl]imidazole (AAH), a photoaffinity label analog of histamine, has been observed previously to produce a photolysis-dependent, specific and irreversible antagonism of histamine-induced contractile responses of the guinea-pig vas deferens. The pharmacological effects of AAH in isolated guinea-pig aorta (GPA) and dog trachealis (DT) were evaluated in the present study. Photolysis of 3 × 10^?5 M AAH for 5 min with visible light in organ baths containing the GPA resulted, after washout of AAH, in a nonequilibrium competitive antagonism of contractile responses to histamine; responses to norepinephrine and KCl were not affected. In contrast, photolyzed AAH (3 × 10^?5 M, one or two photoalysis treatments; 10^?4 M AAH, two treatments) did not antagonize contractile responses of the DT to histamine, nor were responses to acetylcholine or KCl affected. To test the possibility that AAH lacks affinity for histamine receptors in the DT, molar K_B values were obtained for nonphotolyzed AAH used as a conventional equilibrium competitive antagonist; K_B values for GPA and DT were not different (?log K_B were 5.48±0.18 and 5.04±0.23 for GPA and DT, respectively; P>0.05). pA₂ values for diphenhydramine, an H₁-histamine receptor antagonist, indicated a moderately greater potency in GPA compared to DT (pA₂ were 7.58±0.10 and 6.89±0.13 for GPA and DT, respectively; P<0.05); however the diphenhydramine: AAH potency ratio did not explain the resistance of the DT to photolyzed AAH. Cimetidine (10^?6?10^?4 M), an H₂-receptor antagonist, potentiated contractile responses of the GPA to histamine but was without an effect in the DT. No evidence for relaxation by histamine in preparations with induced tone was obtained; the resistance of the DT to photolyzed AAH therefore does not involve an inhibition of H₂-inhibitory receptors. Photolyzed AAH thus demonstrates tissue-selective antihistamine activity, perhaps as a result of differences in the characteristics of H₁-receptors in the GPA and DT.     

Mechanism of action of relaxant effect of Agastache mexicana ssp.mexicana essential oil in guinea-pig trachea smooth muscle

Context: Agastache mexicana ssp. mexicana (Kunth) Lint &; Epling (Lamiaceae), popularly known as ‘toronjil morado’, is used in Mexican traditional medicine for the treatment of several diseases such as hypertension, anxiety and respiratory disorders.

Objective: This study investigates the relaxant action mechanism of A. mexicana ssp. mexicana essential oil (AMEO) in guinea-pig isolated trachea model.

Materials and method: AMEO was analyzed by GC/MS. The relaxant effect of AMEO (5–50?μg/mL) was tested in guinea-pig trachea pre-contracted with carbachol (3?×?10?^??⁶?M) or histamine (3?×?10?^??⁵?M) in the presence or absence of glibenclamide (10?^??⁵?M), propranolol (3?×?10?^??⁶?M) or 2′,5′-dideoxyadenosine (10?^??⁵?M). The antagonist effect of AMEO (10–300?μg/mL) against contractions elicited by carbachol (10?^??¹⁵–10?^??³?M), histamine (10?^??¹⁵–10?^??³?M) or calcium (10–300?μg/mL) was evaluated.

Results: Essential oil composition was estragole, d-limonene and linalyl anthranilate. AMEO relaxed the carbachol (EC_50?=_?18.25?±?1.03?μg/mL) and histamine (EC_50?=_?13.3?±?1.02?μg/mL)-induced contractions. The relaxant effect of AMEO was not modified by the presence of propranolol, glibenclamide or 2′,5′-dideoxyadenosine, suggesting that effect of AMEO is not related to β₂-adrenergic receptors, ATP-sensitive potassium channels or adenylate cyclase activation. AMEO was more potent to antagonize histamine (pA₂′?=??1.507?±?0.122) than carbachol (pA₂′?=??2.180?±?0.357). Also, AMEO antagonized the calcium chloride-induced contractions.

Conclusion: The results suggest that relaxant effect of AMEO might be due to blockade of calcium influx in guinea-pig trachea smooth muscle. It is possible that estragole and d-limonene could contribute majority in the relaxant effect of AMEO.     

Effect of the Hydroalcoholic Extract of Rauwolfia ligustrina on Smooth and Cardiac Muscles In-vitro

The actions of the hydroalcoholic extract (HE) of Rauwolfia ligustrina (the whole plant) on agonist-induced contractions were analysed in the rat uterus and guinea-pig ileum and trachea, and also in rat atrium contracting spontaneously in-vitro. The HE (100–400 μg mL^?1) caused concentration-dependent rightward shifts of the concentration-response curves and reduced the maximal contraction induced by oxytocin, bradykinin, angiotensin II, prostaglandin F_2α and acetylcholine in the rat uterus. The calculated mean IC50 values were: 300, 147, 158, 197 and 105 μg mL^?1, respectively. In the guinea-pig ileum the HE also caused graded displacement to the right of the concentration—response curves for bradykinin, histamine and carbachol, associated with pronounced inhibition of the agonist-induced maximal contractions. The calculated mean IC50 values were 165, 134 and 241 μg mL^?1, respectively. The HE (100–3000 μg mL^?1) caused graded relaxation (IC50 of 271 μg mL^?1) of strips of guinea-pig trachea precontracted with carbachol (0.2 μM). This effect was not infuenced by propranolol (1 μM), 3-isobutyl-1-methylxanthine (1 μM) or methylene blue (10 μM), but was significantly potentiated (1.5-to 3-fold) by indomethacin (3 μM) and forskolin (1 nM). In addition, N^G-monomethyl-L-arginine (L-NMMA, 100 nM) significantly reduced the HE-induced maximal relaxation, while indomethacin (3 μM) potentiated the HE response. Finally, the HE caused a concentration-dependent and long-lasting inotropic effect in the rat right atrium, contracting spontaneously with a mean EC50 value of 409 μg mL^?1. It is suggested that the effects of the HE of R. ligustrina on smooth and cardiac muscles ‘in-vitro’ may result from its ability to interact, at least partially, with the cAMP pathway.     

Dual Effect of the Muscarinic Agonist McN-A-343 on Vascular Neuroeffector Transmission

Abstract: The site and mechanism of action of McN-A-343 (4-m-chlorophenylcarbamoyloxy)-2-butynyltrime-thylammonium chloride) on sympathetic neuroeffector transmission in the rabbit isolated pulmonary artery was studied. Low concentrations (10^?6 — 3 × 10^?5 M) of McN-A-343 and cocaine enhanced (up to 210 and 236%, respectively) the contractions evoked by electrical-field stimulation, while higher concentrations (10^?4 — 3 × 10^?4 M) inhibited them. McN-A-343 (10^?4 M) caused an initial transitory potentiation (222% of control) of the stimulation-evoked contractions followed by an inhibition. In the presence of cocaine (3 × 10^?5 M), the potentiation caused by McN-A-343 was prolonged and the secondary inhibitory phase was thus abolished. Physostigmine (10^?5 — 10^?4 M), hexamethonium (10^?5 M), atropine (3 × 10^?7 M), suprofen (10^?5 M), and 4-aminopyridine did not alter the effect of McN-A-343 (10^?4 M). Cocaine (3 × 10^?5 M)and(+)-amphetamine (10^?5 M) reversed the McN-A-343-evoked block, while they did not alter the inhibition caused by tetracaine (3.2 × 10^?5 M). Atropine (3 × 10^?7 M) had no effect on the McN-A-343-induced block, while 4-aminopyridine (10^?4 M) caused a partial and transitory reversal. On the aorta McN-A-343 (10^?4 M) did not alter the contractile concentration-response curve of (—)-noradrenaline (10^?9 — 3 × 10^?4 M), while that of serotonin (10^?8 — 3 × 10^?5 M) was moved to the right in a competitive manner. McN-A-343 (10^?4 M) did not alter the contractions evoked by noradrenaline (10^?7 M) during the period corresponding to the stimulation-evoked enhancement and subsequent inhibition. McN-A-343 (10^?4 M) slightly antagonized the contractions caused by tyramine (10^?6 — 10^?3 M) and carbachol (10^?6 — 10^?3 M). It is concluded that McN-A-343 enhances stimulation-evoked transmitter release by a presynaptic facilitatory action mediated via receptors localized on the outer surface of adrenergic neurones and to a lesser extent by inhibition of noradrenaline re-uptake. The enhancement does not involve presynaptic nicotine or muscarine receptors. Furthermore, McN-A-343 inhibits transmitter release by acting as an adrenergic neurone blocking agent at an intraneuronal site. The inhibition does not involve presynaptic muscarine inhibitory receptors and is prostaglandin-independent.     

Inhibition by (−)-Deprenyl of Agonist-Evoked Contractions in Rabbit Aorta

Abstract: The effect of (?)-deprenyl, a relatively selective MAO-B inhibitor, was examined for its ability to inhibit the contractions of rabbit isolated aorta evoked by various agonists and potassium. (?)-Deprenyl (10^?5?3 × 10^?4 M) antagonized the contractions evoked by noradrenaline (10^?8?3 × 10^?4 M); pA₂: 5.10. The antagonism was reversible. It was attenuated by cocaine (3x M); pA₂: 4.38, unchanged by corticosterone (4 × 10^?5 M); pA₂ 4.79 and enhanced by cocaine (3 × 10^?5 M) plus corticosterone (4 × 10^?5 M); pA₂: 5.48. (+)-Deprenyl (10^?6?10^?4 M) did not alter the contractions evoked by noradrenaline (3 × 10^?9?10^?4 M). Clorgyline (10^?5 and 10^?4 M) antagonized the noradrenaline-evoked contractions. Pargyline (10^?4 and 3 × 10^?4 M) had no effect. (?)-Deprenyl (10^?5?3 × 10^?4 M) antagonized the contractions evoked by phenylephrine (10^?8?10^?4 M); pA₂: 5.10. Removal of the endothelium did not alter the antagonism; pA₂: 5.35. (?)-Deprenyl (10^?5?3 × 10^?4 M) antagonized the contractions evoked by either 5-hydroxytryptamine (3 × 10^?8?3 × 10^?4 M); pA₂: 4.61 or by histamine (10^?6?3 × 10^?2 M); pA₂: 4.84. (?)-Deprenyl (3 × 10^?4 M) caused a non-competitive antagonism of the contractions evoked by potassium (1.5-5.5 × 10^?2 M). It is concluded that (?)-deprenyl is a weak inhibitor of postjunctional α-adrenoceptors, 5-hydroxytryptamine (5-HT₂) receptors, and histamine (H₁) receptors.