Mediation by 5-HT2 Receptors of 5-Hydroxytryptamine-Induced Contractions of Human Placental Vein

• 1.In isolated human placental chorionic vein segments, 5-hydroxytryptamine (5-HT; 10⁻⁸ to 5×10⁻⁵ M) elicited concentration-dependent contractions with EC₅₀=5.5 (5.2–5.7)×10⁻⁸ M) and E_max=93.1±7.3% of 75 mM KCl-induced contraction.
• 2.The agonist of 5-HT₂ receptors, α-methyl-5-hydroxytryptamine, and the selective agonist of 5-HT₁ receptors, N,N-dipropyl-5-carboxamidotryptamine and 5-carboxamidotryptamine, induced pronounced concentration-related contractions, which reached 71.1±6.0%, 53.0±5.0% and 75.0±7.8% at the highest dose tested, respectively. The agonist of 5-HT₃ receptor, 2-methyl-5-hydroxytryptamine, reached a maximum averaging 36.7±5.1% of the maximal response to KCl.
• 3.The 5-HT₁ and 5-HT₃ receptor antagonists, methiothepin and metoclopramide (10⁻⁷ to 10⁻⁶ M) did not alter the response to 5-HT. However, ketanserin (10⁻⁷ to 10⁻⁶ M), a 5-HT₂ receptor antagonist, induced significant inhibition of the concentration–response curve to 5-HT.
• 4.Contractile responses to 5-carboxamidotryptamine and 2-methyl-5-hydroxytryptamine were not affected by methiothepin and metoclopramide, respectively, whereas ketanserin significantly attenuated the contractile response to these agonists.
• 5.In conclusion, our study shows that 5-HT₂ receptors mediate contraction of the human placental vein with no obvious role for 5-HT₁-like, or 5-HT₃ receptors.

     

Characterization of 5-HT Receptors in Rat Proximal Colon

• 1.In view of its multiple sites of action, we investigated the activity of 5-hydroxytryptamine (5-HT, serotonin) on various potential receptors in the isolated proximal colon of rats.
• 2.5-HT induced concentration-dependent contractions of colonic strips (pEC₅₀=7.54±0.12).
• 3.The 5-HT₁ receptor agonist, 5-carboxamidotryptamine, induced concentration-dependent contractions (pEC₅₀=5.93±0.27); however, neither the 5-HT₃ receptor-agonist, phenylbiguanide, nor the 5-HT₄ receptor-agonist, renzapride, caused contractions at concentrations as high as 10⁻⁴ M.
• 4.The 5-HT_1/2 receptor antagonist, methiothepin, caused concentraction-dependent nonsurmountable antagonism. The 5-HT₃ receptor antagonist, tropisetron, inhibited the contractions to a concentration of 5-HT⩾10⁻⁶ M. Ketanserin had no effect on responses to 5-HT.
• 5.Tetrodotoxin and atropine had no effect on responses to 5-HT.
• 6.We conclude that contractions to 5-HT are mediated by 5-HT_1-like and probably 5-HT₃ receptors that activate tetrodotoxin insensitive mechanisms.

     

5-HT receptors on identified Lymnaea neurones in culture: Pharmacological characterization of 5-HT3 receptors

• 1.1. The selective agonist, 1-(m-chlorophenyl)-biguanide (m-CPBG) and antagonist, 3-tropanyl-3,5-dichlorobenzoate (MDL 72222) were used to characterize the 5-HT₃ receptors in cultured identified neurones; the serotonin-containing cerebral giant cells (CGCs) and some follower neurones in the buccal ganglia of Lymnaea stagnalis.
• 2.2. 5-HT and its agonists were pressure ejected, while the 5-HT antagonists were bath applied.
• 3.3. Although m-CPBG evoked mostly depolarizing responses, hyperpolarizing responses were sometimes evoked.
• 4.4. At 10⁻⁴ M, m-CPBG failed to mimic the responses of 5-HT, but at a concentration higher. 10⁻³ M, pressure-ejected m-CPBG mimicked most 5-HT responses.
• 5.5. The 5-HT₂ antagonist ketanserin failed to block the m-CPBG-evoked responses, whilst partially blocking the 5-HT responses.
• 6.6. These results suggest the presence of 5-HT₃ receptors similar to those found in mammalian neurones, and that multiple subtypes of these receptors may be present in Lymnaea neurones.

     

5-HT3 receptor blocking properties of the antiparkinsonian agent,talipexole

• 1.1. Talipexole showed moderate displacement activity of ³H-GR 65630 binding to 5-HT₃ receptors in both rat cortical and intestinal membrane fractions with Ki values of 0.35 μM and 0.22 μM, respectively.
• 2.2. Bromocriptine failed to displace the binding activity in either experimental system even at a concentration of 10 μM.
• 3.3. Both talipexole and tropisetron were found to significantly inhibit 5-HT₃ receptor-mediated effects of 5-HT in isolated guinea-pig ileum or atrium; however, the effect of talipexole was weaker than that of tropisetron.
• 4.4. Bromocriptine, in contrast, had no antagonistic effects on 5-HT₃ receptor-mediated activity in guinea-pig ileum or atrium.
• 5.5. It was concluded that talipexole might act as an antagonist on 5-HT₃ receptors in both brain and intestinal tissues.

     

Pre- and postjunctional effects of 5-hydroxytryptamine in dog cephalic veins of neonates

• 1.1. This investigation was undertaken to determine the existence of pre- and post junctional effects of 5-hydroxytryptamine (5-HT) in the cephalic vein of newborn dogs. For the sake of comparison, some experiments were also carried out on the veins of adult animals.
• 2.2. 5-HT reduced, in a concentration-dependent manner the overflow of tritium evoked by electrical stimulation of tissues previously loaded with ³H-noradrenaline for the same range of concentrations (0.01–1μM 5-HT) in both neonates and adults. The maximal reduction of tritium overflow caused by 5-HT was 36±6% and 77±5% (n=4; P<0.001) in neonates and adults, respectively.
• 3.3. Postjunctionally, 5-HT caused concentration-dependent contractions of vessels from both neonates and adults and its EC₅₀ values were not significantly different at the two ages. The maximal effect of 5-HT was smaller in newborn (0.69±0.03 g/mg) than in adult (1.16±0.06 g/mg) animals (n=9; P<0.01).
• 4.4. Metitepin antagonized 5-HT effects while ketanserin was ineffective, both pre- and postjunctionally, in newborn and adult dogs.
• 5.5. It is concluded that there are 5-HT receptors at pre- and postjunctional level at birth and that these receptors probably belong to the 5-HT₁ type.

     

Effect of naringin and naringenin on contractions induced by noradrenaline in rat vas deferens—I. Evidence for postsynaptic alpha-2 adrenergic receptor

• 1.1. Naringin at all doses (2 × 10⁻⁶, 5 × 10⁻⁷, and 1 × 10⁻⁷ M) significantly increased contractions induced by noradrenaline in rat vas deferens but the increments of maximal contraction were not concentration-dependent.
• 2.2. In a medium containing 1 × 10⁻⁶ M yohimbine (a selective blocker of α₂-adrenoceptor) and naringin, the curve constructed with noradrenaline decreased below the control curve.
• 3.3. Naringenin (aglycone of naringin) (2 × 10⁻⁶ and 1 × 10⁻⁷ M) increased the contractile effect of noradrenaline and the maximal effect evoked was related to the maximal dose of naringenin.
• 4.4. The α₂ antagonism produced by yohimbine in the naringenin-noradrenaline association were retained at two doses of naringenin tested and we noticed a similar behaviour when we used clonidine-noradrenaline.

     

No evidence for dopamine-induced relaxation in isolated human mesenteric arterial strips from elderly patients

• 1.1. We investigate the effects of dopamine in isolated mesenteric artery from elderly patients.
• 2.2. Noradrenaline (10⁻¹¹ to 10⁻⁴ M) and dopamine (2.7 × 10⁻⁶ to 1.4 × 10⁻³ M) induced a concentrationdependent contraction that was antagonized by prazosin. Fenoldopam (10⁻⁸ to 10⁻⁴ M) and clonidine (10⁻⁹ to 10⁻⁴ M) did not produce any contractile effects.
• 3.3. Potassium chloride (80 mM) produced a well-maintained plateau contraction and dopamine-induced contraction in these conditions, which was decreased by prazosin (10⁻⁸ M). Neither fenoldopam nor isoprenaline (10⁻¹⁰ to 10⁻⁵ M) modified the well-maintained plateau.
• 4.4. Our results suggest that post-synaptic dopamine receptors are not present in this preparation but α₁-adrenoceptors are present.

     

M3-Type Muscarinic Receptors Predominantly Mediate Neurogenic Quick Contraction of Bovine Ciliary Muscle

• 1.The present experiments were designed to investigate which subtypes of muscarinic receptors are involved in the neurogenic quick contraction of bovine ciliary muscle in connection to quick eye focal accommodation.
• 2.Transmural electrical stimulation (TES) produced a transient contraction, which was abolished in the presence of 3×10⁻⁷ M tetrodotoxin and 10⁻⁶ M atropine, but greatly augmented by 3×10⁻⁷ M physostigmine.
• 3.The exogenously applied acetylcholine (ACh: 10⁻⁹ to 3×10⁻⁶ M) produced a concentration-dependent contraction, which was competitively antagonized by 10⁻⁶ M atropine and augmented by 3×10⁻⁷ M physostigmine, but unaffected by 3×10⁻⁷ M tetrodotoxin.
• 4.The magnitude and time to peak of the maximal contraction produced by TES were significantly greater (1267.5±86.0 mg, P<0.005) and shorter (9.0±0.2 sec, P<0.005) than corresponding values (97.0±9.9 mg and 20.3±2.1 sec, respectively) of the phasic contraction caused by exogenously applied 10⁻⁵ M ACh, at which concentration the agonist caused the maximal contraction. The velocity (140.6±7.8 mg/sec) of the transient contraction caused by TES was approximately 28-fold greater than that of the phasic contraction caused by ACh (5.1±0.9 mg/sec).
• 5.The contractions produced by TES were greatly attenuated by 4-diphenylacetoxy-N-methylpiperidine (4-DAMP) as an M₃ antagonist and slightly by pirenzepine as an M₁ antagonist (20.2±7.9% inhibition at the highest concentration), but not by methoctramine (MET) as an M₂ antagonist. The IC₅₀ value (−log M) for 4-DAMP was determined to be 7.17±0.14.
• 6.Scatchard plot analysis of [³H]-quinuclidinylbenzilate (QNB) binding revealed that the binding sites constituted a single population with a K_d of 31.2±0.8 pM and a B_max of 895.5±93.2 fmol/mg protein. The activity in inhibiting [³H]-QNB binding was most potent with 4-DAMP (-log K_i=7.98±0.02), but less potent with pirenzepine (−log K_i=6.43±0.04) and MET (−log K_i=7.32±0.16). 4-DAMP was approximately 35- and 5-fold more potent than pirenzepine and MET in terms of −log K_i values, respectively, suggesting the predominant localization of M₃ receptor subtypes in the bovine ciliary muscle membrane.
• 7.These results suggest that TES produces a neurogenic quick contraction of the bovine ciliary muscle, which would be mediated mainly by ACh released from the intramural nerve terminals and subsequent excitation of M₃ receptor subtypes localized on the ciliary muscle cells, and that neurogenic quick contraction of the ciliary muscle is possibly involved in part in eye focal accommodation.

     

Effects of an extract of Ginkgo biloba and diverse substances on the phasic and tonic components of the contraction of an isolated rabbit aorta

• 1.1. The effects of phentolamine, propranolol, D 600, theophylline, papaverine and an extract of Ginkgo biloba were studied with respect to the two phases of the contractile response induced by norepinephrine in an isolated rabbit aorta.
• 2.2. Phentolamine (3 × 10⁻⁶ M) inhibits the rapid phase of the contraction of the rabbit aorta brought on by norepinephrine (NE) 10⁻⁵ M more strongly than the tonic phase. Propranolol (10⁻⁶ M) potentiates this rapid phase.
• 3.3. D 600 inhibits the slow phase with an EC₅₀ = to 3.8 × 10⁻⁸ M.
• 4.4. Papaverine and theophylline increase the relaxation that follows the rapid phase of contraction. The slow phase is inhibited only by papaverine.
• 5.5. The extract of Ginkgo biloba (Gb) at a concentration of 3 mg/ml has the same type of effect as papaverine 3 × 10⁻⁵ M.

     

Inhibition of voltage-dependent Ca2+ channels of porcine tracheal smooth muscle by the novel Ca2+ channel antagonist RWJ-22108

• 1.1. We compared electrophysiological effects of the bronchoselective Ca²⁺ channel antagonist RWJ-22108 on voltage-dependent Ca²⁺ channels (VDCs) of porcine tracheal smooth muscle cells to the effects of nicardipine and verapamil.
• 2.2. Each of the three Ca²⁺ channel antagonists tested inhibited inward Ca²⁺ currents (I_Ca) measured by whole-cell patch clamp techniques. Inhibition was dose-dependent with ∼50% inhibition of peak I_Ca at +20 mV obtained with 3 × 10⁻⁶M RWJ-22108, 3 × 10⁻⁷M nicardipine, or 10⁻⁵M verapamil.
• 3.3. Both RWJ-22108 (3 × 10⁻⁶M) and nicardipine (3 × 10⁻⁷M) shifted the voltage dependence of steady-state inactivation to more negative potentials; however, the change in the potential of half-maximal inactivation induced by RWJ-22108 (−18 mV) was significantly greater than that induced by nicardipine (−12 mV). Verapamil did not alter the voltage dependence of inactivation.
• 4.4. We conclude that inhibition of VDCs by RWJ-22108 is qualitatively similar to that by nicardipine but with a greater stabilizing effect on the inactivated channel state.

     

Effects of NIK-247 and Tacrine on Muscarinic Receptor Subtypes in Rats

• 1.The purpose of this study was to compare the effect of NIK-247 on muscarinic receptor subtypes with that of tacrine (THA) in rats.
• 2.NIK-247 and tacrine dose dependently inhibited the binding of [³H]pirenzepine (M₁), [³H]AF-DX 384 (M₂), and [³H]4-DAMP (M₃). The IC₅₀ values for NIK-247 were 4.4×10⁻⁶ M, 1.1×10⁻⁵ M, and 1.5×10⁻⁵ M, respectively, whereas those for tacrine were 5.8×10⁻⁷ M, 2.0×10⁻⁶ M, and 5.8×10⁻⁶ M, respectively.
• 3.Gpp[NH]p, a GTP analogue, slightly shifted the curve of displacement of [³H]AF-DX 384 binding for NIK-247 to the right. However, Gpp[NH]p did not shift the curve of displacement of [³H]pirenzepine and [³H]4-DAMP binding to the right.
• 4.NIK-247 moderately decreased the rate of beating in right atrial preparations, but did not decrease it below 50% of control level.
• 5.These findings indicate that NIK-247 is an M₁ antagonist, M₂ partial agonist, and M₃ antagonist.

     

Calcium antagonistic action involved in vasodilation by brovincamine

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1. 1.1. Possible mode of vasodilative action of brovincamine was assessed in isolated cardiovascular preparations in comparison with verapamil and papaverine.
2. 2.2. Brovincamine (IC₅₀: 1.2 × 10⁻⁵ M), verapamil (IC₅₀: 3.5 × 10⁻⁷ M) or papaverine (IC₅₀: 2.5 × 10⁻⁵ M) caused a dose-dependent relaxation of potassium (30 mM)-contracture in the rabbit pulmonary arterial segment. This relaxation by verapamil or brovincamine, but not by papaverine, was antagonized by increasing external Ca²⁺ concentration to 12.4 mM.
3. 3.3. Duration of slow action potentials of partially depolarized guinea-pig papillary muscle was reduced by 15 min exposure to brovincamine (5 × 10⁻⁵ M) or verapamil (10⁻⁵ M).
4. 4.4. These results suggest that brovincamine produces a vasodilation via a slow Ca²⁺-channel blockade.

     

Characterization of muscarinic receptors on the isolated guinea pig ileum at pharmacologically low concentrations

• 1.1. Several selective and non-selective muscarinic agonists (McN-A-343, RS-86, arecoline, oxotremorine-M, pilocarpine, cis-dioxolane, and acetylcholine) were examined for relaxant activity in the isolated guinea-pig ileum at pharmacologically low concentrations.
• 2.2. The concentrations studied include: 1 × 10⁻¹²M, 3 × 10⁻¹²M, 1 × 10⁻¹¹M, 3 × 10⁻¹¹M and 1 × 10⁻¹⁰M.
• 3.3. None of the compounds exhibited relaxant activity in both the field and non-field stimulated ileum.
• 4.4. All of the above compounds exert muscarinic agonist activity in a concentration range of 1 × 10⁻⁹M to 1 × 10⁻⁶M (Williams et al., 1992).
• 5.5. Thus, in the isolated guinea-pig ileum, muscarinic agonists do not exert relaxant activity of the gastrointestinal tract at low concentrations.

     

Influence of hormonal status in relaxant effect of diethylstilbestrol and nifedipine on isolated rat uterus contraction

• 1.1. The effects of diethylstilbestrol (DES, 10⁻⁷-10⁻⁵ M) and nifedipine (10⁻¹⁰-10⁻⁷ M) on KCl (60 mM)-induced tonic contraction in the uterus of ovariectomized and 17β-estradiol (0.1 mg/kg/day, s.c.)-, 17α-estradiol (0.1 mg/kg/day, s.c.)-, or progesterone (2 mg/kg/day, s.c.)-treated rats have been assayed.
• 2.2. The dose-dependent relaxation produced by nifedipine in ovariectomized rats (EC₅₀ = 5.59 ± 1.25 × 10⁻⁹ M) is potentiated in uterus of rats treated with 17β-estradiol and progesterone (EC₅₀ = 0.59 ± 0.1 and 0.49 ± 0.1 × 10⁻⁹ M, respectively) but not in the 17α-estradiol-treated rats (3.01 ± 0.6 × 10⁻⁹ M).
• 3.3. The relaxation produced by DES on ovariectomized rats (EC₅₀ = 0.84 ± 0.14 × 10⁻⁶ M) is reduced when the rats are treated with 17β-estradiol (EC₅₀ = 2.22 ± 0.2 × 10⁻⁶ M) or progesterone (EC₅₀ = 1.24 ± 0.08 × 10⁻⁶ M), but unmodified by 17α-estradiol (EC₅₀ = 0.58 ± 0.01 × 10⁻⁶ M).
• 4.4. The nifedipine-induced relaxation is reversed with Bay K 8644 (10⁻¹⁰-10⁻⁶ M) in all experimental conditions. However, Bay K 8644 counteracted the relaxation of DES at 45.7% on ovariectomized rats but this was lower than 30% in the other groups.
• 5.5. Our results suggest that in ovariectomized rats the effects of both nifedipine and DES are similar, but 17β-estradiol and progesterone produce a contrary effect on the relaxation induced by nifedipine and DES (by increasing the nifedipine and decreasing the DES effects).
• 6.6. The modifications produced by 17α-estradiol are similar to those produced by the ovariectomy and this suggests that 17α-estradiol is a drug lacking estrogenic activity.

     

Actions of a calcium antagonist,the D-600, on electrical and mechanical properties of frog skeletal muscle

• 1.1. On the isolated frog sartorius muscle, D-600, a purported calcium antagonist, depressed action potential production by inhibiting ionic conductances.
• 2.2. D-600 in low concentrations (< 3 × 10⁻⁵ M) potentiated twitch tension while higher concentrations (> 3 × 10⁻⁵ M) depressed twitch tension.
• 3.3. It is proposed that D-600 inhibits the excitation-contraction coupling (ECC) via a variety of mechanisms and not merely by inhibition of calcium fluxes.

     

Clonidine-induced rhythmic activity in rabbit anococcygeus muscle

• 1.1. Clonidine 0.5 mM induced an extremely regular rhythmic activity in isolated rabbit anococcygeus muscle. The movements were resistant to tetrodotoxin effect.
• 2.2. Prazosin (5 × 10⁻⁸M-5 × 10⁻⁶M) and yohimbine (1.5 × 10⁻⁷M-5 × 10⁻⁴M) showed no remarkable effect on clonidine-induced rhythmic activity.
• 3.3. The clonidine-induced contractions were dependent on extracellular calcium and could be inhibited by the omission of calcium from medium or the introduction of verapamil (IC₅₀=1.3 × 10⁻⁷M) or nifedipine (IC₅₀=7.5 × 10⁻⁸M).
• 4.4. Pretreatment of animals with reserpine made the preparations 2800-fold more sensitive to this action of clonidine.
• 5.5. It can be concluded from this study that clonidine is able to induce rhythmic activity in rabbit anococcygeus muscle through a mechanism that increases intracellular concentration of Ca ⁺⁺ via membrane calcium channels.

     

Effects of tandospirone on second messenger systems and neurotransmitter release in the rat brain

• 1.1. We studied the effects of tandospirone, a novel serotonin (5-HT)_1A receptor-related anxiolytic, on the intracellular second messenger systems and neurotransmitter release.
• 2.2. Tandospirone inhibited forskolin-stimulated adenylate cyclase activity in rat hippocampal membranes by activation of 5-HT_1A receptors and had high efficacy comparable to 5-HT_1A receptor agonists such as 5-HT and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT).
• 3.3. Tandospirone suppressed carbachol-stimulated phosphatidyl-inositol metabolism (PI response), which was shown to be a 5-HT_1A receptor-mediated event.
• 4.4. Tandospirone did not affect the release of 5-HT, norepinephrine (NE), dopamine (DA) and acetylcholine (ACh) from rat brain slice preparations.
• 5.5. These findings suggested that tandospirone shows high agonistic efficacy on the postsynaptic 5-HT_1A receptors but does not affect the presynaptic autoreceptors located on nerve endings. The modulation of the second messenger system via postsynaptic 5-HT_1A receptors might be involved in the anxiolytic efficacy of tandospirone.

     

Progesterone and pregnanolone derivatives relaxing effect on smooth muscle

• 1.1. The effect of gestagens, 5α-hydroxyprogesterone (10⁻⁶−6 × 10⁻⁵ M), 5β-hydroxyprogesterone (10⁻⁶−3 × 10⁻⁵ M), progesterone (6 × 10⁻⁶−10⁻⁴ M), pregnanolone (10⁻⁶−10⁻⁵ M), allopregnanolone (10⁻⁶−10⁻⁴ M) and epipregnanolone (10⁻⁶−6 × 10⁻⁵ M) on rat uterine contractions induced by KCl (60 mM), has been assayed.
• 2.2. All drugs assayed relaxed the tonic-contraction induced by KCl in a concentration-dependent way. The respectives IC₅₀ were 31.3 ± 4.1 × 10⁻⁶ M (progesterone), 8.9 ± 0.8 × 10⁻⁶ M (5α-hydroxyprogesterone 3.8 ± 0.3 × 10⁻⁶ M (5β-hydroxyprogesterone), 3.1 ± 0.1 × 10⁻⁶ M (pregnanolone), 21.2 ± 3.1 × 10⁻⁶ M (allopregnanolone) and 6.3 ± 1.3 × 10⁻⁶ M (epipregnanolone). This relaxing effect was partially or totally counteracted by CaCl₂ (1–10 mM)
• 3.3. Cycloheximide (10 μg/ml) significantly shifted to the right the effect of allopregnanolone but not the effect of the other drugs. Actinomycin D (5 μg/ml) did not modify the effect of allopregnanolone.
• 4.4. Our results suggest that the relaxing effect of gestagens in the rat uterus could be related to inhibition on calcium influx and mainly occur through non-genomic mechanisms.

     

Investigation into the effect of 5-hydroxytryptamine on fluid transport in the rat small intestine

• 1.1. 5-Hydroxytryptamine (5-HT) has been shown to cause a consistent secretory effect in the rat small intestine only when administered luminally or by close intraarterial infusion. Intraluminal 5-HT-induced secretion is possibly mediated by 5-HT₄ receptors. Therefore, it was decided to investigate the effect of 5-HT and selective 5-HT₄ receptor agonists (SC 53116 and DAU 6236) on intestinal fluid transport in rat jejunum and ileum. The study also investigated the effect of a selective 5-HT₄ receptor antagonist (GR 113808) against the intraluminally administered 5-HT.
• 2.2. 5-HT receptor agonists and antagonists were administered intraluminally in pentobarbitoneanesthetized rats. Changes in intestinal fluid transport across the intestinal wall were measured by a single pass technique.
• 3.3. Intraluminal 5-HT produced significant antiabsorptive effects is both the jejunum and ileum. The 5-HT-induced responses were blocked by intraluminal administration of the 5-HT₄ receptor antagonist GR 113808. The 5-HT₄ agonist SC 53116 induced antiabsorptive effects in both regions of the small intestine, but DAU 6236 did not affect the rates of fluid transport.
• 4.4. The results indicate that a 5-HT₄ receptor has a role in the luminal 5-HT-induced antiabsorptive effect on intestinal fluid transport in the rat.

     

Effects of μ-, δ- and κ-opioid antagonists in atrial preparations from nonfailing and failing human hearts

• 1.1. We examined the effects of naloxone (preferentially μ-antagonist), naltrindole (selective δ-antagonist) or nor-binaltorphimine (nor-BNI, selective κ-antagonist) on auricular myocardium tissue from nonfailing and failing human hearts.
• 2.2. The opioid antagonists used in this study induced inhibitory effects in auricular strips from failing and nonfailing human hearts. In addition, the maximal effect, the IC₅₀, and the slope of concentration-response curves obtained with μ-, δ-, and κ-opioid antagonists were similar in failing and nonfailing human heart tissues.
• 3.3. The K-antagonist was more effective than naltrindole or naloxone. Moreover, the IC₅₀ for nor-BNI (0.25±0.01 × 10⁻⁵M) was lower than the IC₅₀ for naloxone (26.5±5.0 × 10⁻⁵M) and naltrindole (13.8±2.0 × 10⁻⁵M). Similar results were obtained in auricular strips from failing human hearts.
• 4.4. Our results demonstrate that the failing heart does not modify the inhibitory cardiac effects obtained with selective opioid antagonists.