Relaxant effect of dopamine on the isolated rat uterus

Summary The effect of dopamine was studied on the isolated uterus of diethylstilboestrol-treated rats. Dopamine, at concentrations (10⁷–10^–4 M) produced a concentration-dependent relaxation in the K⁺-depolarized rat uterus. On a molar basis, dopamine was about 500 times less potent than adrenaline in relaxing the uterus, the maximum degree of relaxation obtained with both drugs was the same. Pretreatment of the rats with reserpine (5 mg/kg) did not produce any modification of the dose-response curve to dopamine. Similarly, cocaine (3 × 10^–6 M) failed to modify the relaxant effect of dopamine. The dopamine induced relaxation was inhibited by propranolol (10^–9–10^–7 M) in a dose-dependent manner. Prazosin (10^–7 M), SCH 23390 (10^–7 M) and sulpiride (10^–7 M) did not affect the dopamine dose-response curve. In the isolated rat uterus which was not preconstricted by KCl neither dopamine nor adrenaline produced any effect when added to the organ bath. This lack of response to both catecholamines was present even in tissues pretreated with propranolol or sulpiride. It is concluded that dopamine produced a concentration-dependent relaxation of the uterus from diethylstilboestrol-treated rats by direct activation of beta-adrenoceptors. There was no evidence for indirect action (catecholamine release and neuronal uptake mechanisms) and specific dopamine receptor mediated relaxation and alpha-adrenoceptor mediated contractions have not been found in this preparation. Send offprint requests to F. J. Morales-Olivas at the above address     

Phencyclidine and ketamine: Comparison with the effect of cocaine on the noradrenergic neurones of the rat brain cortex

Summary In slices of the rat occipital cortex, the influence of phencyclidine and ketamine on the accumulation of ³H-noradrenaline and the subsequent outflow of tritium was investigated, and was compared with the effect of cocaine.-All three drugs inhibited the accumulation of tritium during incubation of the slices with ³H-noradrenaline. Phencyclidine was slightly, whereas ketamine was much less effective than cocaine.-All three drugs accelerated the spontaneous outflow of tritium from slices preincubated with ³H-noradrenaline. The acceleration caused by low concentrations probably reflects an inhibition of the re-uptake of spontaneously released ³H-noradrenaline; in addition, high concentrations (10^–4M phencyclidine, 3×10^–4–10^–3M cocaine and 10^–3–3×10^–3M ketamine) appear to release tritiated compounds from the neurones. The distance between uptakeinhibiting and releasing concentrations was much greater for cocaine than for phencyclidine and ketamine.-All three drugs enhanced the overflow of tritium evoked by electrical field stimulation. The increase probably reflects an inhibition of the re-uptake of released ³H-noradrenaline; in addition, phencyclidine appears to enhance the release of noradrenaline per pulse.-The actions of phencyclidine and ketamine on central noradrenergic neurones may contribute to the characteristic psychotropic side-effects of these general anaesthetics.     

Characteristics of histamine tachyphylaxis in canine tracheal smooth muscle

Summary In isolated canine tracheal smooth muscle, repeated administrations of histamine result in a rapid reduction in contractile response to about 15% of the initial contraction (tachyphylaxis). Development of this tachyphylaxis is specific inasmuch as: 1) it does not develop to acetylcholine (10^–6 M or 10^–4 M), or serotonin (10^–5 M); and 2) maximally developed histamine tachyphylaxis is not associated with a parallel reduction in response to acetylcholine. Pretreatment with propranolol (10^–5 M) or phentolamine (10^–4 M) does not prevent tachyphylaxis: however, pretreatment with atropine (10^–4 M) does prevent tachyphylaxis in about 50% of the animals tested.Tachyphylaxis to histamine can be reversed in a dose- and time-dependent fashion with prostaglandin synthesis inhibiting agents. The order of potency obtained with such compounds (indomethacin > mefenamic acid > oxyphenbutazone > acetylsalicylic acid) is consistent with potencies for inhibition of prostaglandin synthesis found in the literature. Also, in indomethacin pretreated strips in which tachyphylaxis to histamine was prevented, exogenous addition of PGE₂ (1.42×10^–10 M to 2.84×10^–9 M) and PGA₂ in a high concentration (2.9×10^–9 M) are capable of selectively reducing the response to histamine without an effect on acetylcholine-induced contractions. These data suggest that the mechanism of histamine tachyphylaxis in the canine tracheal smooth muscle preparation involves prostaglandin synthesis.This report is part of a dissertation to be presented by W. H. A. to the University of South Florida College of Medicine in partial fulfillment of the requirements for a Doctor of Philosophy degree     

Histamine and histamine methyltransferase in the gastric mucosa of man,pig, dog and cow

Summary High histamine concentrations and histamine methyl transferase activity were demonstrated in the gastric mucosa of man, dog, pig and cow. Modified methods for the determination of histamine and histamine methyltransferase were developed. Histamine was identified by its fluorescence spectrum, by thin-layer chromatography in 8 different solvent systems and by bioassay. Histamine methyltransferase from pig antral mucosa was purified 6-fold by ultra-centrifugation and fractional precipitation by ammonium sulfate. ItsK _m for histamine as substrate was 2.3×10^–5 M, for S-adenosylmethionine 4.3×10^–5 M, the pH-optimum was found to be pH 7.4. Nicotinamide in concentrations up to 1×10^–2 M had no effect on the activity of the enzyme.We thank the Deutsche Forschungsgemeinschaft for a grant (Sonderforschungs-bereich 37).     

Influence of fentanyl,levorphanol and pethidine on the release of noradrenaline from rat brain cortex slices

Summary In slices of rat brain cortex preincubated with (–)-³H-noradrenaline, the influence of fentanyl, levorphanol and pethidine on the efflux of tritium was investigated. The spontaneous outflow of tritium was not changed by low, and was accelerated by high concentrations of the drugs. The overflow of tritium evoked by electrical stimulation at 3 Hz was diminished by 10^–8–10^–7 M fentanyl and by 10^–7–10^–6 M levorphanol, but was augmented by 10^–5 M levorphanol. Naloxone prevented the inhibitory effect of fentanyl and levorphanol. In contrast to fentanyl and levorphanol, pethidine did not decrease, but at concentrations of 10^–6–10^–5 M greatly increased the stimulation-induced overflow of tritium. However, the increase was abolished, and the stimulation-evoked overflow slightly reduced, after the re-uptake of noradrenaline had been blocked by cocaine. It is concluded that fentanyl, levorphanol and pethidine share with morphine the ability to inhibit the release of transmitter from cerebrocortical noradrenaline neurones evoked by nerve impulses.     

Release of [3H]noradrenaline induced by 5-hydroxy-tryptamine from cat pial arteries

Pial arteries of cats were used to analyse the effects of 5-hydroxytryptamine (5-HT) on the release of [³H]noradrenaline. To achieve this the vessels were preincubated with [³H]noradrenaline and the effect of different concentrations of 5-HT (10^?6, 10^?5, 10^?4 M) on the release of tritium was studied. 5-HT elicited release of radioactivity in a dose-dependent manner. Removal of both superior cervical sympathetic ganglia 15 days before the experiment or pretreatment of the animals with reserpine (3 mg kg^?1, total dose) produced a significant decrease in the outflow of tritium induced by 5-HT. In these arteries, the amount of radioactivity retained at the end of the experiment was much diminished. Cocaine (10^?6 M) caused a significant decrease in the tritium efflux induced by 5-HT (10^?5 M). These results show that 5-HT has an indirect adrenergic effect in the pial arteries of the cat only at high doses of 5-HT, and confirm that sympathetic innervation of these vessels mainly comes from the superior cervical ganglia.     

Indirect adrenergic effect of histamine in cat right atrium

Superfused cat atrial fragments preincubated with [3H]noradrenaline showed an increased tritium release under the action of 10(-4) M histamine. Reserpine pretreatment of the animals, external calcium removal or the presence of 10(-6) M cocaine, 10(-6) M diphenhydramine or 10(-3) M colchicine in the superfusion medium significantly reduced this effect of histamine (10(-4) M). Diphenhydramine (10(-5) M) also decreased the release of tritium brought about by 10(-6) M tyramine. These results suggest that histamine may release neurotransmitter from cardiac sympathetic nerve endings by means of an exocytotic process and needs to enter the nerve terminals through the amine uptake system.     

Effects of compound 48/80 on mast cells,histamine and cyclic AMP in isolated superior cervical ganglia

Summary Superior cervical ganglia of the rat contain mast cells which are sensitive to degranulation by compound 48/80. The granulation process is shown to the independent of the ATP content of the ganglion. Compound 48/80 released histamine into the incubation medium, thereby decreasing the histamine content of the ganglia. Moreover, the release of ³H-noradrenaline was accelerated by the compound. Histamine and adrenaline induced a rapid accumulation of cyclic AMP in the ganglia. This effect of the amines was specifically blocked by diphenhydramine or propranolol with an ID₅₀ of 1.5×10^–9 M and 2.2×10^–7 M, respectively.In contrast to other findings with isolated mast cell preparations, compound 48/80 induced a rapid and marked accumulation of cyclic AMP in intact ganglia and an enhanced release of cyclic AMP into the incubation fluid. Diphenhydramine prevented the accumulation in the tissue but only partly inhibited the enhanced appearance of cyclic AMP in the medium. The accumulation of the cyclic nucleotide in the tissue was partly blocked by propranolol, suggesting an additional action of compound 48/80 on cyclic AMP through catecholamines.The cyclic nucleotide phosphodiesterase activity in homogenates of superior cervical ganglia was completely inhibited by compound 48/80 at 7 g/ml when low cyclic AMP concentrations were used.In addition to cyclic AMP release, rapid and marked efflux of ATP into the medium was observed during incubations with compound 48/80. The lactate dehydrogenase activity in the incubation medium was significantly enhanced with incubation periods of 40 to 60 min indicating rather slowly occurring toxic damage to cell membranes by compound 48/80.This work was supported by the Deutsche Forschungsgemeinschaft (SFB 70).     

Mechanism of the indirect adrenergic effect of histamine in cat cerebral arteries

KCl (50 mM), tyramine (10(-7) M), and histamine (10(-4) M) induced an increase in tritium release from cat cerebral arteries preincubated with [3H]noradrenaline, this increase being due in part to noradrenaline. When calcium was absent from the superfusion medium, only tyramine (10(-7) M) enhanced the tritium outflow. Colchicine (10(-3) M) partially inhibited the increase in radioactivity brought about by 10(-4) M histamine. KCl (50 mM) also evoked release of radioactivity from cerebral arteries preloaded with [3H]histamine; this release was unaffected by reserpine pretreatment or removal of both superior cervical sympathetic ganglia. Neither tyramine (10(-7) M) nor compound 48/80 (300 micrograms ml-1) altered the spontaneous tritium outflow from cerebral blood vessels preincubated with [3H]histamine. These results suggest that histamine is not accumulated by sympathetic nerve endings and elicits its noradrenaline-releasing effect by means of an exocytotic process.     

Effect of phentolamine on noradrenaline uptake and release

Summary The influence of phentolamine on the uptake of exogenous noradrenaline infused into the aortic cannula and on the overflow of endogenous noradrenaline caused by sympathetic nerve stimulation was investigated in the isolated perfused rabbit heart. 10^–6 M phentolamine doubled the overflow of endogenous noradrenaline, but did not change noradrenaline uptake. 10^–5 M phentolamine increased the stimulation-induced overflow of noradrenaline 4-fold and inhibited amine uptake by about 50%. 10^–4 M phentolamine elevated the overflow of noradrenaline less than 10^–5 and 3×10^–5 M did. The augmentation of transmitter overflow was only partly reversed by 13 min perfusion with drug-free medium.Pretreatment of hearts with 1.5×10^–5 M cocaine or with 10^–7 or 10^–6 M desipramine did not change the effect of phentolamine on the overflow of noradrenaline evoked by nerve impulses. Pretreatment of hearts with 10^–5 M, but not with 10^–6 M, phentolamine prevented the increase of transmitter overflow by cocaine.It is concluded that low concentrations of phentolamine potentiate the overflow of noradrenaline during nerve stimulation by a mechanism different from that of cocaine, i.e. different from inhibition of neuronal re-uptake. The nature of this mechanism is discussed.This work was supported by the Deutsche Forsehungsgemeinschaft. We have the pleasure to thank Mrs. Ch. Arts, Miss B. Piel and Mr. E. Hagelskamp for skilful technical assistance.     

Direct and indirect actions of dopamine on tracheal smooth muscle

Summary The effects of dopamine (DA) were studied on guinea-pig isolated tracheal chains. At a low concentration (10^–6M) DA occasionally produced a small contraction; this was followed by a dose-dependent relaxation 3×10^–6–3×10^–3 M).On a molar basis, DA was about 40 times less potent than noradrenaline (NA) in relaxing tracheal chains, and about 2700 times less potent than isoprenaline (ISO). The maximum degree of relaxation obtained with each drug was the same.Pretreatment of the guinea-pig with reserpine (5 mg/kg) resulted in a 3-fold shift of the DA curve to the right without concomitantly affecting the ISO doseresponse curve. Reserpine completely abolished the relaxant effects of tyramine, but a small contractile response remained.Desipramine (DMI), at a concentration of 10^–5 M, caused a 4-fold shift of the DA curve to th right. The same concentration of DMI resulted in a shift to the left of the NA dose-response curve by about 8-fold. Benztropine (10^–5 M) and haloperidol (10^–5 M and 3×10^–5 M) did not affect the DA dose-response curve.The DA-induced relaxation was inhibited by propranolol (10^–8–10^–6 M) in a dose-dependent manner. The higher concentrations of propranolol (10^–7 and 10^–6 M) unmasked the contractile effect of DA. In the presence of propranolol, phentolamine (10^–5 M) abolished the contractile effect of DA.It is concluded that DA has both direct and indirect actions on guinea-pig isolated tracheal smooth muscle. The relaxant effects of DA are predominantly due to a direct action on smooth muscle -adrenoceptors, with a component due to release of NA from adrenergic nerves. The contractile effects, which under normal conditions are masked by the relaxant effect of DA, are mediated by functional -adrenoceptors. There is no evidence for either specific dopaminergic nerves, uptake mechanisms or receptors in guinea-pig trachealis muscle.     

Effect of triphenyltin chloride on the release of histamine from mast cells

The effects of triphenyltin chloride (TPTC) on the release of histamine from rat and mouse mast cells in vitro and in vivo were investigated. The results obtained are summarized as follows: (a) At doses between 1 and 3 mg/kg, TPTC inhibited the dye leakage due to passive cutaneous anaphylaxis mediated by IgE antibody in mouse ear. At the same doses, TPTC inhibited the swelling due to reversed cutaneous anaphylaxis mediated by IgG antibody in rat. However, TPTC did not affect dye leakage due to histamine, serotonin, and LTC₄ in rat skin; (b) Histamine release by antigen and IgE antibody in rat peritoneal cavity was inhibited by the administration of TPTC at doses between 0.3 and 3 mg/kg; (c) Histamine release by calcium ionophore A 23187 from purified rat peritoneal mast cells in vitro was inhibited by TPTC at concentrations between 10^–7 and 10^–6 M. At the same concentration, TPTC, itself, caused neither the release of histamine nor any change in cell viability which was supported by the activity of lactate dehydrogenase (LDH) from purified rat peritoneal mast cells. All this evidence suggests that TPTC has an inhibitory effect on the release of histamine from mast cells without direct cytotoxicity.     

Presynaptic α-adrenoceptor blocking properties among tri- and tetra-cyclic antidepressant drugs

1 The effect of various antidepressants (5 × 10^-8 to 2 × 10^-5 M) on the resting overflow of tritium, on the evoked overflow and the contractile response to electrical stimulation (2.5 Hz, 2.0 ms) has been determined in mouse vas deferens previously incubated with [³H]-(—)-noradrenaline.

2 Mianserin and ORG GC 94 produced a concentration-dependent increase of more than two fold in the electrically evoked overflow and the contractile response and, at the highest concentration, slightly increased resting release. These effects were largely unchanged in the presence of a concentration of cocaine effective in blocking noradrenaline uptake (1.1 × 10^-5 M).

3 The ability of phentolamine (1 × 10^-5 M) to increase both the evoked overflow of tritium and the contractile response was greatly reduced when these parameters were already elevated by the presence of mianserin or ORG GC 94.

4 The inhibitory effect of exogenous (—)-noradrenaline on evoked overflow was greatly reduced in the presence of mianserin or ORG GC 94 (4 × 10^-6 M).

5 The inhibitory effect of clonidine on the twitch response of the mouse vas deferens was antagonized by mianserin and ORG GC 94 in a competitive manner (pA₂ values 7.3 and 7.1 respectively).

6 Maprotiline, desipramine and nortriptyline (> 3 × 10^-6 M) produced a parallel fall in both evoked tritium overflow and in the contractile response and increased the resting overflow at higher concentrations. These effects were largely unchanged in the presence of cocaine (1.1 × 10^-5 M).

7 Doxepin, imipramine and iprindole all increased resting overflow at high concentrations (2 × 10^-5 M) but produced only small changes in evoked overflow and in the contractile response at lower concentrations.

8 It is concluded that mianserin and ORG GC 94 produce a blockade of presynaptic α-adrenoceptors which could contribute to an antidepressant effect but that this type of action is not common to all antidepressants.

     

Analysis of the contractile effect of 5-hydroxytryptamine on the isolated posterior communicating artery of the cat

5-Hydroxytryptamine (5-HT) induced dose-dependent increases in tension on the isolated posterior communicating artery (PCA) of the cat were significantly antagonized by lysergic acid diethylamide (LSD, 6 times 10^?9 m). In the presence of phentolamine (10^?6 m) the contraction induced by the two lowest doses of 5-HT was significantly reduced. Pretreatment of the animals with reserpine (3 mg kg^?1, i.p., total dose) did not modify the dose-response curve to 5-HT except for the lowest dose. Removal of both superior cervical sympathetic ganglia 15 days before the experiment brought about a significant increase in the vasoconstriction induced by 5-HT at all the doses compared with the control. Cocaine (10^?6m) induced a significant shift to the left of the dose-response curve to 5-HT but the maximum response was the same as in the control. The augmented response to 5-HT after denervation was partially antagonized by LSD (6 times 10^?9 m) but not by phentolamine (10^?6 m). These results show that the vasoconstriction elicited by 5-HT in the PCA of the cat is mainly due to direct stimulation of tryptaminergic receptors. The participation of an indirect adrenergic component in the contractile effects of 5-HT seems to be negligible.     

Influence of morphine and naloxone on the release of noradrenaline from rat brain cortex slices

Summary In slices of rat brain cortex preincubated with (–)-³H-noradrenaline, the influence of morphine and naloxone on the efflux of tritium was investigated. The spontaneous outflow of tritium was not changed by 10^–7–10^–5 M morphine and by 10^–6–10^–4 M naloxone, but was accelerated by 10^–4 M morphine. Electrical field stimulation augmented tritium outflow. The overflow evoked per ppulse decreased as the frequency of stimulation was increased from 0.3 to 3 Hz, but remained approximately constant when it was further increased to 10 Hz. At frequencies of 0.3, 1, and 3 Hz, but not at 10 Hz, morphine in concentrations of 10^–7–10^–5 M depressed the stimulation-induced overflow of tritium. 10^–4 M morphine did not influence the overflow induced by stimulation at 0.3 and 1 Hz and increased that evoked by stimulation at 10 Hz. Naloxone (10^–6–10^–4 M) did not change the response to stimulation. In the presence of 10^–4 M naloxone, 10^–6 M morphine did not diminish, and 10^–5 M morphine even enhanced the stimulation-induced overflow of tritium. The inhibitory effect of 10^–6 M morphine was not reduced, after tyrosine hydroxylase had been blocked by -methyltyrosine-methylester. It is concluded that morphine through an action on specific opiate receptors inhibits the release of transmitter from cerebrocortical noradrenergic neurones evoked by nerve impulses. By an action unrelated to opiate receptors, morphine at high concentrations increases the stimulation-induced overflow of noradrenaline, presumably by inhibiting its re-uptake into nerve endings.     

Noradrenergic component in the vasoconstriction induced by 5-hydroxytryptamine in goat cerebral arteries

5-Hydroxytryptamine (5-HT) elicited dose-dependent increases in tension in the middle cerebral artery of the goat, which were significantly antagonized by lysergic acid diethylamide (LSD, 10^?8 M) and methysergide (10^?7 M). In the presence of phentolamine (10^?6 M), the dose-response curve to 5-HT was shifted to the right, the pA₂ value for this antagonism was 6·52. Pretreatment of goats with reserpine (0·02 mg kg^?1 day^?1 for three days) or removal of both superior cervical ganglia 15 days before the experiment brought about a significant decrease in the vasoconstriction induced by doses of 5-HT higher than 10^?7 M. The remaining contraction produced by 5-HT in arterial segments from reserpinized or gangliectomized goats was further reduced in the presence of LSD. In addition, high concentrations of 5-HT induced tritium release from goat pial arteries preloaded with (?)-[³H]noradrenaline, 2 × 10^?7 M) which was significantly decreased in vessels from gangliectomized or reserpinized goats. These results in goat cerebral arteries indicate that in the contraction evoked by 5-HT there are two components. The first appears with low concentrations (up to 10^?7 M) in which 5-HT acts directly on 5-HT receptors. The second occurs at high doses (>10^?7 M) in which 5-HT also acts indirectly on α-adrenoceptors by release of noradrenaline from noradrenergic nerve endings.     

A partial involvement of histamine in ultrasonically nebulized distilled water-induced bronchoconstriction in guinea-pigs

1. Inhalation of ultrasonically nebulized distilled water (UNDW) can induce bronchoconstriction only in asthmatics, but mechanisms of the response are not well known. We recently reported a guinea-pig model of UNDW-induced bronchoconstriction (UNDW-IB) in which UNDW induces bronchoconstriction when UNDW is inhaled 20 min after a challenge with aerosolized ovalbumin (OA) in passively sensitized, anaesthetized and artificially ventilated guinea-pigs.
2. To elucidate the role of histamine in the UNDW-IB, we examined the effects of antihistamines, diphenhydramine hydrochloride (DH) and chlorpheniramine maleate (CP), and measured histamine content in bronchoalveolar lavage fluid (BALF) in the animal model.
3. DH in doses of 0.1, 1.0 and 10 mg kg⁻¹ and CP in doses of 0.01, 0.1 and 1.0 mg kg⁻¹ administered intravenously 15 min after the OA challenge partially reduced the UNDW-IB at 1 and 2 min after the UNDW inhalation in a dose-dependent manner. Histamine content in BALF recovered 10 min after the UNDW inhalation following the OA provocation was significantly increased compared with that after saline inhalation and before the UNDW inhalation following the OA challenge.
4. Intravenous atropine in a dose of 0.5 mg kg⁻¹ or inhaled disodium cromoglycate in concentrations of 1 and 10 mg ml⁻¹ did not alter the UNDW-IB.
5. These results suggest that histamine is involved in part in the UNDW-IB in our animal model.

     

A study of the actions of histamine on the isolated rat heart

1. The effects of histamine on cardiac force, heart rate and coronary perfusion pressure were studied in the isolated rat heart, using the Langendorff perfused heart preparation. 2. Single injections of histamine induced dose-dependent decreases in contractile amplitude, heart rate and coronary perfusion pressure. 3. Perfusions of metiamide (above 1 × 10^-4 M) had a depressant effect on contractile force and heart rate, whereas diphenhydramine (4 × 10^-6 M) reduced only the heart rate. Both agents caused a fall in coronary perfusion pressure. 4. The negative inotropic and chronotropic effects of histamine on the isolated rat heart were not significantly influenced by either metiamide or diphenhydramine, or a combination of these drugs. However, the fall in coronary perfusion pressure induced by injections of histamine was significantly antagonized by metiamide or diphenhydramine. 5. These results suggest that the effects of histamine on the isolated rat heart may not be due entirely to stimulation of H₁- or H₂-receptors on the cardiac muscle cells. Evidence is presented for the existence of histamine H₁- and H₂-receptors in the coronary vessels.     

Human gastric mucosal adenylate cyclase: Activation by histamine-H2-receptor stimulation and inhibition by cimetidine in vitro and in peptic ulcer patients

Summary Biopsy specimens of human fundic mucosa from 96 subjects were assayed for adenylate cyclase activity to characterize specificity of the histamine receptor with selective agonists and antagonists in vitro, and to study the effect of cimetidine therapy. Histamine and the selective histamine H₂-receptor agonist dimaprit were almost equally potent throughout the concentration-response curve (10^–7–10^–3 mol/l); maximal stimulation was obtained with concentrations of 10^–4–10^–3 mol/l, and half maximal stimulation with about 10^–5 mol/l. The selective H₁-receptor agonist PEA 10^–5 and 10^–3 mol/l failed to stimulate adenylate cyclase. Mepyramine 10^–6 mol/l, a selective H₁-receptor antagonist, and cimetidine 10^–6 mol/l, a selective H₂-receptor antagonist, did not affect basal adenylate cyclase activity. Histamine-stimulated adenylate cyclase was inhibited in a concentration dependent manner by cimetidine 10^–7 and 10^–5 mol/l, but not by the same concentrations of mepyramine. Almost identical basal adenylate cyclase activities of about 150 pmol cAMP/mg protein/20 min were found in gastric mucosal biopsies from controls and from peptic ulcer patients, whether or not treated with cimetidine. Histamine 10^–5 mol/l doubled adenylate cyclase activity in the controls and the untreated ulcer group, but was completely ineffective in specimens from the cimetidine-treated peptic ulcer patients. The data underline the concept that the effects of histamine on acid secretion and on adenylate cyclase activity are linked together and that the therapeutic effect of cimetidine in ulcer treatment is related to histamine H₂-receptor blockade followed by inhibition of adenylate cyclase.     

Studies on the positive inotropic effect of dopamine in the guinea-pig heart

Summary The positive inotropic effect of dopamine has been studied in isolated ventricular strips of guinea-pig heart.The concentration-inotropic response curve for dopamine was significantly shifted to the right by pretreatment with reserpine.In preparations obtained from animals pretreated with reserpine (2.5 mg/kg, 24 h prior to the experiment) the dose-response curve was not significantly affected by haloperidol, a dopamine vascular receptor antagonist (10^–6–3×10^–6 M).The inotropic effect of dopamine was antagonized by practolol (3×10^–7–10^–6 M), but not by phentolamine (3×10^–6–10^–5 M); moreover the alpha-adrenoceptor blocking drug (10^–5 M) did not affect the curve for dopamine in the presence of practolol (3×10^–7 M).In preparations in which fast sodium channels were blocked by K⁺-rich medium, slow electrical responses (calcium-mediated action potentials) as well as contractions were induced by high concentrations of dopamine (10^–4–3×10^–4 M); again these responses were unaffected by phentolamine or haloperidol, but were blocked by practolol.It was concluded that in the guinea-pig ventricular muscle dopamine induced a positive inotropic effect through both indirect and direct action, and that the latter is due to the activation of beta-adrenoceptors.