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Biomedical subjects

E Poli

Publications and source records attributed to E Poli.

At least 37 records · Page 2Linked to original sources
PubMed1994

Positive inotropic activity of the novel histamine H2-receptor agonist, amthamine, on the human heart in vitro.

1. We tested the novel thiazole derivative, amthamine, for its ability to stimulate histamine H2-receptors in the human myocardium. 2. Experiments were carried out on isolated, electrically-driven pectinate muscle segments, excised from atrial appendages of patients undergoing corrective heart surgery. 3. Amthamine (0.3-100 microM) induced a positive inotropic activity, resembling histamine in terms of potency and efficacy. In comparison, impromidine was 10-30 times more active than histamine and amthamine, but its maximum effect was significantly lower, while dimaprit was as effective as histamine, but 10 times less potent. 4. The selective histamine H2-blocker, famotidine antagonized in a competitive fashion the amthamine-induced positive inotropic effect. pA2 value of famotidine against amthamine (7.21 +/- 0.45) was close to that measured against histamine (6.88 +/- 0.31) in the same conditions. 5. The effect of amthamine was not modified by beta-adrenoceptor blockade, excluding direct or indirect sympathomimetic activities of the compound. 6. These data provide evidence that amthamine is a selective and full acting histamine H2-receptor agonist in the human heart in vitro.

Cardiotonic Agents↗
PubMed1994

Activity of the new histamine H2-receptor antagonist zolantidine at cardiac and gastric H2-receptors.

The effect of the new histamine H2-receptor antagonist zolantidine was studied in different cardiac and gastric H2-receptor assays in comparison with ranitidine. Zolantidine (0.1-10 mumol/l) competitively antagonized the positive effects of histamine in the spontaneously beating guinea pig atria and in the electrically stimulated guinea pig papillary muscle (pA2 values were 6.98 and 6.78, respectively). At the highest concentrations zolantidine also reduced basal heart rate and cardiac contractility. In the isolated rat gastric fundus zolantidine up to 100 mumol/l did not modify histamine-induced acid secretion; it was similarly ineffective against dimaprit-induced acid secretion in the gastric fistula of conscious cats (up to 3 mumol/kg i.v.) and against histamine in the anesthetized rat with lumen-perfused stomach (up to 30 mumol/kg i.v.). In all these gastric secretory models ranitidine, as expected, antagonized histamine H2-receptor-mediated responses, showing a potency comparable to that found in cardiac preparations (pA2 values were 6.84, 6.38 and 6.78 in the atria, papillary muscle and gastric fundus, respectively). These data clearly showed that zolantidine is a very peculiar histamine H2-receptor antagonist, capable of distinguishing between cardiac and gastric H2-receptors; however, it still has to be elucidated whether this depends on a true heterogeneity in the histamine H2-receptor population or on the physicochemical properties of the drug.

Animals↗
PubMed1994

Signal transducing mechanisms coupled to histamine H3 receptors and alpha-2 adrenoceptors in the guinea pig duodenum: possible involvement of N-type Ca++ channels.

The signaling pathways following histamine H3 receptor activation by (R)alpha-methylhistamine (MHA) have been examined in the isolated guinea pig duodenum, in which selective excitation of cholinergic neurons was induced by electrical field stimulation (EFS). The effect of MHA on electrically evoked contractions was compared with that induced by the alpha-2 adrenoceptor agonist clonidine (CLON). The inhibitory effect of MHA on EFS-induced contractions was significantly reduced by increasing CA++ content in the nutrient fluid from 2.5 to 5 mM and by the Ca++ agonist Bay K 8644 (10(-8) M); conversely, the effect of MHA was significantly enhanced by lowering Ca++ content in the medium (from 2.5 to 1.25 mM) and by the N-type Ca++ channel blocker omega-conotoxin (CTX) (10(-8) M). The L-type Ca++ channel blocker nifedipine (NIF) (10(-7) M) did not modify the effect of MHA, although it significantly reduced both EFS- and exogenous acetylcholine (ACH)-induced contractions. Similar to MHA, the inhibitory effect elicited by CLON was enhanced by low external Ca++ and by CTX, but it was slightly affected by the compound Bay K 8644 (10(-7) M) or by high Ca++ concentrations (5 mM) and it was unaffected by NIF. 4-Aminopyridine (4-AP) (10(-4) M) reduced the effects of both MHA and CLON. The present data indicate that histamine H3 receptor activation in electrically stimulated duodenum is closely associated with a restriction of Ca++ access into the nerve terminal through N-type Ca++ channels; the same mechanism appears to be responsible for the inhibitory effect induced by alpha-2 adrenoceptor activation.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1994

Unmasking of activated histamine H3-receptors in myocardial ischemia: their role as regulators of exocytotic norepinephrine release.

We had previously found that histamine H3- receptors are negatively coupled to norepinephrine exocytosis in atrial tissue. We report here that in the presence of H1- and H2- receptor blockers, histamine significantly inhibits the tachycardia and norepinephrine release elicited by sympathetic nerve stimulation is isolated guinea pig hearts, an effect prevented by the H3 antagonist, thioperamide. Sympathetic nerve stimulation also caused a 1.5-fold increase in histamine overflow, which was insufficient to activate H3 receptors because thioperamide affected neither the tachycardia nor the norepinephrine release. Hence. We questioned whether H3 receptors become activated when adrenergic activity is greatly enhanced, as in myocardial ischemia. Guinea pig hearts underwent 10-min global ischemia. At reperfusion, norepinephrine exocytosis was markedly augmented and was associated with a 3.5-fold increase in histamine overflow. (R)alpha-methylhistamine, an H3 agonist, did not modify norepinephrine release, whereas thioperamide doubled it. Thus, in physiologic conditions, cardiac H3 receptors are quiescent, yet available for activation by exogenous ligands. In contrast, in the ischemic myocardium, H3 receptors appear to be fully activated by an endogenous ligand, probably histamine. Hence, cardiac H3 receptors may play an important role by negatively modulating exocytotic norepinephrine release associated with ischemic states.

Animals↗
PubMed1994

Histamine H3-receptor signaling in the heart: possible involvement of Gi/Go proteins and N-type Ca++ channels.

Discovered as inhibitory autoreceptors in central histaminergic pathways, histamine H3-receptors may also modulate peripheral cholinergic and central adrenergic function. Recently, H3-receptors were reported to inhibit adrenergic inotropic responses in guinea pig atria, possibly at prejunctional sites. We have assessed whether the H3-mediated modulation of cardiac adrenergic activities results from a reduction in norepinephrine release. We have found that (R) alpha-methylhistamine, the selective histamine H3-receptor agonist, attenuates the inotropic and chronotropic response of isolated guinea pig atria to transmural stimulation of adrenergic nerve endings. This attenuation was associated with a marked reduction in endogenous norepinephrine release. In contrast (R) alpha-methylhistamine did not modify the chronotropic effect of exogenous norepinephrine. The attenuation of adrenergic responses by (R) alpha-methylhistamine was 1) prevented by thioperamide, the selective H3-receptor antagonist; 2) attenuated by pertussis-toxin pretreatment and 3) potentiated by the N-type Ca(++)-channel blocker omega-conotoxin, which also potentiated the sympathetic modulatory effects of adrenergic-alpha 2 and adenosine-A1 receptor agonists. Our findings indicate that prejunctional histamine H3-receptors modulate the depolarization-dependent norepinephrine release from sympathetic nerve endings in the guinea pig myocardium. These receptors are probably coupled to a pertussis-toxin-sensitive Gi/Go protein and probably effect a reduction in Ca++ current. We have previously reported that sympathetic stimulation elicits a frequency-dependent release of cardiac histamine, whereas others had found that adrenergic activity regulates histamine's rapid turnover pool. Accordingly, presynaptic H3-receptors are likely to serve a modulatory role in cardiac adrenergic function.

Adrenergic Fibers↗
PubMed1993

In vitro cardiac pharmacology of the new histamine H2-receptor agonist amthamine: comparisons with histamine and dimaprit.

The cardiac activity of the novel histamine H2-receptor agonist amthamine was investigated in a variety of isolated heart preparations from guinea pigs and humans and in the isolated rabbit aorta. Amthamine caused an increase in the sinus rate of spontaneously beating guinea-pig atria (pD2 = 6.72) and in the contractility of the electrically driven guinea-pig papillary muscle (pD2 = 6.17) and of the human atrium (pD2 = 5.38). In all these systems, amthamine behaved as a full agonist with a potency comparable to or slightly higher than that of histamine and 10 times higher than that of dimaprit. The positive effects of amthamine were competitively antagonized by ranitidine which had pA2 values (6.46 and 6.25 in the guinea-pig atria and papillary muscle, respectively) comparable with those calculated against histamine and dimaprit. In the isolated rabbit aorta amthamine was devoid of H1-mediated activities up to 3 x 10(-4) M. These results indicate that amthamine is a potent and selective histamine H2-receptor agonist which can be considered a valuable tool for investigating H2-receptor mediated effects in cardiac tissues.

Animals↗
PubMed1993

Histamine H3-receptor-induced inhibition of duodenal cholinergic transmission is independent of intracellular cyclic AMP and GMP.

1. The inhibitory effect of the histamine H3-receptor agonist (R) alpha-methylhistamine on cholinergic neurotransmission was studied in the isolated guinea pig duodenum in the presence of different compounds which alter intracellular levels of cyclic nucleotides and of the G proteins blocker pertussis toxin. 2. The action of (R) alpha-methylhistamine on electrically-evoked contractions was not modified either by forskolin and isobutylmethylxanthine (which increase cyclic AMP) or by zaprinast and methylene blue (which increase and decrease, respectively intracellular cyclic GMP). Drugs affecting cyclic nucleotide levels were also ineffective against the inhibitory effect of the alpha 2 adrenergic agonist clonidine. 3. Pertussis toxin significantly reduced the maximum inhibition induced by (R) alpha-methylhistamine and clonidine, without influencing the effect of low concentrations of the above compounds; conversely it shifted to the right in a parallel way the inhibitory effect of adenosine. 4. These data suggest that H3-receptor-mediated inhibition of cholinergic transmission in the guinea pig duodenum is not linked to intracellular nucleotide changes. Moreover the signal transducing mechanism activated by (R) alpha-methylhistamine involves pertussis toxin both sensitive and insensitive G proteins.

1-Methyl-3-isobutylxanthine↗
PubMed1992

Effects of the novel calcium channel blocker, anipamil, on the isolated rabbit heart. Comparison with verapamil and gallopamil.

The calcium channel blocking activity of the novel phenylalkylamine derivative, anipamil, was tested on the isolated rabbit heart, in comparison with verapamil and gallopamil. Anipamil and the other calcium channel blockers lower left ventricular pressure in the same concentration range (10(-8)-10(-4) mol/l). The negative inotropic effect of anipamil is only partially reversed (nearly 65%) by rising calcium concentration in the perfusion fluid, whilst a complete recovery is observed for verapamil and gallopamil. The negative inotropic effect of anipamil is of rapid onset but long lasting, being still present 12 h after washout. On the contrary, that of gallopamil or verapamil completely disappears within 3 h of washout. Verapamil and gallopamil (10(-8)-10(-4) mol/l) depress spontaneous heart rate up to asystolia and abolish the vasopressin- and Bay K 8644-induced coronary spasm. Anipamil, on the contrary, does not modify coronary spasm elicited by both stimulants and spontaneous heart rate up to 10(-4) mol/l. These observations suggest that anipamil, in the isolated rabbit heart, possesses a peculiar pharmacological profile, since its calcium channel blocking activity is confined to the myocardial muscle.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1992

Antimuscarinic activity of telenzepine on isolated human urinary bladder: no role for M1-muscarinic receptors.

1. The antimuscarinic activity of the selective M1-blocking drug, telenzepine, was investigated on the isolated human urinary bladder, contracted with exogenous muscarinic agonists and with field stimulation. 2. Telenzepine (3 x 10(-8)-10(-5) M) concentration-dependently shifted to the right the dose-response curves of bethanechol, acetylcholine and McN-A343, and partially depressed the electrically-evoked twitch responses. 3. pA2 values of telenzepine against bethanechol and McN-A343 were very close. 4. McN-A343 did not modify twitch responses elicited by field stimulation up to 10(-5) M. 5. The lack of muscarinic M1 receptors in human detrusor muscle is confirmed.

Adult↗
PubMed1992

Actions of two novel prostaglandin analogs, SC-29169 and SC-31391, on guinea pig and human isolated urinary bladder.

1. We examined the effects of two novel PGE1 analogs, SC-29169 and SC-31391, on bladder muscle isolated preparations from guinea pig and man, in comparison with some naturally-occurring prostanoids and misoprostol. 2. In the guinea pig detrusor muscle, both prostaglandin analogs enhanced twitch responses elicited by field stimulation in the following order of potency: SC-31391 greater than SC-29169 greater than PGF2 alpha greater than or equal to PGE2, while a well-defined contractile effect was elicited only by SC-31391. 3. In the human detrusor muscle, nerve-mediated responses were not modified by prostaglandin analogs, as well as by PGF2 alpha or PGE2, while a contractile effect was observed with the same compounds: PGF2 alpha = SC-31391 greater than SC-29169 = PGE2 = PGE1. 4. The selective EP1-agonist, misoprostol did not induce any effect, in both guinea pig and human bladder. 5. These data suggest that the effect of prostaglandins in the bladder muscle differs according to the animal species and that, in the human detrusor muscle, SC-31391 and SC-29169 probably stimulate FP receptors.

Adult↗
PubMed1991

Histamine receptors in isolated guinea pig duodenal muscle: H3 receptors inhibit cholinergic neurotransmission.

A series of histamine H3 receptor agonists and the H3 receptor antagonist thioperamide were tested in the isolated guinea pig duodenum, to investigate the role of this new receptor subtype in the intestinal contractility. At the same time the selectivity of the different compounds for the various histamine receptor subtypes was investigated. In the presence of famotidine (10(-6) M) and thioperamide (10(-5) M), histamine, N alpha-methylhistamine (NMH) and (R)-alpha-methylhistamine (alpha-MH) exerted a concentration-dependent contractile effect through activation of H1 receptors; the ratio of potency was histamine = NMH greater than alpha-MH (this last compound was approximately 500 times less potent). In the presence of pyrilamine (10(-6) M) and thioperamide (10(-5) M), histamine, dimaprit and impromidine caused a slight contractile effect, showing a high degree of tachyphylaxis; this effect was abolished by tetrodotoxin (10(-6) M) and by famotidine (10(-6) M). alpha-MH was ineffective up to 10(-4) M. The H2 receptor agonists dimaprit (10(-4) to 10(-3) M) and impromidine (10(-6) to 10(-5) M) caused a relaxant effect on the contraction elicited by acetylcholine (ACh), BaCl2 and electrical stimulation. This effect, which was unaffected by famotidine, was not mimicked by alpha-MH and not reversed by thioperamide (10(-5) M). In the presence of pyrilamine (109-6) M) and famotidine (10(-6) M), histamine, NMH and alpha-MH inhibited the twitch responses to electrical stimulation, with EC50 values of 1.17 x 10(-7), 6.76 x 10(-8) and 2.45 x 10(-8) M, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Histamine H3-receptor activation inhibits acetylcholine release from the guinea pig myenteric plexus.

The role of histamine H3-receptors in the control of acetylcholine release from peripheral cholinergic neurons was evaluated in the isolated guinea pig ileum, previously loaded with 3H-choline. When tested in the presence of H1- and H2-blockade, histamine (0.1-100 mumol/l) and (R) alpha-methylhistamine (0.01-1 mumol/l) dose-dependently reduced the electrically-evoked choline outflow, with (R) alpha-methylhistamine being a partial agonist. Selective H3-receptor blocking drugs, thioperamide (0.1 mumol/l) and impromidine (0.1 mumol/l) reversed the histamine-induced inhibitory effect. These data suggest that intestinal cholinergic nerves are endowed with histamine H3-receptors whose activation produces an inhibitory effect upon acetylcholine release. The practical implications of these findings are obvious.

Acetylcholine↗
PubMed1991

Histamine H3 receptors regulate acetylcholine release from the guinea pig ileum myenteric plexus.

The effect of selective histamine H3-receptor agonists and antagonists on the acetylcholine release from peripheral nerves was evaluated in the guinea pig longitudinal muscle-myenteric plexus preparations, preloaded with (3H)choline. In the presence of H1 and H2 blockade, histamine (10(-7)-10(-4) M) and (R)-alpha-methylhistamine (10(-8)-10(-6) M) inhibited the electrically-evoked acetylcholine release, being (R)-alpha-methylhistamine more active than histamine, but behaving as a partial agonist. The effect of histamine was completely reversed by selective H3-blocking drugs, thioperamide and impromidine, while only submaximal doses of (R)-alpha-methylhistamine were antagonized. Furthermore, thioperamide and impromidine enhanced the electrically-evoked acetylcholine release. On the contrary, the new H3-blocker, HST-7, was found substantially ineffective, both as histamine antagonist and as acetylcholine overflow enhancer. These data suggest that histamine exerts an inhibitory control on the acetylcholine release from intestinal cholinergic nerves through the activation of H3 receptors.

Acetylcholine↗
PubMed1991

Different effects of captopril and other angiotensin converting enzyme inhibitors on cardiovascular preparations.

The effects of captopril and of other angiotensin-converting enzyme inhibitors (zofenopril, fosenopril and enalaprilic acid) were tested on the isolated rabbit heart and aorta. Captopril elicited an erratic negative inotropic effect and a reduction in basal coronary perfusion pressure (10(-5)-10(-4) M). The increase of coronary perfusion pressure induced by vasopressin, methoxamine, angiotensin II and Bay K 8644 was partially antagonized by captopril (10(-7)-10(-4) M) in a non-specific manner. These actions were not modified by saralasin or indomethacin and by ex vivo pretreatment with captopril itself. On the aortic strips, the contraction plateau induced by KCl and angiotensin II was partially inhibited (10(-6)-10(-4) M), while no effect was observed on those induced by noradrenaline, serotonin and PGF2 alpha. The Ca2+ concentration-response curve appeared shifted to the right in a non-competitive manner. The other angiotensin-converting enzyme inhibitors showed no effect up to 10(-4) M on isolated heart or aorta. Results obtained with captopril were consistent with vasorelaxant activity independent of the tissue renin-angiotensin system. Modulatory activity on the intracellular calcium movement may be involved.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1991

Review article: the histamine H3-receptor: a novel prejunctional receptor regulating gastrointestinal function.

This review examines the evidence for the existence in the gastrointestinal tract of a new subtype (H3) of histamine receptors, previously described in the central nervous system. Study of these receptors is facilitated by the availability of the highly selective agonist (R) alpha-methylhistamine and the selective antagonist, thioperamide. H3-receptors seem to exert negative control on gastric acid secretion evoked by indirect cholinergic stimuli: their localization is unclear but it seems to be outside the parietal cell. H3-receptors also seem to be located on cholinergic and non-adrenergic non-cholinergic (NANC) neurones of the myenteric plexus, where they negatively control the release of neurotransmitters.

Animals↗
PubMed1991

Positive inotropic effect of endothelin-2 on human atrium preparations in vitro.

The inotropic effect of endothelin-2 was investigated on isolated preparations of human atrium taken from patients undergoing cardiac surgery. Pectinate muscle fragments were set up in isolated organ chambers under isometric conditions and electrically stimulated through two ring platinum electrodes. Endothelin-2 (10(-11)-10(-8) M) increased both the force and velocity of contraction in a concentration-dependent manner, giving a maximum response of about 70% of that attainable with histamine or epinephrine. The putative endothelin B receptor agonist, the C-terminal hexapeptide endothelin-(16-21), did not affect inotropic activity. The action of endothelin-2 was not modified by indomethacin and propranolol, thus excluding an involvement of endogenous prostaglandins or catecholamines. The adenylate-cyclase activator, forskolin, and the calcium agonist, Bay K 8644, at concentrations able to enhance the inotropic effect induced by histamine and epinephrine, did not modify the action of endothelin-2. The data show that endothelin-2 has a strong positive inotropic effect on the isolated human myocardium. The effect seems to be independent of the sympathetic system and is unlikely to involve slow channel conductance or cyclic AMP. The lack of activity of endothelin fragment suggests that an endothelin receptor subtype, similar to that found in rat aorta, is present on human atrium.

Endothelins↗
PubMed1990

Ranitidine but not famotidine releases acetylcholine from the guinea pig myenteric plexus.

The effects of the histamine H2-receptor antagonists ranitidine and famotidine on acetylcholine release have been studied in the guinea pig myenteric plexus longitudinal muscle preparation incubated with [3H]-choline. Ranitidine (3 x 10(-5)-3 x 10(-4) M) dose-dependently increased the resting release of acetylcholine and that evoked by electrical stimulation. The effect was present only in strips perfused with 10(-5) M physostigmine. The effect of ranitidine was inhibited by tetrodotoxin and hexamethonium. Famotidine (10(-5)-3 x 10(-4) M) was totally ineffective in modifying both the resting release and that evoked by field stimulation. Ranitidine did not antagonize the inhibitory effect of oxotremorine, which specifically activates negative feedback mechanisms via presynaptic muscarinic receptors.

Acetylcholine↗