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In anaesthetized ventilated guinea-pig, acetaldehyde (CAS 75-07-0) (40-80 mg/kg i.v.) elicits a dose-dependent increase in intratracheal pressure accompanied by an increase in circulating histamine. When acetaldehyde is injected repeatedly at 15 min intervals in capsaicin-desensitized animals, it already loses its activity at the second administration (50% reduction; p < 0.01); this does not happen in control animals. This phenomenon is even more marked when acetaldehyde is given at the dose of 80 mg/kg i.v., since at the third injection both the bronchoconstriction and the increase in blood histamine are almost completely reduced to baseline values. The increase in intratracheal pressure caused by acetaldehyde (20, 40, 80 mg/kg i.v.) is associated with a dose related increase in microvascular permeability and leakage of protein-bound Evans blue in lower tracheal tissue. This event and the bronchoconstrictor response caused by acetaldehyde (40 mg/kg i.v.) are 87% and 35% inhibited, respectively, (p < 0.01) in tachykinin-depleated animals. On the contrary, thiorphan (2 mg/kg i.v.) remarkably potentiates both the rise in intratracheal pressure (110%; p < 0.01) and Evans blue extravasation (215%; p < 0.01) induced by acetaldehyde (20 mg/kg i.v.) in normal guinea-pigs. Furthermore, treatment with CP-96,345, a selective tachykinin NK1-receptor antagonist, only prevents plasma extravasation in lower tracheal tissue (82% inhibition; p < 0.01) without affecting the bronchoconstriction caused by acetaldehyde (40 mg/kg i.v.).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaldehyde administered intravenously at various doses (20, 40 and 80 mg/kg) elicits a dose-dependent increase in intratracheal pressure (ITP) and a proportional rise in histamine blood concentration in anaesthetized guinea-pigs. Similar effects were observed in ovalbumin-sensitized guinea-pigs upon aerosol of acetaldehyde (20 mg/ml) which has been administered at the flow rate of 0.1 ml/min for 2 min. Theophylline (CAS 58-55-9) antagonized both the increase of ITP values and the rise of histamine in the blood caused by acetaldehyde given intravenously (ED50 = 5.8 mg/kg i.v.) or by aerosol (ED50 = 4.9 mg/kg i.v.). Furthermore, in animals where combined treatment with pyrilamine (2 mg/kg i.v.) and captopril (2 mg/kg i.v.) resulted in a remarkable potentiation of the bronchoconstrictor response to acetaldehyde (20 mg/kg i.v.), the administration of theophylline (5 mg/kg i.v.) or of the substance P (SP) receptor antagonist, [D-Pro4, D-Trp7.9] SP 4-11 (10 mg/kg i.v.) reduced the augmented action of acetaldehyde on respiratory airways induced by captopril by more than 50%. Moreover, the bronchoconstriction induced by acetaldehyde (40 mg/kg i.v.) was also associated with a significant increase of extravasation of Evans blue in tracheal tissue. Both these effects of acetaldehyde were inhibited by theophylline (10 mg/kg i.v.), whereas a NK1-TK (neurokinin 1-tachykinin) receptor antagonist (412 micrograms/kg i.v.) reduced (81%; p < 0.001) only the vascular permeability changes caused by acetaldehyde.(ABSTRACT TRUNCATED AT 250 WORDS)

Using isolated perfused rabbit heart electrically paced, we assessed the relevance of both nitric oxide (NO) and prostacyclin (PGI2) in regulation of resting coronary perfusion pressure (CPP). In preparations in which NO-synthase was inhibited by NG-monomethyl-L-arginine (L-NMMA, 10 microM), resting CPP increased significantly; this phenomenon was potentiated by indomethacin infusion (3 microM), prevented by L-arginine (100 microM) and significantly reduced by iloprost (55 nM) and defibrotide (200 micrograms/ml). Furthermore, the increase in resting CPP induced by graded doses of endothelin-1 (ET-1 0.6-160 pmol), was further augmented by blocking of prostaglandin biosynthesis with indomethacin (3 microM) and was substantially reduced when the rate of formation of PGI2 was enhanced by defibrotide (200 micrograms/ml). Moreover, the coronary vasoconstriction induced by ET-1 (2, 4, and 8 pmol) was increased in hearts in which NO-synthase was blocked by L-NMMA (10 microM) and this event was abolished in preparations in which PGI2 synthesis was stimulated by defibrotide (200 micrograms/ml). These results further emphasize that rabbit coronary vessels are continuously dilated by NO released from endothelial cells. They also indicate that PGI2 takes part in NO generation in the endothelial-derived relaxing mechanism. Inactivation of this mechanism, owing to decreased formation of NO and PGI2 in rabbit heart, induces hyperreactivity of coronary smooth muscles to ET-1. Finally, an increase in PGI2 production (such as that caused by defibrotide) may counterbalance impaired NO generation and attenuate hyperreactivity of the coronary vasculature.

The specific binding of broxaterol, a potent new orally active antiasthmatic drug, to beta 1- and beta 2-adrenoceptors was characterized by receptor binding studies with rat heart and lung membrane preparations. Broxaterol showed high affinity and selectivity for the beta 2-component of [3H]dihydroalprenolol binding in both lung (58% beta 2-sites, Ki = 130 nM) and heart membranes (19% beta 2-sites, Ki = 98 nM), whereas the binding to the beta 1-component was at lower affinity (42% beta 1-sites, Ki = 4100 nM in the lung and 81% beta 1-sites, Ki = 3460 mM in the heart). The influence of temperature changes on the binding properties of broxaterol towards beta-adrenoceptors was also investigated. A marked increase in the affinity of broxaterol for lung beta-receptors was observed on lowering the assay temperature, whereas the affinity for heart beta-receptors was little affected by temperature changes. Thermodynamic analysis of the binding data showed that the binding of broxaterol as well as isoproterenol to lung beta-receptors was associated with a large decrease in enthalpy, which correlates well with the full agonistic properties of this compound at beta 2-receptors.

A series of 1-(3-substituted-5-isoxazolyl)-2-alkylaminoethanol derivatives was synthesized in order to evaluate the effectiveness of the isoxazole ring in replacing the catechol moiety of beta-adrenergic compounds. Among the investigated compounds, 1-(3-bromo-5-isoxazolyl)-2-tert-butyl aminoethanol hydrochloride, named broxaterol hydrochloride (laboratory code Z 1170), resulted to be the most potent and selective beta 2-agonist of the series. In vitro studies confirmed the beta 2-agonist profile of broxaterol, which showed a marked bronchodilating activity in different experimental models. Interestingly, besides its direct effect in relaxing bronchial smooth muscle, broxaterol was, also, very effective in inhibiting asthmogenic mediator release both in vitro and in vivo. The preclinical studies demonstrated that the similar potency observed in vitro for both broxaterol and salbutamol resulted in a higher effectiveness of broxaterol with respect to salbutamol, when the compounds were given by oral route. These findings account for a probably greater bioavailability of broxaterol after oral administration.

A series of pyrroles bearing an ethanol- or an iso-propanolamine side-chain in the beta-position was prepared and their adrenergic activity evaluated. The absence of any appreciable activity suggests that the pyrrole ring is not suitable for replacing the phenol nucleus in derivatives possessing an adrenergic activity. Noteworthy is the amphetamine-like activity observed in amino-ketone (XXIII).

We investigated the effect of bestatin, a specific inhibitor of aminopeptidase and thiorphan, a specific inhibitor of enkephalinase A, on the analgesic effect induced by the intracerebral injection of heptapeptide [Met5]enkephalin-Arg6-Phe7 (MEAP) in cannulated rats. In contrast with the results obtained when [Met5]enkephalin (ME) was used, bestatin clearly potentiated the analgesic effect of MEAP, but thiorphan was totally ineffective. These observations indicate that the predominant inactivating mechanism for MEAP is the action of an aminopeptidase whereas this enzyme seems to be little involved in the catabolism of ME. The existence of two different catabolic pathways for MEAP and ME suggests that MEAP may act not only as a precursor of ME but also as an independent neuromodulator.

The synthesis of the stereoisomers of the centrally acting analgesic 1-[1-(2-chlorobenzyl)-pyrrol-2-yl]-2-di-sec.-butylamino-ethanol (viminol) is described. Their absolute configuration has been shown by comparing the circular dichroism (CD) curves with those of some phenyl analogs: for one of the viminol stereoisomers the postulated configurational assignment has been recently confirmed by an X-ray analysis. The pharmacological properties shared by the viminol stereoisomers are also described. The R,R configuration of the sec.-butyl groups and the S configuration of the hydroxy group appear to be essential for the agonistic effects: analgesia, tolerance and physical dependence in rodents. The S,R,R configurated viminol does not substitute, however, for morphine in monkeys, using the single dose suppression test. S,S or R,S(S,R) configurations of the sec.-butyl groups are associated with antagonistic properties. The binding capacity of the viminol stereoisomers to the opiate receptors and their influence on the acetylcholine release from the intestinal cholinergic terminals electrically stimulated are also described.

The synthesis of new 2-(3-substituted-5-isoxazolyl)-2-methoxyiminoacetic acids and their condensation derivatives with a suitable cephalosporanic nucleus, is reported. Their antibacterial properties were tested in vivo and in vitro also against beta-lactamase producer microorganisms; particularly the oral bioavailability of some of these new derivatives was studied.

The synthesis and pharmacological evaluation of a number of symmetrical bivalent ligand type beta-adrenolytics related to practolol are reported. The best results have been observed with N,N'-bis[3-[2-hydroxy-3-[1-methylethyl)amino]propoxy]phenyl] ethanediamide.

The effect of the inhibition of aminopeptidase and enkephalinase A on the pain threshold of mice and rats was investigated, using bestatin and thiorphan as selective peptidase inhibitors. The results indicate that both enzymes are relevant to the catabolism of enkephalins in vivo; however, their simultaneous activation requires particular conditions. These conclusions are based on the following observations: (1) Only concomitant intracerebral treatment with both inhibitors led to an increase in the threshold of animal pain, whereas, in the presence of exogenous peptides, the concomitant injection of both inhibitors in mice elicited an analgesic response greater than the sum of the effects of each single inhibitor. (2) This response could be seen only after acute trauma; in fact, when the drugs were injected through a plastic cannula, only enkephalinase A inhibition was effective in increasing analgesia induced by exogenous peptides.

Opioids' modulation of beta-receptors' density and function has been investigated in a cultured cell line system. Rat C6 glioma cells do not have opioid receptors or, at least, the number of these receptors is very low, but cell exposure to desmethylimipramine (DMI) causes expression of functional opioid receptors as indicated by the increased [3H]DHM binding and by the acquired ability of opioids to inhibit ISO-stimulated cAMP accumulation. Cell exposure to DMI also causes beta-receptors' down-regulation as indicated by the decline in [3H]DHA binding coupled to a reduced ability of isoproterenol (ISO) to stimulate cAMP accumulation in intact cells. In the present paper we show that cell exposure to opioid agonists during DMI treatment counteracted DMI-induced beta-receptor loss. Similarly, opioid agonists added at the beginning of ISO exposure in DMI-pretreated cells, inhibited ISO-induced beta-receptor tachyphylaxis. These results suggest that opioids may exert a protective effect on beta-receptor function and this appears to be a common mechanism which is operant when overstimulation of beta-receptors takes place.

A series of 1-(3-subst-5-isoxazolyl)-2-alkylaminoethanol derivatives was synthesized and tested in order to evaluate the effectiveness of the isoxazole ring in replacing the catechol moiety of beta-adrenergic compounds. Direct binding studies and the influence on beta-receptors mediated responses in isolated guinea-pig atria and guinea-pig trachea were investigated to determine the pharmacological profile of the new derivatives. The results indicate that some derivatives with proper substitution in the isoxazole ring and in the aminoalcohol chain displayed a marked selectivity towards beta 2 tracheal receptors. In vivo studies confirmed this profile, and the derivative 1-(3-bromo-5-isoxazolyl)-2-tert.butyl aminoethanol hydrochloride was selected and further developed as a potential bronchodilatory agent.

Evidence has been obtained suggesting that cathinone-induced analgesia depends upon stimulation of alpha-adrenoceptors, followed by release of opioid peptides and by activation of serotonergic pathways. This hypothesis is supported by the following. (1) Cathinone potentiated morphine analgesia and the whole effect was antagonized by naloxone whereas onto the cathinone potentiation was counteracted by phenoxybenzamine. (2) Bestatin potentiated cathinone-induced analgesia and this effect was sensitive to both naloxone and phenoxybenzamine blockade. (3) The analgesic effect of cathinone + bestatin was further potentiated by the serotonin uptake inhibitor citalopram.

A number of symmetrical as well as asymmetrical bis-arenoxypropanolamines have been synthesized and evaluated for their beta-adrenolytic properties. The pharmacological characterization of these compounds was performed in vitro by direct studies (3H-dihydroalprenolol was used as the specific ligand for beta-receptors), and by determining the beta-blocking capacity on isoproterenol (ISO)-induced increased heart rate (isolated guinea-pig atrium); and in vivo by evaluating the antagonism on ISO-induced hypotension and tachycardia, as well as the intrinsic sympathomimetic activity (ISA) on reserpinized and vagotomized rats. The best result was observed with the simplest derivative, i.e. the bis-phenoxypropanolamine compound, which shows in vitro and in vivo potencies almost comparable to propranolol and, moreover, significant bronchodilating activity.

On the frog rectus abdominis muscle and on sciatic nerve-tibialis anterior muscle preparations, beta-diethylaminoethyl 3,3-diphenylpropylacetate (SKF 525A) antagonized the actions of acetylcholine and potassium chloride as well as having an antiveratrine action. The blocking action at the skeletal neuromuscular junction of suxamethonium and its disulphonium analogue, decamethonium, tubocurarine and gallamine was enhanced by SKF 525A in the rabbit and in the isolated rat phrenic nerve-diaphragm preparation. The activity of suxamethonium and decamethonium in the cat was reduced. On the rat phrenic nerve-diaphragm preparation, pretreatment with SKF 525A abolished both the mutual antagonism between suxamethonium and tubocurarine and the antagonizing effect of tetraethylammonium against suxamethonium. Theantagonism between tetraethylammonium and tubocurarine was unimpaired.