Biomedical subjects
Publications and source records attributed to L Berrino.
S 5984 is a combination of tertatolol (S 2395-1) and indapamide. A positive synergism between these two constituents with regard to antihypertensive activity was demonstrated in the rat and the dog.
The anti-inflammatory, analgesic and antipyretic activities of S-(+)-2(4-fluorophenyl)-alpha-methyl-5 benzoxazole acetic acid (flunoxaprofen: Flu), a new non-steroidal anti-inflammatory drug, were compared with those of indomethacin and other non-steroidal anti-inflammatory drugs (NSAIDs) in experimental animals. Flu showed strong inhibitory activity on acute and subacute inflammation tests in rats, such as carrageenin hind paw oedema (oral: 6-25 mg/kg; rectal: 50-100 mg/kg); pellet-induced granuloma formation (5-20 mg/kg/day) and adjuvant-induced arthritis (10 mg/kg/day). Its potency was comparable with that of indomethacin (I) and higher than that of acetyl salicylic acid (ASA), ibuprofen (IBU) or phenylbutazone (P). The analgesic activity of Flu, evaluated by the hot plate method and tail pinching in mice, was slightly lower than that of I but higher than that of ASA and IBU. In pyretic rabbits Flu showed an antipyretic activity higher than that of ASA and IBU. The ability of Flu to affect platelet aggregation, mucopolysaccharide synthesis by fibroblasts and the proteolytic action of trypsin was also investigated.
The synthesis of two series of N-substituted 4,7,7-trimethyl-3-(1-piperidinyl)bicyclo[2.2.1]hept-2-ene 2-carboxamides (I d-h) and 2-carbothioamides (I i-o), as well as of some N-aryl 4,7,7-trimethyl-3-(1-pyrrolidinyl)bicyclo[2.2.1]hept-2-ene 2-carboxamides (I a-c), by reaction of camphor piperidinoenamine and pyrrolidinoenamine with aryl isocyanates and isothiocyanates is described. On the whole compounds (I d-h) showed a weak hypotensive activity in rats.
The synthesis of two series of amides and glycinamides starting from N-phenyl benzonorbornen-2-endo-amine, prepared from benzonorbornen-2-one via sodium borohydride reduction of its N-phenyl imine, is described. Some amides showed a remarkable hypotensive activity in rats, whereas amides and glycinamides usually exhibited a moderate infiltration anesthesia in mice. Effects on heart rate in rats and antiarrhythmic activity in mice are also reported.
The effects of alpha 2-adrenergic stimulating agents (clonidine and guanabenz) and beta-adrenolytic agents (atenolol and propranolol) on the systemic arterial pressure, heart-rate, blood glucose level and intraocular pressure, as well as on the concentrations of glucose, Na+, K+ and Ca++ in the lens and aqueous and vitreous humours, are evaluated in the rabbit. alpha 2-adrenergic stimulating agents cause a significant increase of the glucose concentration in the blood, lens, aqueous and vitreous humours; whereas the beta-adrenolytic agents cause insignificant effects. Neither of the two drugs alters the concentration of Na+, K+ and Ca++ in the lens and aqueous and vitreous humours.
Spermidine (SPD) and spermine (SPM) produced in anaesthetized dogs significant cardiovascular changes at higher doses than other transmitters, i.e. l-noradrenaline, l-adrenaline, histamine, acetylcholine, which produce cardiovascular effects at doses of 0.01-0.05 micrograms/kg given intravenously. SPD was shown to be more active than SPM. The hypotensive response observed after i.v. injection is due to histamine release. The hypotensive and bradycardic effects observed after microinjection of SPD into III cerebral ventricle or into the vertebral artery and of SPM into the vertebral artery are due to an increase in parasympathetic output. Spermidine increased and spermine decreased the baroreceptor reactivity. SPD and SPM did not change the vascular beta- and alpha-adrenergic, cholinergic and histaminergic receptor reactivity.
Putrescine produced in anesthetized dogs significant cardiovascular changes at higher doses than other transmitters. The hypotensive response observed after intravenous injection is due to histamine release. Tachycardic effects seem to be due both to release of histamine and to a reflex stimulation of carotid-sinus baroreceptors. The hypotensive and bradycardic effects observed after microinjection of putrescine into the III cerebral ventricle or into the vertebral artery are due to an increase in parasympathetic output.
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The synthesis of 6-cis-dimethylamino-1,3,3-trimethyl-2-oxabicyclo[2.2.2]octan-5-trans-ol (III) starting from 1,3,3-trimethyl-6-nitrimino-2-oxabicyclo[2.2.2]octane is described. Starting from aminoalcohol (III), a series of N-substituted urethanes (IV) and esters (V), as well as the rigid analogue of acetylcholine (VII), were prepared. A number of compounds (V) and particularly (IV) showed remarkable hypotensive and bradycardic activities in rats, whereas the p-aminobenzoate (V h) showed infiltration anesthesia in mice comparable to that of lidocaine. Antiarrhythmic activity in mice and antiacetylcholine activity in vitro are also reported.
A group of ethyl 6-methylimidazo[2,1-b]thiazole-5-carboxylates and 2-methylimidazo[2,1-b]benzothiazole-3-carboxylates was prepared by reaction of ethyl 2-chloroacetoacetate with some 2-aminothiazoles and 2-aminobenzothiazoles, respectively. Such reactions may sometimes afford a side product which was isolated and characterized. The ethyl esters were then converted into the corresponding acids by hydrolysis. Three of these acids were evaluated for antiinflammatory, analgesic, and antipyretic activities, as well as for ulcerogenic potential.
The aim of the study was to examine whether endothelin-1 (ET-1) injected into dorsolateral periaqueductal gray (PAG) area of mice produces antinociception. ET-1, from 1 to 4 pmol/mouse, induced antinociceptive effect in a dose-dependent manner. This antinociceptive effect was prevented by NMDA receptor antagonists (2-APV and MK-801) injected in the same area (2-APV) or by intraperitoneal route (MK-801). CNQX, a non-NMDA receptor antagonist, did not inhibit the ET-1 effects. Prazosin, an alpha 1-adrenergic blocking agent, also prevented the ET-1 antinociceptive effect. We suggest that the activation of NMDA glutamatergic receptors in the PAG area may be a necessary step for ET-1 induced antinociception.
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The periaqueductal gray (PAG) area seems to play an important role in modulating several biological functions such as the triggering of stereotyped defence and reproductive behaviour, pain, anxiety and cardiovascular and respiratory activities. Anatomically this midbrain area is made up of symmetric neuronal columns arranged along the long axis of the aqueduct. In this paper we review the most important findings of the last 10-15 years about the interaction between the PAG area and the cardiovascular function. It is shown that these neuronal columns within the PAG area exhibit a viscerotropic organization which elicits both hypertensive and hypotensive responses. In particular, the stimulation of the ventral neuronal column evokes a hypotensive response associated with a regional decrease in the vascular resistance. On the contrary, the stimulation of the dorsal and lateral neuronal columns evokes arterial hypertension associated with specific changes of the vascular resistance. Recently the authors demonstrated that the glutamergic system in the PAG area (prevalently through NMDA subtype receptor) may also be involved in the control of cardiovascular system. Moreover, the involvement of the arginine vasopressin neuropeptide in the hypertension induced by administration of excitatory amino acids into the PAG area has been demonstrated.
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The expression profiles of genes involved in cell proliferation, differentiation and programmed death were investigated in carotids of spontaneously hypertensive rats (SHR) treated with a model of surgical injury that mimics events occurring during arterial grafts, endarterectomy and organ transplantation. The mRNA level of the c-myc, angiotensin II receptor 1 (AT1), Rb/p105, Rb2/p130, Bcl-2 and Bax-alpha genes was assessed by a semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) technique at different times up to 48 h after injury, while the morphological changes were evaluated 30 days after injury. The proliferation marker c-myc increases almost immediately, peaks after 4 h and returns to basal levels after 24 h; the AT1 receptor mRNA reaches its maximal level 48 h after injury. The level of cell cycle exit markers Rb/p105 and Rb2/p130 gradually decreases after injury. The apoptosis marker Bcl-2/Bax-alpha ratio shows a significant reduction only 4 h after injury, resuming the initial value after 24 and 48 h. Morphological analysis reveals that surgical injury in SHR induces adventitial and medial constrictive remodeling changes rather than intima proliferation as in balloon angioplasty. Both molecular and histological data show substantial differences with respect to normotensive rats.