Biomedical subjects
Publications and source records attributed to M Massi.
Emphysematous pyelonephritis is an unusual and serious infection, associated with the formation of gas by choliphormi bacteria. The authors present a case of monolateral emphysematous pyelonephritis in an obese and diabetic patient, put under observation and treated successfully through percutaneous drainage and antibiotic therapy.
Our previous studies have shown that i.c.v. injections of the selective tachykinin NK3 receptor agonist [Asp5,6,MePhe8]substance P(5,11), also referred to as NH2-senktide (NH2-SENK), inhibit salt intake in rats in a two-bottle intake test. The present study evaluated the effect of i.c.v. injections of NH2-SENK on intraoral intake and taste reactivity responses elicited by intraoral infusions of water or NaCl solutions (0.03, 0.15, 0.25 and 0.5 M) in sodium-replete rats. The effect of NH2-SENK on the intake of 0.03, 0.15 and 0.25 M NaCl solutions and of water was also evaluated in a two-bottle intake test. In this test, 31 ng/rat of NH2-SENK significantly reduced the intake of 0.15 and 0.25 M NaCl, but not that of water or of 0.03 M NaCl. The dose of 31 ng/rat of NH2-SENK reduced the intraoral intake of 0.25 and 0.5 M NaCl, while 125 ng/rat reduced the intraoral intake of 0.15, 0.25 and 0.5 M NaCl; neither dose reduced the intraoral intake of water or of 0.03 M NaCl. Taken together, these findings indicate that the effect of NH2-SENK on salt intake is dependent on the concentration of the NaCl solution offered; moreover, the intraoral intake data suggest that the effect of NH2-SENK on salt intake may be exerted to a large extent on the consummatory processes of salt ingestion. NH2-SENK, 31 or 125 ng/rat, altered taste reactivity responses shortly after the beginning of the intraoral infusion. The most peculiar effect was an increase in passive dripping during the first min of intraoral infusion of 0.15, 0.25 and 0.5 M, but not of water or of 0.03 M NaCl. This finding suggests that NH2-SENK elicits a prompt alteration of taste mechanisms for salt, which may account for its antinatriorexic action.
The angiotensin AT1 receptor antagonists, losartan (2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'(1H-tetrazol-5-yl)biphen yl-4- yl)methyl]imidazole potassium salt), EXP3174 (2-n-butyl-4-chloro-1-[(2'(1 H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic acid), GR117289 (1-[[3-bromo-2-[2-(1 H-tetrazol-5-yl)phenyl]-5-benzofuranyl]methyl]-2-butyl-4-chloro-1 H-imidazole-5-carboxylic acid) and LR-B/081 (methyl-2-[[4-butyl-2-methyl-6-oxo-5-[[2'-(1 H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1(6H)-pyrimidinyl]met hyl]-3- thiophenecarboxylate), given by intraperitoneal (i.p.) injection 15 min before intracerebroventricular administration of angiotensin II, inhibited drinking with the following order of potency: EXP3174 > GR117289 > losartan > LR-B/081. When 20 mumol/kg of each antagonist was i.p. injected 15 min, 4, 12 or 24 h before angiotensin II, EXP3174 and GR117289 inhibited water intake at each observation time, losartan at 4, 12 and 24 h, LR-B/081 only at 4 and 12 h. After per os administration of the same dose 4 or 12 h before angiotensin II, losartan reduced drinking at 4, but not at 12 h; LR-B/081 did not inhibit drinking either at 4 or 12 h. The present results suggest that EXP3174 and GR117289 cross the barrier readily. The effect of i.p. losartan on central angiotensin mechanisms is not prompt, suggesting that it may require conversion to EXP3174. LR-B/081 apparently crosses the barrier less readily than the other antagonists following both i.p. and per os administration.
The 5-HT2 receptor antagonist, ritanserin, reduces alcohol intake in rats and the nucleus accumbens (NAC) has been proposed as a site of action for the drug. Recent microdialysis studies have shown that acute subcutaneous (SC) administration of ritanserin increases extracellular 5-HT levels in the NAC. The present study evaluated, in genetically heterogeneous rats with developed preference for 3% ethanol, whether the attenuation of ethanol intake induced by ritanserin might be related to its effect on the synaptic availability of 5-HT in the NAC. Damaging 5-HTergic neurons by intracerebroventricular infusion of 5,7-dihydroxytryptamine (5,7-DHT) abolished the effect of ritanserin on ethanol consumption. Injections of the 5-HT3 receptor antagonist MDL 72222 into the NAC significantly reduced the inhibitory effect of SC injection of ritanserin, 1 mg/kg, and completely abolished the effect of ritanserin, 0.1 mg/kg. Subcutaneous injections of MDL 72222, 0.3 mg/kg 3 times/day, suppressed the effect of SC ritanserin, 0.1 mg/kg. The present findings, together with those of previous experiments showing that the tryptophan hydroxylase inhibitor p-chlorophenylalanine abolishes the effect of ritanserin, support the hypothesis that its effect on ethanol intake may be due to increased synaptic availability of 5-HT into the NAC.
New doxazosin-related compound (1-3) with a N,N'-dimethyl alkanediamine chain replacing the piperazine ring, have been synthesized and their pharmacological properties have been tested together with some prazosin analogues (4-8) bearing either a similar structural modification or a substituted piperazine moiety. In the in vitro study, on alpha 1- and alpha 2-adrenoceptors of rat vas deferens tissues, 1-3 displayed high alpha 1-antagonist activity, 2 and 3 being equipotent to doxazosin but markedly less selective in respect to alpha 2-adrenoceptors. Replacement of the piperazine ring with an alkanediamine chain resulted in a strong fall in alpha 1-selectivity, owing to increased alpha 2-antagonist activity, as in the prazosin-related series. In in vivo studies, the antihypertensive activity of tested compounds was investigated on spontaneously hypertensive rats (SHR) following both intragastric (IG) and intraperitoneal (OP) administration. Among the tested compounds, 7 and 8, which conserved a substituted piperazine ring, proved the most interesting drugs displaying a marked hypotensive effect. The other prazosin- and doxazosin-related compounds, in which an alkanediamine chain replaced the piperazine nucleus, showed an antihypertensive activity markedly lower than that of parent compounds, prazosin (CAS 19216-56-9) and doxazosin (CAS 74191-85-8), although a high alpha 1-antagonist activity in in vitro tests was conserved. These results suggest that the piperazine ring of the prazosin- and doxazosin-related compounds, although not crucial for alpha 1-antagonist activity, may play an important role in the antihypertensive effect, probably by influencing the pharmacokinetic properties of the antagonist.
LR-B/081, methyl-2-[[4-butyl-2-methyl-6-oxo-5-[[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl] methyl]-1(6H)-pyrimidinyl] methyl]-3-thiophenecarboxylate, is a recently developed nonpeptide antagonist selective for angiotensin AT1 receptors. The drug has been reported to be an insurmountable angiotensin AT1 receptor antagonist endowed with long-lasting antihypertensive activity. A large body of evidence indicates that angiotensin AT1 receptors mediate the dipsogenic action of angiotensin II in the central nervous system. The present study evaluated the ability of LR-B/081, in comparison with losartan and with its active metabolite EXP3174, to inhibit drinking induced by central injection of angiotensin II in water-sated rats. LR-B/081, in the dose range of 10-1000 pmol/rat, dose dependently inhibited the drinking response to angiotensin II, 10 pmol/rat. The ID50 of LR-B/081 was 25.9 pmol/rat, while that of losartan and EXP3174 was 357 and 3.9 pmol/rat, respectively. Therefore LR-B/081 was about 7 times less potent than EXP3174, but about 14 times more potent than the parent molecule losartan. LR-B/081 altered neither carbachol-induced water intake, nor 15% fat milk intake in rats, suggesting that its effect on angiotensin II-induced drinking is a behaviourally selective effect. These findings show that LR-B/081 potently inhibits central angiotensin AT1 receptors involved in behaviourally selective effect. These findings show that LR-B/081 potently inhibits central angiotensin AT1 receptors involved in the control of body fluid homeostasis and suggest that this drug might be an interesting pharmacological tool to further investigate the role of the central renin-angiotensin system in physiological or pathological conditions.
The present study evaluated the effect of the selective and long-acting dopamine D1 receptor antagonist SCH 39166 on several aspects of the ingestive behaviour of genetically selected alcohol-preferring rats, bred from Sardinian alcohol-preferring rats. The effect of subchronic (8 days) subcutaneous drug administration was evaluated on the simultaneous daily intake of 10% ethanol, food and water. SCH 39166, 0.1 mg/kg, did not significantly modify the intake of the three ingesta. The dose of 1 mg/kg differentially modified rat ingestive behaviour, inhibiting intake of 10% ethanol, without modifying total fluid and food intake. The higher dose of 5 mg/kg produced a non-selective suppression of ingestive behaviour, which was accompanied by behavioural impairment. Acute drug injection was tested on 2-h intake of 10% sucrose, 0.1% saccharin, water or food. The doses of 0.1 and 1 mg/kg markedly inhibited the 2-h intake of 10% sucrose and 0.1% saccharin, but they did not modify either the 2-h water intake in water deprived and water sated rats or the 2-h food intake in food deprived rats. These findings suggest an important role of mechanisms mediated by D1 receptors in the control of alcohol and sweet solution intake, but not in water and food intake. Moreover, they indicate that SCH 39166, in relation to its selectivity and long-lasting activity, is an interesting pharmacological tool to investigate further the role of D1 receptor mechanisms in the control of ingestive behaviour.
Neuropeptide gamma (NP gamma) is a 21 aminoacid peptide belonging to the tachykinin (TK) family and including neurokinin A (NKA) in its C-terminal sequence. NP gamma possesses higher affinity than NKA for central NK-2 receptors; it shows lower affinity for NK-1 receptors, however, it potently stimulates salivary secretion, which is mediated by NK-1 receptor activation. Pulse intracerebroventricular (pICV) injection of TKs selectively inhibits water intake in rats. Our studies have suggested that NK-1 receptors may mediate the inhibition of angiotensin II-induced drinking, while NK-2 receptors that of drinking induced by cell dehydration. The present study evaluated the effect of pICV injections of NP gamma on water intake in rats. The injection of NP gamma, 8-250 ng/rat, markedly inhibited angiotensin II-induced drinking, and its effect was blocked by the NK-1 receptor antagonist WIN 62577. NP gamma potently inhibited also drinking induced by SC hypertonic NaCl load or water deprivation. The threshold dose for these effects was 31 ng/rat. Also carbachol-induced drinking was inhibited, but at higher doses. On the other hand, NP gamma did not modify food intake in food deprived rats or 0.1% saccharin intake in water and food sated rats, at the same doses effective on drinking. Present findings support the idea that TKs selectively inhibit water intake in rats and are in keeping with our hypothesis that NK-1 and NK-2 receptors mediate, respectively, inhibition of angiotensin II- and cell dehydration-induced drinking.(ABSTRACT TRUNCATED AT 250 WORDS)
The selective NK3 tachykinin agonist senktide evokes in rodents 5-HT mediated behaviors, including 5-HT2 receptor-mediated wet dog shakes (WDS) and head shakes (HS). It was observed previously that genetically selected Sardinian alcohol-preferring (sP) rats show a small number of WDS and HS following intracerebroventricular (ICV) injection of senktide. The present study was aimed at confirming these observations and at providing information on the reasons accounting for the anomalous response of sP rats. Senktide (500-2000 ng/rat, ICV) produced a much lower number of WDS and HS in sP rats than in nonselected Wistar (nsW) rats. Both behaviors were suppressed by the 5-HT2 antagonist ritanserin (1 mg/kg, subcutaneously), confirming that 5-HT2 receptors mediate the response. HS induced by the ICV injection of 5-HT agonists endowed with marked activity at 5-HT2 receptors, such as quipazine (1500-6000 ng/rat) or DOI (500-3500 ng/rat), were much less pronounced in sP rats than in nsW rats. Moreover, WDS following peripheral injection of 5-hydroxytryptophan, 25-100 mg/kg, and carbidopa, 12.5 mg/kg, were less intense in sP and in ethanol-naive sP rats than in nsW and in Sardinian alcohol-nonpreferring rats. These findings suggest that sP rats have an inherent different regulation of central 5-HT2 mechanisms.
The present study evaluated the effect of the selective 5-HT4 receptor antagonist, GR113808, on ethanol intake in alcohol-preferring rats. Rats were offered 10% ethanol 2 h/day. In the first experiment, rats had food and water ad lib and 10% ethanol was offered from 1800 to 2000 h. In the second experiment, food was freely available, 10% ethanol was offered 2 h/day, from 1800 to 2000 h, and water was offered for 4 h, from 1800 to 2200 h. In both experiments GR113808 was subcutaneously injected at doses of 1, 3, or 10 mg/kg for 4 consecutive days, 5 min before access to ethanol. From the first day of administration, GR113808 significantly reduced the volitional ethanol intake in water sated rats at the three doses tested. In water-deprived rats, it reduced ethanol intake at 3 and 10 mg/kg, without modifying total fluid and food intake. In both experiments the effect of GR113808 remained rather stable during the 4 days of administration. The present findings, showing that the 5-HT4 receptor antagonist, GR113808, selectively reduces ethanol intake in alcohol-preferring rats, suggest that 5-HT4 receptors may play a role in alcohol intake control.
The present study evaluated the effect of SC injections of the selective NK3 tachykinin agonist, Suc-[Asp6,MePhe8]substance P(6-11), also referred to as senktide (SENK), on 8% alcohol intake in genetically selected alcohol-preferring rats. Animals were offered access to 8% ethanol for 2 h/day (between 1800 and 2000 h) and to tap water for 4 h/day (between 1800 and 2200 h); SENK was injected 10 min before access to fluids. The peptide significantly reduced alcohol intake at doses of 125 and 250 micrograms/kg, but not at 62.5 micrograms/kg. The reduction in alcohol intake was accompanied by a sharp increase in water intake, so that total fluid intake was never significantly modified. The same SC doses of SENK did not modify water intake in rats with access to water, as the only fluid, for 4 h/day. In food-deprived rats food intake was not altered by 125 micrograms/kg, whereas 250 micrograms/kg produced a reduction in food intake that was smaller in intensity and shorter lasting than the reduction in alcohol intake. The same doses of SENK did not modify 0.1% saccharin intake, nor did they elicit major competing behaviors. The results of the present study are in keeping with those obtained following central injection of NK3 agonists, and show that a behaviorally selective reduction of alcohol intake can be evoked also by peripheral administration of SENK.
The present study investigated the effect of 24-h continuous ICV infusion of four different tachykinins on the enhanced need-free sodium intake induced by previous repeated sodium depletions in female rats. Female rats were employed because, in response to sodium depletions, they develop a higher need-free sodium intake than male rats. The following tachykinins were used: eledoisin, substance P (SP), [Sar9,Met(O2)11]SP and [Asp5,6,MePhe8]SP(5-11), also referred to as NH2-senktide, all at the same doses of 300 or 600 ng/h x 24 h. Food pellets, water, and 3% NaCl sodium solution were freely available. Eledoisin and NH2-senktide were more potent than SP in reducing the need-free sodium intake. On the other hand, [Sar9,Met(O2)11]SP had no effect. None of the tachykinins employed completely blocked the intake. Water intake was reduced, but this reduction was apparently a consequence of reduced intake of hypertonic sodium chloride solution, because at the same doses TKs did not inhibit water intake in a single-bottle test. Food intake remained unchanged at either dose used. These findings confirm previous studies in which pulse injection of the same drugs potently inhibited sodium intake. They also demonstrate that tachykinins endowed with high affinity for the NK3 receptor are the most potent in inhibiting sodium intake. Furthermore, these findings indicate that the tachykinins reduce the need-free sodium intake only during the infusion period, indicating that in these conditions they do not evoke either aversion for salt, or toxic consequences in the follow-up period.
The present study investigated the effect of the central injection of selective tachykinin (TK) agonists on the need-free intake of 0.9% NaCl in rats. Isotonic NaCl was offered for 60 min (between 1800 and 1900 h); water was offered for 4 h (between 1800 and 2200 h). The TK agonists were injected into the third ventricle just before access to fluids. The NK3-selective agonists [Asp5,6,MePhe8]substance P(5-11) and Succ[Asp6,MePhe8]substance P(6-11), as well as the NK1-selective agonist [Sar9, Met(O2)11]substance P, markedly reduced salt intake, the threshold dose for their effects being 5 ng/rat. The NK2-selective agonist GR64349 reduced salt intake only at 500 ng/rat. At the dose of 31.2 ng/rat, neither the NK1 nor the NK3 agonists inhibited water intake, when water was the only fluid offered (between 1800 and 2200 h), or modified food intake in food-deprived rats. The present study shows that a) TKs inhibit not only the need-induced salt intake, but also the need-free intake of isotonic saline, b) this effect is behaviorally selective, and c) the effect is apparently mediated by NK1 and NK3 receptors. The finding that TKs suppress salt intake in a large variety of experimental conditions supports the idea that the antinatriorexic effect of TKs is independent of the physiological and hormonal status of the animal. It is hypothesized that TKs might modify taste sensitivity or the hedonic evaluation of the salty taste.
The present study evaluated the effect of tachykinin agonists, selective for different neurokinin (NK) receptors, on alcohol intake in genetically selected, Sardinian alcohol-preferring rats. Tachykinins were given by intracerebroventricular injection just before access to fluids. In rats offered both water and 8% ethanol 2 h/day, the NK3 selective agonists [Asp5.6,MePhe8]substance P(5-11), Suc[Asp6,MePhe8]substance P(6-11), and [MePhe7]neurokinin B markedly suppressed alcohol intake. The NK1 selective agonist [Sar9,Met(O2)11]substance P and the NK2 selective agonist GR 64349 did not At doses that inhibited alcohol intake, the NK3 agonists did not modify water intake; total fluid intake was significantly reduced only following 500 ng/rat of [Asp5.6,MePhe8]substance P(5-11). When rats were given a longer access to fluids (8% alcohol for 2 h, but water for 4 h), again, NK3 agonists suppressed alcohol intake, but not total fluid intake. Moreover, NK3 agonists did not modify solid food intake in food-deprived rats, nor water intake in water-deprived rats, when alcohol was not available. These findings indicate that NK3 agonists inhibit alcohol intake in Sardinian alcohol-preferring rats and that their effect is behaviorally selective. They also suggest that central NK3 receptors may be involved in alcohol intake control in rats.
Several prazosin-related compounds have been synthesized and evaluated for their blocking activity toward alpha-adrenoreceptors. The structural modification performed on the prazosin structure included the replacement of the piperazine ring with 2,3-dialkylpiperazine or 1,2-cyclohexanediamine moieties to characterize a lipophilic binding pocket in the alpha 1-adrenoreceptor surface. Cyclohexanediamine derivatives 3-6 were almost devoid of potency and selectivity, whereas dialkylpiperazine compounds 7-14 showed high affinity and selectivity toward alpha 1-adrenoreceptors. The cis derivative 13 (cyclazosin) was the most potent and selective with an alpha 1/alpha 2 selectivity ratio value of 7800. The particular trend of antagonist activity within cis/trans stereoisomeric compounds not only supports the presence of a lipophilic binding area on alpha 1-adrenoreceptor surface but also suggests that the lipophilic pocket is endowed with a well-defined size and spatial orientation. The most active compound of the series, 13, was tested also in vivo for antihypertensive activity on spontaneously hypertensive rats. It showed an interesting long-lasting hypotensive effect, very similar to that of doxazosin, which was statistically significant 12 h after oral administration.
The present study investigated the effect of the 5-HT2/1C receptor antagonist ritanserin, and of the 5-HT2/D2 receptor antagonist risperidone on ethanol preference in Sardinian alcohol-preferring (sP) rats. Rats were offered free access to both tap water and 8% (in one experiment 3%) ethanol solution. Subchronic (10 or 1 mg/kg/day, for 10 days) or chronic (1 mg/kg/day, for 30 days) subcutaneous (SC) ritanserin treatment failed to reduce 8% ethanol preference. Risperidone doses that produce marked 5-HT2, but low dopamine D2, receptor blockade (1 and 0.1 mg/kg/day, SC, for 9 and 10 days, respectively) did not modify 8% ethanol preference. On the other hand, a high risperidone dose (10 mg/kg/day, SC, for 14 days), which produces pronounced dopamine D2 receptor blockade, reduced 8% ethanol preference, like the dopamine receptor antagonist haloperidol. Previous studies have shown that both ritanserin and risperidone evoke long-lasting and pronounced suppression of 3% ethanol preference in genetically nonselected rats. However, in the present study, SC ritanserin treatment (1 mg/kg/day for 10 days) did not modify 3% ethanol preference in sP rats. The failure of 5-HT2 antagonists to reduce ethanol preference in sP rats raises the question whether genetic selection might have resulted in altered regulation of 5-HTergic mechanisms in sP rats.
The present study evaluated the effect of central injections of the 5-HT2/1C receptor antagonist, ritanserin, on ethanol intake in rats with developed preference for 3% ethanol. Intracerebroventricular (ICV) injections of ritanserin (10 micrograms/rat/day for 10 days) decreased ethanol preference, while subcutaneous (SC) treatment with the same dose was ineffective. Ritanserin ICV, 1 microgram/rat/day, did not reduce alcohol preference. Bilateral injections of ritanserin into the nucleus accumbens (NAC; 0.5 microgram/site/day for 10 days) produced a prompt and very pronounced suppression of ethanol preference, without affecting total fluid intake. Bilateral injections of ritanserin (0.5 microgram/site/day for 10 days) into the ventral tegmental area (VTA) or into the medial prefrontal cortex (MPC) evoked only slight and variable reduction of ethanol preference. Injections of ritanserin, 5 micrograms/site/day, into the VTA gave a nonselective suppression of the ingestive behavior. The present results provide evidence for a central site of action for the effect of ritanserin on ethanol intake and suggest that the NAC might be a highly sensitive site for its action. Since the NAC is a major target of the mesolimbic dopaminergic system, they also suggest that the effect of ritanserin might be due to interference with this system.
The present study investigated the effect of the 5-HT2 and dopamine D2 receptor antagonist risperidone on alcohol preference in the rat. Rats with developed preference for 3% ethanol were injected subcutaneously (SC) with 10, 1, or 0.1 mg/kg of risperidone for 7, 10, and 10 days, respectively. Risperidone (10 mg/kg) evoked an inhibitory effect on alcohol preference similar (rapid onset, but short duration) to that observed after treatment with the dopamine D2 receptor antagonist haloperidol, 0.0625 mg/kg, SC. The lowest dose of risperidone (0.1 mg/kg) evoked marked inhibition of ethanol drinking, similar (slow onset, but long-lasting effect) to that produced by the 5-HT2 receptor antagonist ritanserin, 1 mg/kg, SC. Present results demonstrate that risperidone suppresses alcohol preference in the rat and suggest that its effect, depending on the dose, might involve different neurochemical mechanisms (mainly dopaminergic at high doses and mainly serotonergic at low doses). The results obtained with the lowest dose of risperidone (0.1 mg/kg), at which the drug is rather selective for 5-HT2 receptors, are in keeping with previous findings obtained with ritanserin and support the hypothesis that 5-HT2 receptor blockade reduces alcohol intake in rats.