Effects of captopril on the development of rat doxorubicin nephropathy.

The effects of a daily administration of an anti-converting enzyme inhibitor. Captopril (CPT) (100 mg/kg/orally), on the development of functional and morphological alterations induced in rats by a single injection (7.5 mg/kg/iv) of Doxorubicin (DXR) (Adriamycin*), were investigated. Twenty-four-hour protein excretion, urine output, food intake, water intake, and body weight gain were measured weekly for 30 days. Transmission and scanning electron microscopy observations were performed on kidney samples after 30 days. Four groups were studied. Group 1 were control rats. Group 2 were rats injected with DXR. Group 3 were rats injected with DXR and treated with CPT for 30 days. Group 4 were rats injected with DXR and treated with CPT for 15 days (CPT treatment started 15 days after DXR injection). Group 1 did not show significant functional or morphological changes. Group 2 showed severe proteinuria, significant increase in urinary volume within 2 weeks, significant body weight reduction and diffuse morphological changes. These changes mainly consisted of podocyte swelling, severe foot process fusion, and presence of casts within tubular lumen. Group 3, with respect to group 2, showed a significant reduction of the 24 h protein excretion and urine output. This group displayed morphological changes similar to those observed in group 2, but with a focal distribution. Group 4 showed functional and morphological changes comparable with those of group 2. It is concluded that CPT partially inhibits the development of the functional and morphological damage induced by DXR in the rat kidney. However, CPT did not influence the natural development of nephropathy when treatment started 15 days after DXR injection.

Platelet activating factor involvement in splanchnic artery occlusion shock in rats.

Splanchnic artery occlusion shock was induced in anesthetized rats by clamping the splanchnic arteries for 45 min. The survival rate, plasma levels of thromboxane B2 (TxB2) and 6-keto-PGF1 alpha, serum and peritoneal levels of macrophage tumor necrosis factor (TNF alpha), the phagocytotic and killing activity of peritoneal macrophages and white blood cells count were evaluated. Shocked rats died within 2 h, while all sham-shocked rats survived more than 6 h. Plasma TxB2 and 6-keto-PGF1 alpha levels were increased in rats subjected to splanchnic artery occlusion shock compared to the levels in sham-shocked animals. Serum and peritoneal macrophage TNF alpha levels were undetectable in sham-shocked rats, whereas shocked rats exhibited increased levels of TNF alpha. Moreover, splanchnic artery occlusion shock reduced peritoneal macrophage phagocytotic and killing activity, and also produced severe leukopenia. A specific receptor antagonist of platelet activating factor (PAF), L-652, 731 (an i.v. bolus of 3.2 mg/kg 2 min after removal of the clamps followed, 5 min thereafter, by a continuous infusion of 0.16 mg/kg per min for 30 min) significantly increased the survival rate, lowered plasma TxB2 levels and reduced both serum and macrophage TNF alpha levels in shocked rats. In addition, L-652,731 completely restored macrophage phagocytosis, partially improved macrophage killing and significantly inhibited leukopenia. Finally, the administration of L-652,731 had beneficial effects on the cardiovascular changes induced by splanchnic artery occlusion shock. These findings are consistent with the involvement of PAF in splanchnic artery occlusion shock and indicate that PAF produces shock through direct and indirect (TxB2-mediated and TNF alpha-mediated) actions.

Effects of fructose 1,6-diphosphate on splanchnic artery occlusion shock in the rat.

Splanchnic artery occlusion (SAO) shock, produced by clamping splanchnic arteries for 45 min followed by the release of occlusion, was induced in male rats, treated 15 min before surgery, with fructose 1,6-diphosphate (FDP) or with equivalent doses of fructose or inorganic phosphate. Survival rate, peritoneal macrophage phagocytosis and plasma levels of myocardial depressant factor (MDF) were measured. Shocked animals pretreated with vehicle exhibited 24.6 +/- 0.9% phagocytic activity, 110 +/- 3.9 units/ml MDF plasma levels and 0% survival. Sham animals showed the following values: survival 100%; phagocytosis, 49.5 +/- 1.3%; MDF, 22 +/- 2.9 units/ml. Pretreatment with FDP (25 mg/kg/i.v.) significantly improved survival rate (50%) and macrophage phagocytosis (37.9 +/- 0.4%) and reduced plasma MDF levels (77 +/- 3 units/ml). Equivalent doses of fructose and inorganic phosphate did not improve survival, as well as lower doses of FDP. These results suggest a beneficial effect of FDP in SAO shock.

Synergistic anticonvulsant effect of valproic acid and ethosuximide on pentylenetetrazole-induced epileptic phenomena in rats.

The possible synergistic effect of valproic acid and ethosuximide in combination on pentylenetetrazole-induced epilepsy was investigated in rats. Valproic acid and ethosuximide administered intraperitoneally both showed dose-dependent anti-epileptic activity towards pentylenetetrazole-induced myoclonias and tonic-clonic seizures. The valproic acid-ethosuximide combination had a synergistic pharmacological effect. Against myoclonias combined valproic acid-ethosuximide produced a non-significant decrease in the effective dose of both drugs compared with treatment with either drug alone. In the case of tonic-clonic seizures the protective effect against the seizures was significantly increased by combined treatment compared with treatment with either drug alone. Neither plasma concentrations nor any other pharmacokinetic parameters were significantly changed when the same doses of valproic acid and ethosuximide were given, singly or in combination.

Splanchnic artery occlusion shock in the rat: effects of the calcium entry blockers nimodipine and verapamil.

Splanchnic artery occlusion (SAO) shock made by clamping splanchnic arteries for 45 min was performed in female rats infused for 30 min with vehicle, nimodipine, and verapamil before, during, or after SAO. Survival time, macrophage phagocytosis and killing, and white cell count were evaluated in conscious rats. Shocked animals pretreated with vehicle exhibited 24.6 +/- 0.9% phagocytic activity, 5.1 +/- 0.7% killing activity, and survived 177 +/- 1.7 min. Leukopenia was also present. Sham animals survived more than 300 min, and showed the following values: phagocytosis = 52.8 +/- 0.6%, killing = 18.8 +/- 0.6%. Pretreatment with nimodipine (1 microgram/kg/min x 30 min, intravenously [IV]) before SAO significantly prolonged survival time (274 +/- 4.7 min) and improved phagocytosis (38.1 +/- 0.6%) and killing (16.1 +/- 1.1%), but did not change leukopenia. Lower doses of nimodipine (0.25 and 0.5 microgram/kg/min x 30 min, IV), and all the doses of verapamil (100 and 200 micrograms/kg/min x 30 min, IV), when infused before SAO, were ineffective. Neither nimodipine nor verapamil, when infused for 30 min either during or immediately after SAO, were able to influence survival, macrophage functions, or white cell count. Moreover, nimodipine (5, 10, and 25 microM), when added "in vitro" to macrophages collected from SAO-shocked rats, significantly enhanced their phagocytic activity, while verapamil (100 and 200 microM) did not change it. Finally, in anaesthetized rats nimodipine pretreatment had a beneficial effect on the cardiovascular changes occurring during SAO shock. These data suggest that nimodipine has a beneficial effect in SAO-shocked rats only when given before SAO.

Cloricromene improves survival rate and peritoneal macrophage function in splanchnic artery occlusion shock in rats.

Splanchnic artery occlusion (SAO) shock, induced by a transient occlusion of splanchnic arteries for 45 min, was performed in male rats, treated with vehicle or cloricromene, a coumarin derivative, 15 min before surgery. Survival rate, plasma levels of myocardial depressant factor (MDF), macrophage phagocytosis and killing of Candida albicans, and thromboxane B2 (TxB2) synthesis by peritoneal macrophages were evaluated. Of the SAO-shocked animals, 10% survived for 6 hr after the release of the occlusion of the splanchnic arteries, whereas none of the sham-shocked rats died. Peritoneal macrophages of shocked animals exhibited decreased phagocytosis (24.7 +/- 2.7%) and killing (8.0 +/- 2.1%) and increased TxB2 levels (3.23 +/- 0.27 ng/ml) with respect to those collected from sham-shocked animals (phagocytosis 48.8 +/- 3.0%; killing 16.5 +/- 2.4%; TxB2 0.30 +/- 0.18 ng/ml). MDF was also increased (114.3 +/- 21.5 U/ml) compared with sham-shocked animals (31.5 +/- 3.7 U/ml). Cloricromene, given intravenously (i.v.) at doses of 1, 2, and 4 mg/kg, significantly increased survival rate and lowered MDF in shocked rats. Lower doses (0.25 and 0.5 mg/kg/i.v.) were without effect. Doses that were able to reduce mortality partially reverted shock-induced macrophage impairment of phagocytosis, killing of C. albicans, and TxB2 synthesis. In addition, cloricromene (5, 10, and 25 microM) added in vitro to peritoneal macrophages, collected from shocked rats, significantly enhanced their phagocytic activity depressed by shock.

Antihypertensive activity of indolepyruvic acid: a keto analogue of tryptophan.

We studied the effect of indole-3-pyruvic acid (IPA) on systolic blood pressure of normotensive, spontaneously hypertensive, DOCA + salt hypertensive, and Grollman hypertensive rats. Experiments were also carried out in order to investigate whether IPA may influence the development of hypertension in spontaneously hypertensive rats. Age-matched normotensive, spontaneously hypertensive, DOCA + salt hypertensive, and Grollman hypertensive rats treated with N-methylglucamine, were used as controls. Acute oral (up to 50 mg/kg) and intravenous (5 mg/kg) administration of IPA did not change systolic blood pressure in any models of hypertension. By contrast, a repeated administration of IPA (100 mg/kg/day, by oral gavage for 10 days) significantly decreased systolic blood pressure in all models of hypertension, while it elicited no significant effect in normotensive rats. Moreover, when IPA was given daily to 5-week-old spontaneously hypertensive rats for 7 weeks, it partially inhibited the development of hypertension. In addition, chronic administration of IPA caused enhanced levels of tryptophan and 5-hydroxyindoleacetic acid in the cortex and diencephalon. Brainstem serotonin content in both normotensive and spontaneously hypertensive rats was also enhanced by IPA treatment. Our results suggest that IPA lowers blood pressure in different rat models of hypertension and this effect seems to be correlated with an increase in cerebral serotonin metabolism.

Protective effect of cloricromene, a coumarine derivative, in hypovolemic hemorrhagic shock in the rat.

Hypovolemic hemorrhagic shock was induced in male anesthetized rats by intermittently withdrawing blood from an iliac catheter over a period of 20 min until mean arterial pressure (MAP) fell to 30 mm Hg. Survival rate, MAP, plasma myocardial depressant factor (MDF) activity and plasma levels of both TxB2 and 6-keto PGF1 alpha were then evaluated. Cloricromene (0.5, 1, and 2 mg/kg) or an equal volume of vehicle (0.9% NaCl solution) were injected intravenously 5 min after the end of the bleeding. Hemorrhagic shocked rats showed enhanced plasma levels of MDF, TxB2 and 6-keto PGF1 alpha. All vehicle-treated rats died within 25 min. Cloricromene (1 and 2 mg/kg) given curatively significantly increased survival rate and blunted the rise in plasma MDF and TxB2. Moreover, cloricromene reversed the severe hypotension and the ST-segment elevation occurring during hemorrhagic shock. The data suggest that cloricromene exerts beneficial effects in experimental hypovolemic shock, probably reversing myocardial failure.

Effects of intracerebroventricular administration of magnesium sulphate on blood pressure and heart rate in anesthetized normotensive and hypertensive rats.

Intracerebroventricular (i.c.v.) injection of magnesium sulphate (MgSO4:2.5, 5 and 10 mumol in 5 microliters) decreased blood pressure and heart rate in both anesthetized normotensive (WKY) and hypertensive rats (SHR). The effects were greater in WKY than in SHR. Moreover, a pretreatment with hexamethonium (2 mg/kg, i.v.) significantly blunted the hypotensive and bradycardic effects induced by i.c.v. injection of 10 mumol of MgSO4 in both WKY and SHR. Our data suggest that MgSO4 produces hypotensive and bradycardic effects when injected i.c.v. in both WKY and SHR.

A comparison of synthetic human and rat ANP administered intracerebroventricularly in freely moving normotensive and hypertensive rats.

The effects of intracerebroventricular (i.c.v.) injection of alpha-human atrial natriuretic peptide (alpha-hANP) and alpha-rat atrial natriuretic peptide (alpha-rANP) were studied in normotensive [Wistar-Kyoto (WKY)] and spontaneously hypertensive rats (SHR). Intracerebroventricular injection of alpha-hANP (200, 400, and 800 ng in 5 microliters) did not modify mean arterial pressure (MAP), heart rate (HR), and water intake in both WKY rats and SHR. On the contrary, alpha-rANP (200, 400, and 800 ng in 5 microliters) caused strong dipsogenic, pressor, and bradycardic effects that were greater in hypertensive than in normotensive rats. Saralasin (9 microns in 5 microliters), injected 2 min prior to alpha-rANP, abated these effects, thus indicating an involvement of brain angiotensin. Our results suggest that, at least as far as the cerebral effects of ANP are concerned, some difference exists between alpha-rANP and human atrial natriuretic peptide.

Pentylenetetrazol-induced spike wave discharges in rats: a polygraphic study.

14 male Wistar rats were studied, before and after pentylenetetrazol (PTZ) 20 mg/kg i.p., since a petit mal-like electroclinical pattern, either spontaneous or PTZ-induced was recently described in a breeding station where this strain is raised. In particular, surface EEG, muscular, respiratory and cardiac activities were recorded in order to detect possible clinical-electroencephalographic correlations. Spontaneous epileptic phenomena were never observed. In all the animals PTZ-induced short, usually generalized and synchronous spike wave discharges often concomitant with rhythmic twitches of the vibrissae. Epileptic bursts were related to arousal level, disappearing during motor behavior and arousing stimuli. Moreover individual discharges could be interrupted by a sudden noise. Photosensitivity was not present. Muscular tone and autonomic functions were not affected. The features of PTZ-induced generalized nonconvulsive seizures in rats are compared to those of cat penicillin epilepsy and human petit mal.