Renal protective effect of efonidipine hydrochloride (NZ-105), a new calcium antagonist,in spontaneously hypertensive rats

• 1.1. We investigated the renal protective effect of efonidipine hydrochloride (NZ-105) in spontaneously hypertensive rats (SHR). SHR were given a diet containing 0.075% NZ-105 from 8 weeks old for 20 weeks.
• 2.2. 24-hr urinary protein excretion in the control SHR (drug-free diet) increased with age (from 77.3 mg/kg/day at 8 weeks old to 385.4 mg/kg/day at 28 weeks old), while that in NZ-105-treated SHR was maintained at almost the same level as that in Wistar-Kyoto rats (WKY), matched control animals throughout the experimental period.
• 3.3. The histological changes of the kidney were examined by light microscopy at the end of the treatment period. In control SHR, swelling and hyalinization of glomeruli, dilatation of renal tubules containing hyaline casts and arteriolosclerosis were revealed. The long-term administration of NZ-105 markedly suppressed these changes.
• 4.4. The kidney weights and plasma creatinine concentration in control SHR were higher than those in WKY, while they were significantly reduced in NZ-105-treated SHR. The long-term administration of NZ-105 also suppressed the elevation of systolic blood pressure and the increases of plasma renin activity and aldosterone concentration.
• 5.5. These findings suggest that NZ-105 inhibits the development of proteinuria and progressive kidney damage in SHR and may become a useful antihypertensive drug with the renal protective effect.

     

High sodium intake increases the urinary excretion of L-3,4-dihydroxyphenylalanine but fails to alter the urinary excretion of dopamine and amine metabolites in wistar rats

• 1.1. The present study has examined the daily urinary excretion of L-DOPA, dopamine and its metabolites (DOPAC, 3-MT and HVA) during normal salt (NS) and high salt (HS) diets.
• 2.2. Daily urinary excretion of L-DOPA, DA, DOPAC, 3-MT and HVA during the 4-day period of NS diet averaged, respectively, 7.6±0.4, 71±5,217±22, 570±90and1217±110 nmol/kg/day. The slight increase in the urinary excretion of DA, DOPAC and 3-MT (16% to 42% increase), when rats were fed a HS diet, did not achieve statistical significance.
• 3.3. In contrast, the urinary levels of L-DOPA during the HS diet period (11 ± 1 nmol/kg/day) were found to be significantly higher than during the NS diet period; the maximal increase in the urinary excretion of L-DOPA (93% increase) was observed in the first day and then a progressive decline was observed towards the end of the HS intake period.
• 4.4. During the first 5 days of the HS intake period, the urine output of noradrenaline (NA) was found to increase (27% to 83%) and then to progressively decline to baseline values (13.5±0.7 nmol/kg/day).
• 5.5. Urinary excretion of adrenaline (AD) during the HS intake period was found to increase (72% to 146%); the mean daily urinary excretion of AD during the NS diet period averaged 2.5±0.4 nmol/kg/day. NA and DA contents in the kidney of rats on a NS diet were not significantly different from that of rats in a HS diet.
• 6.6. It is concluded that long-term HS intake in Wistar rats fails to change the urinary excretion of DA and of its metabolites (DOPAC, 3-MT and HVA). Furthermore, the discrepant profile in the urinary excretion of L-DOPA and DA during HS intake might be related to a reduction in the tubular uptake of the amino acid, rather than reflecting a decrease in its decarboxylation.

     

Physiological and environmental aspects of drinking stimulated by chronic exposure to amphetamine in rats

• 1.1. To examine whether the hyperdipsic response to chronic administration of d, l-amphetamine (AMPH) is associated with modification of salt appetite, rats were allowed to choose between tap water and a 1.7% NaCl solution.
• 2.2. Under AMPH rats preferred water to saline throughout the experiment.
• 3.3. By testing rats in a distinct test cage environmental influences on AMPH-mediated hyperdipsia were also evaluated.
• 4.4. In the test cage hyperdipsia was suppressed, but preference for tap water was preserved.
• 5.5. Finally, the role of α₂-adrenoceptors in the drinking response to AMPH was evaluated by studying the effects of clonidine and yohimbine on water intake.
• 6.6. We conclude that AMPH-induced preference for tap water over saline is unrelated to hyperdipsia but, being also induced by yohimbine, it may depend on noradrenergic mechanisms.

     

Central and peripheral dopamine D1/DA1 receptor modulation of gastric secretion and experimental gastric mucosal injury

• 1.1. Dopamine D₁ (central)/DA₁ (peripheral) receptors are believed to influence gastrointestinal function and pathology.
• 2.2. When given i.c.v. or i.p., an agonist (SKF38393) and an antagonist (SCH23390) of this DA receptor subtype inhibit and enhance, respectively, gastric secretion and gastric mucosal injury.
• 3.3. When given both i.c.v. and i.p., their respective effects in the gut were amplified.
• 4.4. Antagonist or agonist given i.p., blocked the corresponding protective and worsening effect of the agonist or antagonist given i.c.v.
• 5.5. Both central and peripheral D₁/DA₁ receptors modulate gastric function and response to injury.

     

Effect of vitamin B complex on neurotransmission and neurite outgrowth

• 1.1. The effect of vitamin B complex (vitamin B₁, B₆ and B₁₂) was studied on nerve conduction velocity in acrylamide-neuropathy rats maintained on refined semisynthetic complete vitamin and vitamin B-deficient diets in vivo and on neurite outgrowth in vitro using cells obtained from dorsal root ganglions of mice.
• 2.2. Acrylamide neuropathy was clearer in the group maintained on a refined semisynthetic vitamin B-deficient diet than in those on a refined semisynthetic complete vitamin diet. The neurotoxicity was lowest in the group given vitamin B complex prophylactic-therapeutically, next higher following therapeutic administration and last with no vitamin B complex administration in both groups maintained on a refined semisynthetic vitamin B-deficient diet and a refined semisynthetic complete vitamin diet.
• 3.3. The nerve conduction velocity tended to decrease by treatment with acrylamide. The decrement of nerve conduction velocity was partially inhibited by vitamin B complex. No significant difference was found in the groups treated with acrylamide and given vitamin B complex prophylactic-therapeutically and the control (no acrylamide treatment) in the group maintained on a refined semisynthetic vitamin B-deficient diet.
• 4.4. The greatest neurite outgrowth was found in the group treated with vitamins B₁, B₆ and B₁₂-enriched medium, followed by the groups of vitamin B₁₂-enriched and vitamin B₁-enriched media. All groups treated with a vitamin B-enriched medium had significantly greater (P<0.01) outgrowth than the controls.

     

Renal failure during acute toxicity produced by tullidora ingestion (Karwinskia humboldtiana )

• 1.1. Acute effects of Karwinskia humboldtiana (Kh) were studied in some renal functions and structural patterns of renal tissue.
• 2.2. Haemodinamic changes were observed with decrements of the glomerular filtration rate, renal plasma flow and filtration fraction during acute intoxication.
• 3.3. A marked increment in the fractional excretion of sodium was observed in the rats treated with tullidora fruits (Kh).
• 4.4. Cloudy swelling and hydropic degeneration was seen 72 hr after intoxication, mainly in the proximal convoluted tubules.

     

The sigma-selective ligand NE-100 attenuates the effect of phencyclidine in a rat diving model

• 1.1. Phencyclidine (PCP) reduces the latency of rats diving into a water-filled pool from a hidden platform, without stereotyped behavior.
• 2.2. The sigma-selective ligand, NE-100 (N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride), attenuates the effects of PCP in this procedure.
• 3.3. The serotonin₂ (5-HT₂) antagonist, ritanserin, and the sigma receptor ligands, 1-(cyclopropylmethyl)-4-[2′(4″-fluorophenyl)-2'-oxoethyl]-piperidine HBr (Dup734), 4-[2′-(4″-cyanophenyl)-2′-oxoethyl]-1-(cyclopropylmethyl)piperidine (XJ448), α-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol (BMY14802) and rimcazole similarly attenuate the effects of PCP.
• 4.4. The dopamine D₂/sigma ligands, haloperidol and cis-N-(1-benzyl-2-methyl-pyrrolidin-3-yl)-2-methoxy-5-chloro-4-methylaminobenzamide (YM-09151-2) completely reverse the effects of PCP, whereas the same dose ranges of these drugs produce sedation.
• 5.5. The dopamine D₂-selective antagonist, sulpiride, has no apparent effect on the PCP latency to the rat dive.
• 6.6. Thus, PCP-induced diving behavior was improved by sigma ligands and the 5-HT₂ antagonist. This model of negative symptoms in an experimental animal will facilitate experiments on drug treatments for schizophrenia.

     

Mechanisms of hyperkalemia caused by nafamostat mesilate

• 1.1. Nafamostat mesilate (NM) is a novel serine-protease inhibitor used for the treatment of acute pancreatitis and disseminated intravascular coagulation. Recently, NM has been reported to cause hyperkalemia due to reduced urinary excretion of potassium (K).
• 2.2. This review briefly summarizes the roles of the cortical collecting duct (CCD) in the renal K excretion.
• 3.3. In vitro microperfusion technique was applied to examine whether NM, and its two metabolites, p-guanidinobenzoic acid (PGBA) and 6-amidino-2-naphthol, directly act on the CCD.
• 4.4. It was demonstrated that these compounds act mainly on the apical membrane of the collecting duct cell in the CCD and inhibit the amiloride-sensitive sodium (Na) conductance, resulting in an inhibition of K secretion. PGBA had the most potent action.
• 5.5. This direct action of these two metabolites, rather than NM, could contribute to the NM-induced hyperkalemia.

     

Recent progress in understanding aldosterone secretion

• 1.1. The synthesis and secretion of aldosterone in the adrenal zona glomerulosa in physiologic conditions is controlled by adrenocorticotropin (ACTH), angiotensin II (AII), and extracellular (K⁺).
• 2.2. ACTH effects on aldosterone output are explained by cyclic AMP- (cAMP)- and Ca²⁺-dependent mechanisms.
• 3.3. All effects on aldosterone secretion are initiated by an increase in Ca²⁺ influx through hormone-operated Ca²⁺ channels and G-protein- and phospholipase C- (PLC) dependent hydrolysis of phosphoinositides leading to the generation of inositol 1,4,5 trisphosphate (IP₃) and DAG that induce intracellular Ca²⁺ release and PKC activation, respectively.
• 4.4. ACTH increases DAG formation with marginal or undetectable IP₃ generation. The effect of ACTH on DAG levels is discussed.
• 5.5. The requirement of external Ca²⁺ in PLC activation and aldosterone secretion also is discussed.

     

Treatment with acarbose,an α-glucosidase inhibitor,reduces increased albumin excretion in streptozotocin-diabetic rats

• 1.1. We examined the effect of the α-glucosidase inhibitor acarbose on urinary albumin excretion (UAE) in streptozotocin diabetic rats.
• 2.2. Treatment with acarbose for 8 weeks after induction of diabetes prevented the significant increase in UAE observed in untreated diabetic rats relative to nondiabetic controls.
• 3.3. Acarbose significantly reduced integrated glycemia, which correlated with albumin excretion rates, and exerts a salutary effect on diabetic renal dysfunction.

     

The in vivo and in vitro protective properties of taurine

• 1.1. Taurine is a ubiquitous, free amino acid found in mammalian systems.
• 2.2. The biological functions of taurine are unclear.
• 3.3. Various in vivo data suggest that taurine has a variety of protective functions and deficiency leads to pathological changes.
• 4.4. Depletion in rats of taurine increases susceptibility to liver damage from carbon tetrachloride.
• 5.5. Susceptibility to a variety of hepatotoxicants correlates with the estimated hepatic taurine level.
• 6.6. In vitro data suggest that taurine can protect cells against toxic damage.
• 7.7. Taurine protects isolated hepatocytes against carbon tetrachloride, hydrazine and 1,4-naphthoquinone but not against allyl alcohol, α-naphthylisothiocyanate (ANIT) or diaminodiphenyl methane (DAPM) cytotoxicity.
• 8.8. The mechanisms of protection are unclear but may include modulation of calcium levels, osmoregulation and membrane stabilization.

     

Effects of selective dopamine receptor compounds on single,spontaneously-active neostriatal neurons

• 1.1. The effects of selective dopamine receptor compounds on the spontaneous activity of single neostriatal neurons were examined extracellularly.
• 2.2. Intravenous administration of quinpirole, the D₂ agonist, elicited a dose-dependent depression in discharge rate.
• 3.3. Quinpirole-evoked depression was reversed by the D₂ antagonist eticlopride, but not the D₁ antagonist SCH 23390.
• 4.4. The partial D₁ agonist, SKF 38393 induced depression and excitation in equal proportion.
• 5.5. A dose of 0.25 mg/kg SCH 23390 blocked SKF 38393-induced depression but not excitation.
• 6.6. SKF 38393-induced excitation was antagonized by eticlopride and in some cases by a higher dose of SCH 23390.

     

Dual effects of NMDA-induced intracellular Ca2+ elevations on cGMP levels in cultured cerebellar granule neurons

• 1.1. Cyclic GMP (cGMP) levels were markedly elevated by N-methyl-d-aspartate (NMDA) within 1–3 min of incubation, then gradually decreased with incubation time.
• 2.2. The NMDA-induced intracellular Ca²⁺ elevations showed maximal levels just after adding NMDA and were maintained for 60 min.
• 3.3. NMDA did not show augmentation of cGMP elevation with sodium nitroprusside (SNP), rather it decreased the SNP-induced cGMP elevation after exposure for 60 min.
• 4.4. The NMDA-induced elevation of cGMP was remarkably augmented with the phosphodiesterase inhibitor, 3-isobutyl-l-methylxanthine (IBMX, 1mM), after 60 min of incubation.

     

Age-related changes in nociception,behavior, and monoamine levels in rats

• 1.1. Pain threshold, behavioral parameters, and monoamine levels were compared in two groups of rats: adult (12 months old) and old rats (25 months old).
• 2.2. No differences in nociception were found between the two groups using the tail-shock test.
• 3.3. Behavioral experiments with the holeboard test showed that locomotor activity and exploration activity were lower in aged animals, whereas no significant differences were found in emotivity.
• 4.4. Using high-performance liquid chromatography (HPLC) techniques, we found that serotonin and dopamine showed lower levels in the old group.

     

Sodium nonivamide acetate: A non-pungently antinociceptive capsaicin derivative with unusual anti-inflammatory properties

• 1.1. Bradykinin-induced vascular pain in conscious rats, hyperalgesia in the rat hind paw, rat hind paw edema induced by compound 48/80 and carrageenin and dye exudation induced by intraperitoneal injection of 0.7% acetic acid in mice were all inhibited by sodium nonivamide acetate (SNA).
• 2.2. Collagen and arachidonic acid-induced rabbit platelet aggregations were inhibited by SNA and capsaicin. In human platelet microsomes, prostaglandin E₂ formation in arachidonic acid metabolite was not inhibited by SNA but was inhibited by capsaicin and indomethacin; thromboxane B₂ formation and its synthetase activity were inhibited by SNA and capsaicin.
• 3.3. In the extracellular recording, SNA could not decrease the action potential amplitude of the vagus nerve.
• 4.4. The motor activity of mice induced by caffeine (1.0 mg/kg) was inhibited by SNA and capsaicin.

     

Effect of KRN4884 on lipid metabolism in hyperlipidemic rats

• 1.1. KRN4884 is a novel pyridinecarboxamidine type potassium channel opener.
• 2.2. To determine whether KRN4884 affects lipid metabolism, we investigated its effects on serum lipid levels by using two types of hyperlipidemic rats: genetically hyperlipidemic obese Zucker rats and diet-induced hyperlipidemic rats fed a high fat diet. KRN4884 dose dependently decreased systolic blood pressure in Zucker rats.
• 3.3. Oral administration of KRN4884 (1–10 mg/(kg day) for 14 days dose dependently reduced serum triglyceride levels in Zucker rats. The reductions in serum triglyceride were associated with reductions in triglyceride in chylomicron and very low density lipoprotein.
• 4.4. KRN4884 produced no change in serum insulin and glucose levels in Zucker rats.
• 5.5. KRN4884 exhibited a similar triglyceride lowering effect in diet-induced hyperlipidemic rats.
• 6.6. These results suggest that KRN4884 has a beneficial effect on serum triglyceride levels as well as a hypotensive effect.

     

Effects of vinca alkaloids on rat parotid and submandibular glands function in vivo

• 1.1. Vincristine (1 mg/kg) and vinblastine (2 mg/kg) were injected intraperitoneally into the rats, 24 hr before the experiments.
• 2.2. Animals were anesthetized with 50 mg/kg of sodium pentobarbital and saliva was collected from vincristine-treated, vinblastine-treated and control animals using 8 mg/kg of pilocarpine as secretagogue.
• 3.3. Parotid saliva was analyzed for protein, amylase and Ca²⁺ content, and submandibular saliva for flow rate, protein and Ca²⁺ concentration.
• 4.4. Saliva from two treated groups was significantly lower (P < 0.01) in flow rate, amylase and protein content than that of control groups. Calcium level was significantly increased (P < 0.05) in treated animals.
• 5.5. It is concluded that the antisecretory effects of vinca alkaloids may be consistent with their actions on salivary cell microtubules.

     

Endothelium-derived hyperpolarizing factor does not contribute to the decrease in endothelium-dependent relaxation in the aorta of streptozotocin-induced diabetic rats

• 1.1. We examined the contribution of endothelium-derived hyperpolarizing factor (EDHF) to the impairment of endothelium-dependent relaxation caused by acetylcholine (ACh) in the aorta of streptozotocin-induced diabetic rats, by using N^ω-nitro-l-arginine methylester (L-NAME) and tetraethylammonium chloride (TEA) to inhibit nitric oxide (NO) and EDHF, respectively.
• 2.2. ACh-induced relaxation of the aorta decreased in diabetic rats. In contrast, sodium nitroprusside-induced relaxation was the same in diabetic rats and control rats.
• 3.3. Treatment with 5 × 10⁻⁷ M L-NAME resulted in a right shift of the dose-response curves of ACh-induced relaxation in the aorta. The shift was greater in the control aorta.
• 4.4. Treatment with 5 × 10⁻⁴ M TEA resulted in a similar right shift in both the control and diabetic aorta.
• 5.5. Therefore, while endothelium-derived NO appears to contribute to the impairment of ACh-induced endothelium-dependent relaxation in the aorta of diabetic rats, EDHF does not

.     

Influence of aldose reductase inhibition on the microvascular reactivity in experimental diabetes

• 1.1. To verify if tolrestat, an aldose reductase inhibitor, corrects the impaired responses of microvessels to histamine and bradykinin in alloxan-diabetic rats, the mesenteric microcirculation was studied in vivo in anaesthetised animals.
• 2.2. The impaired responses were corrected by tolrestat 5 mg/kg/day for 7 days p.o. Similar responses to acetylcholine and sodium nitroprusside were obtained in preparations of diabetic and control rats and were not altered by tolrestat treatment.
• 3.3. As in diabetes, galactosemia induced impaired responses to histamine and bradykinin; these altered responses were corrected by tolrestat treatment.
• 4.4. These data allow us to suggest that the polyol pathway activity might be involved in the altered responses of microvessels observed in diabetic rats. It is possible that polyol activation may play an important role in the development of vascular dysfunction in diabetes mellitus.

     

Effects of the selective 5-HT receptor agonists 8-OHDPAT and DOI on behavior and brain biogenic amines of rats

• 1.1. The behavioral responses, as well as the biogenic amines and metabolite contents in discrete brain areas were determined in male rats subcutaneously treated with a 5-HT_1A (8-OHDPAT) or 5-HT_2A (DOI) agonist at doses (0.5-2 mg/kg) sufficient to produce the typical effects of the stimulation of these brain receptor subtypes.
• 2.2. Besides the expected effects (i.e., forepaw treading, flat body posture and inhibition of 5-HT release and turnover), 8-OHDPAT displayed signs of increased dopaminergic transmission.
• 3.3. DOI increased dopamine turnover and provoked stereotypical behavior, in addition to head shakes and body twitches.
• 4.4. Moreover, DOI induced both forepaw treading and flat body posture, which are believed to be typical responses to the stimulation of brain 5-HT_1A receptors.
• 5.5. This finding cannot be explained on the basis of actual knowledge, because the affinity of DOI for 5-HT_1A receptor has been found to be very low, whereas indirect mechanisms of activation of this receptor subtype triggered by stimulation of 5-HT_2A receptor are actually unknown.