Effect of CV-2619 (idebenone) on the half-life and hemolysis of red blood cells in stroke-prone spontaneously hypertensive rats (SHRSP)

The effects of CV-2619 on the half-life and hemolysis of red blood cells (RBC) in stroke-prone spontaneously hypertensive rats (SHRSP) were examined. The half-life of RBC in SHRSP was shorter than that in control Wistar Kyoto rats (WKY) and was significantly prolonged in SHRSP kept on a diet containing 0.1% (w/w) of CV-2619 (calculated at 71.0 mg/kg/day): 11.7 +/- 0.4 days in untreated SHRSP (n = 11); 13.8 +/- 0.1 days in treated SHRSP (n = 5, P less than 0.01); and 14.8 +/- 0.5 days in WKY (n = 6). The hemolysis of RBC in salt-loaded SHRSP was accelerated compared with that in WKY. In SHRSP given CV-2619 (20 or 70 mg/kg/day, p.o.) for 2 weeks, the hemolysis was significantly inhibited; the percent hemolysis was 43.9 +/- 0.9% (n = 10) in the control, 39.5 +/- 0.9% (n = 9, P less than 0.01) in the group given 20 mg/kg CV-2619, and 37.1 +/- 0.8% (n = 9, P less than 0.001) in the group given 70 mg/kg CV-2619. These results suggest that the stabilizing effect of CV-2619 on the membrane of RBC is involved in its therapeutic effects in cerebral vascular disorders.     

Brain distribution of idebenone (CV-2619) and its effect on local cerebral glucose utilization in rats

To investigate the possible action-sites of a cerebral metabolism activator, idebenone (CV-2619), its distribution in the brain and effect on local cerebral glucose utilization (LCGU) were studied both in normal rats (WKY) and in stroke-prone spontaneously hypertensive rats (SHRSP) with cerebrovascular lesions. At 5 min after intravenous administration of [14C] CV-2619 (10 mg/kg), the distribution ratio in the brain was 0.45-0.56% of the dosage. Autoradiographic study showed that 14C levels were higher in the white matter than in the grey matter. When [14C] CV-2619 was administered orally (100 mg/kg) and intraperitoneally (30 mg/kg), 14C levels in eleven brain regions (15 min after administration) were 0.22-0.39 microgram/g (CV-2619 equivalent) and 1.11-1.30 micrograms/g, respectively, in WKY and 0.17-0.28 microgram/g and 1.66-1.87 microgram/g, respectively, in SHRSP. Total 14C levels were not markedly different among the brain regions of the rats. The analysis of unchanged CV-2619 and its metabolites revealed that unchanged CV-2619 in the cerebral cortex, thalamus and cerebellum was relatively higher than that in the other brain regions. Studies on LCGU demonstrated that CV-2619 (30 mg/kg/day, i.p., for 3 days) improved the decrement of LCGU in the temporal cortex, thalamus dorsomedial nucleus, subthalamic nucleus, mamillary body, hippocampus dentate gyrus, caudate-putamen, inferior colliculus and cerebellar nucleus of SHRSP with stroke. Based on these results, the possible action-sites of CV-2619 for its main pharmacological effects were discussed.     

Effects of 2,3-dimethoxy-5-methyl-6-(10'-hydroxydecyl)-1,4-benzoquinone (CV-2619) on myocardial energy metabolism in the hypertrophied heart of spontaneously hypertensive rats

Effects of CV-2619 (10 and 30 mg/kg/day, p.o.) or ubiquinone-10 (Q-10, 10 mg/kg/day, p.o.) treatment for 5 weeks on systolic blood pressure (SBP) and myocardial energy metabolism were studied in spontaneously hypertensive rats of 20 weeks of age. The systolic blood pressure was about 205 mmHg at the start of the experiment, and a slight increase was noted thereafter in the control (vehicle) group. CV-2619, but not Q-10, inhibited the increase in the blood pressure. At 25 weeks of age, cardiac hypertrophy was noted to the same extent in either treated group. Myocardial contents of glycolytic intermediates (glycogen, glucose, pyruvate and lactate) and creatine phosphate (Cr-P), ATP, ADP, and AMP were not significantly influenced by CV-2619 or Q-10 treatment. CV-2619, however, significantly increased the energy charge, an index of myocardial energy state, with higher dose and lowered the lactate/pyruvate ratio with either dose. These results suggest that CV-2619 has a mild antihypertensive effect and improves the myocardial energy state in the hypertrophied heart during the sustained phase of hypertension in SHR rats.     

Beneficial effect of idebenone (CV-2619) on cerebral ischemia-induced amnesia in rats

An experimental model of amnesia induced by cerebral ischemia after one-trial passive avoidance learning was established to test the effects of a novel compound, 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (idebenone, CV-2619), and some commonly used drugs in rats. One day after the vertebral artery was electrocauterized bilaterally, the common carotid artery was transiently occluded bilaterally to produce cerebral ischemia. The amnesia was estimated by the response latency for a rat to step from a light safety compartment to a dark compartment in which a foot-shock was given. The results of the retention test given 24 hr after the ischemia indicated that amnesia was successfully produced when the 200-600 sec ischemia was provided within 20 min after the avoidance learning. The effects of drugs on the amnesia induced by a 200-sec ischemia immediately after the avoidance learning were as follows: CV-2619 (10, 30 mg/kg, i.p. or p.o.) given before the retention test significantly increased the response latency, indicating a reversal effect on the amnesia. Physostigmine (0.1, 0.2 mg/kg, i.p.) and arginine-vasopressin (10 micrograms/kg, s.c.) were also effective, and calcium hopantenate (500 mg/kg, p.o.) showed a slight reversal action. Furthermore, CV-2619 (10 mg/kg, i.p.), given before or after the ischemia, significantly inhibited the appearance of amnesia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of a new dihydropyridine derivative, CV-4093.2HCl, on renal hemodynamics in spontaneously hypertensive rats

The effects of a new calcium antagonist, CV-4093.2HCl, on renal hemodynamics were examined in anesthetized and conscious spontaneously hypertensive rats (SHR). In the anesthetized rats, CV-4093.2HCl (5 and 10 micrograms/ kg, i.v.) showed a long-lasting hypotensive action, dilated renal vasculature, and increased renal blood flow. These renal hemodynamic actions of CV-4093.2HCl were more prominent than those of nicardipine (5 and 10 micrograms/kg). Moreover, CV-4093.2HCl (10 micrograms/kg, i.v.) inhibited renal vascular contractions induced by intravenous norepinephrine and angiotensin II. The inhibitory effect of CV-4093.2HCl was much more marked than that of nicardipine, although the inhibitory effects of both calcium antagonists on systemic pressor responses induced by the vasoactive substances were almost the same. In addition, CV-4093.2HCl (1 and 3 mg/kg, p.o.) increased blood flow in the kidneys but not in the other organs except for the small intestine in conscious SHR. These results suggest that CV-4093.2HCl has a relatively higher affinity for the renal vascular bed (renal resistance vessels), and its effect on renal hemodynamics seems to be beneficial for treating hypertension.     

Antihypertensive effects of betaxolol, a cardioselective beta-adrenoceptor antagonist, in stroke-prone spontaneously hypertensive rats (SHRSP)

Effects of betaxolol, a cardioselective beta-adrenoceptor antagonist, on blood pressure and hypertensive complications in stroke-prone spontaneously hypertensive rats (SHRSP) were investigated. Betaxolol was provided in a dose of 33 +/- 1.8 mg/kg/day, orally in drinking water, throughout the experimental period. The chronic treatment with betaxolol inhibited the development of hypertension in SHRSP and reduced values of blood urea nitrogen, creatinine, total cholesterol, free cholesterol, triglyceride, phospholipid and HDL-cholesterol in serum. Treatment with betaxolol apparently inhibited the incidence of hypertensive lesions such as cardiac fibrosis, mesenteric vasculitis, proliferative and/or necrotic vasculitis and glomeruli showing collapse or vasculitis in the kidneys. To shorten the time before the onset of hypertension and the subsequent stroke, SHRSP were kept on a SP diet containing 0.39% Na instead of the F-2 diet. When the SHRSP were kept on the SP diet, all of the control SHRSP had cerebral apoplexy and severe hypertensive lesions in the heart and kidney. When betaxolol was chronically administered to SHRSP, cerebral apoplexy and hypertensive lesions in the heart and kidney were inhibited, but the effect on blood pressure was slight. Treatment with betaxolol reduced serum creatinine levels. Our observations show that betaxolol reduces blood pressure and potently inhibits hypertensive complications in SHRSP.     

Effects of idebenone (CV-2619) on metabolism of monoamines, especially serotonin, in the brain of normal rats and rats with cerebral ischemia

The effects of 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (idebenone, CV-2619) on the contents, turnover, release and uptake of monoamines, especially serotonin (5-HT), in various brain regions of Wistar rats were studied in vivo and in vitro. In normal rats, an intraperitoneal (i.p.) dose of 100 mg/kg of CV-2619 had no significant effect on the levels of norepinephrine (NE), dopamine (DA) and their metabolites, and 5-HT in the brain regions examined, but it increased the levels of 5-hydroxyindole-3-acetic acid (5-HIAA), the main metabolite of 5-HT, in many brain regions. In rats with cerebral ischemia, a low dose (10 mg/kg, i.p.) of CV-2619 normalized the decreased levels of 5-HIAA in the cerebral cortex, hippocampus, diencephalon and brain stem. A 5-HT biosynthesis inhibitor, DL-p-chlorophenylalanine (PCPA, 150 mg/kg, i.p.), decreased the levels of 5-HT in all brain regions to one-third of the control levels 24 hr after administration in normal rats. CV-2619 (10, 30 or 100 mg/kg, i.p.), administered 24 hr after the treatment with PCPA, accelerated the PCPA-induced 5-HT decreases in the hippocampus, diencephalon and brain stem in a dose-dependent manner. In vitro CV-2619, like p-chloroamphetamine (PCA), stimulated 5-HT release from slices of the hippocampus and diencephalon. CV-2619 slightly inhibited and PCA markedly inhibited 5-HT uptake into hippocampal slices. The mechanism of the 5-HT releasing action of CV-2619 in hippocampal slices seems to be mediated through endogenous calcium. These results suggest that CV-2619 has an enhancing effect on the turnover of 5-HT in the hippocampus, diencephalon and brain stem of rats.     

Antihypertensive action of a new angiotensin converting enzyme inhibitor, (R)-3-[(S)-1-carboxy-5-(4-piperidyl)pentyl]amino-4-oxo-2,3,4,5-tetr ahy dro-1,5-benzothiazepine-5-acetic acid (CV-5975), in various hypertensive models

The antihypertensive activity of a new angiotensin converting enzyme (ACE) inhibitor, CV-5975, (R)-3-[(S)-1-carboxy-5-(4-piperidyl)pentyl] amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid, was examined in normotensive rats and various hypertensive animal models. In spontaneously hypertensive rats, CV-5975 (1 to 10 mg/kg, p.o.) had a dose-related, sustained antihypertensive action, which was more potent and longer than that of enalapril. The potency and duration of action of CV-5975 was intensified when it was administered repeatedly or combined with hydrochlorothiazide. CV-5975 (1 mg/kg, p.o.) inhibited the ACE activity of plasma and tissues; inhibition on the ACE activity of the aorta, kidney, and brain was marked when CV-5975 was administered repeatedly. In 2-kidney, 1 clip hypertensive rats (1 to 10 mg/kg, p.o.) and dogs (0.3 and 1 mg/kg, p.o.), CV-5975 had a marked, sustained antihypertensive action, which was more marked than that of enalapril. In normotensive rats (10 mg/kg), 1-kidney, 1 clip hypertensive rats (3 and 10 mg/kg), and hyporeninemic DOCA/salt hypertensive rats (1 to 10 mg/kg/day), CV-5975 administered orally once or repeatedly reduced blood pressure, whereas enalapril did not. These results indicate that CV-5975 is a potent and long-lasting antihypertensive agent, the action of which is mediated primarily by inhibiting ACE activity and partly by some unknown mechanisms.     

Therapeutic effects of a calcium antagonist, lacidipine, on stroke-prone spontaneously hypertensive rats with cerebrovascular lesions.

The aim of this study was to investigate the therapeutic effectiveness of lacidipine in stroke-prone spontaneously hypertensive rat (SHRSP) with cerebrovascular lesions in comparison with nicardipine. SHRSP were fed 1% saline as drinking water. After the onset of stroke, saline was replaced with water and each drug was administered orally once a day for 3 weeks. In the drug-untreated group, recurrence of stroke was repeated, deterioration and amelioration of neurological deficits (ND) were repeated, and histological examination and measurement of regional blood flow (rBF) using nonradioactive colored microspheres performed at the end of treatment revealed severe damages and significantly decreased rBF in brain and kidney, respectively. In kidney, not only lacidipine (1 mg/kg) but also nicardipine (30 mg/kg) decreased vascular lesions and ameliorated low-rBF significantly. Both drugs also inhibited the recurrence of stroke completely even at a low dose that did not ameliorate severe hypertension. Neuronal damages and ND in each lacidipine-treated group were ameliorated significantly, whereas those in each nicardipine-treated group were slightly improved. Lacidipine at 1 mg/kg alone ameliorated the cerebral low-rBF significantly even at 24 hr after administration. These results suggest that a long-lasting improvement of low-rBF after stroke may be useful in the treatment of SHRSP with cerebrovascular lesions.     

Antihypertensive effect of CV-4093.2HCl, a new calcium antagonist, in three rat models of hypertension

The hypotensive action of CV-4093.2HCl (CV-4093), a new calcium antagonist, was studied in spontaneously hypertensive, renal hypertensive, DOCA-salt hypertensive and normotensive rats. CV-4093 (3 and 10 mg/kg, p.o.) dose-dependently decreased systolic blood pressure in the three types of hypertensive rats. At the dose of 10 mg/kg, the compound decreased the blood pressure to the normotensive level between 1 and 3 hr after it was administered; the antihypertensive effect lasted for at least 8 hr. The systolic blood pressure in normotensive rats was also decreased at 3 and 10 mg/kg, p.o., but less evidently than in the hypertensive rats. When the antihypertensive effect of CV-4093 was compared with that of seven known calcium antagonists in spontaneously hypertensive rats, it was the most potent and the most long-lasting.     

Effects of YM-14673, a new thyroid-releasing hormone analogue, on neurological deficits in stroke-prone spontaneously hypertensive rats

The effects of YM-14673, a new thyroid-releasing hormone (TRH) analogue (N alpha-[[(S)-4-oxo-2-azetidinyl]carbonyl]-L-histidyl-L-prolinamide dihydrate), on neurological deficits were examined in stroke-prone spontaneously hypertensive rats (SHRSP). The neurological deficits were evaluated for more than 21 days after stroke. Administration of YM-14673 was started the day stroke was observed and repeated daily for 3 weeks. YM-14673 (0.1 and 0.3 mg/kg i.p.) improved the neurological deficits and reduced mortality. These results demonstrate that YM-14673 mitigates cerebral ischemic changes in SHRSP.     

Inhibition of angiotensin converting enzyme by CV-3317, a non-sulfhydryl compound

N-[N-[(S)-1-Ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-N-(indan-2- yl)glycine hydrochloride (CV-3317) and its de-esterified products, CV-3317-COOH and CV-3317-(5-OH)-COOH, inhibited rabbit lung angiotensin converting enzyme (ACE) with the IC50s of 1.2 X 10(-7), 4.0 X 10(-8) and 4.9 X 10(-8) M, respectively, angiotensin I (A-I)-induced vasoconstriction of the rat aorta (IC50: 2.6 X 10(-7), 2.6 X 10(-8) and 5.4 X 10(-8) M, respectively), and A-I-induced pressor response of the rat kidney (IC50: 3.9 X 10(-7), 3.5 X 10(-8) and 2.8 X 10(-8) M, respectively). In these 3 experiments, both de-esterified products were 4 to 14 times more potent than captopril. In rats, CV-3317 (0.0138 to 138 mumol/kg, p.o.) inhibited plasma and lung ACEs, and the effects at a dose of 0.46 mumol/kg lasted more than 8 hr. CV-3317 inhibited the A-I-induced pressor action in rats (0.138 to 13.8 mumol/kg, p.o. or 0.046 to 0.138 mumol/kg i.v.) and dogs (0.46 to 4.6 mumol/kg, p.o.) in a dose-related manner. CV-3317 was more potent and longer acting than captopril in these in vivo ACE inhibitions. CV-3317 augmented bradykinin-induced hypotension (dogs) and contraction of the ileum (guinea pigs) less potently than captopril. In spontaneously hypertensive rats (SHR), CV-3317 (3 mg/kg, p.o.) markedly inhibited plasma and tissue (aorta, kidney, lung and brain) ACEs; and when administered daily for 2 weeks, it inhibited the plasma, aorta, kidney and lung ACEs; in particular, it markedly inhibited the aortic ACE. Captopril (30 mg/kg, p.o.) markedly inhibited tissue ACEs and slightly plasma ACE, but its inhibitory effects on tissue ACEs, except for the aorta, were unclear by repeated dosings and its effect on plasma ACE was rather enhanced. Thus, the inhibition of vascular ACE may be particularly important for the antihypertensive effect of the ACE inhibitors, including CV-3317, in SHR.     

In vivo electrochemical detection of 5-hydroxyindoles in the dorsal hippocampus of anesthetized rats treated with idebenone (CV-2619)

The effect of idebenone (CV-2619), 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone, on 5-hydroxyindoles in the dorsal hippocampus of rats was investigated by using in vivo differential pulse voltammetry. CV-2619 (100 mg/kg, i.p.) produced a large increase in oxidation current at 280 mV (peak 2) in the dorsal hippocampus. The increase was statistically significant at 20 and 30 min after the administration. 5-Hydroxytryptophan (150 mg/kg, i.p.) also caused a marked increase in peak 2, which was clearly inhibited by the treatment with pargyline (50 mg/kg, i.p.). Thus, the increase in peak 2 induced by CV-2619 seems to be associated with an increase in the 5-HT metabolite 5-hydroxyindoleacetic acid and also partly with an increase in 5-HT.     

Antihypertensive action of a non-sulfhydryl angiotensin converting enzyme inhibitor (CV-3317) in various hypertensive models

The antihypertensive action of N-[N-[(S)-1-ethoxycarbonyl-3-phenyl-propyl]-L-alanyl]-N-(indan-2-yl) glycine hydrochloride (CV-3317), a nonsulfhydryl compound characterized as an angiotensin converting enzyme inhibitor in our previous work, was examined in hypertensive animal models. In 2-kidney, 1 clip hypertensive rats and dogs, CV-3317 (3 and/or 10 mg/kg, p.o.) produced a sustained antihypertensive action of about 15 to 25 mmHg. Daily oral administrations of CV-3317 (1 to 10 mg/kg/day) to spontaneously hypertensive rats (SHR) for 5 weeks produced a sustained antihypertensive action of 20 to 40 mmHg. When CV-3317 (3 mg/kg) was combined with hydrochlorothiazide (10 mg/kg), its antihypertensive action was intensified in potency and duration. CV-3317 (30 mg/kg) induced a slight hypotension (5 to 10 mmHg) in normotensive rats, but had no effect on the blood pressure of 1-kidney, 1 clip hypertensive rats and on that of a low renin type of DOCA/salt hypertensive rat. The antihypertensive activity of CV-3317 was more potent than that of captopril. In pithed SHR, the pressor response induced by an electrical stimulation of the preganglionic sympathetic nerve, but not the pressor response to norepinephrine, was attenuated by both agents (0.3 mg/kg, i.v.). Both agents may exert their antihypertensive action not only primarily by inhibiting the renin-angiotensin system, but also by inhibiting norepinephrine release from the sympathetic nerve terminals indirectly by reducing the formation of vascular angiotensin II.     

The effect of an antihypertensive drug budralazine on cerebrovascular lesions in salt-loaded SHR

Budralazine was evaluated for its protective effect on the onset of cerebrovascular lesions in SHR given 1.5% NaCl as drinking water. The salt-loading for 67 days rapidly accelerated the development of hypertension in SHR (from 180 to over 250 mmHg, 40 days after the loading). The acceleration of hypertension was accompanied by an increase in the incidence of brain softening, cerebral infarct, angionecrosis and hemorrhage by 30-60% following the thrombosis and necrosis of cerebral arterioles. Renal angionecrosis associated with the interstitial nephrosis was also observed by 90% in the animals. Throughout the salt-loading period, oral administration of budralazine (1, 4 and 15 mg/kg/day) resulted in a dose-dependent inhibition of the accelerated hypertension. At larger doses (4 and 15 mg/kg/day), budralazine almost completely ameliorated the cerebral and renal lesions and significantly attenuated the rise of weight in the brain and heart observed in the salt-loaded control rats. Changes in the serum biochemical findings were also inhibited by this drug. In some of the parameters measured, budralazine appeared to be more efficacious than hydralazine (1, 4 and 15 mg/kg/day, p.o.). These results suggest that budralazine attenuates the serious development of hypertension and reduces the incidence and severity of stroke in salt-loaded SHR.     

Antihypertensive and diuretic effects of YM-09730-5, a new calcium antagonist, in stroke-prone spontaneously hypertensive rats

1. Effects of consecutive administration of YM-09730-5, (3S)-1-benzyl-3-pyrrolidinyl-methyl (4S)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxy lat e hydrochloride, a new calcium antagonist, for 9 wk on blood pressure and urinary excretion of electrolytes were studied in stroke-prone spontaneously hypertensive (SHRSP) rats. 2. YM-09730-5 (1 and 3 mg/kg per day, p.o.) prevented development of hypertension and produced a significant reduction in blood pressure from the first week of the experiment. Nicardipine (15 mg/kg per day, p.o.) produced almost the same degree of antihypertensive effect as YM-09730-5 at a dose of 3 mg/kg. 3. YM-09730-5 produced significant diuresis and increased urinary excretion of electrolytes throughout the experiment. 4. Chronic administration of YM-09730-5 (3 mg/kg) reduced the severity of glomerular lesions in the kidney and vasculitis in the mesenteric artery. 5. These results demonstrate that YM-09730-5 is a potential antihypertensive drug with a potency about 5 times higher than that of nicardipine.     

Cadmium-induced hypertension in rats

Chronic cadmium chloride (CdCl2, 0.5 and 1.0 mg/kg, i.p.) treatment in female albino rats for 2 weeks resulted in elevation of blood pressure. In chronic CdCl2-treated rats the pressor responses to different doses of noradrenaline, angiotensin II and depressor responses to acetylcholine and isoprenaline were unaltered. In rat hindquarter preparation there was elevation of perfusion pressure and the sensitivity of vascular bed to noradrenaline was increased in the CdCl2-induced hypertensive rats. Complete bilateral adrenalectomy or chemical sympathectomy or treatment with captopril did not prevent the development of CdCl2-induced hypertension. Treatment with verapamil (15 mg/kg/day, p.o.) or nifedipine (10 mg/kg/day, p.o.) for 2 weeks prevented the development of hypertension with chronic CdCl2 treatment. It is suggested that chronic treatment of rats with CdCl2 induces hypertension. It is possible that cadmium mimics the calcium ion for the induction of hypertension in rats.     

Enalapril and valsartan improve cyclosporine A-induced vascular dysfunction in spontaneously hypertensive rats

Cyclosporine A causes hypertension and nephrotoxicity in spontaneously hypertensive rats (SHR). In the present study, arterial function was investigated using in vitro vascular preparations after long-term treatment with cyclosporine A. SHR received cyclosporine A (5 mg kg(-1) day(-1) s.c.) and high-Na(+) diet for 6 weeks during the developmental phase of hypertension. Part of the rats were treated concomitantly either with the angiotensin converting enzyme inhibitor enalapril (30 mg kg(-1) day(-1) p.o.) or with an angiotensin AT(1) receptor antagonist valsartan (3 or 30 mg kg(-1) day(-1) p.o.). In renal arteries, contractile responses to noradrenaline and angiotensin II, as well as relaxation responses to acetylcholine (endothelium-dependent) and to sodium nitroprusside (endothelium-independent), were severely impaired by cyclosporine A-treatment. There was also a trend for the dysfunction of the mesenteric arteries, but the impairment did not reach statistical difference. Enalapril and valsartan improved the impaired renal arterial functions. Cyclosporine A-induced hypertension and nephrotoxicity seem to be associated with renal arterial dysfunction in SHR on high-Na(+) diet. Antagonism of the renin-angiotensin system protects from vascular toxicity of cyclosporine A.     

PREVENTATIVE AND THERAPEUTIC EFFECTS OF AE0047 ON RENAL INJURY IN STROKE-PRONE SPONTANEOUSLY HYPERTENSIVE RATS

1. The present study was designed to investigate the preventative and therapeutic effects of AE0047 on renal injury compared with those of nitrendipine in stroke-prone spontaneously hypertensive rats (SHRSP). 2. In the preventative study, drug administration was started before the appearance of renal injury, such as proteinuria. Treatment for 6 weeks with AE0047 (1 and 3 mg/kg, p.o.) led to a dose-related reduction in systolic blood pressure (SBP). Nitrendipine, at doses of 10 and 30 mg/kg, also lowered SBP to a similar degree to that seen with AE0047 at 1 and 3 mg/kg, respectively. 3. In the vehicle-administered SHRSP group, urinary excretion of protei. (U_proteinV) increased progressively from 14 weeks of age for another 6 weeks. AE0047 at both doses maintained U_proteinV within normal levels throughout the experimental period. However, the elevation of U_proteinV was only inhibited in the 30 mg/kg nitrendipine-treated group. Urinary N-acetyl-β-D-glucosaminide (NAG) activity in the vehicle-treated SHRSP group was elevated. Urinary NAG activity remained at a low level only in AE0047-treated groups. 4. Histopathological examination revealed severe lesion. (i.e. fibrinoid necrosis, proliferative vasculitis and glomerular lesions) of the kidney in SHRSP. AE0047 treatment at each dose attenuated the development of renal lesions in SHRSP. In contrast, nitrendipine, at 10 mg/kg, was ineffective against the development of renal lesions. Although nitrendipine at 30 mg/kg suppressed the development of renal lesions, this effect was still weaker than that seen with AE0047 at 1 mg/kg. 5. In the therapeutic study, drugs were administered to 17-week-old SHRSP with moderate renal damage for 10 days. Treatment with AE0047 (1 and 3 mg/kg) produced dose-dependent decreases in U_proteinV. In the nitrendipine-treated group, U_proteinV tended to decrease but the changes were not significant. 6. Histopathological studies revealed that 3 mg/kg AE0047 improved renal lesions, such as fibrinoid necrosis, proliferative vasculitis and glomerular lesions, whereas 30 mg/kg nitrendipine di. not. 7. Taken together, the results indicate that AE0047 is capable of preventing proteinuria as well as renal lesions, in part via a mechanism independent of its depressor action on SBP. Furthermore, AE0047 improves proteinuria and renal lesions in proteinuria-established SHRSP. Thus, AE0047 may have therapeutic potential in suppressing either the development or the progression of renal disease in hypertensive patients.     

Effect of idebenone (CV-2619) on memory impairment observed in passive avoidance task in rats with cerebral embolization

Effect of idebenone (CV-2619) on memory impairment was studied in rats with cerebral embolization. The cerebral embolization, produced by injecting 2000 microspheres into the internal carotid artery, caused a significant impairment in passive avoidance response. Repeated administrations of idebenone (30 mg/kg/day, i.p.), partially but significantly improved the impairment of the passive avoidance response in the embolized rats. The results suggest that the repeated administration of idebenone exerts an ameliorating effect on memory impairment induced by cerebral embolization.