Natriuretic action of manidipine hydrochloride, a new calcium channel blocker, in spontaneously hypertensive rats.

Effects of manidipine, a new dihydropyridine derivative, on sodium and water excretion were examined in conscious spontaneously hypertensive rats. Manidipine (3 mg/kg) significantly increased the sodium and water excretion in the urine collected for 3 hr after the calcium antagonist was orally administered, and its natriuretic action was more prominent than those of nifedipine and nicardipine (3 mg/kg). These results suggest that manidipine may be useful for treating hypertension.

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.

Effects of idebenone on neurological deficits, local cerebral blood flow, and energy metabolism in rats with experimental cerebral ischemia.

Improvement of energy metabolism in ischemic cerebral tissue benefits the therapy of occlusive cerebrovascular disorders. In the present study, the effects of 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (idebenone) on neurological signs, such as ischemic seizures, lactate and ATP contents of the cerebral cortex, and local cerebral blood flow, were assessed in stroke-prone spontaneously hypertensive rats (SHRSP) with experimentally induced cerebral ischemia. Experimental cerebral ischemia was caused by bilateral carotid artery occlusion (BCAO) in male SHRSP (8-10 weeks old). Pretreatment with idebenone (10-100 mg/kg, p.o.) for 3 or 10 days delayed the onset of ischemic seizure (acute stroke) and prolonged survival time in SHRSP roughly in a dose-dependent manner. When the compound (100 mg/kg, i.p.) was given once 30 min after BCAO, it exerted similar ameliorating effects on the neurological deficits. When idebenone (100 mg/kg for 3 days) was given orally, it did not significantly inhibit the decrease in regional cerebral blood flow induced by BCAO. However, the same treatment markedly inhibited increases in the lactate content and lactate/pyruvate ratio and the decrease in ATP content of the cerebral cortex. The compound did not affect cerebral blood flow in normal rats. These results suggest that idebenone ameliorates the neurological deficits related to cerebral ischemia, and that this effect is mediated by improving cerebral energy metabolism.

Effects of idebenone on lipid peroxidation and hemolysis in erythrocytes of stroke-prone spontaneously hypertensive rats.

Stroke-prone spontaneously hypertensive rats (SHRSP) were kept on a 1% NaCl solution as drinking water to shorten the onset-time of a stroke. The level of lipoperoxide (LPO) in the erythrocytes of SHRSP loaded with salt for 22 days was significantly higher than that of the controls. Idebenone treatment (30 mg/kg per day, p.o.) markedly decreased the LPO to the level of the controls. Hemolysis in SHRSP was accelerated by the salt-loading. Idebenone significantly inhibited the hemolysis in a dose-dependent manner. These results suggest that idebenone inhibits lipid peroxidation in erythrocytes and stabilizes the erythrocyte membrane.

[Pharmacological study of the temporary cerebral ischemic rats produced by bilateral vertebral and carotid artery occlusion. Effects of DN-1417].

We investigated the ameliorating effects of DN-1417 (a TRH analog) on the changes of behavior, EEG, neurochemical parameters and regional cerebral blood flow (rCBF) in rats with global cerebral ischemia. Global cerebral ischemia was produced by 10-min occlusion of both common carotid arteries 24 hr after the permanent electrocauterization of bilateral vertebral arteries. DN-1417 was administered intraperitoneally as soon as possible, following recirculation of carotid blood flow. DN-1417 shortened significantly the recovery times of righting reflex (RR) and spontaneous movement (SM) at 2.5 mg/kg and higher doses, and it recovered effectively the EEG activity at 10 mg/kg during recirculation after 10-min cerebral ischemia. In addition, DN-1417 (10 mg/kg) recovered the various changes such as decrease of 5-hydroxytryptamine (5-HT) levels, increase of cyclic AMP (cAMP) levels, inhibition of [3H]-choline uptake, depression of choline acetyltransferase (CAT) and acetylcholine esterase (AChE) activities, and shortened the durations of hyperperfusion and hypoperfusion of rCBF. As a result, it is identified that DN-1417 ameliorates the disturbance of consciousness supposedly caused by behavioral and EEG abnormalities during recirculation following the temporary cerebral ischemia, and the effect of DN-1417 seems to be mediated by normalizing of alterations in the brain monoaminergic and cholinergic systems, as well as rCBF, and the effectiveness for disturbance of consciousness in clinical situations would be expected.

[Regional cerebral blood flow in rats with cerebral ischemia produced by bilateral vertebral and carotid artery occlusion].

Regional cerebral blood flow (rCBF) was measured prior to, during and after global cerebral ischemia in rats. Global cerebral ischemia was produced by 10 or 30-min occlusion of both common carotid arteries which was done 24 hr after the permanent electrocauterization of bilateral vertebral arteries. The rCBF was measured using the radioactive microsphere technique. In rats subjected to 10-min cerebral ischemia, rCBF in 9 brain regions was reduced to 11.3-54.8% (mean: 26.9%) of that of the sham operated control. Ten min after recirculation, hyperperfusion was observed in the cerebral cortex, hippocampus and striatum, and a moderate recovery was detected in the n.accumb. + olfactory tub., thalamus and hypothalamus. However, rCBF in these 6 regions was again decreased 20-30 min later, and it recovered to levels more than 50% of the control 60 min after the ischemic event. In the other 3 regions (cerebellum, colliculus sup. + inf., pons + medulla), rCBF increased toward the control level gradually, and it completely recovered 60 min after recirculation. On the other hand, in rats subjected to 30-min cerebral ischemia, rCBF in 9 brain regions was reduced to 1.77-26.3% (mean: 9.6%) of that of the control. The post-ischemic hyperperfusion in the cerebral cortex and hippocampus and a moderate recovery of rCBF in the striatum and n.accumb. + olfactory tub. were observed 10 min after the cerebral ischemia. However, rCBF in these 4 regions remained under the control levels from 20 to 60 min after recirculation.(ABSTRACT TRUNCATED AT 250 WORDS)

[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.

[Effects of idebenone (CV-2619) on neurological deficits, local cerebral blood flow, and energy metabolism in rats with experimental cerebral ischemia].

Improvement of energy metabolism in ischemic cerebral tissue benefits the therapy of occlusive cerebrovascular lesions. In the present study, the effects of 6-(10-hydroxydecyl)-2, 3-dimethoxy-5-methyl-1, 4-benzoquinone (idebenone, CV-2619) on neurological signs, local cerebral blood flow, and cerebral energy metabolism were assessed in stroke-prone spontaneously hypertensive rats (SHRSP) with bilateral carotid artery occlusion (BCAO). Pretreatment with CV-2619 (10-100 mg/kg, p.o.) for three or ten successive days delayed the onset of ischemic seizure (acute stroke) and prolonged survival time in the SHRSP. When the compound (100 mg/kg, i.p.) was given once 30 min after BCAO, it exerted similar ameliorating effects on the neurological deficits. When CV-2619 (100 mg/kg for 3 days) was given orally, it did not inhibit a decrease in regional cerebral blood flow induced by the carotid artery occlusion. However, the same treatment markedly inhibited increases in lactate content and lactate/pyruvate ratio and a decrease in ATP content in the cerebral cortex. In addition, the compound showed no effect on cerebral blood flow in normal rats. These results suggest that CV-2619 has an ameliorating effect on neurological deficits related with cerebral ischemia, and this effect is mediated by improved cerebral energy metabolism.

Reduced sodium excretory ability in young spontaneously hypertensive rats.

The excretory response of spontaneously hypertensive rats (SHR) and stroke-prone SHR (SHRSP) to acute saline load was compared to that of control Wistar Kyoto rats (WKY) in pre- and early-hypertensive phases. In each of the 3 groups, half of the animals was fed a low salt diet, and the other half a normal diet. At the prehypertensive phase, sodium and water excretion and sodium-potassium ratio in the urine in SHR and SHRSP fed a normal diet were significantly less than those in WKY. The ability of SHR to excrete sodium and water, however, was improved by the elevation of blood pressure that developed between 7 and 10 weeks after their birth. While young SHR fed a normal diet had a reduced ability to excrete sodium, the young SHR fed a sodium-restricted diet did not. Salt restriction significantly delayed the appearance of high blood pressure in both SHR and SHRSP. These results suggest that in both SHR and SHRSP, and elevation of blood pressure is important to compensate for the reduced ability to excrete sodium and water.

[The effect of vinpocetine on brain glucose uptake in mice].

The effects of vinpocetine and ifenprodil on the brain glucose uptake were studied in mice using a glucose analog, 2-deoxyglucose-14C, as a tracer of glucose. The brain glucose uptake was 1.42 +/- 0.06 mg/g/10 min (n = 8, Mean +/- SEM) in fasted control mice (5 ml/kg of 2% ascorbic acid). Thirty min after 5 and 20 mg/kg (p.o.) of vinpocetine, the uptake was increased to 106 +/- 6% (n = 9, P greater than 0.05) and 115 +/- 5% (n = 9, P less than 0.05) of the control value, respectively. The uptake was not increased by oral administration of 5 and 20 mg/kg of ifenprodil tartrate. Ten min after intraperitoneal injection of 1 and 5 mg/kg of vinpocetine, the glucose uptake was increased to 106 +/- 5% (n = 10, P greater than 0.05) and 112 +/- 4% (n = 10, P less than 0.05) of the control value, respectively. These results indicate that vinpocetine increases cerebral energy metabolism in mice after oral administration as well as intraperitoneal injection.

[Protective effect of vinpocetine on experimental brain ischemia].

The protective effect of vinpocetine on experimental brain ischemia was studied in stroke-prone spontaneously hypertensive rats (SHRSP) with bilateral carotid artery occlusion (BCAO) and in Wistar-Kyoto rats (WKY) subjected to BCAO and hemorrhage (1% of body weight). In SHRSP with BCAO, intraperitoneal (i.p.) injection of vinpocetine (1 mg/kg) 10 min before BCAO significantly prolonged the time required for the onset of ischemic seizure from 65 +/- 13 min (mean +/- SEM) to 117 +/- 19 min. In WKY with BCAO and hemorrhage, vinpocetine (5 mg/kg, i.p.) reduced the lactate level in the cerebral cortex from 11.6 +/- 2.7 mmol/g to 5.9 +/- 1.2 mmol/g and elevated the concentration of ATP from 2.05 +/- 0.09 mmol/g to 2.25 +/- 0.03 mmol/g. These results suggest a protective effect of vinpocetine against brain ischemia.

Mechanism of increased sensitivity to cerebral ischemia following carotid artery occlusion in stroke-prone spontaneously hypertensive rats: importance of genetic factors.

Neurological symptoms and cerebral metabolism following bilateral carotid artery occlusion (BCAO) were observed in stroke-prone spontaneously hypertensive rats (SHRSP), stroke-resistant SHR (SHRSR), normal Wistar-Kyoto rats (WKY) and the F1 and F2 hybrids between SHRSP and SHRSR or WKY. Systolic blood pressure recorded before BCAO was found to rank in the following order: SHRSP greater than F1 (SHRSP X SHRSR) greater than SHRSR greater than F1 (SHRSP X WKY) greater than WKY. The effect of BCAO in these rats tended to be proportional to the blood pressure. F1 (SHRSP X WKY) was more sensitive to brain ischemia than SHRSR. In addition, though none of the SHRSR (average blood pressure 155 mm Hg) developed acute stroke symptoms, many animals of the F2 generation, in which the blood pressure was equal to or lower than that of SHRSR, developed stroke symptoms. Lactate and ATP changes in the F2 generations did not correlate with the blood pressure. The results suggest that genetic factors may play an important role in susceptibility to brain ischemia in the stroke-prone rats.

Implication of renal perfusion pressure in stroke of spontaneously hypertensive rats.

To elucidate the significance of hypertension associated with cerebrovascular lesions (CVL), renal perfusion pressure (RPP) was controlled by aortic clips of two different sizes in stroke-prone spontaneously hypertensive rats kept under normal or salt-loaded conditions. Tail and femoral arterial pressures (RPPs) in the mildly and severely clamped animals were reduced in proportion to the severity of the clamping. In contrast, carotid pressures in both clamped groups were significantly higher than that in the controls. Proteinuria and hyperreninemia accompanied by arteriolar changes in the renal cortex were observed in the controls prior to the onset of CVL. The renal changes were inhibited by both types of clamping. The onset of CVL was delayed by the mild clamping in salt-loaded animals, but accelerated by the severe clamping in both the normal and salt-loaded animals. Renal cortical blood flow was decreased only by the severe clamping. The results suggest that reduction in RPP and/or renal ischemia, which seems to be due to the hypertensive arteriolar changes in the renal cortex, may be related to the pathogenesis of CVL in the stroke-prone rats with or without hyperreninemia.

Renin-angiotensin system in stroke-prone spontaneously hypertensive rats.

The development of malignant hypertension was studied in stroke-prone spontaneously hypertensive rats (SHR) kept on 1% NaCl as drinking water. Along with salt-loading, blood pressure gradually increased and reached a severe hypertensive level (greater than 230 mmHg), which was followed by increases in urinary protein (greater than 100 (mg/250 g body wt)/day) and plasma renin concentration (PRC, from 18.9 +/- 0.1 to 51.2 +/- 19.4 (ng/ml)/h, mean +/- SD). At this stage, renal small arteries and arterioles showed severe sclerosis and fibrinoid necrosis. Stroke was observed within a week after the onset of these renal abnormalities. The dose of exogenous angiotensin II (AII) producing 30 mmHg rise in blood pressure increased with the elevation of PRC, from 22 +/- 12 to 75 +/- 36 ng/kg, which was comparable to that in rats on water. The fall of blood pressure due to an AII inhibitor, [1-sarcosine, 8-alanine]AII (10(microgram/kg)/min for 40 min) became more prominent with the increase in PRC in salt-loaded rats, but was not detected in rats on water. These findings suggest that the activation of renin-angiotensin system participates in malignant hypertension of salt-loaded stroke-prone SHR rats that show stroke signs, proteinuria, hyperreninemia, and renovascular changes.