To investigate the central and regional hemodynamics after long-term administration of CS-905, a novel calcium blocker, we administered the agent (1 and 3 mg/kg/day) for 15 weeks in spontaneously hypertensive rats. At the end of the dosing period, hemodynamic changes were examined using the radioactive microsphere technique. CS-905 produced a sustained dose-dependent antihypertensive effect without inducing tolerance during the 1 5-week dosing period and prevented cardiac hypertrophy. The agent increased cardiac output, decreased blood pressure and thus decreased total peripheral resistance in a dose-related manner. Regional blood flows measured by the microsphere technique were increased in the kidney and brain despite the lowered blood pressure. There was no organ where regional blood flow was decreased. These changes after chronic treatment with CS-905 would be beneficial in the long-term therapy of hypertension.
PCPGABA, injected into the cisterna magna, significantly stimulated gastric acid secretion in the perfused rat stomach preparation. This secretagogue action was dose-dependent (0.5-2 μg/rat). The peak response occurred within 60 min and lasted up to 100 min The secretagogue action by PCPGABA was completely reduced by truncal vagotomy. Intracisternal injection of 5-aminovaleric acid, a GABAB-receptor antagonist, did not alter basal gastric acid output, and it also failed to antagonize the acid secretory response to intracisternal PCPGABA. These results demonstrate that intracisternal PCPGABA caused hypersecretion of acid through vagal dependent mechanisms partially independent of GABAB-receptors.
The present study was performed to clarify the role of the ovarian carbonyl reductase (OCR) in ovarian function in immature rats. The OCR activities towards three specific substrates, 13, 14-dihydro-PGF2α, 4-benzoylpyridine and menadione, were photometrically and radiochemically determined in the 9, 000×g supernatants of ovaries, and OCR content was measured by Western-blot-peroxidase anti-peroxidase (PAP) analysis. Immunohistochemical localization of the enzyme in the ovary was performed by the avid in-biotin-complex (ABC) method for paraffin sections. Positive immunoreactivity with OCR antibody was observed for the theca cells and interstitial gland cells at 72 hr after pregnant mare serum gonadotropin (PMSG) treatment when ovulation was confirmed, and the granulosa cells were consistently negatively stained. The OCR activity was significantly increased by PMSG, human chorionic gonadotropin (hCG) and PMSG-hCG treatments, but estradiol and tamoxifen overcame the effect of PMSG on the enzyme activity.
Pharmacological properties of 5-(3-((2-(3, 4-dimethoxyphenyl)ethyl)-amino)-1-oxopropyl)-2, 3, 4, 5-tetrahydro-1, 5-benzothiazepine fumarate (KT-362), a newly synthesized calcium release blocker, were studied by comparing its vascular selectivity and cardiovascular actions with those of verapamil, a calcium entry blocker. The relaxing effect of KT-362 in rabbit femoral and basilar artery strips contracted with norepinephrine was greater than that in aortic and coronary artery strips. In anesthetized mongrel dogs, KT-362 (0.1-3.0 mg/kg, i.v.) decreased the mean blood pressure, heart rate and total peripheral resistance in a dose-dependent manner, while cardiac output increased slightly despite a decrease in left ventricular pressure. This is consistent with the data on verapamil. Both La. and i.v. injections of KT-362 produced a marked dose-dependent increase in vertebral and femoral blood flow. Pretreatment of atropine, propranolol or diphenhydramine exerted no significant effect on the KT-362-induced vasodilation. Verapamil caused a marked increase in the vertebral and coronary blood flows after the injections, but only a slight increase in femoral blood flow. KT-362 at the dose of 10 mg/kg, i.v., had no significant effect on the PQ interval on the electrocardiogram in anesthetized dogs, but 0.1 mg/kg of verapamil increased this interval significantly. These results suggest that KT-362 has properties similar to calcium entry blockers such as verapamil on systemic hemodynamic actions except for the reactivity of vasculatures.
The protective effects of DM-9384 [N-(2, 6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl) acetamide] against cerebral anoxia were investigated using various animal models. Oral administration of DM-9384 resulted in a significant prolongation of survival time in mice and rats subjected to the normobaric hypoxia; its minimal effective doses were 30 and 10 mg/kg, respectively. A significant protection by this drug against hypobaric hypoxia, histotoxic anoxia and cerebral ischemia also occurred in mice at a dose of 100 mg/kg, p.o. Bifemelane (100-300 mg/kg, p.o.) was protective against these models except for hypobaric hypoxia, and the effects of piracetam, aniracetam and pramiracetam (1000 mg/kg, p.o.) were variable depending on the type of anoxia model used. DM-9384 (100 mg/kg and lower) attenuated the hypolocomotion and the disturbance of cerebral energy metabolism such as a decrease in ATP, an increase in lactate and lactate/pyruvate ratio induced by hypoxia in rats. The spontaneous motor activity, uptake and utilization of brain glucose in normal animals, however, were not influenced by this drug. Based on these results, DM-9384 is characterized as a broad spectrum anti-anoxic drug with negligible CNS depression, and the cerebral protective effect of this drug may be, at least in part, attributable to its ability to improve the cerebral energy metabolic disturbance.
Effects of recombinant human epidermal growth factor (hEGF) on survival of primary cultured neurons from various regions of fetal rat brain were compared with those of recombinant human basic fibroblast growth factor (hbFGF). Addition of hEGF (0.001-10 ng/ml) in chemically-defined serum-free medium enhanced significantly the survival of cultured neurons from all regions tested, i.e., cerebral cortex, septum, striatum, hippocampus, thalamus, colliculus and cerebellum. However, its effective concentration differed considerably with the regions. The most sensitive regions were the colliculus and cerebellum (minimum effective concentration, 0.001 ng/ml), while the least sensitive was the cerebral cortex (minimum effective concentration, 10 ng/ml). Maximum numbers of surviving neurons in the presence of hEGF were smaller than those of hbFGF in all regions. Maximum effects of hEGF compared with those of hbFGF was greatest in the striatum and smallest in the cerebral cortex. These results suggest that hEGF may exert neurotrophic effects for limited populations of brain neurons. When hEGF (1-10 ng/ml) and hbFGF (0.01-10 ng/ml) were added together, hEGF increased the effects of a lower concentration of hbFGF in an additive manner, but the maximum effects of hbFGF were not potentiated by hEGF in all regions tested. Therefore, mechanisms underlying the effects of hEGF very probably overlap with those of hbFGF.
Using a repeated acquisition procedure in a 3-panel runway apparatus, the effect of WEB 1881 FU on impairment of working memory produced either by scopolamine or by cerebral ischemia was investigated in rats and compared with those of aniracetam and Ca hopantenate. Intraperitoneal injection of scopolamine at 0.56 mg/kg significantly increased the number of errors (pushes made on the two incorrect panels of the three panel-gates located at each choice point). WEB 1881 FU at 10-32 mg/kg, p.o., caused a dose-related reduction in the increase of errors expected in the scopolamine-treated rats. Aniracetam at 10-100 mg/kg, p.o., or Ca hopantenate at 100 and 560 mg/kg, p.o., also significantly diminished the increase in errors induced by 0.56 mg/kg of scopolamine. Cerebral ischemia for 5 min significantly increased errors in the 3-panel runway task. WEB 1881 FU at 32 and 56 mg/kg, administered p.o. immediately after blood flow recirculation and again 1 hr before the runway test, conducted 24 hr after ischemia, significantly reduced the increase in errors expected to occur after 5 min of ischemia. Aniracetam at 32 and 100 mg/kg, p.o., similarly diminished the increase in errors in ischemic rats. These findings suggest that WEB 1881 FU has a beneficial effect on memory that has been impaired by scopolamine or by cerebral ischemia.
Effects of single and repeated administration of pentazocine (5 times at intervals of 3-4 days) were compared with those of morphine and methamphetamine by means of ambulatory activity in mice. The interactions among these 3 drugs were also investigated. Pentazocine (25 mg/kg, s.c.), morphine (10 and 20 mg/kg, s.c.) and methamphetamine (2 mg/kg, s.c.) significantly increased the activity, and the effect progressively enhanced (defined here as development of reverse tolerance) during the repeated administration schedule. The induction of reverse tolerance to pentazocine was less dependent on the environmental conditions, and it was abolished within 2 months. A cross reverse tolerance was demonstrated from methamphetamine to pentazocine and to morphine, and from morphine to pentazocine. However, no significant cross reverse tolerance was induced from pentazocine to morphine and to methamphetamine, and from morphine to methamphetamine. The present results suggest that pentazocine possesses an ambulation-increasing effect, although the characteristics are different from that of either morphine or methamphetamine.
The role of descending noradrenergic fibers in the spinal motor systems was investigated using spinal reflexes in acutely spinalized rats. In rats pretreated with the MAO inhibitor clorgyline-HCl (1 mg/kg, i.v.), L-3, 4-dihydroxyphenylalanine (L-dopa) (5 mg/kg, i.v.), a precursor of dopamine and noradrenaline, markedly potentiated the mono- (MSR) and polysynaptic reflexes (PSR). Selective blockade of α1-adrenoceptors by pretreatment with prazosin-HCl abolished these facilitatory effects on the MSR and the PSR and revealed the inhibitory effect of L-dopa on the PSR. The depression of PSR was antagonized by the α2-antagonist piperoxan. Clonidine-HCl (0.05 mg/kg, i.v.), a so-called α2-agonist, and tizanidine-HCl (0.1 mg/kg, i.v.) decreased the MSR and the PSR in rats pretreated with prazosin. These inhibitions were antagonized by piperoxan. These results suggest that α1- and α2-adrenoceptors mediate facilitation and attenuation of motor transmission in the rat spinal cord, respectively.
Amnesia produced by scopolamine and cycloheximide were reversed by morphine given 30 min before the test trial (pre-test), and pre-test morphine also facilitated the memory retrieval in the animals administered naloxone during the training trial. Similarly, pre-test scopolamine partially reversed the scopolamine-induced amnesia, but not significantly; and pre-test cycloheximide failed to reverse the cycloheximide-induced amnesia. These results suggest that the facilitation of memory retrieval by pre-test morphine might be the direct action of morphine rather than a state dependent effect.
Omeprazole, a gastric mucosal proton pump inhibitor, significantly and dose-dependently prevented the delayed healing of acetic acid-induced gastric ulcers in response to repeatedly administered indomethacin to rats. Both basal and histamine-stimulated gastric acid secretions in rats with acetic acid-induced ulcers that were given indomethacin were markedly and persistently (>24 hr) inhibited after 4 weeks treatment with omeprazole. The prevention of delayed ulcer healing by omeprazole appears to be due to its long-lasting antisecretory activity.
We have studied the fibrinolytic effect of VIP in rats. Intravenous injection of VIP enhanced blood fibrinolytic activity in a dose-related manner. The euglobulin fraction obtained from intact rat plasma incubated with VIP did not produce an increase in fibrinolytic activity, while dextran sulfate (DS) and urokinase (UK) showed the activity. VIP solution placed on a plasminogen-rich fibrin plate did not show fibrinolysis. VIP had neither a plasminogen activator nor plasmin activity. VIP may release plasminogen activators into the blood.
A comparison was made of the cerebrovascular responses of humans, monkeys and dogs to noradrenaline (NAd) and dopamine (DA) as well as to their N-methylated derivatives, adrenaline (Ad) and N-methyl dopamine (methyl DA). The present experiments demonstrated that N-methylation of both NAd and DA enhanced the contractile responses of these agents in human cerebral arteries, while only N-methylation of DA enhanced the contraction of monkey cerebral arteries, and such an enhancement was not seen in dog cerebral arteries.
Effects of serotonin (5-HT) on plasma glucose and serum insulin levels were studied in mice. In normal mice, 5-HT induced a dose-dependent hypoglycemia and an increase in serum insulin levels. 5-HT significantly inhibited glucose-induced hyperglycemia and increased glucose-stimulated insulin release. However, in streptozotocin-induced diabetic mice, 5-HT changed neitheir the glucose nor insulin levels. These results strongly suggest that 5-HT-induced hypoglycemia is brought on by increasing serum insulin levels.