Effects of VA-045, a novel apovincaminic acid derivative,on age-related impairment evidence in electroencephalograph,caudate spindle,a passive avoidance task and cerebral blood flow in rats

• 1.1. The ability of VA-045 to improve aged-related impairment on electroencephalograph (EEG), caudate spindle, performance on a passive avoidance task and cerebral blood flow (CBF) were evaluated in rats.
• 2.]2. The cortical EEG of the aged rats showed a higher incidence of spontaneous spindle burst (SSB) than seen in young rats. VA-045 decreased the incidence of SSB in aged rats. In contrast, vinpocetine increased the incidence of SSB in aged rats.
• 3.3. Electrical stimulation of the striatum in aged rats lead to a higher incidence of neocortical high voltage spindle (CS) than seen in young rats. In young rats, VA-045 had no effect on the CS, whereas an age-related increase in CS was blocked by VA-045, but was enhanced by vinpocetine.
• 4.4. There were no differences in the cortical EEG arousal response elicited by stimulation of the reticular formation of the brain stem in rats of all ages. VA-045 and vinpocetine had no effect on the cortical EEG arousal response in both young and aged rats.
• 5.5. VA-045, but not vinpocetine, attenuated the age-related decreased step through latency (STL) on a passive avoidance task. VA-045 and vinpocetine did not enhance the acquisition of learning behavior in a passive avoidance task in young rats.
• 6.6. VA-045 increased the cerebral blood flow (CBF) in both young and aged rats and the potency in aged rats was greater than that in young rats. Vinpocetine had no effect on CBF in either young or aged rats.
• 7.7. The pharmacological effects of VA-045 on age-related neuronal dysfunction are discussed.

     

Decrease in cerebral free magnesium concentration following closed head injury and effects of VA-045 in rats

• 1.1. We examined the alterations in cerebral free Mg²⁺ concentration in closed head injury (CHI) in rats and the effects of VA-045, a novel apovincaminic acid derivative, on them with in vivo ³¹P-NMR.
• 2.2. Free Mg²⁺ decreased by about 30% within 20 min after head impact and, afterward, it gradually decreased further to reach about 60% of the control level after 3 hr. VA-045 inhibited the decrease.
• 3.3. In nonimpacted rats, VA-045 did not alter the free Mg²⁺ level.
• 4.4. The decrease in cerebral free Mg²⁺ following CHI may be a critical factor in the development of irreversible tissue injury, and VA-045 may prevent it.

     

Effect of VA-045 on central noradrenergic neuronal system in rats

• 1.1. Administration of VA-045 [2-(nitrooxy)ethyl apovincaminate] and thyrotropin-releasing hormone (TRH) led to improvement in the closed head injury (CHI)-induced neuronal dysfunction such as the loss of righting reflex and disruption of spontaneous movement in rats
• 2.2. The improvement seen with effect of VA-045, but not TRH, was abolished in rats pretreated with N-2-chloroethyl-N-ethyl-2-bromobenzylamine (DSP4), a selective noradrenaline (NA) neurotoxin. DSP4 reduced endogenous NA levels in all central nervous system (CNS) regions analyzed.
• 3.3. The extracellular concentrations of NA in the frontal cortex (FC) and in the locus coeruleus (LC) of urethane-anesthetized rats were measured using in vivo microdialysis coupled with high-performance liquid chromatography (HPLC) with electrochemical detection. VA-045 had no effect on extracellular concentrations of NA, in both FC and LC. Perfusion with clonidine, an α₂adrenoceptor agonist, led to inhibition in NA output in both FC and LC, and VA-045 antagonized the effect of clonidine.
• 4.4. These findings indicate that the mode of action of VA-045 may be, at least in part, related to central NA neuronal systems.

     

Calcium antagonistic action involved in vasodilation by brovincamine

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1. 1.1. Possible mode of vasodilative action of brovincamine was assessed in isolated cardiovascular preparations in comparison with verapamil and papaverine.
2. 2.2. Brovincamine (IC₅₀: 1.2 × 10⁻⁵ M), verapamil (IC₅₀: 3.5 × 10⁻⁷ M) or papaverine (IC₅₀: 2.5 × 10⁻⁵ M) caused a dose-dependent relaxation of potassium (30 mM)-contracture in the rabbit pulmonary arterial segment. This relaxation by verapamil or brovincamine, but not by papaverine, was antagonized by increasing external Ca²⁺ concentration to 12.4 mM.
3. 3.3. Duration of slow action potentials of partially depolarized guinea-pig papillary muscle was reduced by 15 min exposure to brovincamine (5 × 10⁻⁵ M) or verapamil (10⁻⁵ M).
4. 4.4. These results suggest that brovincamine produces a vasodilation via a slow Ca²⁺-channel blockade.

     

Effects of VA-045 on learning and memory deficits in traumatic brain injury (TBI)-induced retrograde and anterograde amnesic mice

1. No specific regimen has been developed to treat post-traumatic amnesia in man. In the present study, we examined the effects of (+)-eburnamenine-14-carboxylic acid (2-nitroxyethyl) ester (VA-045), a novel derivative of apovincaminic acid, on learning and memory deficits associated with a mild traumatic brain injury (TBI) in mice.
2. Two kinds of amnesia, TBI-induced retrograde amnesia (TRA) and anterograde amnesia (TAA), were produced by means of post- and pre-acquisition head injury, respectively, by a simple weight-drop device. A novel procedure of water-finding task was used to assess learning and memory functions.
3. Both TRA and TAA mice were dramatically impaired in the task performance, with prolonged latencies for finding and drinking in either retention test or retest, indicating that retention was impaired in TRA mice while learning and retention were impaired in TAA mice.
4. VA-045 administered 30 min post-trauma in TRA mice dramatically shortened the prolonged latencies for finding and drinking in both retention test and retest, indicating that VA-045 significantly improved the retention deficit observed in TRA mice.
5. VA-045 administered 30 min post-trauma in TAA mice dramatically attenuated the prolonged latencies for finding and drinking in both retention test and retest, indicating that VA-045 significantly improved the learning and retention deficits observed in TAA mice.
6. Administration of VA-045 30 min pre-trauma in normal mice markedly attenuated the delay of latencies for finding and drinking after trauma in both retention test and retest, which shows that VA-045 significantly prevented learning and retention deficits after TBI.
7. Motor activities were not significantly affected by either the TBI or the chemical treatment at the time of task examination in either experimental model.
8. It is concluded that VA-045 may have potential effects on learning and memory deficits observed in either TBI-induced retrograde or anterograde amnesia.

     

Differential Effects of rANF and Chronic Guanabenz to Presynaptic and Postsynaptic α2-Adrenoceptor-Mediated Cardiovascular Response in Pithed Rats

• 1.In normal rats, intracerebroventricular (ICV) guanabenz induced a decrease in blood pressure (BP) and heart rate (HR), and this hypotension or bradycardia was not changed by rANF pretreatment (3 μg ICV).
• 2.In pithed rats, intravenous (IV) guanabenz, an α2-adrenoceptor agonist, produced an increase in mean blood pressure (MBP) in a dose-dependent manner. The pressor response by guanabenz was attenuated by infusion of rANF. This attenuation was additive when incubated in combination with yohimbine.
• 3.In pithed rats, the pressor response due to the increase of sympathetic outflow with electrical stimulation was partially blocked by rANF infusion or chronic guanabenz treatment. This reduction was not augmented by chronic guanabenz plus rANF treatment.
• 4.The inhibitory action of guanabenz in tachycardia evoked by electrical stimulation at the C7–T1 site was attenuated by rANF, but not by chronic treatment with guanabenz.

     

Neurochemical actions of vigabatrin and tiagabine alone and in combination in mouse cortex

• 1.1. The effects of repeated administration of the anticonvulsant compounds, vigabatrin (VGB) and tiagabine (TGB), on γ-aminobutyric acid (GABA) concentration and the activities of GABA-transaminase (GABA-T) and glutamic acid decarboxylase (GAD) were investigated in mouse cortex.
• 2.2. VGB alone increased GABA levels and decreased GABA-T and GAD activities.
• 3.3. TGB alone was essentially without effect.
• 4.4. Low doses of VGB and TGB in combination increased GABA levels when neither drug had such an effect alone.
• 5.5. Despite this observation, this study failed to establish any conclusive evidence for an interaction between VGB and TGB that might help to explain their reported clinical synergism.

     

Cardiovascular Effects of Lovastatin in Normotensive and Spontaneously Hypertensive Rats

• 1.Lovastatin (1, 1.5, and 2 mg/kg) decreased systolic (SBP) and diastolic blood pressure (DBP) in spontaneously hypertensive rats (SHRs) and did not modify the basal values of blood pressure in normotensive rats.
• 2.Lovastatin decreased heart rate in a dose-dependent manner, and significant effects were observed in SHRs 180 min after lovastatin administration.
• 3.Lovastatin did not act as a diuretic drug at any of the doses used.
• 4.Lovastatin (10⁻⁶ M–3×10⁻⁴ M) depresses contractions evoked by KCl (80 mM) in isolated thoracic aorta from SHRs and WRs and had almost no relaxant effects on NA-induced (10⁻⁵ M) contractions.
• 5.It is concluded that the main antihypertensive mechanism of lovastatin is due to the relaxation of rat aorta by inhibiting Ca²⁺ influx through voltage-sensitive calcium channels.

     

Hemodynamic effects of barnidipine hydrochloride in conscious squirrel monkeys

• 1.1. The effects of barnidipine, a new dihydropyridine Ca²⁺ antagonist, on cardiovascular and renin-angiotensin-aldosterone systems were investigated in conscious squirrel monkeys.
• 2.2. Barnidipine (0.3–3 mg/kg p.o.) produced a dose-related decrease in systolic blood pressure. The hypotensive action after 3 mg/kg p.o. lasted more than 8 hr.
• 3.3. Barnidipine increased heart rate, but did not affect the PQ-interval of the electrocardiograph.
• 4.4. Barnidipine (1 and 3 mg/kg p.o.) increased plasma renin activity dose-dependently. However, it had no significant effect on plasma aldosterone concentration.
• 5.5. These results indicate that barnidipine produces a sustained hypotension without affecting atrioventricular conduction time and plasma aldosterone concentration in conscious squirrel monkeys.

     

Effects of oxotremorine and pilocarpine on striatal acetylcholine release as studied by brain dialysis in anesthetized rats

• 1.1. The effects of oxotremorine and pilocarpine on striatal acetylcholine (ACh) release were investigated using brain microdialysis techniques in urethan-anesthetized rats.
• 2.2. Oxotremorine (0.1 and 0.5 mg/kg, IV), a preferential M₂ agonist, dose-dependently decreased ACh release in the striatum. On the other hand, pilocarpine, at 5 mg/kg (IV), showed a tendency to decrease ACh release in the striatum but, at 7.5 and 10 mg/kg (IV), significantly enhanced release in a dose-dependent manner.
• 3.3. The effect of oxotremorine was blocked by scopolamine (0.1 mg/kg, IV) but not by pirenzepine (10 mg/kg, IV), a selective M₁ antagonist.
• 4.4. Pilocarpine (10 mg/kg, IV) enhancement of striatal ACh release was not affected by 10 mg/kg pirenzepine, but 5 mg/kg pilocarpine significantly increased ACh release in scopolamine (0.1 mg/kg) pretreated rats without affecting the release by itself.
• 5.5. These results suggest that oxotremorine-induced decrease in striatal ACh release is due to stimulation of presynaptic M₂ autoreceptor, and that the increase of striatal ACh release by pilocarpine is mediated by mechanism(s) other than effects on muscarinic ACh receptors.

     

Interplay between milrinone and adenosine in the inhibition of human platelet response

• 1.1. In this study, we investigated the influence of the isotropic agent and coronary vasodilator milrinone on platelet aggregation and intracellular levels of 3′,5′ cyclic adenosine monophosphate (cAMP) in human platelet-rich plasma (PRP) and whole blood (WB). Furthermore, we evaluated the influence of milrinone on the effects of adenosine, which reduces the platelet aggregation through an elevation of intraplatelet cAMP levels.
• 2.2. Milrinone decreased the platelet aggregation in response to agonists in both PRP and WB. A dose-dependent increase of intraplatelet cAMP levels was demonstrated: this result is in accordance with an effect on platelet phosphodiesterases.
• 3.3. Milrinone at low concentration and adenosine exerted additive effects on platelet aggregation and intraplatelet cAMP levels.
• 4.4. An interplay between milrinone and adenosine was shown in WB. Furthermore, dipyridamole, which prevents the uptake of endogenous adenosine, markedly enhanced the milrinone antiaggregating effect, whereas the adenosine receptor blocker, theophylline, decreased it.
• 5.5. The present data provide evidence that milrinone modulates the platelet function through an influence on intraplatelet levels of cAMP and it is able to interplay with substances stimulating adenylyl cyclase.
• 6.6. The interplay between milrinone and adenosine in the inhibition of the human platelet function could be effective during milrinone administration in the treatment of heart failure, when blood adenosine levels are significantly increased. These milrinone effects could be advantageous from a therapeutic point of view, since patients with heart failure are at risk of thrombosis and ischemic heart disease.

     

On the relation of calcium channel blockers to rat parotid and submandibular glands function in vivo

• 1.1. The effects of nifedipine, verapamil and diltiazem on rat parotid and submandibular glands function were studied.
• 2.2. Nifedipine (5 mg/kg), verapamil (5 mg/kg) and diltiazem (10 mg/kg) were injected intraperitoneally 15 min before saliva collection.
• 3.3. Animals were anesthetized with 50 mg/kg of sodium pentobarbital and 8 mg/kg of pilocarpine was used as secretagogue.
• 4.4. Submandibular saliva was analyzed for flow rate, protein and calcium concentrations; and parotid saliva for calcium and amylase contents.
• 5.5. In treated groups, flow rate and calcium of submandibular saliva were significantly lower than controls. Parotid calcium in the nifedipine group was decreased and in verapamil and diltiazem groups was increased. Parotid amylase was significantly decreased in both the nifedipine and diltiazem groups.
• 6.6. It is concluded that a blockade of calcium channels in salivary glands acinar cells by CCBs causes some alterations in salivary secretions.

     

The effect of physostigmine on acid-base status in arterial and venous blood of anaesthetized rabbits following hypovolemic shock

• 1.1. The effects of physostigmine (70 μg kg⁻¹intravenously) on acid-base status in arterial and venous blood were studied in anaesthetized rabbits subjected to hemorrhagic hypovolemia.
• 2.2. Hemorrhagic shock was produced using intermittent bleeding of 50% of the estimated blood volume, during 30 min. Experimental group was treated with physostigmine (70 μg kg⁻¹ body mass, intravenously) and the control group with the same volume (0.1 ml) of saline, immediately after bleeding. Blood samples were taken before and after bleeding (0, 15 and 60 min).
• 3.3. It was found that physostigmine increased the mean arterial blood pressure, did not change the heart rate, and improved survival of the animals.
• 4.4. These effects of physostigmine were associated with significant decrease in venous pH, produced mainly by increased PCO₂. This can partly be explained in terms of additional vasoconstriction due to physostigmine action.
• 5.5. In arterial blood decreased pH, decreased standard bicarbonate, negative values of excess base and decreased PCO₂ were observed both in physostigmine-treated and the control group of animals, indicating partly respiratory compensated metabolic acidosis. These findings indicate that the hypertensive effect of physostigmine in shock was not accompanied by more severe disturbance in arterial acid-base status than was observed in hypovolemic shock alone.

     

Effect of KRN2391 on canine ventricular arrhythmia models

• 1.1. KRN2391 (3–30 μg/kg, i.v.) produced a decrease in mean blood pressure (MBP) with concomitant increase in heart rate (HR) and change in electrocardiogram (ECG) such as the shortening of PP and PQ intervals and the prolongation of QTc and these changes in HR and ECG were attenuated by pretreatment with propranolol (1 mg/kg) in normal dogs.
• 2.2. KRN2391 at 30 μg/kg induces neither suppression nor aggravation of ventricular arrhythmias caused by adrenaline and digitalis.
• 3.3. In two-stage coronary ligation-induced arrhythmia, KRN2391 inhibited arrhythmia at 48 hr.
• 4.4. These results suggest that KRN2391 may be effective on arrhythmia related to ischemia. In addition, it is considered that arrhythmia is not induced even by a high dose of KRN2391 in the normal condition.

     

Muscarinic receptor subtypes in the bisected vas deferens of the rat

• 1.1. The nature of muscarinic receptor subtypes in the isolated prostatic and epididymal segments of the vas deferens of the rat were studied.
• 2.2. Presynaptic receptors were characterized in segments under neurogenic transmural stimulation; postsynaptic receptors in segments without stimulation.
• 3.3. The present work suggests that the potency of ACh required to activate muscarinic receptors is higher in the prostatic than in the epididymal segment.
• 4.4. McN-A-343 was only able to induce dose-dependent contractions in the prostatic segment.
• 5.5. The pA₂ value for 4-DAMP suggests that in the prostatic segment the postsynaptical ACh receptors seem to be pharmacologically similar to the ACh-M₃ subtype.
• 6.6. Antagonism of the presynaptic ACh receptor subtype by pirenzepine supports the evidence that these receptors belong to the ACh-M₁ subtype.

     

Different influences of adenosine receptor agonists and antagonists on morphine antinociception in mice

• 1.1. Subcutaneous (s.c.) administration of morphine to mice induced a dose-dependent antinociception.
• 2.2. Pretreatment of animals with adenosine receptor antagonists NECA (5′-N-ethylcarboxamidermadenosine) and l-PIA (N⁶-phenylisopropyladenosine) potentiated, while adenosine agonist CHA (N⁶-cyclohexyladenosine) decreased the morphine response.
• 3.3. Adenosine antagonist theophylline decreased, but adenosine receptor antagonist 8-PT (8-phenyltheophylline) increased the antinociception effect of morphine. Inhibitory effect of CHA on morphine antinociception was also reversed by 8-PT pretreatment.
• 4.4. NECA or l-PIA induced a high degree of antinociceptive effect in animals pretreated with 8-PT.
• 5.5. Dipyridamole pretreatment did not alter the effect of morphine.
• 6.6. It is concluded that A-1 and/or A-2 adenosine receptors are involved in morphine antinociception and the adenosine mechanism(s) may exert a modulatory role in this respect.

     

Breastmilk can mediate chemical imprinting. Benzpyrene exposure during lactation reduces the thymic glucocorticoid receptor density of the offspring

• 1.1. Prolonged benzpyrene treatment during lactation reduced the number of glucocorticoid receptors of offspring in adulthood significantly without altering the receptor affinity.
• 2.2. Dexamethasone treatment identical to benzpyrene exposure had no effect either on receptor number or affinity.
• 3.3. The results of the present investigations draw attention to the possible way of receptor alteration via breastmilk.

     

Central effects of opioid agonists and naloxone on blood pressure and heart rate in normotensive and hypertensive rats

• 1.1. The central cardiovascular effects of several opioid receptor selective agonists and the nonselective opioid antagonist, naloxone, were studied in anesthetized normotensive control rats, in spontaneously hypertensive rats (SHR), and in foot-shock-stressed rats.
• 2.2. Receptor-selective agonists injected into the rostral ventrolateral medulla (RVLM), paraventricular nucleus (PVN), and dorsal hippocampus (dHip) were DAGO (μ), DADLE (δ), and U50, 488H (κ).
• 3.3. DAGO and DADLE (3 nM) decreased arterial pressure and heart rate in RVLM and PVN of all rat strains, while U-50,488H (9 nM) had only minimal effects in these areas.
• 4.4. In dHip, only DADLE (3 nM) had depressor and bradycardic effects, and then, only in SHR, with DAGO and U50,488H being ineffective in any strain, even at 9 nM.
• 5.5. Prior injection of naloxone (10 nM) into the RVLM, PVN and dHip blocked and postinjection reversed the cardiovascular effects of the agonists. Naloxone alone increased blood pressure and heart rate in all three areas, in all rat strains except SHR, suggesting a tonic depressor effect of endogenous opioids.
• 6.6. Lack of significant quantitative differences in opioid agonist and antagonist effects between normotensive and hypertensive or stressed rats argues against a role for endogenous brain opioids in experimental hypertension.

     

Decreased contractile effect of endothelin-1 on hyperplastic prostate

• 1.1. The contractile activity, binding activity and localization of endothelin (ET)-1 were evaluated in human nonhyperplastic (control) and hyperplastic prostates.
• 2.2. ET-1 caused contraction of both prostates in a dose-dependent manner. However, this contraction was markedly decreased in hyperplastic prostates.
• 3.3. B_max and K_d values of hyperplastic prostates were greater than those of the control.
• 4.4. The muscle and proliferative epithelium of hyperplastic prostates showed strong staining for the anti-ET-1 antibody. However, the glandular epithelium of control prostates was weakly stained.
• 5.5. These findings indicate that responsiveness to ET-1 is decreased, though the ET-1 and ET-1 receptors increase in the hyperplastic prostate. Namely, the increase in ET-1 receptors is not effective in regulating the contractile response of the prostate, because its expression is rather dominant in proliferated gland.
• 6.6. These suggest that ET-1 may not have an important role in the release of the obstructive symptoms of benign prostatic hypertrophy.