Effects of calcium channel blockers and hydralazine on epinephrine-induced hyperglycemia in vivo

Effects of calcium channel blockers from structurally different classes and hydralazine on epinephrine-induced hyperglycemia were studied in vivo. Nifedipine (0.05-0.20 mg/kg, i.p.) and nicardipine (0.40-0.80 mg/kg, i.p.) markedly potentiated the epinephrine-induced hyperglycemia in a dose-dependent manner. In contrast to these dihydropyridine calcium channel blockers, verapamil and diltiazem did not significantly affect the epinephrine-induced hyperglycemia at doses of 0.10-1.0 mg/kg, i.p. At higher doses (10 mg/kg, i.p.), significant potentiation of epinephrine-induced hyperglycemia was observed by these non-dihydropyridine calcium channel blockers. Hydralazine also markedly increased the epinephrine-induced hyperglycemia. These calcium channel blockers and hydralazine had no significant effect on the basal plasma glucose levels at any dose used here. As judged from the rates of glucose disappearance (K values), dihydropyridines significantly impaired the glucose tolerance in much lower doses than those of non-dihydropyridines and hydralazine. Furthermore, epinephrine-induced impairment of glucose tolerance was markedly potentiated by these calcium channel blockers and hydralazine at doses which potentiated the epinephrine-induced hyperglycemia. These results suggest that, at least in part, the potentiation of epinephrine-induced hyperglycemia by dihydropyridines, non-dihydropyridines and hydralazine is related to the inhibition of peripheral glucose utilization produced by insulin.     

Study of the mechanism of hydralazine-induced myocardial necrosis in the rat

Hydralazine, 25 mg/kg ip given on 2 consecutive days, causes myocardial necrosis in rats. Propranolol, 10 mg/kg sc twice daily, or verapamil, 10 mg/kg sc twice daily, protected against this effect. Hydralazine alone caused marked tachycardia, but bradycardia occurred when hydralazine and propranolol were given in combination. Verapamil caused a mild tachycardia which was increased further by hydralazine. Pretreatment with dihydrotachysterol, 1 mg/kg po for 3 days, aggravated the hydralazine-induced lesion. ⁴⁵Ca measurements indicated increased calcium concentration in the heart 6 hr after hydralazine administration. The data suggest that the lesion is induced by the pharmacological effects of hydralazine and that hypoxia and increased intracellular calcium play a role in the development of necrosis.     

Rapid desensitization of central beta-adrenoceptors in rat after subacute treatment with imipramine and calcium entry blockers.

The subcutaneous (s.c.) administration of isoprenaline to rats produced a dose-dependent increase in water drinking which was effectively antagonized by propranolol. This dipsogenic response was significantly inhibited after the intraperitoneal (i.p.) administration of imipramine (15 mg/kg/day), together with either of the following calcium entry blockers, for four days: diltiazem (15 mg/kg/day), verapamil (10 mg/kg/day), nifedipine (10 mg/kg/day) or nicardipine (15 mg/kg/day). Simultaneous injection of the inhibitor of the synthesis of serotonin, p-chlorophenylalanine (200 mg/kg/day, i.p.), did not affect this attenuation of the isoprenaline-induced response. Similarly, the selective 5-HT2 receptor agonist, 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) or the 5-HT2 receptor antagonist, ketanserin, had no significant effect on the attenuation of isoprenaline-induced drinking behaviour. The inhibition of isoprenaline-induced drinking, was, however, effectively attenuated after treatment of the animals with 6-hydroxydopamine (2.5 micrograms) or clonidine (30 micrograms), injected intracerebroventricularly (i.c.v.). These results indicate that the calcium entry blockers accelerate the desensitization of central beta-adrenoceptors possibly by an action on central adrenoceptors of the rat.     

Effect of yohimbine on urethane-induced hyperglycemia in rats

Urethane is a widely used anesthetic and yohimbine is a well-known alpha 2-adrenergic antagonist. In fasted Wistar rats urethane at an anesthetic dose (1.25 g/kg, i.p.) caused an increase in plasma glucose, while pentobarbital at an anesthetic dose (40 mg/kg, i.p.) did not. Urethane caused no change in plasma glucose in adrenalectomized rats. The hyperglycemic effect of urethane was not inhibited by pretreatment with propranolol (1 mg/kg, p.o.) or prazosin (10 mg/kg, p.o.), but was reduced by pretreatment with phentolamine (10 mg/kg, p.o.) or yohimbine (10 mg/kg, p.o.). Urethane caused an elevation of plasma adrenaline, and yohimbine reduced the elevation. In addition, the pretreatment of yohimbine potentiated the urethane-induced increase in plasma insulin. These results indicate that yohimbine may inhibit the urethane-induced hyperglycemia that is mediated by the central and peripheral alpha 2-adrenergic systems.     

Reversal of acute theophylline toxicity by calcium channel blockers in dogs and rats

Theophylline, widely used in the treatment of pulmonary diseases, has a narrow therapeutic index; the recommended plasma levels being 10–20 μg/ml in humans. The misuse or abuse of theophylline can cause life-threatening central nervous system and cardiovascular effects. Increased intracellular Ca²⁺ levels are thought to play an important role in theophylline toxicity and death. The objective of this study was to determine whether Ca²⁺ channel blockers, e.g. verapamil, nifedipine, or diltiazem, prevent sudden death caused by theophylline treatment in rats and dogs. Groups of Sprague-Dawley rats were treated with theophylline alone (150 mg/kg i.p.) or with theophylline pretreatment followed by administration of verapamil (0.25 to 0.5 mg/kg i.p.), nifedipine (0.25 to 1.0 mg/kg i.p.), or diltiazem (0.5 to 1.0 mg/kg i.p.), 2.5 to 15 min later. The rats were observed for toxic signs and survival over a period of 15 days. All three calcium channel blockers significantly reduced the theophylline-induced sudden death in rats. In a separate study, neither verapamil (0.5 mg/kg i.p.) nor nifedipine (1.0 mg/kg i.p.) prevented the theophylline-induced myocardial necrosis in the rat. In beagle dogs, verapamil (0.5 mg/kg i.v.) prevented theophylline (15 mg/kg/min i.v. for 10 min)-induced hypotension, arrhythmias, and sudden death. Our results support previously reported findings that calcium plays a major role in theophylline-induced toxicity and death.     

The differential effects of prazosin and hydralazine on sympathoadrenal activity in conscious rats

The ability of the vasodilator hydralazine and the alpha 1-adrenoceptor antagonist prazosin to increase sympathoadrenal outflow was compared by measuring plasma norepinephrine and epinephrine concentrations, norepinephrine clearance and norepinephrine spillover rate into plasma in conscious Sprague-Dawley rats and spontaneously hypertensive rats (SHR). Even though the vasodepressor effect of 1 mg/kg (i.p.) of prazosin (-23 mm Hg) was significantly less than that caused by 1 mg/kg (i.p.) of hydralazine (-31 mm Hg) in normotensive rats, the increases in plasma norepinephrine concentration and norepinephrine spillover rate were significantly larger in prazosin-treated rats. In conscious SHR, 0.5 mg/kg (i.p.) of prazosin and 0.3 mg/kg (i.p.) of hydralazine lowered blood pressure to the same extent (-22 mm Hg), but prazosin again produced significantly larger increases in plasma norepinephrine concentration and norepinephrine spillover rate. Neither prazosin nor hydralazine affected norepinephrine clearance, and only prazosin elicited a significant rise in plasma epinephrine concentration. This differential effect of prazosin and hydralazine on sympathoadrenal activity is best explained by the differing effects of these drugs on venous return and thus the afferent activity of the cardiopulmonary baroreceptors.     

Acute hyperglycemia attenuates nerve conduction velocity and nerve blood flow in male Sprague–Dawley rats: reversal by adenosine

Hyperglycemia is implicated to play a major role in development of diabetic neuropathy. Since most of the diabetics are hyperglycemic much before they develop full-blown diabetes, we felt, it would be very important to know the effects of acute hyperglycemia on nerve function so that early pathophysiological events could be understood and appropriate therapeutic intervention can be made. Moreover, effect of acute hyperglycemia on motor nerve conduction velocity (MNCV) and nerve blood flow (NBF) is not known. Hence, we studied the effects of acute hyperglycemia on sciatic MNCV and sciatic NBF in healthy male Sprague-Dawley (SD) rats. Three different animal models of acute hyperglycemia (50% glucose (3 g kg(-1), i.v. (intra-venous) or i.p. (intra-peritoneally)) or 24 h post-streptozotocin (STZ) injected rats were used. Acute hyperglycemia but not mannitol or sucrose significantly attenuated MNCV and NBF. Adenosine (10 mg kg(-1), i.p.) prevented the acute hyperglycemia-induced attenuation of MNCV and NBF in all the three rat models of acute hyperglycemia. Adenosine effects were blocked by theophylline (50 mg kg(-1), i.p.) suggesting the role of adenosinergic receptor mediated mechanisms in acute hyperglycemia-induced neuropathy. Acute glucose administration in 8 weeks, STZ diabetic rats did not further affect MNCV or NBF. Adenosine (10 mg kg(-1), i.p.) did not produce any adverse effects on the blood pressure and heart rate. From the results, we conclude that acute hyperglycemia attenuates MNCV and NBF via an adenosinergic receptor-dependent mechanism.     

Drug effects on plasma renin activity in the mouse

To investigate the possible effects of newly synthesized beta-adrenergic blockers on plasma renin activity, an assay was developed using unanesthetized mice and radioimmunoassay. Renin activity was significantly increased by the administration of hydralazine (1 mg/kg, i.p.), furosemide (20 mg/kg, i.v.), and isoproterenol (0.1 mg/kg, s.c.). Unlike isoproterenol, norepinephrine (1 mg/kg, s.c.) and epinephrine (1 mg/kg, s.c.) were active but considerably less effective stimulants. The increase caused by isoproterenol was blocked by clonidine, pindolol, bunolol, atenolol, and l-propranolol, but not d-propranolol. The beta-blockers with intrinsic sympathomimetic activity such as pindolol were found to increase renin activity when given alone, but blocked an increase in renin activity when given prior to isoproterenol. In general, nonselective beta-blocking drugs possessing both beta 1- and beta 2-(vascular) blocking activity were found to be most effective in blocking plasma renin activity on oral administration.     

The influence of divalent cations on the analgesic effect of opioid and non-opioid drugs

It is generally accepted that divalent cations are involved in the nociceptive pathway. The effect of systemic co-administration of magnesium sulfate and calcium channel blockers (nifedipine, verapamil) on the analgesic effect of opioid (mixed mu/kappa: butorphanol) and non-opioid drugs (paracetamol) was investigated. Albino mice and rats were used as experimental animals. Magnesium sulfate and calcium channel blockers were given i.p., 30 min before the administration of butorphanol tartrate and paracetamol. Analgesia was measured using "hot-plate" ( 52.5( composite function)C), "tail-flick" (radiant heat source), "writhing" (acetic acid, 1%, i.p.) and "tail-clip" tests. The pain threshold was evaluated before and after the administration (i.p.) of the different agents. The effect of the combined administration of different agents on behavior, blood pressure and heart rate, was also determined. Nifedipine (5 mg kg(-1), i.p.) and verapamil (10 mg kg(-1), i.p.) potentiated the analgesic effect of butorphanol tartrate (0.25-2 mg kg(-1), i.p.) in all tests (synergism) and enhanced analgesic effect of paracetamol (50-125 mg kg(-1), i.p.), only in acetic acid writhing and tail-clip tests. Magensium sulfate (2.5 mg kg(-1), i.p.) potentiated the analgesic effect of butorphanol, but not that of paracetamol. Co-administration of nifedipine and verapamil with either of butorphanol (0.25-2 mg kg(-1)) or paracetamol (50-125 mg kg(-1), i.p.) produced no significant effects on motor coordination, motor performance, locomotor activity, long-term memory or on the blood pressure and heart rate of experimental animals. Co-administration of magnesium sulfate, however, significantly induced sedation, inhibition of locomotor activity, motor performance and coordination, as well as impairing of long-term memory, as compared with butorphanol and paracetamol, administered alone. We conclude that the systemic co-administration of calcium channel blockers potentiated the analgesic effect of butorphanol against thermal, mechanical and chemical pain but enhanced that of paracetamol only against mechanical and chemical pain. Magensium sulfate enhanced the analgesic effect of butorphanol, but not that of paracetamol. These findings, merit further studies in animals and humans to evaluate the potential therapeutic benefits of such interactions.     

Pyritinol reduces nociception and oxidative stress in diabetic rats

The purpose of this study was to assess the antinociceptive and antiallodynic effect of pyritinol as well as its possible mechanism of action in diabetic rats. Streptozotocin (50 mg/kg) injection caused hyperglycemia within 1 week. Formalin-evoked flinching was increased in diabetic rats as compared to non-diabetic rats. Oral acute administration of pyritinol (50-200 mg/kg) dose-dependently reduced flinching behavior in diabetic rats. Moreover, prolonged administration of pyritinol (12.5-50 mg/kg, every 2 days for 2 weeks) reduced formalin-induced nociception. 1H-[1,2,4]-oxadiazolo [4,3-a] quinoxalin-1-one (ODQ, a guanylyl cyclase inhibitor, 2 mg/kg, i.p.), but not naltrexone (a non-selective opioid receptor antagonist, 1 mg/kg, s.c.) or indomethacin (a non-selective cycloxygenase inhibitor, 5 mg/kg, i.p.), blocked the pyritinol-induced antinociception in diabetic rats. Given alone ODQ, naltrexone or indomethacin did not modify formalin-induced nociception in diabetic rats. Oral acute (200 mg/kg) or prolonged (25 mg/kg, every 2 days for 2 weeks) administration of pyritinol significantly reduced streptozotocin-induced changes in free carbonyls, dityrosine, malondialdehyde and advanced oxidative protein products. Four to 8 weeks after diabetes induction, tactile allodynia was observed in the streptozotocin-injected rats. On this condition, oral administration of pyritinol (50-200 mg/kg) reduced tactile allodynia in diabetic rats. Results indicate that pyritinol is able to reduce formalin-induced nociception and tactile allodynia in streptozotocin-injected rats. In addition, data suggest that activation of guanylyl cyclase and the scavenger properties of pyritinol, but not improvement in glucose levels, play an important role in these effects.     

Are 5-HT receptors or beta-adrenoceptors involved in idazoxan-induced food and water intake?

Idazoxan (10 mg/kg, i.p.) produces an unexpected increase in food intake in freely-feeding rats which has been linked to its high affinity for non-adrenoceptor idazoxan binding sites. In this study, a dose-related antagonism of idazoxan-induced food intake by the beta-adrenoceptor antagonist (-)-propranolol (5-20 mg/kg, i.p.), which also blocks 5-HT1 (5-hydroxytryptamine1) receptors has been demonstrated. (+)-Propranolol (10, 20 mg/kg, i.p.) did not attenuate idazoxan-induced feeding. (-)-Propranolol (10 mg/kg, i.p.) but not the (+)-enantiomer (10 mg/kg, i.p.) also significantly inhibited the food intake, induced by the 5-HT1A agonist 8-OH-DPAT (0.25 mg/kg, i.p.). Idazoxan-induced feeding was not altered by the selective beta-adrenoceptor antagonists betaxolol (beta 1; 5 mg/kg, i.p.) and ICI 118,551 (beta 2; 5 mg/kg, i.p.) but was potentiated by the 5-HT receptor antagonist metergoline (5 mg/kg, i.p.). The anomalous findings with metergoline may reflect its action at different sub-types of 5-HT receptor. The water intake induced by idazoxan and the peripherally-active alpha 2-adrenoceptor antagonist L-659,066 was also blocked in a stereoselective manner by propranolol (10 mg/kg) but not significantly by either metergoline (5 mg/kg, i.p.), the beta 1-adrenoceptor antagonist betaxolol (5 mg/kg, i.p.) nor by the beta 2-adrenoceptor antagonist ICI 118,551 (5 mg/kg, i.p.). These results suggest that the food intake induced by idazoxan (and perhaps mediated by non-adrenoceptor idazoxan binding sites) may involve the 5-HT system, although further studies, using antagonists acting selectively at the different sub-types of 5-HT receptor, are required to confirm this.(ABSTRACT TRUNCATED AT 250 WORDS)     

Calcium channel antagonists suppress nicotine-induced place preference and locomotor sensitization in rodents

The influence of calcium channel antagonists on the behavioral sensitization to nicotine-induced hyperlocomotion and place preference was investigated. Locomotor sensitization in mice was produced by injecting nicotine (0.5 mg/kg, i.p.) for 5 consecutive days before placement in an apparatus in which locomotor activity was evaluated for 1 h. One week later, activity of mice was recorded after challenge with the same dose of nicotine. The L-type voltage-dependent calcium channel antagonists: nimodipine (5, 10 and 20 mg/kg, i.p.), verapamil (5, 10 and 20 mg/kg, i.p.) and diltiazem (5, 10 and 20 mg/kg, i.p.) were injected 15 min before each injection of nicotine (induction of sensitization) or acutely 15 min before a challenge nicotine injection (expression of sensitization). It was shown that the calcium channel blockers attenuated both the induction and expression of nicotine-induced locomotor sensitization in a dose-dependent manner. In the place preference paradigm, nicotine produced a place preference to the initially less-preferred compartment paired with its injections during conditioning (0.5 mg/kg, i.p., 4 drug sessions). Pretreatment with nimodipine (10 mg/kg, i.p.), verapamil (10 mg/kg, i.p.) and diltiazem (10 mg/kg, i.p.) blocked nicotine-induced place conditioning. These results suggest the common calcium-dependent mechanisms of nicotine-induced behavioral sensitization and place preference.     

Bradykinin causes inhibition of methacholine-induced bronchoconstriction in vivo in mice

In this study the influence of bradykinin on airway responses was investigated in anaesthetised and ventilated mice. Airway resistance in mice was monitored using whole body plethysmography. Intravenous (i.v.) administration of bradykinin (4-40 microg/kg) did not cause a direct effect on airway resistance. Also pretreatment with propranolol (1 mg/kg, i.v.), atropine (1 mg/kg, i.v.) or indomethacin (5 mg/kg, i.v.) did not result in any effect of intravenous bradykinin on baseline airway resistance. However, i.v. bradykinin (4-40 microg/kg) caused a dose-dependent inhibition of the (0.5 mg/kg, i.v.) methacholine-induced bronchoconstriction, with an ED50 value of 3.4 +/- 0.4 microg/kg. The maximal inhibition of the bronchoconstrictor response to methacholine was 65.5 +/- 2.0%. The inhibition of the methacholine-induced bronchoconstriction by bradykinin could be prevented by treatment with the B2 receptor antagonist icatibant (Hoe 140, 0.13 mg/kg, i.v.). Also pretreatment with either propranolol (1 mg/kg, i.v.), L-NAME (30 mg/kg, i.v.) or indomethacin (5 mg/kg, i.v.) completely blocked the inhibition of the methacholine-induced bronchoconstriction by bradykinin. The inhibition of the methacholine-induced bronchoconstriction after bradykinin was not affected by the NK1 receptor antagonist RP 67580 (17.5 microg/kg, i.v.). In conclusion, the results of this study demonstrate that bradykinin causes a dose-dependent inhibition of the methacholine-induced bronchoconstriction in vivo in mice. This response is B2 receptor-mediated and at least involves the activation of beta-adrenoceptors and the synthesis of nitric oxide and cyclo-oxygenase products.     

Calcium-dependent mechanisms of the reinstatement of nicotine-conditioned place preference by drug priming in rats

Reinstatement of drug-seeking behaviour in animals is relevant to relapse to drug taking in humans. We used the conditioned place preference version of the reinstatement model to investigate the establishment, extinction, reinstatement and cross-reinstatement of nicotine-induced place conditioning in rats. Nicotine produced a place preference to the compartment paired with its injections during conditioning (0.5 mg/kg, i.p., three drug sessions). Once established, nicotine place preference was extinguished by repeated training. Following this extinction phase, nicotine-experienced rats were challenged with nicotine (0.5 mg/kg, i.p.), a cannabinoid receptor agonist WIN55,212-2 (0.5 mg/kg, i.p.), ethanol (0.5 g/kg, i.p.) or d-amphetamine (2 mg/kg, i.p.). The priming injections of nicotine, WIN55,212-2 and ethanol, but not of d-amphetamine renewed a preference for the compartment previously paired with nicotine. Finally, we examined the influence of the calcium channel antagonists, nimodipine (5 and 10 mg/kg, i.p.) and flunarizine (5 and 10 mg/kg, i.p.), on the reinstatement of nicotine place conditioning induced by WIN55,212-2 and ethanol. It was shown that the calcium channel blockers attenuated the reinstatement of nicotine-conditioned response induced by both drugs. As reinstatement of drug-seeking is a factor for the development of dependence, the L-type calcium channel antagonists may be useful in the relapse-prevention phase of addiction treatment, including cannabinoid, ethanol, and/or nicotine dependence.     

The discriminative stimulus properties of (+)-HA-966, an antagonist at the glycine/N-methyl-D-aspartate receptor

Using a two-lever operant drug discrimination paradigm, rats have been trained to discriminate between the administration of saline and R-(+)-HA-966 (R-(+)-3-amino-1-hydroxypyrrolid-2-one, 30 mg/kg i.p.) an antagonist at the glycine modulatory site on the N-methyl-D-aspartate (NMDA) receptor/ion channel complex. Drug-appropriate responding was not induced in stimulus generalisation experiments when the non-competitive NMDA receptor antagonist, phencyclidine (PCP, 1-8 mg/kg i.p.) was substituted for (+)-HA-966. Similarly, (+)-HA-966 (6-50 mg/kg i.p.) did not induce drug-appropriate responding in animals trained to discriminate PCP (3 mg/kg i.p.) from saline. The results suggest that the behavioural profile of compounds attenuating the actions of NMDA via blockade of the glycine modulatory site may be substantially different from those acting at the ion channel of the NMDA receptor complex.     

Involvement of Noradrenergic Neurotransmission in the Stress- but not Cocaine-Induced Reinstatement of Extinguished Cocaine-Induced Conditioned Place Preference in Mice: Role for ��-2 Adrenergic Receptors

The responsiveness of central noradrenergic systems to stressors and cocaine poses norepinephrine as a potential common mechanism through which drug re-exposure and stressful stimuli promote relapse. This study investigated the role of noradrenergic systems in the reinstatement of extinguished cocaine-induced conditioned place preference by cocaine and stress in male C57BL/6 mice. Cocaine- (15 mg/kg, i.p.) induced conditioned place preference was extinguished by repeated exposure to the apparatus in the absence of drug and reestablished by a cocaine challenge (15 mg/kg), exposure to a stressor (6-min forced swim (FS); 20–25°C water), or administration of the α-2 adrenergic receptor (AR) antagonists yohimbine (2 mg/kg, i.p.) or BRL44408 (5, 10 mg/kg, i.p.). To investigate the role of ARs, mice were administered the nonselective β-AR antagonist, propranolol (5, 10 mg/kg, i.p.), the α-1 AR antagonist, prazosin (1, 2 mg/kg, i.p.), or the α-2 AR agonist, clonidine (0.03, 0.3 mg/kg, i.p.) before reinstatement testing. Clonidine, prazosin, and propranolol failed to block cocaine-induced reinstatement. The low (0.03 mg/kg) but not high (0.3 mg/kg) clonidine dose fully blocked FS-induced reinstatement but not reinstatement by yohimbine. Propranolol, but not prazosin, blocked reinstatement by both yohimbine and FS, suggesting the involvement of β-ARs. The β-2 AR antagonist ICI-118551 (1 mg/kg, i.p.), but not the β-1 AR antagonist betaxolol (10 mg/kg, i.p.), also blocked FS-induced reinstatement. These findings suggest that stress-induced reinstatement requires noradrenergic signaling through β-2 ARs and that cocaine-induced reinstatement does not require AR activation, even though stimulation of central noradrenergic neurotransmission is sufficient to reinstate.     

Influence of ACTH on the effects of imipramine, desipramine and lithium on duration of immobility of rats in the forced swim test.

We examined the effects of adrenocorticotropic hormone (ACTH) on the immobilization of rats in the forced swim test with the administration of imipramine, desipramine, or lithium. A single administration of either imipramine (10-30 mg/kg, i.p.) or desipramine (30 mg/kg, i.p.) significantly decreased the duration of immobility in normal rats in a dose-dependent manner. Lithium (10-100 mg/kg, p.o.), however, had no affect on the performance of rats in the forced swim test. ACTH (100 microg/day), administered subcutaneously to rats for 1, 3, 7, and 14 days, had no apparent effect on the duration of immobility in this test. The immobility-decreasing effect induced by a single administration of either imipramine (10-30 mg/kg, i.p.) or desipramine (30 mg/kg, i.p.) was blocked by chronic administration of ACTH for 3-14 days. The reduction of immobility, induced by chronic administration of imipramine (10 mg/kg, i.p.) for 15 days, was blocked by treatment with ACTH for 14 days. When lithium (100 mg/kg, p.o.) was administered for 15 days concurrently with imipramine (10 mg/kg, i.p.), we observed a significant decrease in immobility in rats treated with ACTH for 14 days. We suggest that chronic treatment of rats with ACTH may prove to be an effective model of tricyclic antidepressants-treatment-resistant depression.     

Evaluation of calcium entry blockers and alpha2-adrenergic antagonists on B-HT 920-induced presser responses in the autonomically blocked dog

Several calcium entry blockers and alpha2-adrenergic receptor antagonists were evaluated for inhibition of presser responses induced by the selective alpha₂ agonist B-HT 920 in pentobarbital-anesthetized dogs pretreated with prazosin (0.5 mg/kg, i.v.), propranolol (0.5 mg/kg, i.v.), and hexamethonium (10 mg/kg i.v.). In this preparation, autonomic blockade (alpha₁, beta, and ganglionic block) persists for approximately 4 hr. The B-HT 920 administered intravenously causes dose-related increases in mean arterial blood pressure (ED₅₀ = 4.90 μg/kg, i.v., dose causing a 50 mm Hg rise in mean arterial blood pressure). Maximum increases in mean arterial pressure approximate 80 mm Hg at 100 μg/kg, i.v. Repeated bolus administration of B-HT 920 over a 4-hr period shows no significant reduction in the pressor response, suggesting good stability of this experimental model and no rapidly developing tolerance. Calcium entry blockers (nifedipine, D-600, and diltiazem) and alphaz-adrenergic receptor antagonists (yohimbine and idazoxan) inhibit the B-HT 920-induced presser response in a dose-related manner. The ED₅₀ values (dose of antagonist that causes a 50% inhibition of B-HT 920-induced pressor response) were calculated. Idazoxan and yohimbine have ED₅₀ values (mg/kg, i.v.) of 0.086 and 0.063, respectively, whereas D-600, nifedipine, and diltiazem have values of 0.074, 0.111, and 0.542, respectively. The data show that calcium entry blockers and alpha2-adrenergic blockers are potent inhibitors of B-HT 920 pressor responses in the autonomically blocked dog. This experimental model is appropriate for the evaluation of calcium entry blockers and/or alpha₂-adrenergic antagonists in vivo.     

Involvement of 5-hydroxytryptamine(1A) receptors in nicotine-induced tail tremor in rats

Involvement of the serotonergic system in tail tremor induced by repeated administration of nicotine was investigated in rats. Tail tremor induced by nicotine (0.5 mg/kg, s.c.) was suppressed by a 5-HT(1A) receptor antagonist, N-?2-[4-(2-methoxyphenyl)-1-piperazinyl-]ethyl?-N-(2-pyridinyl)cycloh exanecarboxamide trihydrochloride (WAY-100635; 0.3-3 mg/kg, i.p.), but not by a 5-HT(2) receptor antagonist, ketanserin (0.1-0.3 mg/kg, i.p). The 5-HT(1A) receptor agonists, buspirone (1-20 mg/kg, i.p.), gepirone (1-10 mg/kg, i.p.), tandospirone (1-10 mg/kg, i.p.) and (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.01-0.1 mg/kg, s.c.), enhanced the tail tremor. The enhancement of tail tremor by buspirone (10 mg/kg, i.p.) was blocked by WAY-100635 (0.3-3 mg/kg, i.p.). These findings suggest that nicotine-induced tail tremor is mediated by 5-HT(1A) receptors and that 5-HT(1A) receptor antagonists are effective in the treatment of tremor.     

Paradoxical short-term effects of cyproheptadine on insulin and glucagon release in the rat.

The administration of cyproheptadine (25 mg/kg; i.p.) resulted in an increase of plasma insulin and glucagon (measured using 30 K antibody) 30, 60 and 120 min after injection to fasted rats. This dose of cyproheptadine also induced a hyperglycemia whereas a lower dose (5 mg/kg; i.p.), which did not alter plasma hormone levels, was associated with a hypoglycemia. Fed rats showed a reduction of plasma insulin with a similar elevation of blood glucose after cyproheptadine. Administration of an exogenous load of arginine resulted in increases of plasma insulin and glucagon of a greater magnitude than induced by cyproheptadine, however, cyproheptadine pretreatment (25 mg/kg) completely suppressed the pancreatic response to the amino acid, resulting in blood hormone levels similar to values seen after cyproheptadine administered alone. Cyproheptadine pretreatment also prevented the hyperinsulinemia and hypoglucagonemia resulting from glucose loading. alpha-Adrenergic receptor blockade (with phentolamine), beta adrenergic receptor blockade (with propranolol) and adrenodemedullation did not alter pancreatic responsiveness to the drug.