Anna Maria Gianni

Effects of calcium antagonists on biogenic amines in discrete brain areas

Discrete brain sections were obtained from rats given i.p. verapamil, nifedipine, diltiazem or flunarizine (0, 10, 20 or 40 mg/kg). The biogenic amines and metabolites in the hypothalamus, brainstem hippocampus, striatum, thalamus-midbrain and cortex were determined by high-performance liquid chromatography with electrochemical detection. The treatments induced several changes in the levels of neurotransmitters and metabolites, displaying regional specificity and differences according to the various compounds. It was speculated that some effects could have been due to indirect actions and/or to interactions of the compounds with receptors other than the voltage-sensitive calcium channels. However blockade of these channels could account for the following effects. (a) The nifedipine-induced increases in the 5-hydroxy-3-indoleacetic acid levels and, in general, the signs of activation of the serotonergic systems. (b) The fall in the 3,4-dihydroxyphenylacetic acid levels and, in general, the signs of attenuation of dopaminergic neurotransmission induced by nifedipine, verapamil and diltiazem. (c) The fall in the norepinephrine levels induced by all the compounds studied.

Comparison among the effects of nifedipine, nimodipine and nisoldipine on the brain biogenic amines of normal or haloperidol treated rats

1. Previous studies have shown that dihydropyridine calcium antagonists affected the metabolism of the brain biogenic amines more extensively than the non-dihydropyridine ones. The effects of three dihydropyridines (nifedipine, nimodipine or nisoldipine, 0.05-0.10 mmol/kg i.p.) on brain monoamines and metabolites have been evaluated on both normal and haloperidol treated rats. 2. The small changes induced by the drugs on normal rats were markedly increased in the haloperidol treated rats, clearly showing an inhibition of dopaminergic systems. 3. These effects were selective for the striatum and cerebral cortex, with nisoldipine being more effective than nimodipine or nifedipine. 4. The effects of the three drugs on serotonergic systems were similar or more marked on haloperidol treated rats than on normal rats. These effects, showing activation of serotonergic systems, displayed some regional specificity and different potency of the three compounds. Nisoldipine also appeared to be the most effective drug on serotonergic systems. 5. In conclusion nisoldipine, as well as other calcium antagonists, may have a place in the treatment of some mood disorders.

Effects of nitrendipine and nisoldipine on biogenic amines in discrete areas of rat brain

1. Biogenic amines and metabolites were determined in discrete brain sections obtained from rats once or repeatedly treated with nitrendipine or nisoldipine. 2. The increase in both the 5-HIAA levels and the 5-HIAA/5-HT ratio suggested that the drugs activated the serotonergic system in various brain areas. 3. Moreover, nisoldipine decreased the HVA content and the HVA/DA ratio in the striatum. 4. This suggested that nisoldipine, but not nitrendipine, inhibited dopaminergic neurotransmission in this brain area. 5. The effects induced by repeated treatment with nitrendipine or nisoldipine were reduced as compared to those caused by a single administration of these drugs. 6. All these facts could be explained on the basis of the pharmacokinetic properties of nitrendipine and nisoldipine and by the ability of these drugs to interact with the brain VSCC.

Effects of isradipine and darodipine on serotonergic system of the rat brain.

Isradipine and darodipine are dihydropyridine calcium antagonists that easily pass into the brain, showing high affinity for cerebral L-type voltage-sensitive calcium channel (VSCC). These drugs were IP administered to rats to study their effects on serotonergic systems of discrete brain areas. Isradipine (0.05-5.0 mg/kg) and darodipine (0.3-20 mg/kg) increased the 5-HIAA/5-HT ratio, mostly enhancing the metabolite (5-HIAA) content in various brain areas, suggesting that serotonin (5-HT) turnover was increased. This increase appeared to depend on facilitation of serotonergic neurotransmission, because low doses of isradipine (< 0.075 mg/kg) or darodipine (< 0.6 mg/kg) enhanced the number of head twitches induced by L-5-hydroxytryptophan (L-5-HTP). However, higher doses of isradipine (1.5 mg/kg) or darodipine (5 mg/kg) also appeared to stimulate a negative feedback mechanism, which predominated over the facilitation when the serotonergic neurotransmission was strongly activated. Thus, higher drug doses decreased both the serotonin turnover and the number of head twitches on rats treated with L-5-HTP. It was speculated that the observed effects were due to brain VSCC blockade, although the studied compounds showed a peculiar profile of properties when compared to other previously studied calcium antagonists. Moreover, it was concluded that darodipine appeared to be more effective and selective than isradipine regarding the effects on brain serotonergic systems.

Calcitonin enhances the effects of nimodipine on biogenic amines of rat brain

1. Nimodipine affects the brain biogenic amines suggesting both inhibition of the striatal dopaminergic system and activation of serotonergic systems in various brain areas. 2. Salmon calcitonin affects serotonergic systems as nimodipine does. 3. It was hypothesized that these effects could be more than additive since they all have been ascribed to inhibition of neuronal calcium influx. 4. Biogenic amines and metabolites were determined in brain areas obtained from rats pretreated with saline or salmon calcitonin (10 MRC U/kg, s.c.) and treated with nimodipine (2.5-20 mg/kg, i.p.). 5. The effects of nimodipine and salmon calcitonin appeared to be merely additive.

Dialysable and non‐dialysable hydroxyproline in the rat's urine: age related and diurnal variations

1. Urinary dialysable and non‐dialysable hydroxyproline, which are considered good indices of bone resorption and neoformation respectively, were determined in rats under conditions that modify skeleton metabolism, such as body growth and parathyroid or calcitonin administration. It was also investigated whether dialysable and non‐dialysable hydroxyproline excretions showed significant circadian fluctuations in rats of different ages.

Interaction between dihydropyridine calcium antagonists and morphine on the brain biogenic amines

1. Nifedipine, nimodipine or nisoldipine, were i.p. administered to normal, morphine treated or morphine abstinent rats in order to study their effects on brain biogenic amines and metabolites. 2. On various brain areas, the compounds studied decreased DOPAC and/or HVA levels, but increased 5-HIAA levels, leaving unchanged DA and 5-HT contents. 3. This suggested that DA turnover was decreased, whereas 5-HT turnover was increased, by inhibition of neuronal calcium influx. 4. Calcium antagonists: (a) further enhanced the effect of morphine on 5-HT turnover, which may involve an indirect inhibition of voltage sensitive calcium channels; (b) antagonized the effects of morphine on DA turnover, which are believed to be mediated by disinhibition of dopaminergic pathways. 5. The dihydropyridine calcium antagonists showed some differences in regional specificity and in profile of effects.