ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1989.tb00471.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Summary—The interactions of calcium antagonists or channel activators with the different classes of calcium channel are reviewed with particular emphasis on interactions with neuronal tissue; reasons for the failure of calcium antagonists to inhibit neurotransmitter release under normal circumstances are outlined. Calcium antagonists may be protective in several pathological situations and the possibilities of protection against ischaemic damage in the central nervous system are evaluate

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1989.tb00472.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Summary—Recent advances in central dihydropyridine (DHP)‐binding sites are reviewed. DHP‐binding sites are pre‐synaptically and post‐synaptically localized in the brain. The functional role of post‐synaptic sites is still unknown, whereas pre‐synaptic sites seem to contribute to the control of calcium uptake and of neurotransmitter release. DHP‐binding sites may be modulated in physiological (age, sex) and pathological events (hypertension, ischaemia, neurological diseases) or after drug treatments (alcohol, morphine, etc.). The reviewed data suggest new therapeutic implications of DHP calcium channel antagonists in the treatment of other diseases and of drug with

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1989.tb00473.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Summary—Intracerebroventricular (i.c.v.) injections of dihydropyridine derivatives calcium channel agonist (BAY K8644) and antagonists (nifedipine, nicardipine, PN 200–110) induced opposite long‐lasting changes in blood pressure (BP) in pentobarbital anesthetized spontaneously hypertensive rats (SMR). I.c.v. nifedipine (NIF), nicardipine (NIC), and PN 200–110 decreased mean blood pressure dose‐dependently and stereoselec‐tively, (+) NIC and (+) PN being 8 and 3 times more potent than their (‐) isomers, respectively. The decrease in BP was due to a withdrawal of the sympathetic tone, since NIF‐ and NIC‐induced falls in BP were suppressed after either hexamethonium (HXM), 6 OHDA or bilateral adrenalectomy. I.c.v. BAY K8644 increased BP dose‐dependently. The i.c.v. BAY K8644‐induced hypertensive effect was inhibited: a), by NIF and (+) PN but not by (‐) PN, therefore probably occurring at central DHP sites; b), by HXM and reserpine, thus probably mediated by an increase in sympathetic tone; c), by i.c.v. methylatropine (MA) while i.v. MA and i.c.v. HXM had no inhibitory effect, thus probably involving central muscarinic sites. In SHR, NIC did not after the K+‐evoked ACh release but suppressed the BAY K8644‐induced increase in ACh release. In anesthetized normotensive control rats (WKY), neither i.c.v. NIF, NIC or BAY K8644 changed BP, nor did the latter after ACh release. Moreover, in conscious WKY, i.c.v. nicardipine increased BP and HR while, in conscious SHR it decreased BP without any change in HR. These data suggest that central DHP sites may be involved in the cholinergic transmission and may participate in genetic hype

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1989.tb00474.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Summary—Several pharmacological and clinical studies have suggested that calcium channel antagonists (CCA) can exert central actions. The aim of the present study was to investigate their putative central cardiovascular properties in dogs. In normotensive pentobarbital‐anesthetized dogs, intravenous (I.V.) nicardipine, — nifedipine — verapamil or diltiazem — induced a dose‐dependent decrease in systolic and diastolic blood pressures followed by tachycardia due to baroreflex activation. By contrast, central (in‐tracisternal: I.C.) administration of the same CCA (at doses ineffective by the I.V. route) induced an increase in both blood pressure and heart rate. Two kinds of neurogenic hypertensive sinoaortic dener‐vated (SAD) dogs were used to study whether the central sympathoexcitatory effects of CCA depend on the level of the sympathetic tone. In acute SAD dogs (where the sympathetic tone is nearly maximum), I.V. administration of nicardipine, nifedipine, verapamil or diltiazem significantly reduced the SAD‐induced increase in blood pressure and heart rate, thus demonstrating the sympathoinhibitory properties of CCA when sympathetic tone is maximum. In chronic SAD awake dogs (where the sympathetic tone is high but not maximum), I.V. nicardipine significantly decreased arterial blood pressure, but also induced both a marked tachycardia and a significant increase in plasma noradrenaline and adrenaline release. However, this direct central activation was not observed with verapamil I.V. under the same experimental conditions (chronic SAD awake dogs). The present data show that CCA could exert central cardiovascular actions in dogs. The positive chronotropic effects of CCA not only result from a baroreflex activation (following the decrease in blood pressure) but also from a direct centrally‐mediated effect on sympathetic tone. Moreover, the magnitude of this sympathoexcitatory effect seems to vary according to the CCA group (phenylalkylamines being less potent that dihydropyridines) and to depend on the level of sympathetic tone: CCA exert stimulant effects when the sympathetic tone is low (normal dogs) and depressor actions when it

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1989.tb00475.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Summary—The tachycardia elicited by decreases in aortic pressure produced by various calcium antagonists, regardless of their chemical structures, is not always simply related to the reduction in pressure. Several experimental and clinical experiments have clearly demonstrated that some of these compounds interfer with the baroreceptor reflex control of heart rate. The voltage‐dependent calcium channel blockade induced by these antagonists is probably not involved in the baroreceptor mechanotransduction, but central modulation of the baroreceptor reflex is probably an important site for action of these drugs at therapeutic levels. During chronic treatment of hypertension with calcium antagonists, a resetting of the reflex occurred with parallel shift of the set‐point and of the baroreceptor reflex‐response curve towards lower pressures, thus explaining the lack of change in heart rate despite a permanent reduction in blood pressure under these conditions. However, these effects of calcium antagonists on the baroreceptor reflex do not provide evidence that such interactions could play a role in their antihypertensive action during chronic

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1989.tb00476.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Summary—The present study aims at reviewing the preclinical evidence suggesting that calcium antagonists exert bio‐behavioural effects that may have some relevance to CNS pharmacology, and thus to psychiatry. We briefly address the question of whether calcium antagonists share the following profiles: anxiolytic, antidepressant, neuroleptic, anticonvulsant, analgesic and memory‐enhancing. This survey suggests that calcium antagonists and, more especially, dihydropyridine derivatives share all these profiles together. There are, however, important limitations in the interpretation of these preclinical data. Whether the various calcium antagonists may have varying profiles, and thus varying potential psychiatric applications, cannot be explored in depth as there are few comparative data on these drugs on a large variety of animal models. In addition, the doses of calcium antagonists reported to produce behavioural responses are generally higher than the doses sufficient to produce other pharmacodynamic actions. Thus, the possibility that these former responses could be secondary to these latter actions cannot be exc

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1989.tb00477.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Summary—Flunarizine, a diphenylalkylamine, is one of the most popular antivertiginous drugs used nowadays in France. However, until now, there are very few preliminary data about the physiological or pathophysiological functions of calcium in the vestibular system. Moreover, experimental and clinical arguments are still insufficient to clearly demonstrate that 1) flunarizine is an effective antivertiginous drug and 2) this putative antivertiginous property is really due to the anticalcic action of the drug and not to a more classical antagonistic effect on Hl receptors. Much more work is needed before accepting the indication of any anticalcic drug as an effective antivertigo treatmen

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1989.tb00478.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Summary—Experimental and clinical data clearly demonstrate that calcium antagonists (CA) may have an action on the central nervous system (CNS). The cerebrovascular action of CA justifies their use in cerebral ischaemia, vasospasm and hypoxia. Several clinical trials have demonstrated such beneficial effects. On the other hand a number of reports indicate that CA may have a direct neuronal effect, although most of such trials have not been verified or are mere case reports. In addition, the large number of conditions susceptible to being corrected by CA is impressive: epilepsy, pain, dystonia, dyskinesia, psychiatric conditions, etc. Other papers are disconcerting that report extrapyramidal disorders induced by flunarizine and cinnarizine in the elderly, whereas nicardipine does not produce such side effects and may even alleviate some parkinsonian symptoms. In various experimental models (e.g. stroke, oedema), pharmacological effects have been shown to vary from one compound to the other. Two main questions are yet to be answered: 1) has the direct neuronal effect of CA been clearly established? 2) are the multiple clinical effects on the CNS really linked to calcium antagonis

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1989.tb00479.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY