Effects of calcium antagonists, felodipine and nicardipine, on cerebral circulation in dogs

The effects of a calcium antagonist of the dihydropyridine type, felodipine, on the cerebral circulation were studied in comparison with those of nicardipine in pancuronium-bromide immobilized unanesthetized dogs. Felodipine (0.3-10 micrograms/kg, i.v.) and nicardipine (0.3-10 micrograms/kg, i.v.) produced a dose-related decrease in mean blood pressure with almost equal potencies. However, at a dose of 3 micrograms/kg, felodipine produced a more prominent increase in cerebral blood flow (CBF) than nicardipine. Decreases in cerebral vascular resistance were significantly greater in the felodipine group at doses of 0.3 and 3 micrograms/kg, when compared with the nicardipine group. Cerebral oxygen consumption calculated by multiplying the arterio-venous difference of oxygen content by CBF was increased by these two drugs, but the changes were minimal. These data suggest that the increase in CBF produced by felodipine and nicardipine was primarily due to the direct dilatation of the cerebral blood vessels.     

Responses of cerebral circulation produced by adrenoceptor agonists and antagonists in rats

The effects of intravenous administration of adrenoceptor agonists and antagonists on relative cerebral blood flow, cerebral perfusion pressure, intracranial pressure, mean arterial blood pressure and heart rate were assessed in rats under urethane anesthesia. Administration of phenylephrine (a preferential alpha 1-adrenoceptor agonist), adrenaline (a mixed alpha/beta-adrenoceptor agonist), noradrenaline (a mixed alpha/beta-adrenoceptor agonist) raised mean arterial pressure, cerebral perfusion pressure, cerebral blood flow and intracranial pressure, but lowered heart rate. On the other hand, administration of isoproterenol (a beta-adrenoceptor agonist), phentolamine (an alpha-adrenoceptor antagonist) or propranolol (a beta-adrenoceptor antagonist) lowered mean arterial pressure, cerebral perfusion pressure or cerebral blood flow. In addition, phentolamine raised both intracranial pressure and heart rate, whereas propranolol lowered both intracranial pressure and heart rate. However, isoproterenol produced a decrease in heart rate, without affecting intracranial pressure. There was no significant difference between the groups of animals for PCO2, PO2 or pH throughout the studies. The results suggest that adrenoceptor agonists or antagonists act through breakthrough of autoregulation, with acute hypertension or hypotension, to enhance or to reduce cerebral blood flow in rats.     

Calcium antagonists: effects on cerebral blood flow and blood-brain barrier permeability in the rat

1 Because they affect isolated cerebral arteries, some calcium antagonists have been studied on the intact cerebral circulation of the rat.

2 Global cerebral blood flow (¹³³Xe clearance technique) was measured in anaesthetized rats. Neither perhexiline (0.1 μg/kg to 1.0 mg/kg, i.v.) nor diltiazem (0.06-0.6 mg/kg, i.v.) had any significant effect on resting cerebral blood flow when measured 5 min after each dose. A high dose of nifedipine (1.0 mg/kg, i.v.) was administered during induced hypocapnia. Nifedipine failed to modify the hypocapnic vasoconstriction of the cerebral vasculature when compared to vehicle-treated rats.

3 The possibility of discrete changes in regional cerebral blood flow was investigated. Local cerebral blood flow was measured in a number of brain regions by the [¹⁴C]-ethanol technique 15 min after the administration of nifedipine (20 or 100 μg/kg, i.v.). Nifedipine had no apparent effect on regional blood flow in the rat brain.

4 Acute arterial hypertension increases protein leakage into the brain, a phenomenon susceptible to drugs that act on endothelial pinocytosis which is known to be calcium-dependent. The increase in protein extravasation, induced by the intravenous administration of either angiotensin II or adrenaline, was unchanged in rats previously treated with either nimodipine (20 μg/kg, i.v.) or nifedipine (50 μg/kg, i.v.) when dissolved in ethanol alone. However, nifedipine (20 μg/kg, i.v.) when dissolved in a solution of polyethylene glycol and ethanol further enhanced the hypertension-induced increase in brain albumin permeability.

5 In conclusion, we have been unable to demonstrate any apparent effects of various calcium antagonists on the intact cerebral circulation of the rat, despite the number of different experimental models used.

     

Calcium channel antagonists: clinical uses--past, present and future

The calcium channel antagonists are a mature group of drugs directed at cardiovascular diseases including hypertension, angina, peripheral vascular disorders and some arrhythmic conditions. Their sites and mechanisms of actions have been well explored over the past two decades and their interactions at the alpha(1) subunit of L-type channels (Ca(V)1.1-1.4) have made them valuable molecular tools for channel classification and localization. With the realization that other members of the voltage-gated calcium channel family exist--Ca(V)2.1-2.3 and Ca(V)3.1-3.3--considerable effort has been directed to drug discovery at these channel types where therapeutic prospects exist for a variety of disorders including pain, epilepsy, affective disorders, neurodegenerative disorders, etc. In contrast to the situation with the L-type channel antagonists success in developing small molecule antagonists of therapeutic utility for these other channel types has thus far been lacking. The reasons for this are explored and potential new directions are indicated including male fertility, bone growth, immune disorders, cancer and schistosomiasis.     

Calcium antagonists as antiatherosclerotic drugs

The effects of calcium antagonists on mobilization of calcium stores critical for induction and development of atherosclerosis are only beginning to be delineated. The idea that these types of agents (by selectively altering either platelet function or smooth muscle proliferation and accumulation of lipids and calcium) can arrest or even reverse the course of atherosclerosis presents an attractive approach. Available experimental information on the actions of calcium antagonists in atherosclerosis is suggestive rather than definitive in this regard. A number of calcium-sensitive steps in platelet aggregation and secretion as well as in smooth muscle accumulation and deposition of calcium are identified. Related experimental findings in models of arteriosclerosis and hypertension also support the concept that blockade of calcium accumulation in vascular smooth muscle can retard or prevent subsequent interactions leading to enhanced disease states. Thus technical approaches to delineation of the actions of calcium antagonists are available, and, though the therapeutic value of these types of agents is not established, their potential as novel antiatherosclerotic agents is attractive.     

Calcium antagonists. Pharmacokinetic properties

An understanding of the pharmacokinetics of the calcium antagonists (slow-channel blocking drugs) is essential in order to design appropriate dosage regimens which will provide optimum therapeutic efficacy with these agents. This review summarises and evaluates the current state of knowledge of the absorption and disposition characteristics of the 3 most extensively used calcium antagonists in cardiovascular therapeutics: verapamil, diltiazem and nifedipine. While an extensive literature regarding the kinetics of verapamil exists, reports dealing with diltiazem and nifedipine are limited. This is, in part, due to difficulties in developing simple, specific and sensitive analytical procedures. All 3 drugs undergo extensive metabolism in the liver. Metabolites of verapamil (norverapamil) and diltiazem (desacetyldiltiazem) accumulate in the plasma of patients and have been shown to produce some effects similar to those of their parent compounds. The bioavailability of diltiazem and nifedipine has not been well studied, and no investigations of the absolute bioavailability of these compounds have been reported. However, the bioavailability of verapamil has been studied extensively; about 22% of an orally administered dose of verapamil is systemically available. Bioavailability is increased when liver function is impaired, such as in patients with hepatic cirrhosis. The high first-pass extraction of verapamil has been suggested to be stereoselective, with preferential elimination of the (-) isomer. The plasma concentration-time curves of verapamil and diltiazem have been studied following oral administration. The elimination half-lives of verapamil and diltiazem are about 8 and 5 hours, respectively. All 3 drugs are highly protein-bound in the plasma. Several other drugs have the ability to displace verapamil from plasma protein binding sites, but the clinical significance of this interaction is doubtful. Other drug interactions have been investigated with these agents. Verapamil causes digoxin plasma levels to rise during concomitant administration, but no drugs have been shown to alter the disposition of verapamil. Diazepam affects the plasma levels of diltiazem leading to a decrease. The mechanism of this interaction has not been reported, but an effect on bioavailability has been suggested. Age has been shown to be a factor in the disposition of both diltiazem and verapamil. Older patients tend to have lower clearances of these 2 drugs than do younger patients. It has also been shown that hepatic cirrhosis leads to a decreased clearance of verapamil. Plasma level monitoring may be helpful for adjusting doses of both verapamil and diltiazem, despite the absence of a definition of therapeutic plasma concentrations. These agents all have low, and highly variable, systemic availability, and plasma concentrations cannot be predicted after oral administration.     

Calcium antagonists and calmodulin: effect of verapamil, nifedipine and diltiazem

The effect of three calcium antagonists (verapamil, nifedipine and diltiazem) on the calcium-induced activation of phosphodiesterase (a calmodulin dependent process) was investigated. Therapeutically relevant concentrations of verapamil, nifedipine and diltiazem were used. In the presence of calmodulin, phosphodiesterase activity was stimulated by calcium in the range 4 X 10(-6)-2.5 X 10(-5) M. Diltiazem (10(-6) M), verapamil (10(-6) M) and nifedipine (10(-7) and 10(-6) M) had no influence on phosphodiesterase activity in the presence or absence of calmodulin at any concentration of calcium employed. By contrast trifluoroperazine abolished the Ca2+ activation of the phosphodiesterase enzyme. From this it is concluded that while the interaction of calcium antagonists with calmodulin may be of interest in the study of the mode of action of calmodulin, it probably does not contribute to their vasodilator activity.     

Calcium antagonists prevent cyclosporin a-Induced nephrotoxicity

Because of their favorable effects on renal haemodynamics, calcium antagonists (CATs) have a major role in preventing certain types of acute renal failure, including cyclosporin A (CSA) induced renal dysfunction. Verapamil (VP) given into the renal artery after revascularization significantly improved renal parenchymal blood flow velocity on the first post-transplant day and prevented CSA-induced decrease in renal blood flow. Kidney function was also improved and by post-transplant day 7, the majority or 77% of patients receiving VP had serum creatinine levels below 2.0 mg/100 ml versus 34% of controls. Glomerular filtration rates (GFR) increased with VP treatment between days 1 and 7 from 35±25 ml/min to 44±22 ml/min versus 19±19 ml/min to 28±22 ml/min for no VP. VP administration also decreased the need for post-transplant haemodialysis from 25% to 7%. The improved renal function occurred despite two times higher CSA blood levels in VP patients compared with controls. There were also fewer rejections in VP-treated patients (14%) than in controls (56%). Finally, graft survival at one year was 93% with VP treatment compared with 72% in control patients. The improved graft survival was most striking in repeat transplants, with 90% graft survival at one year for VP recipients versus 50% for controls. The combination of intraoperative VP and blood volume expansion acts synergistically resulting in larger urine volumes, improved renal function and decreased incidence of delayed function. The beneficial effects of CATs on post-transplant outcome may be related to cellular protection from ischaemia, preferential vasodilatation of the afferent arteriole, inherent immunosuppressive properties, and elevated CSA blood levels. CATs offer great potential to improve the outcome of solid organ transplantation.     

Interactions of calmodulin antagonists with calcium antagonists binding sites

Calmodulin antagonists have calcium entry blocking properties. In order to quantitatively investigate the interactions of these drugs with calcium channels, their effect on [³H]nitrendipine and [³H]d-cis-diltiazem binding to rat cerebral cortex membrane preparations was compared to their inhibitory effect on the activation of cyclic nucleotide phosphodiesterase by calmodulin. The potency of most antagonists to inhibit [³H]nitrendipine binding was correlated with their calmodulin inhibitory potency. However, bepridil (K_0.5 = 280 nM), chlorpromazine (K_0.5 = 3 μM), triflupromazine (K_0.5 = 1.5 μM), imipramine (K_0.5 = 3 μM) and propranolol (K_0.5 = 14 μM) were much more active on [³H]d-cis-diltiazem binding than on either [³H]nitrendipine binding or calmodulin, suggesting that these compounds bind to higher affinity sites on the calcium antagonist target proitein. Moreover, the potencies of these compounds to compete with [³H]d-cis-diltiazem and to inhibit calcium-induced contractions in depolarized smooth muscle were correlated (R = 0.76, p < 0.02). These data suggest that love concentrations of these hydrophobic drugs which have calcium and calmodulin antagonistic properties inhibit smooth muscle contraction through calcium entry blockade, not calmodulin antagonism.     

Calcium antagonists and blood glucose in normal rabbits

The effects of the calcium antagonists verapamil and nifedipine on blood glucose levels, glucose tolerance, insulin secretion during glucose tolerance and hypoglycaemic effect of tolbutamide were studied in normal nondiabetic rabbits. Daily dosage of 40 mg/kg verapamil and 5 mg/kg nifedipine given orally up to 7 days did not affect blood glucose level, glucose tolerance, insulin secretion during glucose tolerance and hypoglycaemic activity of tolbutamide 250 mg/kg p.o.     

神经元钙通道及钙拮抗剂的抗脑缺血作用

目的综述中枢神经系统内钙通道在脑缺血方面的作用及钙拮抗剂的抗脑缺血作用。方法根据近年国内外公开发表的有关文献,从神经元钙通道的分型及功能、胞内Ca2+与缺血性神经元损伤以及各类钙拮抗剂对脑缺血及其所致神经元损伤的影响等方面,阐述神经元钙通道及钙拮抗剂的抗脑缺血作用。结果至少有6种形式的电压依赖性钙通道,在不同部位的分布与特定功能相关,对调节神经元的兴奋性、神经递质的合成与释放、神经元的营养和发育起重要作用。脑缺血时脑细胞的损伤与L-电压依赖性钙通道开放致Ca2+内流有关,NMDA受体和L-电压依赖性钙通道是脑缺血时神经元Ca2+增多从而致细胞死亡的源头。结论深入认识中枢神经系统钙通道各亚型及其在脑缺血时神经元的信号转导过程中的作用,有助于钙拮抗剂的开发,为神经保护剂的研发提供了可能。