Effects Of Calcium Antagonists Research Articles

Introduction

Since their introduction >30 years ago, calcium antagonists have become one of the most widely used classes of pharmacotherapeutic agents for the treatment of hypertension. Of the 20–25 million patients receiving medication for hypertension in the United States, about one-quarter are taking calcium antagonists. Their wide appeal may be attributed to favorable characteristics such as efficacy, metabolic neutrality, and tolerability. 1 Epstein M. Calcium antagonists in the management of hypertension. in: Epstein M. Calcium Antagonists in Clinical Medicine. 2nd ed. Hanley and Belfus, Philadelphia1998: 155-176 Google Scholar , 2 Frishman W.H. Current status of calcium channel blockers. Curr Prob Cardiol. 1994; 19: 637-688 Abstract Full Text PDF PubMed Scopus (46) Google Scholar Some investigations have focused on their possible protective effects on target organs such as the heart and kidney, 3 Epstein M. Calcium antagonists and renal protection Current status and future perspectives. Arch Intern Med. 1992; 152: 1573-1584 Crossref PubMed Scopus (94) Google Scholar , 4 Messerli F.H. McLoughlin M. Cardiac effects of calcium antagonists in hypertension. in: Epstein M. Calcium Antagonists in Clinical Medicine. Hanley and Belfus, Philadelphia1992: 137-150 Google Scholar further enhancing their appealMurray Epstein, MD.

Effect of calcium antagonists on the response to noradrenaline in the whole and bisected rat vas deferens.

1. The present study was carried out to look at the effect of different calcium antagonists on the response to noradrenaline in the whole and bisected rat vas deferens considering that the response consisted of three components (I) the phasic response (II) the tonic response and (III) the spikes (rhythmic contractions). 2. Nifedipine (3 x 10(-9)-1 x 10(-7) M) inhibited all the components at the same concentration range, verapamil (1 x 10(-7)-1 x 10(-5) M) inhibited the phasic and tonic response but not the rhythmic activity. This latter component, at a certain concentration range and especially in the prostatic portion was markedly potentiated. Diltiazem and flunarizine lay in an intermediate position. 3. Papaverine, a Ca2+ antagonist that acts mainly intracellularly, inhibited preferentially the tonic component; ryanodine was practically inactive. 4. Cromakalim inhibited only partially the phasic and tonic components but totally inhibited the rhythmic contractions. 5. These results can be explained by postulating two types of calcium channels opened by alpha-adrenoceptor stimulation. The first one is verapamil- and nifedipine-sensitive and allows the entry of Ca2+ directly available for the contraction and responsible for the phasic and partially responsible for the tonic component. The second channel is merely nifedipine-sensitive and allows the entry of Ca2+ trigger which can release Ca2+ from intracellular sites: the mobilized Ca2+ is able to sustain the tonic component and is the main one responsible for the rhythmic activity. There is the possibility that this second channel is associated with ATP-sensitive K+ channels.

The Effect of Isradipine on Maximal Electroshock Seizures in Mice

1. The aim of this study was to investigate the possible anticonvulsant effect of a dihydropyridine calcium antagonist, isradipine, which easily crosses the blood–brain barrier displaying high affinity and specificity for the brain L-type voltage-sensitive calcium channel, on maximal electroshock seizures in mice. 2. Isradipine at IP doses of 2.5 mg/kg and 5.0 mg/kg was found to cause a statistically significant increase in the convulsion threshold of maximal electroshock seizures in a dose-dependent manner ( P=0.047 and P=0.022, respectively). 3. It was concluded that the mode of action of the anticonvulsant effect of isradipine is related to blockade of the intraneuronal calcium currents, which play an important role in epileptic activity.

Effects of calcium antagonist on renal filtration and reabsorbtion in spontaneous hypertensive rats

Many behavioral, physiological, and anatomical studies utilize animal models to investigate human striatal pathologies. Although commonly used, rodent striatum may not present the optimal animal model for certain studies due to a lesser morphological complexity than that of non-human primates, which are increasingly restricted in research. As an alternative, the tree shrew could provide a beneficial animal model for studies of the striatum. The gross morphology of the tree shrew striatum resembles that of primates, with separation of the caudate and putamen by the internal capsule. The neurochemical anatomy of the ventral striatum, specifically the nucleus accumbens, has never been examined. This major region of the limbic system plays a role in normal physiological functioning and is also an area of interest for human striatal disorders. The current study uses immunohistochemistry of calbindin and tyrosine hydroxylase (TH) to determine the ultrastructural organization of the nucleus accumbens core and shell of the tree shrew (Tupaia glis belangeri). Stereology was used to quantify the ultrastructural localization of TH, which displays weaker immunoreactivity in the core and denser immunoreactivity in the shell. In both regions, synapses with TH-immunoreactive axon terminals were primarily symmetric and showed no preference for targeting dendrites versus dendritic spines. The results were compared to previous ultrastructural studies of TH and dopamine in rat and monkey nucleus accumbens. Tree shrews and monkeys show no preference for the postsynaptic target in the shell, in contrast to rats which show a preference for synapsing with dendrites. Tree shrews have a ratio of asymmetric to symmetric synapses formed by TH-immunoreactive terminals that is intermediate between rats and monkeys. The findings from this study support the tree shrew as an alternative model for studies of human striatal pathologies.

Effects of Verapamil on Indexes of Heart Rate Variability After Acute Myocardial Infarction

In patients with previous myocardial infarction (MI), depressed heart rate variability (HRV) may reflect a reduction in vagal activity and lead to cardiac electrical instability. Interventions designed to increase HRV may be of clinical interest. Data on the effects of calcium antagonists on HRV in post-MI patients are very limited. The aim of our study was to assess the effects of verapamil on HRV and on the sympathovagal balance after MI. Fifty consecutive patients with a first MI, stable sinus rhythm, and left ventricular ejection fraction >0.40 were studied. Each patient underwent two 24-hour Holter recordings, 1 at baseline and another after 4 days of treatment with verapamil retard (180 mg 2 times daily). Time and frequency domain parameters of HRV were analyzed. All time domain measurements increased significantly after verapamil: the standard deviation of all NN intervals (SDNN) from 87.1 ± 31.4 to 98.1 ± 30.3 ms (p <0.05) and the log-transformed percentage of pairs of adjacent NN intervals that differ >50 ms (pNN50) from 0.57 ± 0.42 to 0.76 ± 0.45 (p <0.01). The standard deviation of the averages of RR interevals (SDANN) (75.9 ± 30.1 vs 86.3 ± 29.4 ms, p <0.05), root-mean-square of successive differences between RR intervals (rMSSD) (23.0 ± 11.7 and 28.1 ± 13.1 ms, p <0.01), and the triangular HRV index (28.3 ± 9.6 vs 23.4 ± 8.6, p <0.001) also increased. A significant inverse correlation was found between improvement in HRV indexes induced by verapamil and baseline values. Spectral analysis showed a significant increase in high-frequency power of 58.5% without changes in low and very low components. With normalized units, significant reductions in low-frequency power and low- to high-frequency ratio were observed. Diabetic patients did not show any significant changes in HRV on administration of verapamil. These findings indicate that verapamil, administered during the subacute phase of MI, improves both global and short-period indexes of HRV and induces a shift in the sympathetic-parasympathetic interaction toward vagal predominance. This effect may contribute to an explanation of the beneficial effects of verapamil that have been reported in post-MI patients.

Effect of calcium antagonists on the kidney graft injury induced by long-term cold ischemia

Ultrastructural changes in kidney graft induced by long-term cold ischemia and effect of calcium antagonists on these alterations are studied. It is shown that calcium antagonists prevent activation of lipid peroxidation and erythrocyte agglutination and adhesion in capillaries.

Effects of CD-832, a new calcium antagonist, on intracranial pressure in anesthetized dogs

Effects of a new calcium antagonist, CD-832, on intracranial pressure (ICP), vertebral blood flow (VBF) and common carotid blood flow (CCBF) were investigated in dogs and the results were compared with findings for nifedipine and diltiaem. Dogs were anesthetized with sodium pentobarbital and a 20-gauge needle was inserted into the cisterna magna for ICP determination. Mean arterial blood pressure (MBP), heart rate (HR), ICP, VBF and CCBF were measured before and during the continous intravenous infusion of CD-832 (0.3, 1 and 3 μg/kg/min), nifedipine (0.1, 0.3 and 1 μg/kg/min) or diltiazem (1, 3 and 10 μg/kg/min). Although the three drugs caused a comparable hypotension, differences were evident in effects of these agents on ICP, VBF and CCBF. Nifedipine and diltiazem but not CD-832 significantly increased ICP, VBF and CCBF. These results suggest that CD-832 is a unique calcium antagonist which does not increase ICP during hypotension. Because the most evident side effects of calcium antagonists are caused by vasodilation and include headache and flushing, CD-832 may possibly be useful to treat subjects with hypertension or angina pectoris.

E088 Renoprotective effects of a new calcium antagonist, efonidipine, in SHR with glomerular injury

E088 Renoprotective effects of a new calcium antagonist, efonidipine, in SHR with glomerular injury

E075 Effects of different dihydropyridine calcium antagonists on pretibial subcutaneous tissue pressure in hypertensive patients

E075 Effects of different dihydropyridine calcium antagonists on pretibial subcutaneous tissue pressure in hypertensive patients

The effects of nifedipine and other calcium antagonists on the glibenclamide-sensitive K+ currents in smooth muscle cells from pig urethra.

1. The effects of nifedipine on both levcromakalim-induced membrane currents and unitary currents in pig proximal urethra were investigated by use of patch-clamp techniques (conventional whole-cell configuration and cell-attached patches). 2. Nifedipine had a voltage-dependent inhibitory effect on voltage-dependent Ba2+ currents at - 50 mV (Ki=30.6 nM). 3. In current-clamp mode, subsequent application of higher concentrations of nifedipine (> or =30 microM) caused a significant depolarization even after the membrane potential had been hyperpolarized to approximately -82 mV by application of 100 microM levcromakalim. 4. The 100 microM levcromakalim-induced inward current (symmetrical 140 mM K+ conditions, -50 mV) was inhibited by additional application of three different types of Ca antagonists (nifedipine, verapamil and diltiazem, all at 100 microM). In contrast, Bay K 8644 (1 microM) possessed no activating effect on the amplitude of this glibenclamide-sensitive current. 5. When 100 microM nifedipine was included in the pipette solution during conventional whole-cell recording at -50 mV, application of levcromakalim (100 microM) caused a significant inward membrane current which was suppressed by 5 microM glibenclamide. On the other hand, inclusion of 5 microM glibenclamide in the pipette solution prevented levcromakalim from inducing an inward membrane current. 6. The levcromakalim-induced K+ channel openings in cell-attached configuration were suppressed by subsequent application of 5 microM glibenclamide but not of 100 microM nifedipine. 7. These results suggest that in pig proximal urethra, nifedipine inhibits the glibenclamide-sensitive 43 pS K+ channel activity mainly through extracellular blocking actions on the K+ channel itself.

Differentiation of the Inhibitory Effects of Calcium Antagonists on Abnormal Behaviors Induced by Methamphetamine or Phencyclidine

The abnormal behaviors induced by methamphetamine (MAP: 1 mg/kg) or phencyclidine (PCP: 10 mg/kg) were measured using behavioral analysis following the microinjection of one of three calcium (Ca) antagonists (nifedipine: Nif, nicardipine: Nic and flunarizine: Flu) into the rat caudate putamen or amygdala. The intraperitoneal administration of MAP or PCP induced abnormal behaviors in a time-dependent manner; the maximum locomotor activity was measured 30–45 min after the administration of MAP or PCP. This hyperactivity was sustained for more than 2 h. Following microinjection of these Ca antagonists into the caudate putamen, each showed a different pattern of inhibition on MAP- or PCP-induced abnormal behaviors. Nic and Flu were effective at reducing these abnormal behaviors, in contrast, Nif was ineffective. In particular, the inhibitory effect of Nic was stronger than that of Flu. Microinjection of these Ca antagonists into the amygdala did not show any reductive effect on the hyperactivity induced by MAP or PCP. These results demonstrate that these Ca antagonists have different pharmacological properties and that both L- and T-type Ca²⁺ channels modulate the dopamine release in the rat caudate putamen. These results further lead us to suggest the presence of a subtype of L-type Ca²⁺ channels in the caudate putamen.

Different effects of calcium antagonists on fluid filtration of large arteries and albumin permeability in spontaneously hypertensive rats

To compare the effects of chronic administration of two dihydropyridines, nifedipine and amlodipine, and the non-dihydropyridine Ca2+ antagonist mibefradil on fluid filtration of large arteries and extravasation of albumin in spontaneously hypertensive rats. Spontaneously hypertensive rats aged 2 months were randomly allocated to oral treatment once a day with 30 mg/kg mibefradil (n=12), 100 mg/kg nifedipine (n=12), 20 mg/kg amlodipine (n=12) or placebo (n=12) for 1 month. Instantaneous blood pressure of rats under pentobarbital anaesthesia was recorded at the end of the treatment Fluid filtration across the carotid arterial wall was determined in situ in the isolated carotid artery. Extravasation of 25 mg/kg Evans Blue dye that had been injected intravenously was used to assess whole vascular permeability to albumin after chronic treatment with mibefradil. Similar reductions in mean arterial pressure were obtained in all Ca2+ antagonist-treated rats. Heart rate was similar in rats in control, nifedipine and amlodipine groups but was significantly lower in mibefradil-treated rats (by 19%, P< 0.001). Fluid filtration across the carotid wall was greater in all Ca2+ antagonist-treated animals. However, fluid filtration was significantly less in mibefradil-treated rats than it was in nifedipine-treated, and amlodipine-treated rats. Furthermore, administration of mibefradil did not significantly modify extravasation of albumin in all tested tissues (pancreas, testis, spleen, lung, kidney, intestine, liver, skeletal muscle) except for cardiac and brain tissues, in which the permeability of albumin was increased by 24 and 33%, respectively, compared with values for the control group (P < 0.05). These results indicate that Ca2+ antagonists increase fluid filtration through large arteries from spontaneously hypertensive rats. That the lower fluid filtration in mibefradil-treated rats was associated with no change in extravasation of albumin in most tissues and especially in skeletal muscle suggests that vascular permeability in hypertensive rats was impaired less by mibefradil treatment than it was by dihydropyridine Ca2+ antagonist treatments.

Different Effects of Calcium Antagonists in a Rat Model of Heart Failure

Calcium antagonists have, to date, shown disappointing effect in chronic heart failure (CHF), possibly due to their cardiodepressant effects and/or reflex increases in sympathetic tone. Mibefradil is a new, selective T-channel calcium antagonist which has no relevant effects on cardiac contractility, sympathetic activity or neurohormonal levels. This study compares the effect of mibefradil with an angiotensin-converting enzyme (ACE) inhibitor on systemic and cardiac hemodynamics, cardiac structure and survival in a rat model of CHF. Rats underwent coronary artery ligation followed by 9 months treatment with mibefradil, cilazapril or no treatment. Both mibefradil and cilazapril increased survival rate to a similar extent over the study treatment period. Both periods reduced systolic blood pressure compared with untreated rats, although the reduction was slightly more marked with cilazapril than mibefradil. Both treatments decreased left ventricular (LV) end-diastolic and central venous pressures without any change in the first derivative LV pressure over time or heart rate. Mibefradil decreased LV weight without effecting right ventricular (RV) weight. Both drugs normalized LV collagen density. The data from this study show that long-term treatment with mibefradil results in a survival benefit comparable to that observed with an ACE inhibitor in a rat model of CHF. Mibefradil was also associated with improvements in cardiac hemodynamics, a reduction in LV weight and fibrosis. Mibefradil may be beneficial in the treatment of CHF.

Calcium Channel Blockers in Heart Failure

A considerable effort has been made in the last 15 years to evaluate the safety and efficacy of calcium channel blockers (CCBs) in the treatment of patients with chronic congestive heart failure (CHF). Available studies have provided strong evidence for a potential detrimental effect of the first-generation calcium antagonists in patients with CHF, indicating the need for great caution when these drugs are used in patients with significant depression of left ventricular systolic function. A number of second-generation CCB have demonstrated a strong vasodilatory effect and favorable hemodynamic action but failed to show a similar improvement in exercise capacity, morbidity and mortality. Moreover, drugs such as nicardipine and nisoldipine have resulted in a detrimental effect in some patients and, therefore, cannot be considered safe when used in patients with moderate-to-severe heart failure. Available information from the V-HeFT III study demonstrate a lack of an unfavorable effect of felodipine on exercise tolerance in patients with chronic heart failure. Although mortality rate was similar in both the felodipine and the placebo group, because of the relatively small number of patients in this study, no clear conclusion can be drawn regarding the effect of felodipine on mortality in patients with CHF. An encouraging signal regarding a potential role of CCB in the treatment of chronic heart failure has been provided by the recently completed PRAISE study. This prospective large-scale study demonstrated the safety of amlodipine, a long-acting dihydropyridine derivative, when used in patients with heart failure due to coronary artery disease. Furthermore, this study demonstrated a substantial reduction in mortality in patients with CHF due to nonischemic cardiomyopathy and provided a strong indication for a potential therapeutic benefit of amlodipine when added to standard CHF therapy in this patient population. No clear explanation is available at the present time regarding the reason for the deleterious effect demonstrated with some of the dihydropyridines and the contrasting benefit seen with amlodipine. Finally, more information regarding the safety and efficacy of dihydropyridines should become available in the next year. The PRAISE II study is ongoing and will provide further information regarding the therapeutic role of amlodipine in patients with nonischemic dilated cardiomyopathy. The MACH-1 study is evaluating the effect of mibefradil, a predominant T-type channel blocker with an ideal activity profile, on morbidity and mortality in patients with chronic CHF.

Effect of calcium and calmodulin antagonists on ethylene biosynthesis in tomato fruits

The aim of this work was to elucidate the mode of action of calcium in calcium-inhibited ethylene biosynthesis. In one experiment, mature green tomatoes were treated with 1.5% (w/v) CaCl 2 + 60 μM N-6(aminohexyl)-1-naphthalene-sulphonamide (W5). 1.5% (w/v) CaCl 2 + 60 μM N-6(aminohexyl)-5-chloro-1-naphthalenesulphonamide (W7), 1.5% (w/v) CaCl 2 alone or distilled water (control). The control and the W7 treatment had much higher ethylene production than either the CaCl 2 treatment alone or the CaCl 2 + W5 treatment. In another experiment, similar tomatoes were treated with 1.5% (w/v) CaCl 2 + 15 μM trifluoperazine (TFP), 1.5% (w/v) CaCl 2 only, or distilled water (control). The treatment with 1.5% CaCl 2 + 15 μM TFP gave higher ethylene production than 1.5% (w/v) CaCl 2 without TFP, and nearly the same level as the control towards the end of the experimental period. For enzyme and intermediate metabolite assays, mature green tomatoes were treated with 1.5% (w/v) CaCl 2 plus either W5 or W7. W5 treatment had a lower ethylene forming enzyme (EFE) activity, higher 1-aminocyclopropane-l-carboxylic acid (ACC) concentration, similar levels of ACC synthase activity and 1-(malonylamino)-cyclopropane-1-carboxylic acid concentration, compared to the control and W7 treatment. As W7 is a more potent calmodulin antagonist than W5, these results suggest a calcium-calmodulin inactivation of EFE activity.

Effect of Diltiazem on Sympathetic Hyperactivity in Patients With Vasospastic Angina as Assessed by Spectral Analysis of Arterial Pressure and Heart Rate Variability

The autonomic nervous system importantly regulates coronary arterial tone and vascular resistance. To evaluate a role of autonomic nervous activity and the effects of calcium antagonist in patients with vasospastic angina (VSA), 13 VSA patients with patent coronary arteries (58 ± 8 years) and 8 normal subjects (58 ± 12 years) were studied. Arterial pressure and electrocardiogram were continuously recorded with the patient in a supine position under controlled respiration (0.2 Hz). Low-frequency (LF) and high-frequency (HF) components of the beat-to-beat variabilities of systolic arterial pressure and RR interval were then estimated by autoregressive power spectral analysis. The LF power (normalized unit) of both systolic arterial pressure (0.53 ± 0.17 vs 0.30 ± 0.17, p <0.01) and RR variabilities (0.51 ± 0.20 vs 0.31 ± 0.16, p <0.05) in patients with VSA were greater than that in normal subjects. There was no significant difference in the HF power. Seven patients with VSA who were treated with diltiazem (60 to 200 mg/day) had normalized LF power (normalized unit) of both systolic arterial pressure (0.62 ± 0.12 vs 0.33 ± 0.16, p <0.01) and RR variabilities (0.55 ± 0.23 vs 0.36 ± 0.14, p <0.05), together with clinical improvement. An increased sympathetic vasomotor tone and cardiac sympathetic predominance may play an important role in patients with VSA. Diltiazem improves these sympathetic hyperactivities.

Lercanidipine: Short Plasma Half-life, Long Duration of Action and High Cholesterol tolerance: Updated Molecular Model to Rationalize its Pharmacokinetic Properties

Calcium-channel antagonist drugs of the 1,4-dihydropyridine type have been shown to bind to the L-type calcium channel. These drugs are not only amphiphilic, but new molecular designs have become increasingly lipophilic and can readily transport across cell membranes, accessing both hydrophilic and hydrophobic environments, despite becoming more soluble in the membrane bilayer. This biophysical understanding appears not only to define the molecular pathways for drug binding to the calcium-channel receptor, but also to explain differences in the overall clinical pharmacokinetics observed for different drugs in this class. The pharmacokinetic profile of calcium antagonists, although influenced to some degree by interactions with their target calcium-channel receptor, appears to be largely dictated by their interactions with cell membranes at the molecular level. There appears to be a correlation between the duration of action of such membrane-active drugs and the membrane partition coefficient in conjunction with the washout rate. This class of drugs has evolved from a drug such as amlodipine, with a long duration of action related to prolonged plasma half-life, to lercanidipine, which has the shortest plasma half-life relative to its intrinsically long duration of action. Recently, it was discovered that membrane cholesterol reduces the amount of calcium-channel antagonist that can partition into the membrane. Atherosclerotic disease results in increased levels of membrane cholesterol in smooth muscle cells. Latest generation calcium antagonists, which have a long duration of action, can better overcome this negative effect. Lercanidipine has now been shown to have one of the highest measured tolerances to cholesterol, which may indicate its ability to treat a broad range of hypertensive patients with varying degrees of progressive atherosclerotic disease. On what criteria should the effectiveness of calcium antagonists be evaluated? A good calcium antangonist needs to exhibit a placebo-like side-effect profile, thus ensuring good patient compliance. However, an intrinsically long-lasting, once-a-day dose is also pharmacokinetically desirable. To be a truly optimal calcium antagonist, it should function and be efficacious over a broad range of hypertensive patients. It should be able to control blood pressure in light of other complications such as progressive atherosclerotic disease. Recent studies indicate that during the progression of atherosclerosis, cholesterol levels within cell membranes of the arterial wall increase, a process that can reduce the effective concentration of calcium antagonists in these membranes. What is needed is a calcium antagonist that is slow acting to reduce vasodilatory induced side-effects and intrinsically long lasting to ensure once-a-day dosage, and that possesses a high cholesterol tolerance factor to overcome the molecular and compositional changes taking place in the arterial wall, so that it can treat effectively a broad range of hypertensive patients.

カルシウムきっ抗薬の血圧日内変動に及ぼす影響

カルシウムきっ抗薬の血圧日内変動に及ぼす影響

Combination of ACE inhibitors and calcium antagonists: a logical approach.

An increasing body of evidence indicates that impairment of endothelial function is crucially involved in the pathogenesis of cardiovascular disease. Injury to the endothelium precipitates atherosclerosis by causing smooth-muscle cell migration and proliferation, induction of expression of growth factors, and impairment of plasma coagulation and endogenous fibrinolysis. Angiotensin-converting enzyme (ACE) inhibitors and calcium antagonists are widely used in patients with cardiovascular disease and have beneficial vascular effects beyond blood pressure control alone. Both exhibit a synergistic hemodynamic profile. Whereas calcium antagonists dilate large conduit and resistance arteries, ACE inhibitors inhibit the renin-angiotensin system (RAS) and reduce sympathetic outflow. Certain calcium antagonists, such as verapamil and diltiazem, reduce heart rate, whereas dihydropyridines tend to increase it. In the blood vessel wall, the local vascular effects of ACE inhibitors and calcium antagonists are complementary. ACE inhibitors diminish transformation of angiotensin I (Ang I) into angiotensin II (Ang II) and prevent degradation of bradykinin [which stimulates nitric oxide (NO) and prostacyclin formation]. Calcium antagonists inhibit the effects of Ang I and endothelin-1 (ET-1) at the level of vascular smooth muscle by reducing Ca2+ inflow and facilitating the vasodilator effects of NO. The resistance circulation is particularly dependent on extracellular Ca2+, thereby explaining why nifedipine and verapamil effectively inhibit ET-induced vasoconstriction in vitro and in vivo. In hypertension, ACE inhibitors and calcium antagonists markedly improve structural changes and increase the media/lumen ratio in resistance arteries. Long-term combination therapy with verapamil and trandolapril is particularly effective in reversing endothelial dysfunction in hypertensive animals. ACE inhibitors substantially reduce morbidity and mortality in patients with left ventricular dysfunction after myocardial infarction (MI). There is a strong trend indicating benefit with verapamil as well, but this is confined to patients with a normal left ventricular ejection fraction. Clinical studies have confirmed that calcium antagonists exhibit antiatherogenic properties. However, the clinical relevance of these findings has recently been disputed because short-acting dihydropyridines are reported to increase risk for MI. Because ACE inhibitors and calcium antagonists exhibit synergistic hemodynamic, antiproliferative, antithrombotic, and antiatherogenic properties, combination therapy provides a promising concept in patients with cardiovascular and renal disease.

Efficient Inhibition of the Development of Cardiac Remodeling by a Long-Acting Calcium Antagonist Amlodipine

The purpose of the present study was to examine the effects of a long-acting calcium antagonist, amlodipine, on the development of cardiac remodeling. Dihydropyridine calcium antagonists have been used widely for many years in the treatment of hypertension and angina pectoris. It has been reported, however, that a prototype of dihydropyridines, nifedipine, does not reduce mortality of patients with ischemic heart disease, possibly because of reflex stimulation of the sympathetic nervous system. A calcium antagonist, amlodipine, has been reported to have potential benefits by virtue of a gradual onset of action and a long duration of effects. Amlodipine (8 mg/kg per day, once a day) or nifedipine (24 mg/kg per day, three times a day) was administered to spontaneously hypertensive 12-week-old rats for 12 weeks. Left ventricular wall thickness was measured by echocardiography, and relative amounts of myosin heavy chain isoforms were assessed by pyrophosphate gels. Expressions of "fetal type" genes and type 1 collagen gene were examined by Northern blot analysis. Amlodipine and nifedipine both markedly reduced systolic blood pressure. However, the decrease in systolic blood pressure caused by nifedipine continued for no more than 8 hours, whereas the blood pressure-lowering effect of amlodipine continued for more than 16 hours post dose. Amlodipine markedly reduced left ventricular wall thickness, whereas nifedipine only weakly attenuated an increase in the wall thickness. Amlodipine, but not nifedipine, prevented an increase in the relative amount of V3 myosin heavy chain isoform and suppressed an increase in mRNA levels of beta-myosin heavy chain, skeletal alpha-actin, and type 1 collagen. Unlike nifedipine, amlodipine effectively prevented cardiac remodeling secondary to high blood pressure at biochemical levels and morphological levels. These results suggest that a long-acting calcium antagonist is more effective than a short-acting one in preventing organ injury in hypertensive subjects.