dihydropyridines and Cardiomegaly

Left ventricular hypertrophy (LVH) represents an important intermediate end-point for, for example, the progression to heart failure. The persistence or progression of LVH despite antihypertensive therapy probably reflects the persistence or activation of mechanisms that negatively affect the cardiovascular system and, consequently, long-term outcome.. Long-term treatment with rapid-onset (and usually short-acting) dihydropyridine calcium antagonists is significantly less effective than angiotensin converting enzyme (ACE) inhibition in reducing left ventricular mass (LVM) in hypertensive patients. Both intermittent, and probably only partial, blood pressure control and an increase in sympathetic activity resulting from rapid decreases in blood pressure following dosing with such calcium antagonists may contribute to this relative ineffectiveness. In contrast, more recent studies have demonstrated that the longer acting dihydropyridines can reduce LVM as effectively as ACE inhibitors.. Among the 1,4-dihydropyridines, drugs such as amlodipine and nifedipine in the gastrointestinal therapeutic system (GITS) maintain good blood pressure control over the full 24-h dosing period and do not cause dose-related increases in sympathetic activity. In contrast, extended-release felodipine has been shown to provide only intermittent blood pressure control, still leading to sympathetic activation. Notably, during short periods of noncompliance, blood pressure control is maintained with intrinsically long-acting agents such as amlodipine but not with slow-release formulations of short-acting agents such as nifedipine GITS.. It is possible that the rate of onset and duration of action of various dihydropyridines may be pivotal factors in determining their effects on cardiovascular outcomes. Thus, the least beneficial dihydropyridines may be rapid-onset, short-acting agents, such as nifedipine capsules, and the most beneficial may be the slow-onset, long-acting agents such as amlodipine.

Topics: Antihypertensive Agents; Cardiomegaly; Dihydropyridines; Humans; Hypertension; Remission Induction; Treatment Outcome

Ambulatory blood pressure (BP) and heart rate (HR) profile are proposed to be related to renal deterioration and cardiovascular complication in hypertension and chronic kidney disease (CKD). In this study, we examined the beneficial effects cilnidipine, a unique L/N-type calcium channel blocker (CCB), in addition to renin-angiotensin system inhibitors, on ambulatory BP and HR profile, as well as cardiorenal function in hypertensive CKD patients. Forty-five patients were randomly assigned to the cilnidipine replacement group (n = 21) or the control CCBs group (n = 24) during a 24-week active treatment period. Although clinical BP values were similar in the cilnidipine and control CCBs groups after the treatment period, the results of ambulatory BP monitoring showed that the 24-h and daytime systolic BP levels in the cilnidipine group were significantly lower compared with the control group after the study. Furthermore, the left ventricular mass index (LVMI) was significantly decreased in the cilnidipine group compared to the control group after the study (LVMI, 135.3 ± 26.4 versus 181.2 ± 88.4, p = 0.031), with a significant difference in the changes in the LVMI between the cilnidipine and control groups (change in LVMI, -12.4 ± 23.7 versus 26.2 ± 64.4, p = 0.007). These results indicate that cilnidipine is beneficial for the suppression of pathological cardiac remodeling, at least partly, via a superior improving effect on ambulatory BP profile compared with control CCBs in hypertensive CKD patients.

Topics: Aged; Aged, 80 and over; Angiotensin Receptor Antagonists; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Cardiomegaly; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hypertension; Male; Middle Aged; Renal Insufficiency, Chronic; Renin-Angiotensin System; Treatment Outcome

The aim of this study was to assess the effects of long-term (9-month) treatment with isradipine, alone or combined with bopindolol, on blood pressure, left ventricular hypertrophy (LVH), and diastolic function. Thirty-five hypertensive patients with LVH and supine diastolic blood pressures (DBPs) greater than or equal to 100 and less than or equal to 120 mm Hg received increasing doses of isradipine (1.25, 2.5, and 5 mg twice daily); if blood pressure was not controlled, bopindolol (0.5-2 mg once daily) was added to the treatment. Clinical and laboratory investigations were carried out after placebo for baseline values, and after 5 and 9 months of isradipine treatment alone (n = 11) or combined with bopindolol (n = 24). At the end of the study, blood pressure was significantly decreased while heart rate did not change with isradipine alone, but decreased significantly after the addition of bopindolol. Although the DBP was normalized (less than or equal to 90 mm Hg) in 28 patients (80%), complete reversal of the left ventricular mass index (LVMI) was seen in only 7 patients (20%). The ratio of early to atrial filling did not change, but the deceleration time was significantly decreased after 9 months. No laboratory abnormalities or important side effects were observed. Although isradipine alone or combined with bopindolol was effective in controlling blood pressure and significantly reduced the LVMI after 5 months, improvement in diastolic function was seen only after 9 months of active treatment.

Topics: Adolescent; Adult; Aged; Calcium Channel Blockers; Cardiomegaly; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hypertension; Isradipine; Male; Middle Aged; Pindolol; Ventricular Function, Left

We evaluated the effects of lacidipine and hydrochlorothiazide on blood pressure and left ventricular mass in hypertensive patients of mild-to-moderate degree. Both antihypertensive agents significantly decreased systolic and diastolic blood pressure without relevant symptoms and signs of reflex activation of the sympathetic nervous system. Posterior wall and interventricular septal thickness and the left ventricular mass were significantly decreased by lacidipine and hydrochlorothiazide after 3 and 6 months of treatment without clinical symptoms of reduced cardiac function.

Topics: Blood Pressure; Calcium Channel Blockers; Cardiomegaly; Dihydropyridines; Double-Blind Method; Heart Rate; Humans; Hydrochlorothiazide; Hypertension; Time Factors

Previous studies have demonstrated that lercanidipine, a calcium channel blocker, may protect against cardiac hypertrophy; however, the underlying mechanisms remain unclear. In the present study, the effects of lercanidipine on hypertrophy and the mechanisms involved were investigated. Cardiomyocytes isolated from neonatal rats were cultured and treated with angiotensin II (Ang II) in the presence or absence of lercanidipine or tacrolimus (FK506, a calcineurin inhibitor). Reverse transcription‑quantitative polymerase chain reaction was used to assess the mRNA expression of genes of interest, whereas the protein expression of calcium‑dependent signaling molecules was detected using western blot analysis. In addition, the cell surface area and the nuclear translocation of target proteins were evaluated using immunofluorescence. The results of the present study demonstrated that lercanidipine and FK506 inhibited Ang II‑induced cardiomyocyte hypertrophy, as evidenced by decreases in fetal gene (atrial natriuretic peptide and brain natriuretic peptide) expression levels and cell surface area. Notably, lercanidipine suppressed Ang II‑induced activation of calcineurin A (CnA) and nuclear factor of activated T cells 3 (NFAT3). In addition, calcium/calmodulin‑dependent kinase II (CaMKII)‑histone deacetylase 4 (HDAC4) signaling was also inhibited by lercanidipine. In conclusion, the present study demonstrated that lercanidipine may ameliorate cardiomyocyte hypertrophy, possibly partially by blocking Cn-NFAT3 and CaMKII-HDAC4 signaling.

Topics: Angiotensin II; Animals; Atrial Natriuretic Factor; Calcineurin; Calcium Channel Blockers; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cardiomegaly; Cells, Cultured; Dihydropyridines; Gene Expression Regulation; Histone Deacetylases; Myocytes, Cardiac; Natriuretic Peptide, Brain; NFATC Transcription Factors; Rats; Signal Transduction

To compare the effects of amlodipine, benidipine and nifedipine on myocardial hypertrophy and evaluate the underlying mechanism.. Myocardial hypertrophy model was created by transverse aortic constriction (TAC) in C57 BL/6 mice, and plasma catecholamine concentrations were measured 7 days after surgery to confirm the sympathetic activation. The 3 drugs were administered in TAC mice for 7 days and cardiac hypertrophy was evaluated according to the heart-to-body weight ratio (HW/BW). Effects of those drugs on the protein synthesis stimulated by phenylephrine in cultured neonatal cardiac myocytes were also examined.. HW/BW and plasma concentrations of catecholamine were significantly increased in TAC mice one week after surgery in comparison with to sham-operated mice. One week after TAC, the HW/BW ratio was significantly lower in the amolodipine but not nifedipine-treated group than in the TAC group. Administration of nifedipine via minipump infusion for one week did not decrease HW/BW ratio. Treatment with amlodpine or benidipine, but not nifedipine, decreased the neonatal rat myocyte protein synthesis induced by phenylephrine stimulation.. Antihypertrophic effect of DHEs on myocardium is dependent on their potential of blocking N-type calcium channel, and the underlying mechanism involves the sympathetic inhibition.

Topics: Amlodipine; Animals; Calcium Channel Blockers; Calcium Channels, N-Type; Cardiomegaly; Dihydropyridines; Disease Models, Animal; Male; Mice; Mice, Inbred C57BL; Nifedipine

The heart of the canine model of chronic atrioventricular block is known to have a ventricular electrical remodelling, which mimics the pathophysiology of long QT syndrome. Using this model, we explored a new pharmacological therapeutic strategy for the prevention of cardiac sudden death.. The L-type Ca(2+) channel blocker amlodipine (2.5 mg.day(-1)), L/N-type Ca(2+) channel blocker cilnidipine (5 mg.day(-1)), or the angiotensin II receptor blocker candesartan (12 mg.day(-1)) was administered orally to the dogs with chronic atrioventricular block for 4 weeks. Electropharmacological assessments with the monophasic action potential (MAP) recordings and blood sample analyses were performed before and 4 weeks after the start of drug administration.. Amlodipine and cilnidipine decreased the blood pressure, while candesartan hardly affected it. The QT interval, MAP duration and beat-to-beat variability of the ventricular repolarization period were shortened only in the cilnidipine group, but such effects were not observed in the amlodipine or candesartan group. Plasma concentrations of adrenaline, angiotensin II and aldosterone decreased in the cilnidipine group. In contrast, plasma concentrations of angiotensin II and aldosterone were elevated in the amlodipine group, whereas in the candesartan group an increase in plasma levels of angiotensin II and a decrease in noradrenaline and adrenaline concentrations were observed.. Long-term blockade of L/N-type Ca(2+) channels ameliorated the ventricular electrical remodelling in the hypertrophied heart which causes the prolongation of the QT interval. This could provide a novel therapeutic strategy for the treatment of cardiovascular diseases.

Topics: Action Potentials; Amlodipine; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Atrioventricular Block; Benzimidazoles; Biphenyl Compounds; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Cardiomegaly; Chronic Disease; Dihydropyridines; Dogs; Electrocardiography; Epinephrine; Female; Male; Neurotransmitter Agents; Norepinephrine; Tetrazoles; Time Factors

Changes in myocardial expression of Na+/K+-ATPase alpha-subunit isoforms have been demonstrated in different models of cardiac hypertrophy and hypertension. Here we studied the expression of these isozymes in stroke-prone spontaneously hypertensive rats (SHRSP) and the influence of high salt diet and treatment with the dihydropyridine lacidipine. Adult SHRSP were offered either 1% NaCl or water as drinking solution for 6 weeks. Salt-loaded SHRSP were treated or not with 1 mg/kg/day lacidipine. Compared to Wistar Kyoto (WKY) rats, non-salt-loaded SHRSP presented significant hypertension and cardiac hypertrophy. Salt intake markedly enhanced cardiac hypertrophy, an effect blunted by lacidipine. [3H]Ouabain binding assays on total particulate fractions from heart ventricles revealed the existence of two high-affinity sites with Kd approximately 25 and approximately 200 nM, ascribed to the alpha3 and alpha2 isoforms, respectively. Bmax of alpha3 was unexpectedly high (40% of total high-affinity binding) in ventricles from WKY rats but very low in all groups of SHRSP. On the other hand, Bmax of alpha2 was similar in WKY and non-salt-loaded SHRSP; however, salt loading of SHRSP resulted in a Bmax reduction of 20% (P<0.05), an effect blocked by lacidipine. These effects were largely confirmed by immunoblotting analysis, which, in addition, demonstrated that the density of the ubiquitous alpha1 isoform was comparable among the experimental groups. In conclusion, WKY rats showed a high myocardial expression of the Na+/K+-ATPase alpha3 subunit, which was not found in SHRSP; the level of the alpha2 isoform was similar in untreated SHRSP and WKY; salt-loading of SHRSP promoted reduction of the alpha2 isoform, and this effect was completely hampered by lacidipine.

Topics: Animals; Calcium Channel Blockers; Cardiomegaly; Dihydropyridines; Heart Ventricles; Hypertension; Isoenzymes; Male; Ouabain; Protein Subunits; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sodium Chloride, Dietary; Sodium-Potassium-Exchanging ATPase; Stroke

A dihydropyridine calcium (Ca) antagonist, azelnidipine (CAS 123524-52-7, Calblock), exhibits hypotensive effects for a prolonged duration, and has been reported to have a strong antiarteriosclerotic action due to its high affinity for vascular tissues and antioxidative action. It has also been reported that azelnidipine does not cause tachycardia associated with the baroreceptor reflex due to vasodilatation. In this study, the antiarteriosclerotic and cardiac hypertrophy-inhibitory effects, and the autonomic nervous activity in essential hypertension of azelnidipine were investigated. The study was performed using the following 2 protocols: 1) Pulse wave velocity (PWV), carotid arterial intima media thickness (IMT), echocardiography, high sensitive C-reactive protein (hs-CRP), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), adiponectin, brain natriuretic peptide (BNP), and 8-isoprostane were measured after an initial treatment with azelnidipine. 2) The treatment was switched to azelnidipine in patients who had previously been under treatment with amlodipine for essential hypertension, and 123I-metaiodobenzylguanidine myocardial scintigraphy (123I-MIBG), measurements of plasma norepinephrine, atrial natriuretic peptide (ANP), and BNP, Holter electrocardiography, and heart rate variability analysis were performed. PWV, IMT, hs-CRP, IL-6, and TNF-alpha significantly decreased. The levels of 8-isoprostane, an antioxidative marker, were also significantly decreased, while adioponectin levels were significantly increased after the initial treatment with azelnidipine. After switching from amlodipine, azelnidipine exhibited a hypotensive effects comparable to amlodipine, and significantly decreased heart rate and the total number of extrasystoles. Noradrenaline levels and the LF/HF ratio were significantly decreased, and the washout rate was significantly reduced on 123I-MIBG myocardial scintigraphy. These findings suggest that azelnidipine inhibits the enhancement of sympathetic nervous activity and the progression of arteriosclerosis through its antioxidative effects.

Topics: 3-Iodobenzylguanidine; Adipokines; Aged; Antihypertensive Agents; Antioxidants; Arteriosclerosis; Autonomic Nervous System; Azetidinecarboxylic Acid; Calcium Channel Blockers; Cardiomegaly; Carotid Arteries; Catecholamines; Cytokines; Dihydropyridines; Electrocardiography; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Natriuretic Peptide, Brain; Pulse; Radionuclide Imaging; Radiopharmaceuticals

To examine the mechanism and significance of tachycardia-induced cardiac damage, using azelnidipine, a relatively new dihydropyridine calcium channel blocker which does not increase heart rate.. Comparing azelnidipine and amlodipine, we examined the cardiac effects and the direct effects on a sinus node/atrial preparation in stroke-prone spontaneously hypertensive rats (spSHRs). By pacing the right atrium, we examined the effect of tachycardia per se on cardiac oxidative stress. Using apocynin, a reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, we investigated the role of oxidative stress in cardiac remodelling.. Azelnidipine suppressed cardiac hypertrophy, fibrosis, NADPH oxidase and superoxide in spSHRs more potently than amlodipine, and was associated with lower heart rates than amlodipine. Azelnidipine caused a greater reduction than amlodipine in the beat rate of the sinus node/atrial preparation of spSHRs. A 10 or 20% increase in heart rate, independent of blood pressure or sympathetic nerve activity, significantly enhanced cardiac NADPH oxidase activity, superoxide and activated mitogen-activated protein kinases. Reduction of cardiac oxidative stress by apocynin led to the suppression of cardiac hypertrophy, inflammation and fibrosis in spSHRs, beyond its hypotensive effect.. Our work provided evidence that the increase in heart rate per se, independent of sympathetic nerve activity, enhances cardiac oxidative stress and activates mitogen-activated protein kinases, which seem to be responsible for cardiac remodelling. Azelnidipine, without causing an increase in heart rate, has the potential to be useful for the treatment of cardiac remodelling.

Topics: Amlodipine; Animals; Azetidinecarboxylic Acid; Cardiomegaly; Dihydropyridines; Endomyocardial Fibrosis; Hydralazine; Hypertension; Male; Mitogen-Activated Protein Kinases; Oxidative Stress; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Tachycardia; Ventricular Remodeling

The effects of long-acting calcium channel blockers (CCBs) on pressure overload-induced cardiac remodeling are seldom studied in animals. We evaluated the effects of benidipine, a long-acting CCB, on cardiac remodeling.. Rat neonatal cardiac myocytes were used to examine the influence of benidipine on protein synthesis. Cardiac remodeling was induced in C57 B6/J mice by transverse aortic constriction (TAC). Then the effects of benidipine (10 mg/kg/d) were assessed on myocardial hypertrophy and heart failure, cardiac histology, and gene expression.. Benidipine significantly inhibited protein synthesis by cardiac myocytes stimulated with phenylephrine (PE), and this effect was partially abolished by cotreatment with a nitric oxide synthase (NOS) inhibitor [N(G)-nitro-l-arginine methylester (l-NAME)]. Four weeks after the onset of pressure overload, benidipine therapy potently inhibited cardiac hypertrophy and prevented heart failure. The heart to body weight ratio was 6.89+/-0.48 mg/g in treated mice vs. 8.76+/-0.33 mg/g in untreated mice (P<0.01), and the lung to body weight ratio was 7.39+/-0.93 mg/g vs. 10.53+/-0.99 mg/g, respectively (P<0.05). Left ventricular fractional shortening (LVFS) was improved on echocardiography. Plasma NO levels were increased, while B type natriuretic peptide, protein inhibitor of neuronal NOS, and procollagen IV alpha were down-regulated in benidipine-treated mice.. These results indicate that benidipine inhibits cardiac remodeling due to pressure overload at least partly by acting on the nitric oxide signaling pathway.

Topics: Animals; Biomarkers; Calcium Channel Blockers; Cardiomegaly; Cells, Cultured; Collagen Type IV; Dihydropyridines; Disease Progression; Gene Expression Regulation; Heart Failure; Male; Mice; Mice, Inbred C57BL; Muscle Proteins; Myocytes, Cardiac; Natriuretic Peptide, Brain; Nitric Oxide; Signal Transduction; Ventricular Remodeling

Chronic inhibition of nitric oxide (NO) synthesis induces cardiac remodeling independent of systemic hemodynamic changes in rats. We examined whether long-acting dihydropyridine calcium channel blockers block myocardial remodeling and whether the activation of 70-kDa S6 kinase (p70S6K) and extracellular signal-regulated kinase (ERK) are involved. Ten groups of Wistar-Kyoto rats underwent 8 weeks of drug treatment consisting of a combination of NO synthase inhibitor NG-nitro-l-arginine methyl ester (L-NAME), an inactive isomer (D-NAME), amlodipine (1 or 3 mg/kg per day), or benidipine (3 or 10 mg/kg per day). In other groups, L-NAME was also used in combination with a p70S6K inhibitor (rapamycin), a MEK inhibitor (PD98059), and hydralazine. Systolic blood pressure (SBP), heart rate, and left ventricular weight (LVW) were measured, together with histological examinations and kinase assay. L-NAME increased SBP and LVW (1048+/-22 versus 780+/-18 mg, P<0.01) compared with the control, showing a significant increase in cross-sectional area of cardiomyocytes after 8 weeks. Amlodipine, benidipine, or hydralazine equally attenuated the increase in SBP induced by L-NAME. However, both amlodipine and benidipine but not hydralazine attenuated the increase in LVW by L-NAME (789+/-27, 825+/-20 mg, P<0.01, and 1118+/-29 mg, NS, respectively), also confirmed by histological analysis. L-NAME caused a 2.2-fold/1.8-fold increase in p70S6K/ERK activity in myocardium compared with the control, both of which were attenuated by both amlodipine and benidipine but not hydralazine. Both rapamycin and PD98059 attenuated cardiac hypertrophy in this model. Thus, long-acting dihydropyridine calcium channel blockers inhibited cardiac hypertrophy induced by chronic inhibition of NO synthesis by inhibiting both p70S6K and ERK in vivo.

Topics: Amlodipine; Animals; Blood Pressure; Calcium Channel Blockers; Cardiomegaly; Dihydropyridines; Enzyme Inhibitors; Heart Rate; Heart Ventricles; Kinetics; Male; Mitogen-Activated Protein Kinases; Myocardium; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Inbred WKY; Ribosomal Protein S6 Kinases, 70-kDa

Treatment with the angiotensin-converting enzyme inhibitor, quinapril, has been shown to normalize increased dihydropyridine sensitivity and impaired potassium relaxation, characteristic features of arterial smooth muscle in spontaneously hypertensive rats, and also reduce the concentration of plasma digoxin-like immunoreactivity in these animals. However, whether angiotensin II receptor blocker therapy can beneficially influence these variables is not known. Therefore, we compared the effects of 10-week losartan and enalapril treatments (15 and 4 mg/kg/day, respectively) on functional responses of mesenteric arterial rings in spontaneously hypertensive rats and Wistar-Kyoto rats. Both losartan and enalapril normalized blood pressure, cardiac mass, and media to lumen ratio without significantly changing the media cross-sectional area in the mesenteric artery of spontaneously hypertensive rats (i.e. induced outward remodelling). The inhibitory effect of the calcium entry blocker nifedipine on calcium-evoked contractions was similar and less marked in arterial preparations from Wistar-Kyoto rats and losartan- and enalapril-treated spontaneously hypertensive rats than in those from untreated spontaneously hypertensive rats. Furthermore, the relaxations of arterial rings induced by the return of potassium to the organ bath (upon precontractions elicited by potassium-free solution) were used to evaluate the function of vascular Na+,K+-ATPase. The rate of potassium relaxation was faster in losartan- and enalapril-treated spontaneously hypertensive rats and all Wistar-Kyoto groups than in untreated spontaneously hypertensive rats, and the response was effectively inhibited by the sodium pump inhibitor ouabain. Both treatments especially augmented the ouabain-sensitive part of the potassium-relaxation in spontaneously hypertensive rats, indicating the involvement of the sodium pump in this response. However, no significant changes in plasma digoxin-like immunoreactivity were observed. In conclusion, the outward remodelling following long-term AT1-receptor blockade and angiotensin-converting enzyme inhibition in spontaneously hypertensive rats was associated with normalization of the increased dihydropyridine sensitivity of arteries. Both losartan and enalapril treatments also augmented arterial potassium relaxation in spontaneously hypertensive rats, suggesting enhanced function of Na+,K+-ATPase, but this effect could not be attributed to changes in circulating s

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Cardiomegaly; Digoxin; Dihydropyridines; Enalapril; Heart; Hypertension; Losartan; Male; Mesenteric Arteries; Muscle, Smooth, Vascular; Nifedipine; Organ Size; Potassium Chloride; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Sodium-Potassium-Exchanging ATPase; Tunica Media

Benidipine hydrochloride has been developed as an antagonist for the L-type calcium channel and is used as an anti-hypertensive drug. But recent studies have reported that benidipine exerts not only antihypertensive actions but also anti-hypertrophic actions on cardiac muscles. Endothelin-1 (ET-1), one of the endogenous pathological humoral factors of cardiovascular diseases such as hypertension and heart failure, has a strong vasoconstrictive action and could induce hypertension and cardiac hypertrophy. So, it is a matter of great interest whether or not calcium antagonists can decrease cardiac hypertrophy induced by the pathological vasoactive substances such as ET-1. Thus, the present study was designed to elucidate the effects of benidipine on cardiac hypertrophy, and particularly on the interaction with ET-1, using neonatal rat cardiac myocytes (MCs) and cardiac non-myocytes (NMCs) culture systems. Cells were cultured with or without ET-1, benidipine, and nifedipine and the effects of calcium antagonists on cardiac hypertrophy were evaluated by incorporations of [3H]-leucine and [3H]-thymidine into MCs and/or NMCs. Benidipine significantly decreased the ET-1-induced increase of [3H]-leucine and [3H]-thymidine uptake into cardiac MCs and NMCs, whereas no significant effects of nifedipine were observed. Furthermore, benidipine (10(-8)M) attenuated ET-1 secretions from NMCs. In summary, benidipine at least partially decreased the cardiac hypertrophy induced by paracrine mechanisms through its attenuation of ET-1 secretions from NMCs. Benidipine could thus be a useful tool for preventing cardiac hypertrophy due to hypertension.

Topics: Animals; Animals, Newborn; Calcium Channel Blockers; Cardiomegaly; Cells, Cultured; Dihydropyridines; Endothelin-1; Hypertension; Leucine; Muscle Fibers, Skeletal; Myocardium; Nifedipine; Rats; Rats, Wistar; Thymidine; Tritium

To analyze the effect of the long-acting calcium channel blocker lacidipine on cardiovascular remodeling induced by salt loading in a genetic model of hypertension.. We examined the influence of threshold doses of lacidipine, with little blood-pressure lowering effect, on cardiac weight and gene expression in stroke-prone spontaneously hypertensive rats (SHRSP).. SHRSPs (8-week-old) were randomly allocated to four groups: control, salt-loaded SHRSP and salt-loaded SHRSP treated with lacidipine at 0.3 and 1 mg/kg per day. Systolic blood pressure was measured by the tail-cuff method. At the end of 6 weeks of treatment, ventricles were collected and weighed. Ventricular messenger RNA was extracted and subjected to Northern blot analysis.. Lacidipine (0.3 mg/kg per day) not only prevented the salt-dependent cardiac hypertrophy and the slight increase in systolic blood pressure induced by salt, but also prevented, largely or completely, salt-dependent increases in ventricular levels of several gene products: skeletal and cardiac alpha-actin, beta-myosin heavy chain (beta-MHC), type I collagen, long-lasting (L)-type calcium channel and preproendothelin-1. At a higher dose of 1 mg/kg per day, lacidipine further decreased systolic blood pressure below the level of control SHRSP, completely prevented salt-dependent overexpression of the beta-MHC gene and markedly attenuated salt-dependent overexpression of the transforming growth factor-beta1 gene.. Lacidipine prevents the cardiac remodeling and enhanced gene expression induced by salt loading in SHRSP at doses that only minimally affect the high systolic blood pressure.

Topics: Animals; Blood Pressure; Calcium Channel Blockers; Cardiomegaly; Cerebrovascular Disorders; Dihydropyridines; Follow-Up Studies; Gene Expression; Hypertension; Male; Myosin Heavy Chains; Random Allocation; Rats; Rats, Inbred SHR; RNA, Messenger; Sodium Chloride; Ventricular Remodeling

The antihypertensive effects of AE0047, a novel 1,4-dihydropyridine-type calcium antagonist, were investigated in spontaneously hypertensive rats (SHR/crj) and two kidney-one clip renal hypertensive dogs (RHD). AE0047, which was orally administered at the dose of 0.3, 1 or 3 mg/kg once daily for 8 consecutive weeks to SHR/crj, exhibited a dose-related decrease in systolic blood pressure. The antihypertensive action was reinforced during the drug treatment at 0.3 and 1 mg/kg. At each dose, the trough-to-peak (T/P) ratio was above 0.50 two weeks later. Although the reflex tachycardia was observed at 1 or 3 mg/kg on the 1st day, it gradually weakened within 8 weeks. Long-term treatment with AE0047 led to the regression of left ventricular hypertrophy. Furthermore, AE0047 had no influences on lipid and glucose metabolism. In RHD, and AE0047 capsule (GJ-0956) containing 2 or 8 mg of the drug was administered for 2 weeks. GJ-0956 produced no reduction in blood pressure at 2 mg, but enhanced the antihypertensive effect starting at 8 mg. The T/P ratios were 0.52 and 0.67 for the systolic and diastolic pressure, respectively, on the 14th day. These results indicate that AE0047 may be expected to exhibit beneficial effects for the clinical treatment of hypertension.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cardiomegaly; Dihydropyridines; Dogs; Heart Rate; Hypertension; Hypertension, Renal; Male; Rats; Rats, Inbred SHR

1. The tissue-protective effects of calcium channel blockers in hypertension are not well dissociated from their effect on systolic blood pressure (SBP). We have previously shown that lacidipine, a dihydropyridine-type calcium antagonist, reduced the cardiac hypertrophy and the cardiac endothelin-1 (ET-1) gene overexpression occurring in salt-loaded stroke-prone spontaneously hypertensive rats (SL-SHRSP), an effect occurring without systolic blood pressure (SBP) change. In the present study, we have examined whether this action was dose-related and if it could be associated with ET receptor changes. The action of lacidipine was also examined in control SHRSP and in Wistar Kyoto rats (WKY). 2. The daily dose of 0.3 mg kg-1 lacidipine which did not lower SBP but significantly prevented ventricle hypertrophy and cardiac preproET-1-mRNA expression in SL-SHRSP was inactive in control SHRSP. With the higher dose of lacidipine (1 mg kg-1 day-1), we observed a further reduction of cardiac hypertrophy and of ET-1 gene expression in SL-SHRSP and a significant effect on those parameters in control SHRSP but only a small reduction of SBP in both groups. 3. In WKY, salt loading did not induce change in SBP or increase of cardiac ET-1 gene expression and ventricle mass. In these normotensive rats, lacidipine (1 mg kg-1 day-1) did not modulate the basal preproET-1-mRNA expression and did not affect SBP or heart weight. 4. The maximum binding capacity (Bmax) and the dissociation constant (KD) of [125I]-ET-1 binding and the relative proportion of low- and high-affinity binding sites for ET-3 were not significantly affected by salt loading or lacidipine treatment in SHRSP. 5. These results show that lacidipine exerted a dose-related inhibition of ventricle hypertrophy and preproET-1-mRNA expression in SHRSP and indicate that this effect was unrelated to SBP changes. The dose-dependency of this inhibition suggests that salt-induced cardiac hypertrophy could be related to ET-1 gene overexpression. The results further show that ET receptor changes are not involved in the pathophysiological process studied here.

Topics: Animals; Blood Pressure; Calcium Channel Blockers; Cardiomegaly; Dihydropyridines; Dose-Response Relationship, Drug; Endothelin-1; Gene Expression; Male; Rats; Rats, Inbred SHR; RNA, Messenger

The aim of this study was to compare the effects of angiotensin converting enzyme (ACE) inhibition, angiotensin II (AII) AT1-receptor blockade, and dihydropyridine calcium antagonism on hypertrophy and on vascular albumin permeability in kidney, heart, and mesenteric artery in a model combining genetic hypertension and diabetes mellitus. Diabetes mellitus was induced by streptozotocin in 8-week-old spontaneously hypertensive rats. The animals were randomized to receive no treatment, the angiotensin converting enzyme inhibitor ramipril, the AII AT1-receptor blocker valsartan, or the dihydropyridine calcium antagonist lacidipine for 3 weeks. Vascular albumin permeability was measured as the tissue content of intravenously injected Evans blue dye (EB) in kidney, heart, and mesenteric artery and the tissue/plasma EB ratio was calculated. Systolic blood pressure was reduced by all three antihypertensive regimens. Glycemic control was similar in all diabetic groups. Kidney hypertrophy was not affected by any of the antihypertensive drugs. Hypertrophy of the mesenteric artery was enhanced by lacidipine but was not affected by ramipril or valsartan. Relative heart weight was also increased by lacidipine. Vascular albumin permeability, expressed as EB content in micrograms/gram dry weight or as tissue/plasma EB ratio, was higher in the kidneys of lacidipine-treated rats than in any other group of diabetic rats. There was a positive correlation between kidney weight/body weight and kidney/plasma EB ratio in the diabetic rats. These findings indicate that the dihydropyridine calcium antagonist lacidipine is associated with an unfavorable effect on vascular hypertrophy and on vascular albumin permeability in the kidneys in rats with hypertension and diabetes mellitus. Furthermore, there seems to be a coupling in the diabetic kidney between hypertrophy and increased vascular albumin permeability.

Topics: Analysis of Variance; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Glucose; Blood Pressure; Capillary Permeability; Cardiomegaly; Coloring Agents; Coronary Vessels; Diabetes Mellitus, Experimental; Dihydropyridines; Evans Blue; Hypertension; Hypertrophy; Kidney; Male; Mesenteric Arteries; Ramipril; Rats; Rats, Inbred SHR; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin; Serum Albumin; Tetrazoles; Valine; Valsartan

Interest in cardiovascular protection by calcium channel antagonists has grown over the past decade. We investigated the prevention of cardiac remodeling and renal injury by the long-acting calcium channel antagonist benidipine using 12 week-old Dahl salt-sensitive (Dahl S) rats fed a high-salt (4% NaCl) diet. Six-week benidipine treatment (10 mg/kg chow) decreased systolic blood pressure by 22% in Dahl S rats. This blood pressure reduction was associated with decreases in cardiac mass and weight of the aortic wall. Collagen content in the left ventricle tended to decline with benidipine treatment. In addition, glomerular filtration rate increased by 33% and arterial and glomerular lesions improved morphologically with this treatment. Regression of cardiac mass and collagen content in the left ventricle was due mainly to blood pressure reduction; however, collagen content in the low-pressure right ventricle was not only related to systemic blood pressure but to the severity of renal lesions. These data suggest that the calcium channel antagonist benidipine attenuates cardiac and renal injury in hypertensive Dahl S rats, and that part of the cardiac hypertrophy is due to a non-hemodynamic mechanism that might be responsible for, or be a consequence of, the lesions in the kidney.

Topics: Animals; Blood Pressure; Calcium Channel Blockers; Cardiomegaly; Dihydropyridines; Hemodynamics; Hypertension, Renal; Kidney; Myocardium; Rats; Rats, Inbred Strains; Sodium, Dietary

Stroke-prone spontaneously hypertensive rats receiving a high salt diet were orally treated by the calcium antagonist lacidipine, at a dose which did not reduce systolic blood pressure. We observed that lacidipine inhibited the salt-induced cardiac hypertrophy and the concomitant increase of mRNA transcripts for preproendothelin-1 in ventricles. These data show that elevated blood pressure cannot necessarily account for cardiac hypertrophy and indicate that the therapeutic action of lacidipine is not only related to its haemodynamic properties, but also to the inhibition of the gene expression of growth factors such as endothelin.

Topics: Age Factors; Animals; Cardiomegaly; Dihydropyridines; Endothelins; Gene Expression; Heart Ventricles; Rats; Rats, Inbred SHR; RNA, Messenger; Sodium Chloride

We investigated the influence of salt loading on the renal and cardiac production of endothelin-1 (ET-1) in stroke-prone, spontaneously hypertensive rats (SHR-SP). The results show that the dietary salt intake did not change systolic blood pressure or the renal expression of the prepro-ET-1 mRNA but increased cardiac expression of the ET-1 gene transcript with concomitant ventricular hypertrophy. These changes were prevented by oral treatment with lacidipine, a long-lasting calcium antagonist, at a dose that did not reduce systolic blood pressure. This indicates that the cardioprotective properties of lacidipine may be dissociated from its blood pressure-lowering effect and could be related to inhibition of endothelin gene expression.

Topics: Animals; Blood Pressure; Calcium Channel Blockers; Cardiomegaly; Dihydropyridines; Endothelin-1; Endothelins; Gene Expression; Protein Precursors; Rats; Rats, Inbred SHR; RNA, Messenger; Sodium Chloride

Altered calcium channel number or function may be associated with myocardial hypertrophy. Treatment of cultured neonatal rat cardiomyocytes with norepinephrine or serum results in cellular hypertrophy without an increase in cell number. Cell culture is a convenient system for examining possible changes in channels and receptors associated with hypertrophy. The specific objective of this study was to measure the density of calcium channels in serum-free (as control), norepinephrine and serum-treated cardiomyocyte cultures. Measurements of high affinity [3H]nitrendipine binding and 45Ca++ uptake were made in K(+)-depolarized cardiomyocyte cultures. We report that there is an increased density of functional voltage-sensitive calcium channels in the serum-stimulated model of cardiomyocyte hypertrophy. This increased density of calcium channels in the serum-treated cells may represent a mechanism responsible for initiating and promoting cardiomyocyte hypertrophy.

Topics: Animals; Binding Sites; Blood; Calcium; Calcium Channels; Cardiomegaly; Cells, Cultured; Dihydropyridines; In Vitro Techniques; Ion Channel Gating; Myocardium; Rats; Rats, Sprague-Dawley

We investigated the effect on cardiac hypertrophy of a once-daily treatment with lacidipine, at doses that do not reduce systolic blood pressure. Spontaneously hypertensive stroke-prone rats (SHR-SP) were fed a 1% NaCl enriched diet and treated daily by gastric gavage with lacidipine at doses of 0.3, 1, or 3 mg/kg/die or vehicle. At 15 weeks of age the rats were sacrificed. The heart was removed, weighed and processed for transmission electron microscopy, scanning electron microscopy and ultrastructural morphometry. Though the treatment did not reduce systolic blood pressure, heart weight and heart weight/body weight ratio were lower in the lacidipine-treated rats than in those treated with vehicle alone. Medial and subendothelial lesions were visible in coronaries of vehicle-treated SHR-SP but not in animals treated with lacidipine. In the cardiocytes of the lacidipine-treated rats, the myofibrils had a more regular arrangement and the intercalated discs did not show the irregular course and infoldings seen in the vehicle-treated rats. Morphometry showed a significantly higher density of mitochondria in the cardiocytes of lacidipine-treated SHR-SP. Scanning electron microscopy identified a decrease in the width of cardiocytes and in the number and length of lateral branches following lacidipine-treatment. The cardio-protective action of this calcium-antagonist at doses that do not reduce systolic blood pressure is attributable both to its vascular activity and to improvement in cytoplasmic organization of cardiocytes.

Topics: Animals; Calcium Channel Blockers; Cardiomegaly; Cerebrovascular Disorders; Coronary Vessels; Dihydropyridines; Disease Models, Animal; Hypertension; Male; Microscopy, Electron; Microscopy, Electron, Scanning; Myocardium; Rats; Rats, Inbred SHR

The effect of manidipine on cardiac hypertrophy, coronary circulation, left ventricular weight and maximal coronary flow in hypertension was measured in DOCA/salt treated systolic hypertensive rats with and without manidipine treatment. Normotensive rats were used as controls. After feeding with 0.05% manidipine-containing food, blood pressure was reduced only in DOCA/salt hypertensive rats, but not in control rats. After 3 weeks of treatment, sodium excretion was significantly increased in DOCA/salt-treated rats with or without manidipine treatment. Hearts were removed and perfused with modified Krebs-Henseleit solution with adenosine (5 x 10(-5) M) in a Langendorff apparatus. Maximal coronary flow (MCF) was significantly decreased only in DOCA/salt hypertensive rats without treatment, while manidipine treatment restored MCF. Left ventricular weight/body weight was also markedly greater in DOCA/salt-treated rats not given manidipine. Left ventricular weight in DOCA/salt-treated rats given manidipine was significantly reduced compared with DOCA/salt hypertensive rats without treatment, although it was heavier than in the control animals. Morphological examination showed that the increased wall/lumen ratio in DOCA/salt hypertensive rats was reduced by manidipine treatment. These findings suggest that treatment with manidipine in DOCA/salt hypertensive rats lowered high blood pressure and improved impaired coronary circulation with a reduction in left ventricular and vascular hypertrophy.

Topics: Aldosterone; Animals; Antihypertensive Agents; Blood Pressure; Cardiomegaly; Coronary Circulation; Coronary Vessels; Desoxycorticosterone; Dihydropyridines; Electrolytes; Heart Rate; Hypertension; Male; Nitrobenzenes; Piperazines; Rats; Rats, Wistar; Renin; Sodium Chloride

In order to complement earlier short-term observations, we studied the effects of isradipine (1.25 or 2.5 mg twice daily) on blood pressure as well as its action in reversing cardiac hypertrophy in 25 moderately hypertensive patients. We observed that the treatment produced short-term (3 month) and longer-term (9 month) control of blood pressure [decreases in mean arterial pressure (MAP) from 128 +/- 2.3 to 112 +/- 2.7 mm Hg and to 105.5 +/- 2.9 mm Hg; p less than 0.001] while heart rate remained constant throughout the study (from 76.6 +/- 2.3 to 74.7 +/- 2.4 beats/min; NS). Reversal of left ventricular hypertrophy (LVH) obtained after 3 months of treatment (LV mass index from 173.7 +/- 8.8 to 135.7 +/- 4.5 g/m2; p less than 0.001) was accentuated with continued therapy (to 131.0 +/- 4.0 and 124.4 +/- 3.1 g/m2 at 6 and 9 months, respectively; p less than 0.01). These results indicate that significant regression of LVH can be obtained with short-term treatment of hypertension with isradipine and that this effect will be fully obtained with longer-term (9 month) therapy.

Topics: Adult; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cardiomegaly; Dihydropyridines; Female; Humans; Hypertension; Isradipine; Male; Middle Aged

We explored the effect of age and of hypertrophy on Ca2+ antagonist binding site density (Bmax), affinity (Kd), and selectivity in cardiac membranes harvested from the hearts of young adult (9-week-old) and older (25-week-old) Sprague Dawley (SD) rats, Wistar Kyoto rats (WKY), and spontaneously hypertensive rats (SHR). Radioligand binding studies with (+)[3H]PN200-110 failed to show a significant difference between the Bmax obtained for the cardiac membranes of 9-week-old SD, WKY, or SHR. Similarly, at 25 weeks, the Bmax values were the same for each group, but in each group the Bmax tended to increase with age. The Kd and selectivity were unchanged. For (-)[3H]D888 binding, the Kd values changed with age, but there was no hypertension or hypertrophy-linked increase in Bmax. In the SD and SHR series, but not in the WKY, there was a tendency for the Bmax to increase with age. We interpreted these results to mean that age may contribute to the different Kd and Bmax values described for cardiac membranes from 25-week-old WKY and SHR.

Topics: Aging; Animals; Blood Pressure; Body Weight; Calcium Channels; Cardiomegaly; Cell Membrane; Dihydropyridines; Indicators and Reagents; Isradipine; Male; Myocardium; Oxadiazoles; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Rats, Inbred WKY; Receptors, Nicotinic; Time Factors; Verapamil