dihydropyridines and Ventricular-Dysfunction--Left

In arterial hypertension, left ventricular (LV) hypertrophy (H) is a prognostically relevant target organ damage associated with systolic and diastolic LV dysfunction. The level of LV dysfunction seems to be related to the degree of myocardial fibrosis. Prognosis of hypertensive patients who have LVH regression appears to be improved. Therefore, LVH regression is an important antihypertensive treatment goal. The renin-angiotensin-aldosterone system is implicated in LVH development and myocardial fibrosis in essential arterial hypertension. Early studies in the 80s and 90s have led expectations that angiotensin converting enzyme (ACE) inhibitors could induce greater LVH regression than other antihypertensive drugs at similar blood pressure reduction. In the late 90s, the double-blind randomized controlled PRESERVE trial (Prospective Randomize Enalapril Study Evaluating Reversal of Ventricular Enlargement) has been designed to evaluate whether the ACE inhibitor enalapril was more effective than nifedipine GITS in regressing LVH and improving LV diastolic dysfunction. The PRESERVE study demonstrated a mildly higher antihypertensive effect of nifedipine GITS than enalapril, which required more frequently association with hydrochlorothiazide to control blood pressure. However, at similar level of blood pressure reduction achieved with enalapril and long-acting nifedipine in association with hydrochlorothiazide or atenolol, both antihypertensive treatments showed similar efficacy in LVH regression and LV diastolic filling improvement.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Atenolol; Calcium Channel Blockers; Dihydropyridines; Disease Models, Animal; Diuretics; Drug Therapy, Combination; Enalapril; Follow-Up Studies; Humans; Hydrochlorothiazide; Hypertension; Hypertrophy, Left Ventricular; Meta-Analysis as Topic; Nifedipine; Prognosis; Prospective Studies; Randomized Controlled Trials as Topic; Rats; Rats, Inbred SHR; Renin-Angiotensin System; Sodium Chloride Symporter Inhibitors; Time Factors; Ventricular Dysfunction, Left

Patients with heart failure are particularly susceptible to the negative effects of calcium channel blockers because the failing heart demonstrates a defect in the delivery of calcium to the contractile proteins, and an attenuation of the normal sympathetic reflexes. Currently these drugs have no place in the treatment of heart failure caused by systolic dysfunction of the left ventricle. Calcium channel blockers should probably not be described for patients with coronary artery disease and left ventricular dysfunction. When the patient needs additional treatment for angina and beta-blockers or nitrates have not given satisfactory results, it may be appropriate to prescribe amlodipine or felodipine.

Topics: Calcium Channel Blockers; Dihydropyridines; Diltiazem; Heart Failure; Humans; Ventricular Dysfunction, Left; Verapamil

Left ventricular (LV) diastolic dysfunction is associated with hypertension and hyperuricemia. However, it is not clear whether the L- and N-type calcium channel blocker will improve LV diastolic dysfunction through the reduction of uric acid. The aim of this study was to investigate the effects of anti-hypertensive therapy, the L- and N-type calcium channel blocker, cilnidipine or the L-type calcium channel blocker, amlodipine, on left atrial reverse remodeling and uric acid in hypertensive patients. We studied 62 patients with untreated hypertension, randomly assigned to cilnidipine or amlodipine for 48 weeks. LV diastolic function was assessed with the left atrial volume index (LAVI), mitral early diastolic wave (E), tissue Doppler early diastolic velocity (E') and the ratio (E/E'). Serum uric acid levels were measured before and after treatment. After treatment, systolic and diastolic blood pressures equally dropped in both groups. LAVI, E/E', heart rate and uric acid levels decreased at 48 weeks in the cilnidipine group but not in the amlodipine group. The % change from baseline to 48 weeks in LAVI, E wave, E/E' and uric acid levels were significantly lower in the cilnidipine group than in the amlodipine group. Larger %-drop in uric acid levels were associated with larger %-reduction of LAVI (p < 0.01). L- and N-type calcium channel blocker but not L-type calcium channel blocker may improve LV diastolic function in hypertensive patients, at least partially through the decrease in uric acid levels.

Topics: Amlodipine; Atrial Function, Left; Atrial Remodeling; Biomarkers; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; China; Diastole; Dihydropyridines; Down-Regulation; Echocardiography, Doppler; Female; Humans; Hypertension; Hyperuricemia; Male; Middle Aged; Time Factors; Treatment Outcome; Uric Acid; Ventricular Dysfunction, Left; Ventricular Function, Left

We previously demonstrated that a calcium channel blocker, azelnidipine, improves left ventricular relaxation in patients with hypertension and diastolic dysfunction in a multicentre, Clinical impact of Azelnidipine on Left VentricuLar diastolic function and OutComes in patients with hypertension (CALVLOC) trial. The objectives of the present subanalysis were to investigate the differences in diastolic function in hypertensive patients with and without diabetes, and the efficacy of azelnidipine on diastolic function among them.. Subanalysis of a prospective single-arm multicentre study.. 228 hypertensive patients with normal ejection fraction and impaired left ventricular relaxation (septal e' velocity<8 cm/s on echocardiography) enrolled for CALVLOC trial. They were divided into two groups based on presence or absence of diabetes.. Administration of 16 mg of azelnidipine for 8 months (range 6-10 months).. Septal e' velocity before and at the end of the study.. Whereas patients with diabetes (n=53, 23.2%) had lower systolic blood pressure (BP) than patients without diabetes (155±17 vs 161±16 mm Hg, p=0.03), they had lower e' velocity (5.7±1.5 vs 6.1±1.4 cm/s, p=0.04) at baseline. Azelnidipine decreased BP and heart rate, and increased e' velocity similarly in patients with diabetes (5.7±1.5 to 6.3±1.5 cm/s, p=0.0003) and without diabetes (6.1±1.4 to 6.9±1.4 cm/s, p<0.0001). Increase in e' velocity was not influenced by presence of diabetes, and patients with diabetes still had lower e' velocity after treatment (p=0.006). There was a significant correlation between increase in e' velocity and decrease in systolic BP (R=0.25, p=0.0001), which was not influenced by diabetes.. Comorbid diabetes could impair left ventricular relaxation independently in patients with hypertension, which might not be improved solely by BP lowering.

Topics: Adult; Aged; Aged, 80 and over; Azetidinecarboxylic Acid; Calcium Channel Blockers; Diabetic Cardiomyopathies; Dihydropyridines; Echocardiography; Female; Humans; Hypertension; Male; Middle Aged; Prospective Studies; Ventricular Dysfunction, Left; Ventricular Function, Left

We investigated the impact of lowering blood pressure (BP) with azelnidipine, a newly developed calcium channel blocker, generation on the left ventricular (LV) diastolic function and LV filling pressure by assessing non-invasive indices derived from echo Doppler study. This study evaluated 232 hypertensive patients with diastolic dysfunction. This study had two groups: (1) in which azelnidipine was administered to patients as a first-line therapy, and (2) in which amlodipine was converted to azelnidipine. Early diastolic mitral annulus velocity (e', cm s(-1)), the ratio of peak E velocity to e' velocity (E/e' ratio) and level of brain natriuretic peptide (BNP) were measured before and, an average of, 8 months after azelnidipine treatment. In the first-line azelnidipine group, the systolic and diastolic BP reduced by 26 and 11 mm Hg, respectively. The e' increased, and E/e' ratio and BNP level decreased significantly. In the converted-from-amlodipine group, the systolic and diastolic BP decreased by 14 and 6 mmHg, respectively. The e' velocity increased, but the E/e' ratio and BNP level did not change. In both groups, azelnidipine lowered BP and improved LV diastolic function (an increase in the e' velocity). Possible reduction in LV filling pressure (a decrease in the E/e' ratio and BNP level) is observed only in the first-line azelnidipine group.

Topics: Adult; Aged; Aged, 80 and over; Azetidinecarboxylic Acid; Calcium Channel Blockers; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Natriuretic Peptide, Brain; Ultrasonography; Ventricular Dysfunction, Left; Ventricular Function, Left; Young Adult

To estimate the influence of therapy with amlodipine (A) or lacidipine (L) on heart rate variability (HRV) time and frequency domain parameters in hypertensive patients with stable angina pectoris and isolated left ventricular diastolic dysfunction.. After a 1-week washout period, the patients were randomized to receive amlodipine 10 mg (30 patients) or lacidipine 6 mg (30 patients) once-daily for 4 weeks. HRV parameters were determined over a period of 24 h, echocardiography and exercise test were performed before and after treatment.. All HRV time domain parameters after applying amlodipine did not change significantly. A reliable decrease only of the root mean square of differences between adjacent normal-to-normal intervals (RMSSD)-32.9 +/- 13 vs. 27.5 +/- 9-was noticed after treatment with lacidipine. In the lacidipine group, the change of RMSSD negatively correlated with the extent of ST segment depression during exercise testing (R = -0.43; P < 0.05). Both drugs reduced total power (A, 2234 +/- 1270 vs. 1813 +/- 889; L, 2205 +/- 1151 vs. 1825 +/- 896; P < 0.01), very low (A, 1451 +/- 733 vs. 1143 +/- 534; L, 1413 +/- 759 vs. 1213 +/- 616; P < 0.05), and low frequency power (A, 610 +/- 459 vs. 447 +/- 321; L, 569 +/- 323 vs. 442 +/- 241; P < 0.01). After amlodipine, high frequency power remained unchanged, whereas low-high frequency ratio decreased (4.54 +/- 1.72 vs. 3.77+/-1.73; P < 0.05). After lacidipine, high frequency power decreased (178.8 +/- 153.2 vs. 132.1 +/- 79.3; P < 0.05), whereas the ratio of low frequency to high frequency did not change.. Amlodipine and lacidipine reduce the influence of humoral control and sympathetic autonomic nervous system activity. The autonomic balance becomes shifted toward the increased vagal activity only by amlodipine.

Topics: Adult; Aged; Amlodipine; Angina Pectoris; Blood Pressure; Calcium Channel Blockers; Circadian Rhythm; Dihydropyridines; Electrocardiography, Ambulatory; Female; Follow-Up Studies; Heart Rate; Humans; Hypertension; Male; Middle Aged; Treatment Outcome; Ventricular Dysfunction, Left

The purpose of the present study was to examine the mechanisms of improvement in left ventricular (LV) diastolic function in hypertensive patients treated with cilnidipine, a new and unique calcium antagonist that has both L-type and N-type voltage-dependent calcium channel blocking actions, using pulsed Doppler echocardiography and pulsed tissue Doppler imaging. The study comprised 35 untreated patients with essential hypertension (19 men and 16 women; mean age 65+/-10 years). The peak early diastolic and atrial systolic transmitral flow velocities (E and A, respectively) and their ratio (E/A), and the peak early diastolic and atrial systolic motion velocities (Ew and Aw, respectively) of the LV posterior wall and their ratio (Ew/Aw) were determined in all patients before and after 1, 3 and 6 months on cilnidipine (10 mg/day). One month: Systolic and diastolic blood pressures were significantly decreased. E and E/A were significantly increased, whereas there were no significant changes in Ew and Ew/Aw. Three months: Ew and Ew/Aw were significantly increased compared to those before and 1 month after cilnidipine. Six months: E and E/A were significantly increased compared with before and 3 months after cilnidipine, and Ew and Ew/Aw were significantly increased compared with before cilnidipine. Moreover, the LV mass index was significantly decreased compared to that before cilnidipine. In summary, changes in LV diastolic performance in patients with essential hypertension following cilnidipine treatment were biphasic with an initial increase in early diastolic transmitral flow velocity and a later increase in early diastolic LV wall motion velocity. The initial and later changes can be related to an acute change in afterload and a later improvement in LV relaxation.

Topics: Aged; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Diastole; Dihydropyridines; Echocardiography, Doppler, Pulsed; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Systole; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Function, Left

The aim of this study was to assess the cardiovascular effects of BAY y 5959, a calcium promoter modulating myocardial calcium channels, in the presence or absence of congestive heart failure.. There is still a clinical need for short-term administration of intravenous positive inotropes. BAY y 5959 was developed as a new approach to increase myocardial performance by selectively enhancing calcium influx in the myocytes.. Forty-one patients (21 without and 20 with congestive heart failure) were studied in an open label, dose-ranging study. Hemodynamic variables (including left ventricular [LV] angiography) and plasma samples were obtained at baseline and after 20 min of intravenous infusion of BAY y 5959 at doses ranging from 0.25 to 4.5 microg/kg body weight per min.. In both study groups, BAY y 5959 produced dose-dependent increases in the indexes of inotropic state, without affecting isovolumetric relaxation rate. The magnitude of the response was comparable in patients with or without heart failure (average 38% increase in maximal first derivative of LV pressure [dP/dt max] at plasma levels of 100 microg/liter). BAY y 5959 also induced mild but statistically significant bradycardia and significantly decreased end-systolic volume while producing a leftward shift of the pressure-volume loop. Mean aortic pressure was unaffected at doses up to 3.0 microg/kg per min, and cardiac index improved in patients with heart failure at doses of 2.0 microg/kg per min (+23%, p < 0.05). However, at a dose of 4.5 microg/kg per min, mean aortic pressure and LV systolic wall stress increased, suggesting systemic vasoconstriction. The QT interval was also prolonged significantly at most doses.. BAY y 5959 exhibits positive inotropic effects in patients with and without heart failure. The optimal response--combining bradycardia, reduced preload and improved cardiac output--appeared to be achieved at a dose of approximately 2.0 microg/kg per min. The impact of QT prolongation with regard to potential antiarrhythmic or proarrhythmic effects is unclear at this time.

Topics: Calcium Channel Agonists; Cardiotonic Agents; Case-Control Studies; Dihydropyridines; Dose-Response Relationship, Drug; Electrocardiography; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Myocardial Contraction; Stimulation, Chemical; Ventricular Dysfunction, Left

Aldosterone is implicated in the pathogenesis of several cardiovascular diseases, including ischemia reperfusion (I/R) and myocardial infarction, and also causes oxidative stress and inflammation in cardiovascular systems. Benidipine, a long-acting T- and L-type calcium channel blocker, reduces infarct size following myocardial I/R in rabbits. Benidipine also inhibits the production of aldosterone in vitro. However, the precise mechanism of this phenomenon in vivo remains unknown. We therefore evaluated whether benedipine has a beneficial role through the regulation of oxidative stress in myocardial I/R. C57BL/6J mice were subjected to 30 min of left ascending coronary I/R. Benidipine was administered orally at 3 mg kg(-1) daily for 3 weeks without any changes in hemodynamic variables. Benidipine significantly reduced infarction size (13.4±2.5%) compared with controls (25.5±3.6%). Urinary 8-hydroxy-2' deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, increased significantly after I/R. I/R induced increases in 8-OHdG were significantly lower with benidipine. Local myocardial 8-OHdG was also elevated in I/R, but this augmentation was significantly suppressed with benidipine. The plasma aldosterone concentration (PAC) significantly increased 2 days after I/R and remained elevated at least 7 days after I/R. Treatment with benidipine significantly decreased I/R-induced elevation of the PAC. I/R-induced markers of fibrosis in hearts also reduced in benidipine. These results suggest that the administration of benidipine reduces myocardial infarct size as well as systemic oxidative stress after I/R. These phenomena are partially linked to reduced plasma aldosterone levels.

Topics: Aldosterone; Animals; Apoptosis; Calcium Channel Blockers; Dihydropyridines; Disease Models, Animal; Down-Regulation; Hemodynamics; Male; Mice; Mice, Inbred C57BL; Myocardial Infarction; Myocardial Reperfusion Injury; Oxidative Stress; Ventricular Dysfunction, Left

Numerous evidences suggest that diabetic heart is characterized by compromised ventricular contraction and prolonged relaxation attributable to multiple causative factors including calcium accumulation, oxidative stress and apoptosis. Therapeutic interventions to prevent calcium accumulation and oxidative stress could be therefore helpful in improving the cardiac function under diabetic condition.. This study was designed to examine the effect of long-acting calcium channel blocker (CCB), Azelnidipine (AZL) on contractile dysfunction, intracellular calcium (Ca2+) cycling proteins, stress-activated signaling molecules and apoptosis on cardiomyocytes in diabetes. Adult male Wistar rats were made diabetic by a single intraperitoneal (IP) injection of streptozotocin (STZ). Contractile functions were traced from live diabetic rats to isolated individual cardiomyocytes including peak shortening (PS), time-to-PS (TPS), time-to-relengthening (TR90), maximal velocity of shortening/relengthening (± dL/dt) and intracellular Ca2+ fluorescence.. Diabetic heart showed significantly depressed PS, ± dL/dt, prolonged TPS, TR90 and intracellular Ca2+ clearing and showed an elevated resting intracellular Ca2+. AZL itself exhibited little effect on myocyte mechanics but it significantly alleviated STZ-induced myocyte contractile dysfunction. Diabetes increased the levels of superoxide, enhanced expression of the cardiac damage markers like troponin I, p67phox NADPH oxidase subunit, restored the levels of the mitochondrial superoxide dismutase (Mn-SOD), calcium regulatory proteins RyR2 and SERCA2a, and suppressed the levels of the anti-apoptotic Bcl-2 protein. All of these STZ-induced alterations were reconciled by AZL treatment.. Collectively, the data suggest beneficial effect of AZL in diabetic cardiomyopathy via altering intracellular Ca2+ handling proteins and preventing apoptosis by its antioxidant property.

Topics: Animals; Antioxidants; Apoptosis; Azetidinecarboxylic Acid; Calcium; Calcium Channel Blockers; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Dihydropyridines; Male; Myocardial Contraction; Myocardium; Oxidative Stress; Phosphoproteins; Rats; Rats, Wistar; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Superoxides; Time Factors; Troponin I; Ventricular Dysfunction, Left; Ventricular Function, Left

Topics: Animals; Cardiomyopathy, Dilated; Dihydropyridines; Mice; Pyridazines; Survival Analysis; Treatment Outcome; Ventricular Dysfunction, Left

We investigated whether benidipine, a long-acting calcium channel blocker (CCB), can normalize cardiac expression profiles of the endothelin (ET)-1 system in insulin-resistant diabetes. Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of human Type 2 diabetes, were treated for 12 wk with vehicle or benidipine (3 mg.kg(-1).day(-1)). OLETF rats exhibited a significant increase in ET-1 in plasma and left ventricular (LV) tissues compared with nondiabetic controls. Expression of prepro-ET-1, ET-converting enzyme, and ET(A) and ET(B) receptors in LV tissues was also significantly higher in OLETF rats. The two MAPKs, JNK and p38MAPK, both of which are activated by ET-1, were more abundantly expressed in OLETF rat LV tissues. All these alterations were reversed to nondiabetic levels when OLETF rats were treated with the subdepressor dose of benidipine. Furthermore, benidipine therapy resulted in hindering cardiomyocyte hypertrophy and cardiac perivascular fibrosis in OLETF rats. The beneficial actions of benidipine at the subdepressor dose on cardiac remodeling in insulin-resistant diabetes may involve normalization of the upregulated ET-1 system.

Topics: Animals; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Dose-Response Relationship, Drug; Endothelin-1; Male; Rats; Up-Regulation; Ventricular Dysfunction, Left; Ventricular Remodeling

The cardioprotective properties of pranidipine were studied in a rat model of heart failure after autoimmune myocarditis. Twenty-eight days after immunization the surviving rats were divided into three groups and received oral treatment of 0.03 mg/kg/day (group 0.03) or 0.3 mg/kg/day (group 0.3) of pranidipine or vehicle (group V) for 1 month. High-dose pranidipine (group 0.3) improved the survival rate, and significantly reduced heart weight, heart weight to body weight ratio, myocardial fibrosis, central venous pressure and left ventricular end-diastolic pressure than low-dose pranidipine (group 0.03) and group V. Pranidipine at high dose also decreased the left ventricular systolic and diastolic dimensions, and increased fractional shortening compared with group V. The increase in level of TGF-beta1 and collagen-III mRNA were suppressed by pranidipine in a dose-dependent manner. Our results indicated that pranidipine has cardioprotective effects on heart failure, and that the beneficial effect can be partly explained by attenuation of fibrotic response through suppression of TGF-beta1 and collagen-III mRNA expression, and regression of myocyte hypertrophy.

Topics: Animals; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Heart Failure; Heart Rate; Male; Myocarditis; Rats; Rats, Inbred Lew; Transforming Growth Factor beta; Ventricular Dysfunction, Left; Ventricular Remodeling

In heart failure, homologous downregulation of beta-adrenoceptors contributes to impaired adrenergic responsiveness of the myocardium. We evaluated alpha 1-adrenoceptors (alpha 1-AR) in a sparsely innervated and a densely innervated peripheral artery in an experimental model of left ventricular dysfunction post-myocardial infarction.. [3H]Prazosin binding was determined in arterial segments of Wistar-Kyoto rats (WKY), and of Wistar rats 5 weeks after myocardial infarction (MI) or sham operation (SHAM).. In the thoracic aorta (TAO) of WKY, specific prazosin binding was: (i) prevented by the irreversible alpha 1B-AR and relatively selective alpha 1D-AR antagonist, chloroethylclonidine (CEC); (ii) displaced with low affinity (pKi 6.25) by the alpha 1A-AR selective ligand, (+)-niguldipine; and (iii) displaced with both high (pKi 10.4) and low (pKi 7.37) affinity by the alpha 1D-AR antagonist, BMY 7378. In mesenteric small arteries (MSA) of WKY, prazosin binding was: (i) reduced 50% by CEC; (ii) displaced in a biphasic fashion by (+)-niguldipine (pKi 8.60 and pKi 6.22); and (iii) displaced by BMY 7378 with low affinity only (pKi 6.86). Also in TAO of SHAM. prazosin binding was prevented by CEC, but neither 30 nM (+)-niguldipine nor 1 nM BMY 7378 affected it. In MSA of SHAM, prazosin binding was virtually abolished in the presence of 30 nM (+)-niguldipine and was not reduced by 1 nM BMY 7378. In TAO and MSA of MI, compared to SHAM, the density of binding sites tended to be increased rather than decreased and neither the affinity for the ligand nor the effects of alpha 1-AR subtype selective tools were significantly modified.. These findings indicate that: (i) radioligand binding can be applied in intact arterial segments to quantify and characterize alpha 1-AR; (ii) although differences seem to exist between rat strains, alpha 1B-AR and alpha 1D-AR predominate in rat thoracic aorta and alpha 1A-AR and alpha 1B-AR in mesenteric small arteries; and (iii) alpha 1-AR density is not reduced in the poorly innervated aorta and the densely innervated mesenteric small arteries of rats with heart failure due to myocardial infarction.

Topics: Adrenergic alpha-Antagonists; Animals; Aorta; Calcium Channel Blockers; Dihydropyridines; In Vitro Techniques; Male; Mesenteric Arteries; Myocardial Infarction; Piperazines; Prazosin; Protein Binding; Radioligand Assay; Rats; Rats, Inbred WKY; Rats, Wistar; Receptors, Adrenergic, alpha-1; Ventricular Dysfunction, Left