Anti-arrhythmic and hemodynamic effects of oxy nifedipine, oxy nimodipine, oxy nitrendipine and oxy nisoldipine.

Our previous studies have established cardio-protective effects of furnidipine and its active metabolites. We therefore decided to compare the influence of oral and intravenous administration of furnidipine, nifedipine, nitrendipine and nimodipine to examine their effects on hemodynamics and arrhythmias. Since dihydropyridines are oxidatively metabolized in the body and the oxidized metabolites are among the final products, we studied the influence of four oxidized dihydropyridines (oxy nifedipine, oxy nimodipine, oxy nitrendipine and oxy nisoldipine) on the same parameters. In vivo model of ischemia- and reperfusion-induced arrhythmias of rats was used. Dihydropyridines were administered 5 mg/kg orally (24 and 1 h before ischemia) or 5 µg/kg intravenously (10 min before ischemia). 20 mg/kg of the oxidized dihydropyridines was given orally (24 and 1 h before ischemia). The dihydropyridines exhibited significant anti-arrhythmic actions after both forms of administration but their influence on blood pressure was differential and contrasting and depended on route of administration. The oxidized dihydropyridines imparted strong protection against lethal arrhythmias while exerting differential influences on blood pressure with oxy nifedipine and oxy nisoldipine being hypertensive and oxy nitrendipine being most normotensive. The differential effects observed with the dihydropyridines after the two routes of administration lend strength to the hypothesis that their metabolites may have a significant role in mediating the actions of the parent drug. The strong anti-arrhythmic action of the oxidized dihydropyridines along with their differential effect on blood pressure could indicate their potential use as cardio-protective drugs in certain groups of patients.

Nisoldipine Inhibits Influenza A Virus Infection by Interfering with Virus Internalization Process.

Influenza virus infections and the continuing spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are global public health concerns. As there are limited therapeutic options available in clinical practice, the rapid development of safe, effective and globally available antiviral drugs is crucial. Drug repurposing is a therapeutic strategy used in treatments for newly emerging and re-emerging infectious diseases. It has recently been shown that the voltage-dependent Ca2+ channel Cav1.2 is critical for influenza A virus entry, providing a potential target for antiviral strategies. Nisoldipine, a selective Ca2+ channel inhibitor, is commonly used in the treatment of hypertension. Here, we assessed the antiviral potential of nisoldipine against the influenza A virus and explored the mechanism of action of this compound. We found that nisoldipine treatment could potently inhibit infection with multiple influenza A virus strains. Mechanistic studies further revealed that nisoldipine impaired the internalization of the influenza virus into host cells. Overall, our findings demonstrate that nisoldipine exerts antiviral effects against influenza A virus infection and could serve as a lead compound in the design and development of new antivirals.

Mobilization of putative high-proliferative-potential endothelial colony-forming cells during antihypertensive treatment in patients with essential hypertension.

Recent studies have shown that in response to vascular damage or ischemia, bone marrow-derived endothelial progenitor cells (EPCs) are recruited into the circulation. To investigate whether antihypertensive treatment has an influence on the number of circulating EPCs, patients with essential hypertension were treated either with the angiotensin receptor antagonist telmisartan, the calcium channel blocker nisoldipine, or their combination for 6 weeks. At baseline and after 3 and 6 weeks of treatment, EPCs were identified and quantified by fluorescence-activated cell sorting (FACS) analysis and by their capacity to generate colony-forming units of the endothelial lineage (CFU-EC) in a methylcellulose-based assay. During treatment, patients in the nisoldipine groups, but not in the telmisartan group, showed a significant mobilization of EPCs, which in part had the capacity to generate large-sized colonies comprising more than 1,000 cells. Moreover, a remarkable correlation between the number of CFU-EC and the number of circulating CD133(+)/CD34(+)/CD146(+) cells was observed, thereby providing strong evidence that cells with this phenotype represent functional EPCs. No correlation was found between the numbers of CFU-EC and the blood pressure levels at any time point during the treatment. Hence, nisoldipine-induced mobilization of EPCs might represent a novel mechanism by which this antihypertensive compound independently of its blood pressure-lowering effect contributes to vasoprotection in patients with essential hypertension.

Pharmacokinetics of oral doses of telmisartan and nisoldipine, given alone and in combination, in patients with essential hypertension.

This randomized, single-blind, parallel-group study was performed to assess pharmacokinetic interactions potentially occurring during concomitant use of telmisartan and nisoldipine. Patients with essential hypertension (n = 37) were treated with once-daily doses of telmisartan, nisoldipine, or their combination for 6 weeks. The regimen was started at low dose with an increase of dosage after 3 weeks of treatment. AUC(ss) (132%; P < .01) of telmisartan applied in doses of 80 mg was significantly higher after concomitant application with nisoldipine (10 mg), whereas CL/f(ss) (-54%; P < .05) and Vz/f(ss) (-72%; P < .05) were significantly lower. Regarding pharmacokinetic parameters of nisoldipine, significant differences between treatment groups were not detected. In conclusion, the results of this study strongly suggest that concomitant treatment with nisoldipine enhances telmisartan bioavailability in hypertensive individuals. Larger crossover trials will have to establish these observations and investigate whether interaction of both drugs affects telmisartan efficacy and tolerability in clinical use.

Pharmacologic agents in the management of hypertension--nisoldipine coat-core.

Nisoldipine coat-core (CC), a 1,4-dihydropyridine calcium antagonist, is indicated for the treatment of hypertension and may be used alone or in combination with other antihypertensive agents. The CC technology allows for extended delivery of the drug and once-daily dosing. Nisoldipine CC tablets are absorbed across the entire gastrointestinal tract, including the colon. Eighty percent of the total dose is in the slow-release outer coat, while the core has immediate-release characteristics suitable for absorption in the distal gastrointestinal tract. Numerous double-blind, randomized studies of this agent have been done in patients with hypertension. The use of nisoldipine CC reduced both clinic and ambulatory blood pressure to a similar degree when compared with angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and the calcium antagonists amlodipine and felodipine. The drug has also been studied in hypertensive African Americans and demonstrated equivalent efficacy to amlodipine. Tolerability of the drug is good, with the most common side effect of edema at a rate similar to other dihydropyridine calcium antagonists. Thus, results of more than a decade of clinical trial data support the use of nisoldipine CC as once-daily therapy for the treatment of hypertension.

Intensive blood pressure control reduces the risk of cardiovascular events in patients with peripheral arterial disease and type 2 diabetes.

BACKGROUND: Peripheral arterial disease (PAD) and diabetes are both associated with a high risk of ischemic events, but the role of intensive blood pressure control in PAD has not been established. METHODS AND RESULTS: The Appropriate Blood Pressure Control in Diabetes study followed 950 subjects with type 2 diabetes for 5 years; 480 of the subjects were normotensive (baseline diastolic blood pressure of 80 to 89 mm Hg). Patients randomized to placebo (moderate blood pressure control) had a mean blood pressure of 137+/-0.7/81+/-0.3 mm Hg over the last 4 years of treatment. In contrast, patients randomized to intensive treatment with enalapril or nisoldipine had a mean 4-year blood pressure of 128+/-0.8/75+/-0.3 mm Hg (P<0.0001 compared with moderate control). PAD, which is defined as an ankle-brachial index <0.90 at the baseline visit, was diagnosed in 53 patients. In patients with PAD, there were 3 cardiovascular events (13.6%) on intensive treatment compared with 12 events (38.7%) on moderate treatment (P=0.046). After adjustment for multiple cardiovascular risk factors, an inverse relationship between ankle-brachial index and cardiovascular events was observed with moderate treatment (P=0.009), but not with intensive treatment (P=0.91). Thus, with intensive blood pressure control, the risk of an event was not increased, even at the lowest ankle-brachial index values, and was the same as in a patient without PAD. CONCLUSIONS: In PAD patients with diabetes, intensive blood pressure lowering to a mean of 128/75 mm Hg resulted in a marked reduction in cardiovascular events.

Differences between nisoldipine and lisinopril on glomerular filtration rates and albuminuria in hypertensive IDDM patients with diabetic nephropathy during the first year of treatment.

Our objective was to compare the effect of a long-acting calcium antagonist (nisoldipine) versus an ACE inhibitor (lisinopril) on albuminuria, arterial blood pressure, and glomerular filtration rate (GFR) in hypertensive IDDM patients with diabetic nephropathy. We performed a 1-year, double-blind, double-dummy, randomized, controlled study comparing nisoldipine (20-40 mg once daily) with lisinopril (10-20 mg once daily) in 52 hypertensive IDDM subjects with diabetic nephropathy. Three patients dropped out, and results for the remaining 49 (25 nisoldipine, 24 lisinopril) are presented. Diuretics were required in 10 nisoldipine- and 8 lisinopril-treated patients. Every 3 months, 24-h ambulatory blood pressure (TM2420, A&D, Tokyo, Japan) and albuminuria in three 24-h samples (enzyme immunoassay) were measured; GFR (51Cr-EDTA plasma clearance) was recorded every 6 months. Mean arterial blood pressure (24 h) was reduced from (mean +/- SE) 108 +/- 3 mmHg at baseline to 101 +/- 2 in average during treatment in the lisinopril group and from 105 +/- 2 to 103 +/- 2 in the nisoldipine group (P = 0.06 comparing changes in the two groups). Albuminuria was reduced 47% (95% CI 21-65) in the lisinopril group versus an increase of 11% (-3 to 27) in the nisoldipine group (P = 0.001). Fractional albumin clearance was reduced 37% (95% CI 4-59%) in the lisinopril versus an increase of 35% (8-69%) in the nisoldipine group (P < 0.01). GFR decreased from 85 +/- 5 ml x min(-1) x 1.73 m(-2) to 73 +/- 5 in the lisinopril group and from 84 +/- 6 to 80 +/- 7 in the nisoldipine group (P < 0.05). The effect of study medication on albuminuria and GFR was independent of changes in systemic blood pressure and baseline variables in multiple regression analyses. In summary, lisinopril reduced albuminuria, but also GFR, to a greater extent than did nisoldipine in hypertensive IDDM patients with diabetic nephropathy during the 1st year of treatment. Longer follow-up is required to clarify whether these drugs have different renoprotective effects.

Long-term renoprotective effect of nisoldipine and lisinopril in type 1 diabetic patients with diabetic nephropathy.

OBJECTIVE: To compare the long-term effect on kidney function of a long-acting calcium antagonist (nisoldipine) versus a long-acting ACE inhibitor (lisinopril) in hypertensive type 1 diabetic patients with diabetic nephropathy. RESEARCH DESIGN AND METHODS: We performed a 4-year prospective, randomized, double-dummy controlled study comparing nisoldipine (20-40 mg once a day) with lisinopril (10-20 mg once a day). The study was double-blinded for the first year and single-blinded thereafter. The study included 51 hypertensive type 1 diabetic patients with diabetic nephropathy. Three patients dropped out during the first month; results for the remaining 48 patients are presented. RESULTS: At baseline, the two groups were comparable: glomerular filtration rate (GFR) was 85 +/- 5 and 85 +/- 6 ml x min(-1) x [1.73 m](-2); mean 24-h ambulatory blood pressure was 108 +/- 3 and 105 +/- 2 mmHg, and albuminuria was 1,554 mg/24 h (95% CI 980-2,465) and 1,033 mg/24 h (760-1,406) in the lisinopril and nisoldipine groups, respectively. Mean 24-h arterial blood pressure during the study did not differ between the lisinopril and nisoldipine groups (100 +/- 2 and 103 +/- 1 mmHg, respectively). The time-course of albuminuria differed between groups (P < 0.001). Whereas initiation of treatment with lisinopril resulted in a reduction from baseline albuminuria by 52% (95% CI 14-73), albuminuria in the nisoldipine group did not change throughout the study GFR declined in a biphasic manner with an initial (0-6 months) reduction of 1.3 +/- 0.3 ml x min(-1) x month(-1) in the lisinopril group compared with 0.2 +/- 0.4 ml x min(-1) x month(-1) in the nisoldipine group (P < 0.01). The subsequent sustained decline (6 to 48 months or the end of treatment) was identical in the two groups: 0.5 +/- 0.1 ml min(-1) x month(-1) (NS). Two patients in the lisinopril group and three patients in the nisoldipine group entered therapy for end-stage renal failure. CONCLUSIONS: Long-term treatment with lisinopril or nisoldipine has similar beneficial effects on progression of diabetic nephropathy in hypertensive type 1 diabetic patients.

Effects of nisoldipine and lisinopril on left ventricular mass and function in diabetic nephropathy.

OBJECTIVE: To compare the effects of the calcium channel blocker, nisoldipine, and the ACE inhibitor, lisinopril, on left ventricular mass (LVM) and systolic function in type 1 diabetic patients with diabetic nephropathy. RESEARCH DESIGN AND METHODS: M-mode echocardiography was performed in 50 hypertensive type 1 diabetic patients with diabetic nephropathy enrolled in a 1-year, randomized, double-blind, parallel study of antihypertensive treatment with nisoldipine CC (20-40 mg/day) or lisinopril (10-20 mg/day). Ambulatory 24-h blood pressure was measured with the Takeda TM 2420 device (A & D, Tokyo, Japan) every 3 months. Three patients dropped out and seven patients were excluded due to technical difficulties. RESULTS: The 24-h diastolic blood pressure was reduced from 83 to 80 mmHg in the nisoldipine group (P = 0.06) and from 85 to 80 mmHg in the lisinopril group (P = 0.02). The decline in systolic blood pressure was not significant with any of the two treatments, and no difference in reduction of blood pressure was seen between groups. LVM corrected for body surface area (LVMI) was comparable between groups at baseline and increased from 96 +/- 5 to 107 +/- 6 g/m2 (mean +/- SEM; P = 0.007) in the nisoldipine group and from 95 +/- 4 to 103 +/- 5 g/m2 (P = 0.03) in the lisinopril group. The mean difference between the change in LVMI in the two groups was 2.9 (95% CI 6.8 to 12.7) g/m2. The prevalence of left ventricular hypertrophy rose from 18 (95% CI 6-30) to 30% (16-44) during the study period. A multiple linear regression analysis revealed that after 1 year of treatment, LVMI increased with higher systolic blood pressure level and declining glomerular filtration rate (R2 = 0.25). Fractional shortening was within normal range at baseline, 42 +/- 1 vs. 41 +/- 1% with nisoldipine and lisinopril, respectively, and did not change during follow-up. CONCLUSIONS: Antihypertensive treatment with nisoldipine or lisinopril to bring diastolic blood pressure level within the normal target range does not hinder a rise in LVMI in type 1 diabetic patients with diabetic nephropathy.

Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes.

OBJECTIVE: The Appropriate Blood Pressure Control in Diabetes (ABCD) Trial is a prospective randomized blinded clinical trial that compares the effects of intensive versus moderate blood pressure control on the incidence and progression of type 2 diabetic complications. The current article discusses the results of 5.3 years of follow-up of 470 patients with hypertension and evaluates the effects of intensive and moderate blood pressure therapy using nisoldipine versus enalapril as the initial antihypertensive medication for nephropathy, retinopathy, and neuropathy. RESEARCH DESIGN AND METHODS: The 470 hypertensive subjects, defined as having a baseline diastolic blood pressure of > or = 90 mmHg, were randomized to intensive blood pressure control (diastolic blood pressure goal of 75 mmHg) versus moderate blood pressure control (diastolic blood pressure goal of 80-89 mmHg). RESULTS: The mean blood pressure achieved was 132/78 mmHg in the intensive group and 138/86 mmHg in the moderate control group. During the 5-year follow-up period, no difference was observed between intensive versus moderate blood pressure control and those randomized to nisoldipine versus enalapril with regard to the change in creatinine clearance. After the first year of antihypertensive treatment, creatinine clearance stabilized in both the intensive and moderate blood pressure control groups in those patients with baseline normo- or microalbuminuria. In contrast, patients starting with overt albuminuria demonstrated a steady decline in creatinine clearance of 5-6 ml.min-1.1.73 m-2 per year throughout the follow-up period whether they were on intensive or moderate therapy. There was also no difference between the interventions with regard to individuals progressing from normoalbuminuria to microalbuminuria (25% intensive therapy vs. 18% moderate therapy, P = 0.20) or microalbuminuria to overt albuminuria (16% intensive therapy vs. 23% moderate therapy, P = 0.28). Intensive therapy demonstrated a lower overall incidence of deaths, 5.5 vs. 10.7%, P = 0.037. Over a 5-year follow-up period, there was no difference between the intensive and moderate groups with regard to the progression of diabetic retinopathy and neuropathy. In addition, the use of nisoldipine versus enalapril had no differential effect on diabetic retinopathy and neuropathy. CONCLUSIONS: Blood pressure control of 138/86 or 132/78 mmHg with either nisoldipine or enalapril as the initial antihypertensive medication appeared to stabilize renal function in hypertensive type 2 diabetic patients without overt albuminuria over a 5-year period. The more intensive blood pressure control decreased all-cause mortality.

An updated meta-analysis of calcium-channel blockers in the prevention of restenosis after coronary angioplasty.

BACKGROUND: In 1994, a meta-analysis of 5 small randomized trials reported a 30% reduction in the odds of angiographic restenosis when calcium-channel blockers (CCB) were given after percutaneous coronary intervention. Recently, the results of 2 large similar trials (Nisoldipine In Coronary Artery Disease in Leuven [NICOLE], and Coronary AngioPlasty Amlodipine in REstenosis Study [CAPARES]) were published. An extended meta-analysis including the results of the latter trials was performed. METHODS: A total of 2380 patients were analyzed. Statistical analysis included calculation of odds ratios for each trial, common odds ratio, and homogeneity for treatment effects across trials. RESULTS: The incidence of angiographic restenosis was 36% in the CCB-treated group and 42% in the placebo group. The odds ratio of restenosis with CCB therapy was 0.78 (95% CI 0.64-0.95) compared with control patients (P =.01). Treatment effects were homogeneous across the trials. For the combined end point of death, coronary artery bypass grafting, repeat percutaneous transluminal coronary angioplasty, and myocardial infarction, 126 of 626 events occurred in the CCB group and 191 of 655 in the placebo group (odds ratio 0.61 [95% CI 0.47-0.80], P <.001). CONCLUSIONS: This extended meta-analysis confirmed a reduction in the odds of restenosis and clinical events when CCBs were added to standard therapy after percutaneous coronary intervention.

Differential effects of antihypertensive agents on electrocardiographic voltage: results from the Appropriate Blood Pressure Control in Diabetes (ABCD) trial.

BACKGROUND: Serial decline in electrocardiographic voltage in patients with increased left ventricular mass has been associated with a lower risk of cardiovascular events. METHODS: We studied 468 patients with diabetes mellitus and hypertension in the Appropriate Blood Pressure Control in Diabetes (ABCD) trial. Patients were randomized in a stratified design to receive initial treatment with either enalapril or nisoldipine and to either intensive or moderate treatment goals. We measured an electrocardiographic index for increased left ventricular mass, the adjusted Cornell voltage, serially by treatment group. The association between changes in electrocardiographic voltage and cardiovascular events was defined with Cox proportional hazards analysis. RESULTS: In 5 years of follow-up, the decline in adjusted Cornell voltage was significantly greater for patients treated with enalapril than for patients treated with nisoldipine (repeated measures analysis of variance P =.002). In the Cox proportional hazards model, treatment assignment (enalapril vs nisoldipine) was the strongest predictor of cardiovascular events, but the presence of coronary disease at baseline, the duration of diabetes mellitus, and change in voltage were also independent predictors of cardiovascular events. CONCLUSIONS: In the ABCD study, enalapril treatment was associated with a lower risk of myocardial infarction. The reduction in left ventricular mass as reflected by diminished electrocardiographic voltage may explain some, but not all, of the effect of enalapril in this study.

Effects of nisoldipine on myocardial ischemia during exercise and during daily activity.

The antiischemic properties of nisoldipine, a dihydropyridine calcium antagonist, were assessed in a multicenter, double-blind, placebo-controlled trial by repeated exercise testing and 72-hour ambulatory electrocardiographic monitoring in 82 patients with coronary artery disease. Patients with positive treadmill stress test results and greater than or equal to 2 ischemic episodes per 24 hours were included in this study. Administration of all chronic antiischemic medications except beta blockers were discontinued. During the first week all patients received placebo twice daily. During the second and third weeks, 41 patients received nisoldipine 10 mg and 41 patients received placebo twice daily. In the placebo group there were no changes in exercise parameters or in ambulatory electrocardiographic parameters. In the nisoldipine group, exercise duration increased from 403 to 448 seconds (p = 0.0035), time to 1 mm of ST depression increased from 224 to 298 seconds (p = 0.002), time to pain increased from 241 to 321 seconds (p = 0.01), and maximal ST depression was reduced from 2.6 to 2.3 mm (p = 0.002). Among the ambulatory electrocardiographic parameters in the nisoldipine group, only the number of episodes was reduced, from 14.4 to 11.6 (p = 0.0013) per patient. There was no significant reduction in total ischemic time (132 vs 120 minutes per patient). No significant side effects were observed. This is the largest clinical trial to date on the effects of nisoldipine on myocardial ischemia. The results indicate that nisoldipine was effective in improving all exercise parameters and only partially effective in suppressing ischemia during daily activity.

Heart period variability in patients with variant angina.

To clarify how cardiac autonomic control is affected in variant angina, we analyzed heart period variability in 35 patients with variant angina and in 19 control subjects. Patients with variant angina were divided into 1-vessel (group S, n = 17) and multivessel spasm groups (group M, n = 18) according to the site(s) of ST elevation on the electrocardiogram during attacks. The 24-hour Holter electrocardiogram recorded 6 +/- 3 days after the treatment with calcium antagonist was analyzed to avoid the possible influence of spontaneous attacks. In 5 group M patients, the electrocardiogram recorded 1 month after the treatment was also analyzed. There was no difference in the number of spontaneous attacks between groups S and M. The standard deviation of all normal RR intervals (SDNN) and the percentage of differences between adjacent normal RR intervals >50 (pNN50) in variant angina were slightly but significantly lower than those in controls. There were no differences in other indexes between variant angina and controls. When the data were analyzed separately in groups S and M, averaged RR intervals (MN), SDNN, pNN50, high-frequency power, and low-frequency power in group M were significantly lower than those in group S and controls, and the ratio of low- to high-frequency power in group M was significantly higher than that in group S and controls. There was no difference in any index between group S and controls. All abnormal indexes in group M recovered to levels similar to those in controls 1 month after the treatment. In conclusion, depressed cardiac vagal control and sympathetic-dominant sympathovagal interaction were present in patients with variant angina, especially in those with multivessel spasm.

Usefulness of Nisoldipine for prevention of restenosis after percutaneous transluminal coronary angioplasty (results of the NICOLE study). NIsoldipine in COronary artery disease in LEuven.

The NIsoldipine in COronary artery disease in LEuven (NICOLE) study investigates (1) whether nisoldipine, a dihydropyridine calcium antagonist, reduces the progression of minor coronary arterial lesions in the long term, and (2) whether it reduces the restenosis rate after successful percutaneous transluminal coronary angioplasty (PTCA). The NICOLE study is a single-center, randomized, double-blind trial in 826 patients, who underwent a successful PTCA. Nisoldipine 40 mg coat-core or placebo was started the morning after the procedure and continued for 3 years. All coronary arterial segments were measured on preprocedural angiogram and on the second follow-up angiogram at 3 years. On the first follow-up angiogram at 6 months only the dilated segments were measured. Although the study is still ongoing until the primary end point is reached, we report in this study the angiographic restenosis data as well as the clinical events observed at 6-month follow-up. The per-protocol population consisted of 646 patients. Restenosis, defined as a > or =50% loss of the initial gain (National Heart, Lung, and Blood Institute criterion IV) occurred in 49% and 55% of the 308 nisoldipine-treated and the 338 placebo-treated patients, respectively (p = NS). At follow-up, the rates of death and myocardial infarction were low and similar in both groups, but in the nisoldipine group, less patients required early coronary angiography (18% vs 26%, p = 0.006) and subsequent revascularization procedures (32% vs 41%, p = 0.057). Thus, nisoldipine did not significantly reduce the angiographic restenosis rate after PTCA, but reduced the number of repeat revascularization procedures, which may be due to its antianginal action.

Clinical and therapeutic implications of chronic left ventricular dysfunction in coronary artery disease.

In patients with myocardial ischemia, left ventricular dysfunction (LV) may arise from irreversible damage (cell death), myocardial stunning (postischemic dysfunction), or myocardial hibernation (persistent myocardial dysfunction at rest due to underperfusion). Chronic LV dysfunction usually refers to hibernating myocardium. However, stunning might also become chronic, producing persistent myocardial dysfunction. Clinical studies have demonstrated that many patients with coronary artery disease have subsequent recurring ischemic (symptomatic or silent) episodes at short intervals in the same area and that each episode may be followed by myocardial stunning. In these patients the myocardium may not recover fully between episodes and function may remain reversibly depressed for long periods or may even be clinically depressed. The recognition of both stunning and hibernation is very important clinically and therapeutically, since chronic LV dysfunction may have a negative effect on mortality and morbidity in patients with coronary artery disease. Moreover, both clinical states are potentially correctable. Pharmacologic intervention with beta blockers, angiotensin-converting enzyme inhibitors, or calcium antagonists might improve or protect hibernating myocardium. The acute hemodynamic effects of the dihydropyridine calcium antagonist nisoldipine have been investigated in patients with chronic LV dysfunction probably arising from hibernating myocardium. Nisoldipine was found to improve both left ventricular systolic and diastolic function without activating the adrenergic system. The improvement in systolic function may be due to a redistribution of coronary blood flow and to a slight reduction in afterload induced by nisoldipine. On the other hand, nisoldipine may improve diastolic function in these patients by an intrinsic mechanism, Reducing intracellular calcium overload or balancing intracellular calcium homeostasis in the ischemic areas.(ABSTRACT TRUNCATED AT 250 WORDS)

What does nisoldipine coat core (CC) add to current therapy that is clinically meaningful?

Nisoldipine coat core (CC) is a long-acting dihydropyridine with good tolerability. Ambulatory blood pressure measurements in a large, South African multicenter trial show that it has an excellent trough:peak ratio, and that it reduces the early morning rise in blood pressure without any tachycardia. Nisoldipine CC is an effective antihypertensive agent in both black and nonblack South African ethnic groups. In another South African study, regression of left ventricular hypertrophy was achieved in black patients with severe diastolic hypertension. Safety issues are discussed against the background of the testing of this drug in postinfarct left ventricular dysfunction.

Preservation of left ventricular performance with reduced ischemic dysfunction by intravenous nisoldipine.

The effect of intravenous nisoldipine on cardiac performance was examined during pacing-induced ischemia in 14 patients with coronary artery disease. The relative contributions of afterload reduction or prevention of myocardial ischemia were assessed using load-independent global (peak-systolic pressure/end-systolic volume) and regional (peak-systolic pressure/end-systolic radial length) "contractile" indexes. Nisoldipine decreased aortic pressure (predrug, 109 +/- 14 vs postdrug, 88 +/- 13 mm Hg, p less than 0.01) and prevented elevation of left ventricular end-diastolic pressure during rapid atrial pacing (predrug, 7.9 +/- 5.7 vs postdrug, -0.5 +/- 4.9 mm Hg, p less than 0.001). Resting cardiac index (predrug, 3.3 +/- 0.6 vs postdrug, 4.2 +/- 0.7 liters/min/m2, p less than 0.05), and left ventricular ejection fraction (predrug, 68.1 +/- 9.0 vs postdrug, 74.2 +/- 9.4%, p less than 0.05) increased after nisoldipine, which also prevented the deterioration in left ventricular ejection fraction (predrug, -8.1 +/- 7.9 vs postdrug, -1.0 +/- 3.7%, p less than 0.05) and fractional radial shortening (predrug, -8.7 +/- 13.1 vs postdrug, 3.7 +/- 16.4%, p less than 0.01) during rapid atrial pacing. Under these conditions, nisoldipine preserved myocardial function, as determined by global peak-systolic pressure/end-systolic volume (predrug, -0.82 +/- 0.39 vs postdrug, 0.17 +/- 1.54 mm Hg/ml, p less than 0.05) and regional (peak-systolic pressure/end-systolic radial length, predrug, -23.8 +/- 36.1 vs postdrug, 12.7 +/- 36.3 mm Hg/cm, p less than 0.01) "contractile" indexes. Intravenous nisoldipine maintains ventricular performance during rapid atrial pacing via a combination of systemic vasodilation and amelioration of ischemic myocardial dysfunction.

Antihypertensive therapy in type 2 diabetes: implications of the appropriate blood pressure control in diabetes (ABCD) trial.

As the population ages, the incidence of type 2 diabetes will increase as will the incidence of concomitant vascular complications. Hypertension substantially increases the risk of cardiovascular disease in patients with diabetes. Results from the recent Appropriate Blood Pressure Control in Diabetes (ABCD) trial demonstrated an advantage of an angiotensin-converting enzyme (ACE) inhibitor (enalapril) over a long-acting calcium antagonist (nisoldipine) with regard to the incidence of cardiovascular events over a 5-year follow-up period in hypertensive persons with type 2 diabetes. This trial was a prospective, randomized, blinded study comparing the effects of moderate blood pressure control (target diastolic pressure 80-89 mm Hg) with those of intensive control (target diastolic pressure 75 mm Hg) on the incidence and progression of diabetic vascular complications. The study also compared nisoldipine with enalapril as first-line antihypertensive therapy in terms of prevention and progression of complications of diabetes. In 470 hypertensive patients, the incidence of fatal and nonfatal myocardial infarctions was significantly (p = 0.001) higher among those receiving nisoldipine (n = 25) compared with those receiving enalapril (n = 5). Comparison with previous studies suggests that the difference observed between nisoldipine and enalapril resulted from a beneficial effect of enalapril rather than a deleterious effect from nisoldipine. Since these findings in the ABCD trial are based on a secondary endpoint, they require confirmation. Nevertheless, they suggest that ACE inhibitors should be the initial antihypertensive medication used in patients with type 2 diabetes and hypertension.

Effects of nisoldipine in silent myocardial ischemia after healing of acute myocardial infarction.

Silent myocardial ischemia occurring after acute myocardial infarction is classified as Cohn type II and has a frequency of 20-30% in all patients with acute myocardial infarction. Follow-up data of patients with either silent or anginal ischemia show a poor prognosis. Thus, all ischemic episodes occurring after myocardial infarction should be treated aggressively. Many multicenter studies have evaluated whether drug treatment can improve prognosis or protect from a nonfatal second attack. Calcium antagonists, especially those that increase heart rate, have not been considered as drugs of choice for this purpose, despite the many beneficial effects shown on myocardial tissue in experimental studies. In the study reported here, the effect of nisoldipine on postinfarction silent myocardial ischemia was evaluated by ambulatory left ventricular function monitoring. Ten patients were selected for study who showed silent myocardial ischemia after their first acute infarction. Blood pressure fell significantly (p < 0.05) after 4 weeks of treatment with nisoldipine (5-10 mg/day), but heart rate showed no change at rest. Exercise time improved (p < 0.05), with increased peak double products. During exercise, there was no significant change in end-diastolic volume but there was a marked improvement in end-systolic volume, and at the submaximal point the ejection fraction was significantly (p < 0.05) increased. Ejection fraction at rest also improved. The deterioration in ejection fraction due to dipyridamole was ameliorated by nisoldipine. Ejection fraction and blood pressure improved during the calculation test, and work performance also improved.(ABSTRACT TRUNCATED AT 250 WORDS)