dihydropyridines and Coronary-Disease

Japanese Society of Hypertension Committee published Guidelines for the Management of Hypertension in 2009 (JSH2009). The first choices of antihypertensive drugs are calcium channel blockers, angiotensin II receptor blockers, angiotensin converting enzyme inhibitors, diuretics, and beta-adrenergic blockers. Because dihydropyridine calcium channel blockers have the greatest hypotensive efficacy without affecting organ blood flow, they are indicated in the patients with complications and the aged. Positive indications of calcium channel blockers are left ventricular hypertrophy, tachycardia (non-dihydropyridine), angina pectoris, chronic phase of cerebrovascular disease, and elderly patients. Patients with bradycardia are contraindicated by non-dihydropyridine calcium channel blockers.

Topics: Antihypertensive Agents; Calcium Channel Blockers; Cerebrovascular Disorders; Coronary Disease; Diabetes Complications; Dihydropyridines; Evidence-Based Medicine; Humans; Hypertension; Kidney Diseases; Practice Guidelines as Topic

GROUPS OF CALCIUM CHANNEL BLOCKERS: The calcium channel blockers comprise a heterogeneous group of drugs. From both pharmacological and clinical points of view, they can be divided into three groups: the dihydropyridines, the phenylalkylamines and the benzothiazepines. REASONS FOR DIFFERENCES: There are important clinical and functional differences between the three groups. This may be explained by the fact that these families bind at different sites to the calcium channel. In this review, the major differences between the three groups are discussed, with an emphasis on verapamil.

Topics: Antihypertensive Agents; Arrhythmias, Cardiac; Calcium Channel Blockers; Coronary Disease; Dihydropyridines; Drug Therapy, Combination; Humans; Hypertension; Sympathetic Nervous System; Verapamil

Plasma drug concentration and hemodynamic responses to dihydropyridines correlate closely. Differences in pharmacokinetic profile lead therefore to marked differences in blood pressure (BP) control over 24 h and sympathetic tone and side effects, and also appear to determine effects on left ventricular hypertrophy (LVH) and outcome in patients with coronary artery disease (CAD). Fast-absorbed and short-acting agents (eg, nifedipine capsules) cause intermittent control of BP with rapid decreases in BP after each dose. This rapid fall in BP causes, after each dose, an increase in sympathetic activity, which over subsequent hours gradually disappears. In contrast, long-acting formulations, such as nifedipine gastrointestinal therapeutic system (GITS), or agents with a long elimination half-life, such as amlodipine, provide, during long-term treatment, stable hemodynamic and BP effects with little or no activation of the sympathetic nervous system. Intermittent hemodynamic responses and the resulting sympathetic hyperactivity with the rapid-acting agents are possible explanations for outcome of treatment as it relates to regression of LVH and cardiac events in patients with CAD.

Topics: Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Coronary Disease; Dihydropyridines; Humans

The purpose of this study was to assess the effect of the dose of nifedipine, a dihydropyridine calcium antagonist, on the increased risk of mortality seen in the randomized secondary-prevention trials and to review the mechanisms by which this adverse effect might occur.. We restricted the dose-response meta-analysis to the 16 randomized secondary-prevention trials of nifedipine for which mortality data were available. Recent trials of any calcium antagonist and formulation were also reviewed for information about the possible mechanisms of action that might increase mortality. Overall, the use of nifedipine was associated with a significant adverse effect on total mortality (risk ratio, 1.16, with a 95% CI of 1.01 to 1.33). This summary estimate fails to draw attention to an important dose-response relationship. For daily doses of 30 to 50, 60, and 80 mg, the risk ratios for total mortality were 1.06 (95% CI, 0.89 to 1.27), 1.18 (95% CI, 0.93 to 1.50), and 2.83 (95% CI, 1.35 to 5.93), respectively. In a formal test of dose response, the high doses of nifedipine were significantly associated with increased mortality (P = .01). While the mechanism of this adverse effect is not known, there are several plausible explanations, including the established proischemic effect, negative inotropic effects, marked hypotension, recently reported prohemorrhagic effects attributed to antiplatelet and vasodilatory actions of calcium antagonists, and possibly proarrhythmic effects.. In patients with coronary disease, the use of short-acting nifedipine in moderate to high doses causes an increase in total mortality. Other calcium antagonists may have similar adverse effects, in particular those of the dihydropyridine type. Long-term safety data are lacking for most calcium antagonists.

Topics: Angina Pectoris; Arrhythmias, Cardiac; Calcium Channel Blockers; Confidence Intervals; Coronary Disease; Depression, Chemical; Dihydropyridines; Dose-Response Relationship, Drug; Hemorrhage; Humans; Hypotension; Myocardial Contraction; Myocardial Ischemia; Nifedipine; Odds Ratio; Renin-Angiotensin System; Sympathetic Nervous System; Time Factors

To review the pharmacology, pharmacokinetic disposition, dose recommendations, adverse effects, drug interactions, and efficacy of isradipine in patients with hypertension or ischemic heart disease.. Data from scientific literature were extracted, evaluated, and summarized for presentation. A MEDLINE search was conducted using the following indexing terms: isradipine, calcium-channel blockers, hypertension, and angina pectoris. Experiences from studies evaluating isradipine reported in the form of articles, abstracts, or proceedings involving patients or healthy subjects were considered for inclusion.. Special consideration was given to clinical studies that had been designed in a blind, randomized fashion. Studies that compared the effectiveness and safety of isradipine with another antihypertensive or antianginal agent or placebo were included.. Data from human studies published in the English language were evaluated. Trials were evaluated according to sample size, design, and adequacy of description of therapeutic response.. Isradipine is a new dihydropyridine calcium-channel blocker that appears to exert less negative inotropic activity than nifedipine and to selectively inhibit sinoatrial conduction. Pharmacokinetic parameters are quite variable and considerably more work is needed to better describe the kinetic disposition of isradipine. Antihypertensive efficacy has been demonstrated extensively in a number of short-term trials. Antianginal efficacy also has been observed in a few short-term trials and is comparable to that of isosorbide dinitrate and nifedipine. Extensive experience with isradipine is minimal and no clear-cut advantages over existing compounds have been noted thus far.. The place of isradipine in the therapy of hypertension and myocardial ischemia is unclear and its routine use cannot yet be recommended based solely on clinical grounds.

Topics: Angina Pectoris; Calcium Channel Blockers; Clinical Trials as Topic; Coronary Disease; Dihydropyridines; Drug Interactions; Humans; Hypertension; Isradipine; Kidney

Synthetic calcium channel blockers (Ca2+ entry blockers or antagonists) have been reported to induce relaxation of smooth muscle which is not thought to be mediated by any specific action(s) on receptor sites. In addition, it has been suggested that Ca2+ channel blockers increases blood flow in a number of organ regions, including mesenteric, femoral, renal, cerebral and coronary vasculatures, via a direct action on vascular tone by inhibiting Ca2+ influx across the vascular smooth muscle membranes. Such information has prompted clinical studies with the use of Ca2+ channel blockers in the treatment of a wide variety of cardiovascular disorders. The questions, to be answered, however, are whether any of the newly-designed channel blockers can actively produce vasodilatation of arterioles and venules in regional microvasculatures, and these synthetic agents are safe and therapeutically effective. In addition, can one design site-specific (e.g., cerebral vs. coronary vasodilator) Ca2+ channel blockers. But, since the body has a natural Ca2+ antagonist, viz., magnesium ions (Mg2+), one must ask whether such divalent cations act as peripheral vasodilators and are effective as therapeutic agents. The studies reviewed herein: compare the effects of several different Ca2+ channel blockers on resistance and capacitance vessels in different regional microvasculatures (i.e., mesenteric, skeletal muscle, pial) within a single species, namely the rat, by high-resolution TV microscopy, and demonstrate the rationale, effects and mechanisms of action of Mg2+ on regional blood vessels. These data show some of the new, novel synthetic Ca2+ channel blockers (i.e., nisoldipine, nitrendipine, nimodipine) can: exert effects on both arterioles and venules in certain vasculatures; be designed to exert a wide range of potencies; and be designed to act selectively at regional microvasculatures. In addition, the data presented are consistent with the hypothesis that Mg2+ exerts a regulatory role in vascular tone, vascular reactivity and vascular resistance. Certain vascular diseases associated with a Mg2+-deficiency appear to be amenable to treatment with Mg2+.

Topics: Anesthesia; Animals; Arterioles; Blood Pressure; Calcium; Calcium Channel Blockers; Cell Membrane Permeability; Cerebrovascular Circulation; Cerebrovascular Disorders; Coronary Disease; Diabetes Mellitus; Dihydropyridines; Female; Humans; Hypertension; Ketamine; Magnesium; Magnesium Deficiency; Microcirculation; Muscle, Smooth, Vascular; Muscles; Nifedipine; Nisoldipine; Nitrendipine; Nutritional Requirements; Pentobarbital; Pre-Eclampsia; Pregnancy; Pyridines; Rats; Vasoconstrictor Agents; Vasodilator Agents; Venules

Impaired left ventricular (LV) diastolic and long axis functions are common in arterial hypertension and stable angina pectoris patients despite normal LV ejection fraction. Data concerning the effect of calcium channel blockers (CCB) on the LV long axis function in this context are lacking.. Fifty-nine hypertensive patients with associated coronary artery disease (stable angina pectoris) and isolated diastolic dysfunction were randomized to receive amlodipine (30 patients) or lacidipine (29 patients) for 4 weeks. Clinical investigation, exercise testing, echocardiography were performed before and after the active treatment period. LV diastolic function was analysed from transmitral flow using Doppler echocardiography. Mitral annulus motion was investigated for LV long axis function analysis using 2-D guided M-mode echocardiography (amplitudes of motion) and pulsed wave tissue Doppler (velocities). Amlodipine and lacidipine affected LV diastolic and long axis functions differently: during treatment with amlodipine isovolumic relaxation time (IVRT) and deceleration time of LV early filling (DT) decreased (IVRT--from 93 +/- 19 ms to 79 +/- 15 ms, DT--from 206 +/- 36 ms to 188 +/- 27 ms; p < 0.05), early diastolic velocity of mitral annulus motion (E') increased (from 10.0 +/- 1.9 cm/s to 10.8 +/- 1.8 cm/s after treatment; p < 0.05). Lacidipine did not significantly change these parameters (IVRT-- 88 +/- 15 ms before, 87 +/- 13 ms after treatment, DT--214 +/- 34 ms and 218 +/- 42 ms, E'-- 10.4 +/- 1.5 cm/s and 10.6 +/- 1.5 cm/s, respectively). More favourable effects of CCB on LV long axis function was found in patients with post-systolic shortening.. Amlodipine can improve diastolic and long axis functions of the left ventricle in patients with arterial hypertension and stable angina pectoris.

Topics: Aged; Amlodipine; Angina Pectoris; Calcium Channel Blockers; Coronary Angiography; Coronary Disease; Diastole; Dihydropyridines; Exercise Test; Female; Humans; Hypertension; Male; Middle Aged; Mitral Valve; Ultrasonography, Doppler; Ventricular Function, Left

Potassium channel openers and blockers, which belong to a novel class of vasodilator drugs and to the class of specific bradycardic substances, are potential new antianginal drugs. Experimental findings in vivo suggest that bimakalim is a new substance characterized as ATP-sensitive K+ channel openers, since it exerts preferential vasodilation of the collateral circulation of the coronary vasculature and both leads to increase blood flow to ischemic areas and to attenuate the ST segment elevation caused by regional ischemia in the canine heart. Opening of KATP increases the conductivity of potassium ions which results in hyperpolarization of smooth muscle membranes, thus producing vasodilation. Tedisamil is a new bradycardic agent proven to exert antiischemic and antiarrhythmic effects by blockade of the cellular cardiac repolarization K+ currents as well as of multiple neuronal and vascular K+ currents (Ito, Ik, and K+ATP). Using right heart catheterization and exercise tolerance tests, we investigated the hemodynamic, antiischemic and neurohumoral effects of bimakalim and tedisamil in patients with angiographically proven coronary artery disease, stable angina pectoris and reproducible ST segment depression during exercise. In 50 patients with coronary artery disease, the hemodynamic and antiischemic effects of a single oral dose bimakalim of 0.1 mg, 0.3 mg and 0.6 mg were compared to placebo. In a dose-finding baseline-controlled study, a comparable collective was examined for the effects of acute i.v. administration of tedisamil 0.1, 0.2, 0.3 and 0.4 mg/kg bw. A subgroup of 8 patients receiving 0.3 mg/kg bw tedisamil i.v. was compared with a similar group of 14 patients who had received esmolol (i.v. bolus of 500 micrograms/kg, maintenance dose 200 micrograms/kg/min) and gallopamil (initial dose 0.025 mg/kg, maintenance dose 0.0005 mg/kg/h) in a second intra-individual comparison. Furthermore, in 48 patients, short-term (6 days) effects of tedisamil, 2 times 100 mg orally, were compared to 2 times 50 mg atenolol treatment. With a single oral dose of bimakalim antianginal and/or antiischemic effects were lacking, increased doses, however, induced changes in hemodynamics typical of vasodilation, i.e., a significant decrease in systolic blood pressure and a secondary chronotropic response. In contrast to bimakalim, tedisamil produced antiischemic effects and was found to have favorable hemodynamic, neurohumoral and antiischemic effects in comparison to t

Topics: Adrenergic beta-Antagonists; Adult; Aged; Analysis of Variance; Angina Pectoris; Anti-Arrhythmia Agents; Atenolol; Benzopyrans; Bridged Bicyclo Compounds, Heterocyclic; Calcium Channel Blockers; Cardiotonic Agents; Coronary Disease; Cyclopropanes; Dihydropyridines; Electrocardiography; Exercise Test; Gallopamil; Hemodynamics; Humans; Middle Aged; Myocardium; Oxygen Consumption; Potassium Channel Blockers; Potassium Channels; Propanolamines; Time Factors; Vasodilator Agents

The calcium antagonist lacidipine has been shown to be highly vasoselective and to improve myocardial perfusion in hypertensive patients. However, its effects on coronary artery vasomotility and on post-stenotic coronary flow reserve in patients with atherosclerotic heart disease are unknown.. This study was designed to investigate the acute direct effects of repeated infusions of lacidipine on epicardial coronary artery vasomotion and on post-stenotic coronary artery blood flow in patients with stable angina pectoris and angiographic evidence of coronary heart disease.. In 8 patients with stable angina and moderate to severe stenosis of the left coronary artery, measurements of epicardial dimensions (quantitative angiography) and of coronary blood flow (Doppler guidewire) distal to a stenosis were performed at baseline and after 3 repeated intracoronary boluses of 12 microg of lacidipine. Results were compared with those obtained after 10 mg of intracoronary papaverine.. The intracoronary administration of lacidipine was well tolerated, without any adverse effects. Lacidipine significantly increased the minimal luminal diameter of the lesion (peak relative increase of 43.7%), without significant changes in heart rate and systolic aortic pressure. Intracoronary lacidipine caused a dose-dependent increase in coronary flow reserve. Maximal vasodilatory effects were equivalent to those obtained with intracoronary papaverine.. These results suggest that lacidipine acts directly as a potent vasodilator in stenotic epicardial vessels and improves myocardial perfusion distal to a moderately severe stenosis in patients with stable angina.

Topics: Aged; Angina Pectoris; Antihypertensive Agents; Calcium Channel Blockers; Coronary Circulation; Coronary Disease; Coronary Vessels; Dihydropyridines; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Pilot Projects; Vasomotor System

To analyze therapy in patients with arterial hypertension (AH) in 20102020.. Data of hypertensive patients observed in primary health care, entered into the base of hypertension registry for 20102020 years in the whole group (n=44 653) and in a separate subgroup of hypertensive patients in the absence of: ischemic heart disease, a history of myocardial infarction, chronic heart failure (n=20 569).. About 80% of hypertensive patients are patients of high and very high risks (from 2010 to 2020, the proportion of very high cardiovascular risk (CVR) increased from 18.1 to 57.3%). The number of hypertensive patients with a history of myocardial infarction increased in 5 times, in 3 times with ischemic heart disease and with chronic heart failure. The number of prescribed drugs increased: mineralocorticoid receptor antagonist (in 5.8 times), loop diuretics (in 7.2) angiotensin receptor blockers (in 3 times), b-adrenoblockers, calcium channel blockers of the dihydropyridine series, thiazide-like diuretics in 2 times. Patients at high and very high risk are more likely reached target blood pressure values. Angiotensin-converting enzyme inhibitors were prescribed in more than 70% of patients with hypertension and the absence of coronary heart disease, chronic heart failure, history of myocardial infarction; the prescription of b-adrenoblockers, angiotension receptor blockers, thiazide-like and loop diuretics increased.. The proportion of more severe and comorbid patients has increased in observed in primary health care patients with AH over a 10-year period (20102020). This was probably the main factor of increasing antihypertensive therapy and prescribing drugs with additional indications and improving the achievement of target blood pressure in patients with high and very high cardiovascular risk.. Цель. Анализ лечения больных артериальной гипертонией (АГ) в 20102020 гг. Материалы и методы. Проведен анализ медицинских данных 44 653 больных АГ, наблюдавшихся в первичном звене здравоохранения, аккумулированных в регистре АГ за период 20102020 гг. и в подгруппе, включившей 20 569 больных АГ без диагностированных сердечно-сосудистых заболеваний (ССЗ) ишемической болезни сердца, инфаркта миокарда в анамнезе, хронической сердечной недостаточности. Результаты. За 10-летний период среди больных АГ, наблюдаемых в условиях первичного звена здравоохранения, 80% больных были высокого и очень высокого сердечно-сосудистого риска (ССР); с 2010 по 2020 г. регистрируется увеличение доли больных очень высокого ССР с 18,1 до 57,3%. В 5 раз увеличилось число больных АГ, перенесших инфаркт миокарда; в 3 раза ишемическую болезнь сердца и хроническую сердечную недостаточность. Отмечено увеличение назначаемых препаратов: антагонистов минералокортикоидных рецепторов в 5,8 раза, петлевого диуретика в 7,2, блокаторов рецепторов ангиотензина в 3 раза, -адреноблокаторов, дигидропиридиновых блокаторов кальциевых каналов и тиазидоподобных диуретиков в 2 раза. У больных высокого и очень высокого риска чаще достигался целевой уровень артериального давления. У больных АГ без ССЗ (ишемическая болезнь сердца, хроническая сердечная недостаточность, перенесенный инфаркт миокарда) ингибиторы ангиотензинпревращающего фермента назначались более чем 70% больных; чаще стали назначаться -адреноблокаторы, блокаторы рецепторов ангиотензина, тиазидоподобный диуретик, петлевой диуретик. Заключение. В структуре больных АГ, наблюдаемых в первичном звене здравоохранения за 10-летний период, увеличилась доля более тяжелых больных АГ, у которых диагностированы ССЗ. Это, вероятно, явилось основным фактором усиления антигипертензивной терапии и назначения препаратов с учетом дополнительных показаний, что, по-видимому, улучшило достижение целевого артериального давления у больных высокого и очень высокого ССР.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Coronary Disease; Dihydropyridines; Diuretics; Heart Failure; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Sodium Potassium Chloride Symporter Inhibitors; Thiazides

We investigated the effects of an L-type and N-type Ca(2+) channel blocker, cilnidipine, on neurally mediated chronotropic responses to clarify the anti-autonomic profile of cilnidipine in anesthetized dogs. Pretreatment with cilnidipine (0.3, 1.0 and 3.0 microg/kg, i.v.), which decreased mean blood pressure by 5 to 31 mm Hg, inhibited the changes in heart rate and plasma norepinephrine concentration induced by bilateral carotid artery occlusion, whereas it had no effect on vagal nerve stimulation-induced bradycardia. These results suggest that antihypertensive and antisympathetic doses of cilnidipine fail to influence chronotropic responses mediated by parasympathetic nerve activation in the in vivo canine heart.

Topics: Anesthesia, General; Animals; Antihypertensive Agents; Blood Pressure; Bradycardia; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Carotid Arteries; Coronary Disease; Dihydropyridines; Dogs; Electric Stimulation; Heart; Heart Rate; Male; Norepinephrine; Vagus Nerve

We investigated the effects of administration of non-hypotensive doses of ATP-sensitive K+ channel (KATP) openers (nicorandil and bimakalim), and a specific mitochondrial KATP channel blocker (5-hydroxydecanoate) prior to and during coronary occlusion as well as prior to and during post-ischemic reperfusion on survival rate, ischemia-induced and reperfusion-induced arrhythmias and myocardial infarct size in anesthetized albino rabbits. The thorax was opened in the left fourth intercostal space and after pericardiotomy the heart was exposed. In Part I, occlusion of the left main coronary artery and hence, myocardial ischemia-induced arrhythmias were achieved by tightening a previously placed loose silk ligature for 30 min. In Part II, arrhythmias were induced by reperfusion following a 20-min ligation of the left main coronary artery. In Part I, early intravenous infusion of nicorandil (100 microg/kg bolus + 10 microg/kg per min) or bimakalim (3 microg/kg bolus + 0.1 microg/kg per min) just prior to and during ischemia increased survival rate (75% and 67% vs. 60% in the control group), significantly decreased the incidence and severity of life-threatening arrhythmias and significantly decreased myocardial infarct size. In Part II also, early intervention by intravenous infusion of nicorandil (100 microg/kg bolus + 10 microg/kg per min) or bimakalim (3 microg/kg bolus + 0.1 microg/kg per min) just before and during ischemia increased survival rate (86% and 75% vs. 55% in the control group), significantly decreased the incidence and severity of life-threatening arrhythmias and significantly decreased myocardial infarct size. However, late intravenous administration of nicorandil or bimakalim at the onset and during reperfusion did not increase survival rate nor confer any antiarrhythmic or cardioprotective effects. The antiarrhythmic and cardioprotective effects of both nicorandil and bimakalim were abolished by pretreating the rabbits with 5-hydroxydecanoate (5 mg/kg, i.v. bolus), a selective mitochondrial KATP channel blocker. In conclusion, intervention by intravenous administration of nicorandil and bimakalim (through the activation of mitochondrial KATP channels), increased survival rate and exhibited antiarrhythmic and cardioprotective effects during coronary occlusion and reperfusion in anesthetized rabbits when administered prior to and during coronary occlusion.

Topics: Animals; Antihypertensive Agents; Arrhythmias, Cardiac; Benzopyrans; Blood Gas Analysis; Coronary Disease; Decanoic Acids; Dihydropyridines; Drug Combinations; Hemodynamics; Hydroxy Acids; Male; Myocardial Ischemia; Nicorandil; Potassium Channels; Rabbits; Reperfusion Injury; Survival Rate

Recently, there have been some reports indicating that calcium antagonists induce a reflex increase in sympathetic activity, triggering cardiac events, especially in coronary artery disease (CAD) patients. In this study, we assessed heart rate (HR) variability (HRV) using power spectral analysis of the 24-h RR interval in 25 hypertensive outpatients with CAD treated with nifedipine. We compared blood pressure (BP), HR, and HRV variation in the same patients substituting benidipine (long-acting) for nifedipine (intermediate-acting). There were no significant differences in 24-h, daytime, nighttime, and morning BP between the nifedipine phase and the benidipine phase. HRV parameters (LF: low frequency power, HF: high frequency power, LF/HF ratio) also showed no significant differences in 24-h, daytime, nighttime, and morning LF, HF, and LF/HF ratio between the nifedipine phase and the benidipine phase. Blood pressure, HR, and HRV parameters, except the LF component from 2 to 4 h after nifedipine administration (the most effective duration), showed no differences compared to before administration. The LF component after the nifedipine administration was lower than before administration. In conclusion, in hypertensive patients with CAD, whose BP levels were well-controlled by twice-daily use of intermediate-acting nifedipine, switching from nifedipine to a long-acting calcium antagonist, benidipine, maintained well-controlled BP levels to a similar degree, but it may not have additional benefit in sympatho-vagal balance.

Topics: Autonomic Nervous System; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Circadian Rhythm; Coronary Disease; Delayed-Action Preparations; Dihydropyridines; Electrocardiography, Ambulatory; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Nifedipine; Treatment Outcome

Fast-absorbed and short-acting dihydropyridines (e.g., nifedipine capsules) cause intermittent hemodynamic effects associated with sympathetic hyperactivity. In contrast, long-acting dihydropyridines, such as nifedipine GITS and amlodipine, provide, during chronic treatment, stable hemodynamic effects with little or no activation of the sympathetic nervous system. This markedly different pattern of hemodynamic changes may explain why the short-acting drugs cause little to no regression of left ventricular hypertrophy, may make angina worse, and may negatively affect cardiac outcome, whereas the long-acting drugs decrease LV mass as anticipated from the fall in blood pressure and, at least in stable coronary artery disease, produce an outcome comparable with beta-blockers. In hypertension, beta-blocker treatment appears to be associated with a short fall in positive outcome, perhaps in part related to increased rates of sudden death. Such an adverse outcome may also be due to sympathetic hyperactivity, possibly during treatment via cardiac alpha-receptors, but also during the common short periods of noncompliance due to actual increased sympathetic responses. For both drug classes, we suggest that long-acting agents be considered, providing therapeutic coverage well beyond the normal dosing interval.

Topics: Adrenergic beta-Antagonists; Adult; Aged; Calcium Channel Blockers; Coronary Disease; Dihydropyridines; Female; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Nifedipine; Sympathetic Nervous System

Topics: Calcium Channel Blockers; Coronary Disease; Delayed-Action Preparations; Dihydropyridines; Drug Approval; Germany; Humans; Hypertension; Structure-Activity Relationship

The effects of intravenous elgodipine, a new second-generation dihydropyridine calcium antagonist, on hemodynamics and coronary artery diameter were investigated in 15 patients undergoing cardiac catheterization for suspected coronary artery disease. Despite a significant decrease in systemic blood pressure, elgodipine infused at a rate of 1.5 micrograms/kg/min over a period of 10 minutes did not affect heart rate and left ventricular end-diastolic pressure. The contractile responses during isovolumic contraction showed a slight but significant increase in maximum velocity (56 +/- 10 to 60 +/- 10 seconds-1; p less than 0.005), whereas the time constant of early relaxation was shortened from 49 +/- 11 to 44 +/- 9 ms (p less than 0.05). Coronary sinus and great cardiac vein flow increased significantly by 15 and 26%, respectively. As mean aortic pressure decreased, a significant decrease in coronary sinus (-27%) and great cardiac vein (-28%) resistance was observed, while the calculated myocardial oxygen consumption remained unchanged. In all, 69 coronary segments (including 13 stenotic segments) were analyzed quantitatively using computer-assisted quantitative coronary angiography. A significant increase in mean coronary artery diameter (2.27 +/- 0.53 to 2.48 +/- 0.53 mm; p less than 0.000001), as well as in obstruction diameter, (1.08 +/- 0.29 to 1.36 +/- 0.32 mm; p less than 0.02), was observed. The results demonstrate that elgodipine, in the route and dose described, induces significant vasodilatation of both coronary resistance and epicardial conductance vessels, without adverse effects on heart rate, myocardial oxygen demand and contractile indexes.

Topics: Adult; Aged; Analysis of Variance; Cineangiography; Coronary Disease; Dihydropyridines; Female; Heart Rate; Humans; Infusions, Intravenous; Male; Middle Aged; Myocardial Contraction; Vasodilator Agents; Ventricular Function, Left

It is difficult to associate the ATP-sensitive potassium (K-ATP) channel of cardiac muscle with hypoxia/ischemia induced action potential shortening because this occurs before intracellular ATP falls to levels associated in vitro with channel opening. This leaves the cardiac K-ATP channel without any obvious physiological function. We have quantitatively examined the relationship between action potential duration and K-ATP channel activity in enzymatically isolated ventricular myocytes of the guinea-pig. In whole-cell voltage-clamp recording experiments when the K-ATP channel opener SR 44866 (2-10 microM) stimulated an outward membrane current greater than 50 pA at 0 mV membrane potential (the equivalent of 30 open K-ATP channels or 1% of the cell K-ATP channel population) action potential duration was reduced by more than 50%. In the majority of cell-attached membrane patch recordings metabolic inhibition stimulated K-ATP channel open probability of 1-2% which continued for long periods (7-25 min) before cell contracture and coincident major K-ATP channel activation (open probability 65%). Our quantitative analysis thus shows that physiologically relevant activity of K-ATP channels in cardiac muscle is confined to a very small percentage of the possible cell K-ATP current and thus intracellular ATP would not have to fall very far before the opening of K-ATP channels would influence cardiac excitability.

Topics: Adenosine Triphosphate; Animals; Benzopyrans; Coronary Disease; Dihydropyridines; Guinea Pigs; Heart; In Vitro Techniques; Membrane Potentials; Myocardium; Potassium; Potassium Channels

A comparison was made of the anti-ischemic effects of dihydropyridine calcium antagonists in isolated globally ischemic rat hearts. Pretreatment with amlodipine, nifedipine, nitredipine, or nisoldipine reduced reperfusion enzyme (lactate dehydrogenase) release and contracture after 25 min of global ischemia and 30 min of reperfusion. Increasing concentrations of all compounds resulted in proportionally smaller reductions in the severity of ischemia, with larger decreases in nonischemic tissue contractility occurring. Reperfusion function was significantly improved at 30 min with nifedipine only; however, at 60 min reperfusion function was significantly improved for all except nisoldipine. Washout data from nonischemic hearts (rate of disappearance of cardiodepressant effects) showed that the dihydropyridines washed out in the following order (fastest to slowest): nifedipine greater than nitrendipine greater than nisoldipine greater than amlodipine. Thus, these dihydropyridines are anti-ischemic, though at higher concentrations cardiodepressant effects increase disproportionately. Differences in washout also effect the ability of these compounds to improve reperfusion function.

Topics: Animals; Anti-Arrhythmia Agents; Blood Pressure; Calcium Channel Blockers; Coronary Disease; Depression, Chemical; Dihydropyridines; Heart; In Vitro Techniques; L-Lactate Dehydrogenase; Male; Myocardial Reperfusion; Rats; Rats, Inbred Strains

To characterize the effects of a new calcium antagonist of the dihydropyridine type, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic++ + acid methyl 6-(5-phenyl-3-pyrazolyloxy) hexyl ester (CV-159) on the cardiovascular system, experiments were performed in the anesthetized open-chest dogs and in the heart-lung preparation with a support dog in comparison with those of nicardipine. In the anesthetized dog CV-159 (1-30 micrograms/kg) produced a dose-related decrease in mean blood pressure with a decrease in total peripheral resistance, and an increase in coronary flow. There was a reflex increase in heart rate, aortic flow and left ventricular dP/dtmax. Nicardipine (1-30 micrograms/kg) produced qualitatively similar changes in these parameters, although the onset of action was quicker and the duration shorter. Hypotensive effects of CV-159 were approximately three times less potent than those of nicardipine. In doses above 3 micrograms CV-159 produced a long-lasting increase in coronary flow and slight negative inotropic and chronotropic effects in the heart-lung preparation. In doses above 1 microgram nicardipine produced an increase in coronary flow without producing any change in the cardiac functions. The increase in coronary flow produced by these two compounds was not associated with an increase in myocardial oxygen consumption. Studies conducted with 31P-NMR in the isolated perfused heart preparation of the rat demonstrated no improvement of the ischemic derangement of the myocardial energy metabolism with doses of CV-159 and nicardipine producing an increase in coronary flow rate, but no change in myocardial oxygen demand as assessed by heart rate X left ventricular pressure.

Topics: Animals; Blood Pressure; Calcium Channel Blockers; Chemical Phenomena; Chemistry; Coronary Circulation; Coronary Disease; Dihydropyridines; Dogs; Dose-Response Relationship, Drug; Energy Metabolism; Esters; Female; Heart; Heart Rate; Hemodynamics; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Male; Nicardipine; Rats