Effects of Long-Term Nitroglycerin Treatment on Endothelial Nitric Oxide Synthase (NOS III) Gene Expression, NOS III–Mediated Superoxide Production, and Vascular NO Bioavailability

Abstract —Long-term nitroglycerin (NTG) treatment has been shown to be associated with cross-tolerance to endothelium-dependent vasodilators. It may involve increased production of reactive oxygen species (such as superoxide, O 2 ·− ) that rapidly inactivate the nitric oxide (NO) released from the endothelial cells. It remains to be elucidated, however, whether long-term treatment with NTG alters the activity and expression of the endothelial NO synthase (NOS III) and whether this enzyme can contribute to O 2 ·− formation. We studied the influence of long-term NTG treatment on the expression of NOS III as assessed by RNase protection assay and Western blot. Tolerance was measured ex vivo i…

Diagnostic and prognostic performance of myeloperoxidase plasma levels compared with sensitive troponins in patients admitted with acute onset chest pain.

Background— Activation of leukocytes with release of myeloperoxidase (MPO) has been linked to acute coronary disease. To date, studies investigating the diagnostic and prognostic performance of circulating MPO in patients with chest pain (CP) are mainly retrospective, of low size, and lack a cut-off value for MPO. Herein, we prospectively assess the diagnostic and prognostic properties of MPO compared with sensitive troponin I (sTNI) in patients admitted to the emergency room with CP. Methods and Results— One thousand, eight hundred and eighteen consecutive patients (mean age, 61.4±13.5 years; 33.6% female) admitted for CP underwent determination of MPO, sTnI, and B-natriuretic peptide pla…

Determination of alinidine in human plasma by high-performance liquid chromatography.

Dibutyryl cyclic AMP and adrenaline increase contractile force and 45Ca uptake in mammalian cardiac muscle

The effects of dibutyryl cyclic AMP (DB-AMP; 10−3M) and adrenaline (2.2×10−6 M) on contractile force, 45Ca uptake, and total myocardial Ca concentration were investigated in electrically driven left auricles isolated from rat hearts. The experiments were performed at an extracellular Ca concentration of 0.45 mM and at low frequency of stimulation (15 beats/min). 45Ca exposure was 5 min. Under the conditions used, both drugs increased contractile force and enhanced 45Ca uptake (expressed as relative specific activity) by about 30% (DB-AMP) and 40% (adrenaline), respectively. Thus, the results provide evidence that the effects of adrenaline on 45Ca uptake in mammalian cardiac muscle can be mi…

Interruption of the enterohepatic circulation of phenprocoumon by cholestyramine

The effect of cholestyramine (12 gm/day divided into 3 doses) on the pharmacokinetics and pharmacodynamics of a single intravenouse dose (30 mg) of phenprocoumon was studied in 6 normal subjects. Cholestyramine treatment led to an increase in the rate of elimination of phenprocoumon in all. Total clearance increased 1.5- to 2-fold. The total anticoagulant effect per dose was considerably reduced during treatment with cholestyramine. Binding studies in vitro showed that phenprocoumon is strongly bound to cholestyramine and that at a given cholestyramine concentration the percentage of phenprocoumon bound remained constant over a large concentration range of phenprocoumon. The results suggest…

Response of isolated human ventricular myocardium to cyclic AMP and its dibutyryl derivative.

The contractile responses to c-AMP and DB-c-AMP were studied in isolated electrically stimulated human papillary muscle strips. C-AMP (1×10−4 to 1×10−3 M) had no effect on contractile force in all of 6 human papillary muscle preparations studied. In contrast, DB-c-AMP (10−4 to 5×10−3 M) produced a concentration-dependent and reversible positive inotropic effect which was associated by a decrease in time to peak force and in relaxation time and which was not inhibited by 10−6 M propranolol. The possibility of a clinical applicability of DB-c-AMP is discussed.

Stimulatory effects of DB-c-AMP and adrenaline on myocardial contraction and 45Ca exchange. Experiments at reduced calcium concentration and low frequencies of stimulation.

The effects of adrenaline (2.2×10−6 M) and cyclic N6-2′-O-dibutyryl-adenosine-3′,5′-monophosphate (DB-c-AMP; 10−3 M) on mechanical performance, 45Ca uptake and total tissue calcium concentration were investigated in electrically stimulated left auricles isolated from female rats weighing 180–220 g. The experiments were performed at reduced [Ca]e of 0.45 mM and at various frequencies of stimulation (0–120 beats/min). In the first series of experiments 45Ca incubation time was 5 min. Under these conditions DB-c-AMP as well as adrenaline enhanced contractile force to 300–450% of the control values at all frequencies tested (Fig.1). This increase in contractile force was accompanied by a signif…

AT1-receptor blockade with irbesartan improves peripheral but not coronary endothelial dysfunction in patients with stable coronary artery disease

Activation of the renin-angiotensin-aldosterone system plays an important role in the pathogenesis of endothelial dysfunction and atherosclerosis. Studies evaluating the effect of AT1-receptor blockers on endothelial dysfunction in patients with coronary artery disease (CAD) revealed mixed results. Studies addressing the effects of AT1-receptor blockers on the coronary and peripheral function in the same study population, are still lacking. We therefore aimed to test the effects of long-term therapy with the AT1-receptor blocker irbesartan (IRB) on both, the coronary and peripheral endothelial function in patients with CAD. Seventy-two patients with CAD were randomly assigned to double-blin…

Pharmacokinetic analysis of the interaction between dicoumarol and tolbutamide in man

The effect of repeated administration of tolbutamide on the elimination and anticoagulant action of a single oral dose of dicoumarol 600 mg was studied in four healthy male subjects using a crossover design. In all subjects the plasma concentration of dicoumarol in the postabsorptive phase was lower during concomitant tolbutamide treatment. However, the subjects differed with respect to the elimination kinetics of dicoumarol and the effect of tolbutamide on some of the measured pharmacokinetic paramaters. In two subjects dicoumarol was eliminated by apparent first-order kinetics. Tolbutamide led to a pronounced increase in the elimination rate and a shift in the plasma concentration-respons…

Electrical and mechanical activity of mammalian heart muscle fibres treated with papaverine

The action of papaverine on electrical and mechanical activity was investigated in ventricular and atrial heart muscle fibres from guinea-pigs and cats. 1. Papaverine (10−5 M–5×10−5M) had positive, negative or no inotropic effects in ventricular preparations; positive inotropic effects were not observed after pretreatment of the animals with reserpine. In atrial preparations, papaverine (2×10−5M) had a positive inotropic effect that was independent of endogenously stored catecholamines. 2. The effects of isoprenaline and dibutyryl cyclic AMP were potentiated by papaverine (10−5 M–2×10−5M). 3. The action potential duration was always prolonged by papaverine in ventricular as well as in atria…

Extensive characterization of the human DDAH1 transgenic mice

Abstract Purpose of the research Overexpression of the human dimethylarginine dimethylaminohydrolase type 1 (hDDAH1) gene was reported to have beneficial cardiovascular effects in mice. To date, it is unclear whether these effects are related to enhanced metabolic clearance of asymmetric dimethylarginine (ADMA) and l - N G -mono-methyl- l -arginine ( l -NMMA) or increased DDAH1 expression and activity in cardiovascular tissues of hDDAH1 transgenic mice. Principal results DDAH activity (DDAH1 + DDAH2) was found to be markedly increased in aortic and heart tissues but unaltered in liver and kidney tissues of hDDAH1 transgenic as compared to wild-type (WT) mice. In WT mice, DDAH activity was m…

Effectiveness of theophylline to increase cyclic AMP levels and force of contraction in electrically paced guinea-pig auricles. Comparison with isoprenaline, calcium and ouabain

The effects of theophylline (3×10−5 M–5×10−3 M), isoprenaline (10−6 M), excess calcium (7.2 mM) and ouabain (3×10−7 M) on force of contraction and c-AMP content were studied in electrically driven (frequency 3 Hz) left auricles isolated from guinea pigs pretreated with reserpine.

Influence of cyclization and acyl substitution on the inotropic effects of adenine nucleotides.

This study was designed to further elucidate relevance and mechanism of the positive inotropic action of cyclic N6-2′-O-dibutyryl-AMP (DB-c-AMP). For this purpose the effects of cyclic N6-monobutyryl-AMP (N6-MB-c-AMP), noncyclic N6-2′-O-3′-O-tributyryl-5′-AMP (TB-AMP), c-AMP, adenosine and various adenine nucleotides (ATP, ADP, AMP) on myocardial contractile force (CF) were investigated and compared to that of DB-c-AMP. The experiments were performed on isolated, electrically driven (frequency 2 Hz) rat left auricles, i.e. on a preparation in which DB-c-AMP consistently produced positive inotropic effects. The following results were obtained: From the failure of non-cyclic TB-AMP to increas…

Estimation of pulmonary arterial pressure by measuring the size of the right pulmonary artery in the suprasternal echocardiogram.

We studied 175 patients within 24 hr before cardiac catheterization with suprasternal echocardiography to evaluate whether pulmonary arterial hypertension can be derived by measuring the size of the right pulmonary artery. Group I consisted of 103 patients without pulmonary arterial hypertension (enddiastolic less than or equal to 12 mm Hg; mean pressure less than 20 mm Hg) and group II consisted of 72 patients with pulmonary arterial hypertension. The right pulmonary artery could be imaged in 91.2% of the patients studied. The size of the right pulmonary artery at the end of diastole in group I measured 17.9 +/- 0.2 mm (mean +/- SEM) and correlated best to the body surface area in this gro…

Possible role of cyclic AMP in the relaxation process of mammalian heart: effects of dibutyryl cyclic AMP and theophylline on potassium contractures in cat papillary muscles.

The effect of dibutyryl cyclic AMP (DB-c-AMP; 3 X 10(-4)-3 X 10(-3) M) on electrically induced twitch and high potassium (142.4 mM KCl)-induced contracture tension was studied in papillary muscles from normal and reserpinized cats ([Ca]0 1.8 mM; 25 degrees C; pH 7.4). In both groups of preparations, the increase in twitch tension evoked by DB-c-AMP was accompanied by an abbreviation of the time to peak force and of relaxation time. In the same preparations, the high potassium contracture was markedly depressed by DB-c-AMP in a concentration-dependent manner. Similar results were obtained with the N6-monobutyryl derivative of cyclic AMP. The relaxing effects of the cyclic nucleotides on KCl …

Effects of a nitrate-free interval on tolerance, vasoconstrictor sensitivity and vascular superoxide production

Abstract OBJECTIVES In the present study, we tested whether a nitrate-free interval is able to prevent increases in vascular superoxide (O2•−) and the development of hypersensitivity to vasoconstrictors and whether this may result in restoration of vascular nitroglycerin (NTG) sensitivity. BACKGROUND Intermittent NTG-patch treatment (12 h patch on/patch off) has been shown to increase ischemic periods in patients with stable coronary arteries, suggesting a rebound-like situation during the patch-off period. Recently, we demonstrated that long-term treatment with NTG induces tolerance, which was in part related to increases in vascular O2•− and increased vasoconstrictor sensitivity. METHODS …

Adrenaline, DB-c-AMP and myocardial 45Ca exchange. Comparative studies in rat and guinea-pig auricles

The positive inotropic effect of adrenaline has been assumed to result from an increase in the intracellular level of c-AMP which, in turn, might enhance the permeability of the cardiac cell membrane to Ca2+. In order to further test this hypothesis, the effects of cyclic N6-2′-O-dibutyryl-adenosine-3′,5′-monophosphate (DB-c-AMP; 10−3 M) on mechanical performance, 45Ca uptake and total tissue calcium concentration were investigated in electrically stimulated (120 beats/min) left auricles isolated from female rats weighing 180–220 g. The experiments were performed in Tyrode solution containing 0.9 mM CaCl2; the duration of 45Ca exposure was 3–60 min. In this study, DB-c-AMP markedly enhanced…

Local skin necroses after intramuscular injection -Experimental animal studies-.

The pathogenesis of local skin necroses after intramuscular injection of various drugs such as phenylbutazone (Embolia cutis medicamentosa, Nicolau's syndrome) is not clear. In an attempt to simulate this clinical feature experiments were performed on the rabbit ear lobe. A 20% phenylbutazone solution was injected paraarterial, intraarterial and paraarterial after perforation of the vessel. The drug produced a violent inflammation with all kinds of application. The local inflammation induced by paraarterial injection resulted in a fine scarring. Both other kinds of application produced necroses or even perforations. The histological examinations in these cases revealed massive destructions …

Rückgang der Sterblichkeit von Herz-Kreislauf-Erkrankungen

Zusammenfassung Die Zahlenangaben stützen sich auf den Deutschen Herzbericht 2017. Die Krankenhaussterblichkeit kardiovaskulärer Krankheiten nahm von 1990 bis 2016 um nahezu die Hälfte ab. Diese Abnahme war im Wesentlichen durch die deutlich verbesserte Prognose der koronaren Herzkrankheit, des Herzinfarktes und der Herzinsuffizienz bedingt. Unerwartet war dagegen die deutliche Zunahme der Letalität bei Herzklappenerkrankungen und Herzrhythmusstörungen. Bei dieser Zunahme scheint es sich jedoch um eine Pseudozunahme zu handeln, da im gleichen Zeitraum auch die Krankenhausmorbidität und damit die Diagnosehäufigkeit noch deutlicher als die Sterblichkeit anstieg. Bei der koronaren Herzerkranku…

Anticoagulant Activity of the Enantiomers of Acenocoumarol in Man

For the mono-coumarin derivatives warfarin and phen-procoumon it was shown that in man and rats the S(−) enantiomer is several times more potent as anticoagulant than the R(+) enantiomer. These stereoselective differences in the anticoagulant potency reflect differences in the affinity for the receptor site rather than differences in the pharmacokinetics.

The positive inotropic effect of phenylephrine in the presence of propranolol. Increase in time to peak force and in relaxation time without increase in c-AMP.

The effects of phenylephrine on the shape of the contraction curve and on the cyclic adenosine 3',5'-monophosphate (c-AMP) content were studied in electrically driven (frequency 0.2 Hz) cat papillary muscles. All experiments were done in the presence of 1 micron propranolol in order to minimize interference from beta-adrenoceptors. 1. Phenylephrine increased the force of contraction in a concentration-dependent manner. Maximal effects (about 200% of control) occurred at 30 micron phenylephrine. 2. The positive inotropic effect (PIE) of phenylephrine was antagonized by phentolamine. Phentolamine, 5 micron, produced a parallel shift of the concentration-response curve for the PIE of phenyleph…

PLASMA CONCENTRATION-EFFECT RELATIONSHIP OF THE ANTIARRHYTHMIC AGENT LORCAINIDE

The enantiomers of phenprocoumon: pharmacodynamic and pharmacokinetic studies.

The pharmacodynamics and pharmacokinetics of the optical enantiomers of phenprocoumon were studied in 5 normal subjects and compared to the racemic mixture. Each subject received a single oral dose of 0.6 mg/kg of racemic, S(-), and R(+) phenprocoumon. S(-) phenprocoumon was 1.6 to 2.6 times as a potent as R(+) phenprocoumon when the area under the effect/time curve was used to quantify the total anticoagulant effect per dose. Comparing the plasma concentrations that elicited the same anticoagulant effect, S(-) phenprocoumon was 1.5 to 2.5 times as potent as R(+) phenprocoumon. The anticoagulant activity of the racemic mixture was between that of the enantiomers. There was no distinct diffe…

Lorcainid — Pharmakokinetik und Pharmakodynamik

Nutzen und Notwendigkeit der heute praktizierten antiarrhythmischen Therapie sind umstritten. Gerade lebensbedrohliche Arrhythmien erweisen sich einer Standardtherapie mit konventionellen Antiarrhythmika gegenuber haufig als refraktar, wahrend eine erfolgreiche Therapie mit z. T. erheblichen Nebenwirkungen erkauft werden mus. Eine Verbesserung des Therapieerfolges erhofft man sich sowohl aus der Innovation neuer, wirksamerer und nebenwirkungsarmerer Antiarrhythmika, als auch aus der Anderung der therapeutischen Strategie (Ersatz der Standardtherapie durch eine individuell angepaste Dosierung).

�ber die positiv inotrope Wirkung von Dibutyryl-3?,5?-AMP an isolierten Rattenvorh�fen

It is concluded that the positive inotropic action of DB-AMP—at least in isolated rat atria—may resemble that of adrenaline or theophylline in some points, e.g. with regard to its dependence on the [Ca]e. But as no positive inotropic effect could be observed in guinea-pig atria and as the mechanism by which DB-AMP augments contractile force remains obscure, the results are not thought to necessarily support the view that the effects of adrenaline or theophylline on contractile behaviour of mammalian cardiac muscle occur via cyclic AMP.

Lorcainide; II. Plasma concentration-effect relationship

Recanalization of occluded left main coronary artery in unstable angina pectoris

Flow-mediated dilation in patients with coronary artery disease is enhanced by high dose atorvastatin compared to combined low dose atorvastatin and ezetimibe: results of the CEZAR study.

Abstract Background Effects independent from cholesterol reduction on vascular function are considered to importantly contribute to the beneficial effects of statin therapy in cardiovascular disease. We aimed to evaluate the effect of high versus low dose atorvastatin on endothelial dysfunction in patients with coronary artery disease (CAD) in a setting of comparable cholesterol reduction. Methods and results Fifty-eight patients with CAD were randomly assigned to double-blind treatment for 8 weeks with atorvastatin 80mg per day (A80) or atorvastatin 10mg+ezetimibe 10mg per day (A10E10), respectively. Flow-mediated vasodilation (FMD) of the brachial artery, nitroglycerin-mediated endotheliu…

Effect of intravenous flecainide on atrial vulnerability in man.

Sixteen patients were investigated by means of programmed atrial stimulation at two different driving rates: 100 and 120/min. All patients had an increased atrial vulnerability at both driving rates. After intravenous flecainide application (1 mg/kg body weight as a bolus followed by the same amount given by infusion over a period of 20 min) the increased vulnerability was abolished in 11 and 9 patients respectively. In the remaining patients the rate of induced atrial tachyarrhythmia decreased. These findings correlate with a significant prolongation of the effective refractory period of the right atrium and a significant shortening of the relative refractory period of the right atrium. It…

Haemodynamic effects of a single intravenous dose of lorcainide in patients with heart disease

The cardiovascular effects of a single i.v. dose (2 mg/kg over 5 min) of lorcainide were studied in 14 patients with heart disease. In the haemodynamic part of the study (6 patients), the aortic and pulmonary systolic, diastolic and mean pressures, left ventricular systolic and end-diastolic pressures, cardiac output and the rate of rise of left ventricular pressure were measured before and for 30 min after administration of the drug. Lorcainide produced a slight and short-lasting decrease in the aortic and pulmonary systolic pressures, and all other pressure values remained unchanged. The cardiac output and systemic vascular resistance were not altered by lorcainide. It consistently depres…

Wall motion characteristic of the right pulmonary artery in the suprasternal echocardiogram

This study describes the motion pattern of the right pulmonary artery (RPA) as it can be assessed from the suprasternal echocardiogram. The motion characteristic of the RPA is dependent on hemodynamic factors within the lumen of the RPA and those within the left atrium and the aortic arch. During atrial contraction the superior wall of the left atrium separates from the inferior wall of the RPA (IWRPA) and produces an "a" dip in the wall motion of the IWRPA. During isovolumic contraction the RPA is shifted upward (IC point). The incisura in the pulmonary artery pressure curve reflecting pulmonic valve closure can be seen by a sudden decrease in the diameter of the RPA (PC point). In conditi…

Über den Einfluß von Dibutyryl-c-AMP auf die Kontraktionskraft des isolierten menschlichen Ventrikelmyokards

Cyclisches 3′,5′-AMP (c-AMP) soll am Warmbluterherzen neben den metabolischen auch die positiv inotropen Effekte der Katecholamine vermitteln (z. B. Sutherland et al., 1968). Es wurde als Stutze dieser Hypothese angesehen, das das Dibutyrylderivat des cyclischen 3′,5′-AMP (DB-c-AMP) an Herzmuskelpraparaten verschiedener Spezies positiv inotrop wirkt (Kukovetz und Poch, 1970; Skelton et al., 1970). Da diese Hypothese auch hinsichtlich des Wirkungsmechanismus der Katecholamine am menschlichen Herzen von Bedeutung sein kann, wurde gepruft, wie DB-c-AMP die Kontraktionskraft des menschlichen Herzmuskelgewebes beeinflust.

Disposition of azapropazone in chronic renal and hepatic failure.

The disposition of azapropazone 600 mg i.v. was investigated in 6 healthy subjects, 13 patients with cirrhosis and 8 patients with renal failure. In healthy subjects the elimination half-life was 12.2±2.1 h (mean ± SD), the volume of distribution 10.6±3.31 and the total clearance was 597±135 ml·h−1. Renal clearance accounted for about 62% of the total clearance. The free fraction of azapropazone in the plasma was 0.0045±0.0006. The patients with cirrhosis were divided into Group I with modest and Group II with severe impairment of liver function. In Group I the total clearance of azapropazone was not significantly different from that in healthy subjects. There was a 2.5-fold increase in its…

Myeloperoxidase mediates neutrophil activation by association with CD11b/CD18 integrins.

Recruitment and activation of polymorphonuclear neutrophils (PMNs) reflects a primary immunological response to invading pathogens and has also emerged as a hallmark of vascular inflammation. One of the principal enzymes released upon PMN activation is myeloperoxidase (MPO), a heme protein that not only generates cytotoxic oxidants but also impacts deleteriously on nitric oxide-dependent signaling cascades within the vasculature. Because MPO also associates with the membrane of PMN, we evaluated whether MPO could also function as an autocrine modulator of PMN activation. The extent of PMN membrane-associated MPO was elevated in patients with acute inflammatory vascular disease compared with…

DISOPYRAMIDE-INDUCED INTRAHEPATIC CHOLESTASIS

Effect of DB-c-AMP on mechanical characteristics of ventricular and atrial preparations of several mammalian species

Conflicting results exist about the influence of cyclic N6-2′-O-dibutyryl-AMP (DB-c-AMP) on myocardial contractile force. The present study was designed to examine whether the positive inotropic action of DB-c-AMP is restricted to certain model preparations or whether it can be assumed to represent a more general effect of the drug. Therefore, the effects of DB-c-AMP on myocardial force and on various parameters of the isometric contraction curve were examined in isolated electrically driven (0.5–2Hz) ventricular and atrial preparations of several mammalian species (cat, rabbit, calf, sheep, rat and guinea-pig). The following results were obtained:

Combined medical and mechanical recanalization in acute myocardial infarction

A technique of combined medical and mechanical recanalization was employed in 96 patients with acute transmural myocardial infarction. The mean time between onset of symptoms and admission to hospital was 170 +/- 65 min (X +/- SD). After 10 +/- 16 min, 250,000 U streptokinase was administered intravenously for 20 min. Intracoronary thrombolysis was commenced within 38 +/- 14 min. First coronary angiograms demonstrated reperfusion, an open vessel in 25/96 patients (26%). In 15/71 patients (21%) reperfusion occurred during thrombolysis therapy, before mechanical recanalization could be performed. Recanalization was achieved mechanically in 37/71 patients (52%) with occluded coronary vessels. …

Klinische Pharmakologie I

Rifampicin (RMP) induziert nach mehrtagiger Gabe die mischfunktionellen Oxygenasen in der Leber, so das auch sein eigener Metabolismus beschleunigt wird (Eigeninduktion, Acocella 1978a). Wie wir beobachteten, nahmen die RMP-Plasmaspiegel unter oraler Dauertherapie starker ab als bei intravenoser Applikation (Musch et al. 1982; Loos et al. 1983). Klinisch zeigten 30 initial mit RMP intravenos behandelte Patienten mit offener Lungentuberkulose eine schnellere Sputumnegativierung und Rontgenbefundbesserung im Vergleich zu 48 oral therapierten Patienten (Kombinationstherapie: RMP-Isoniazid-Ethambutol). So war z. B. die Sputumkulturkonversion nach dem 1. Behandlungsmonat bei intravenoser RMP-Gab…

Vulnerability of the right ventricle to cathodal, anodal, and bipolar stimulation at double diastolic threshold strength

The repetitive ventricular response (RVR) to three stimulation techniques (bipolar, cathodal and anodal) was investigated in 35 patients. 26 patients suffered from coronary heart disease and 9 patients from dilative cardiomyopathy. The stimulation study was performed at a ventricular driving rate of 120/min with one and two premature ventricular extrastimuli. We used rectangular impulses of 1.8 ms duration at duable diastolic threshold strength. RVR was scored as follows: 0: no RVR, 1: one nonstimulated RVR, 2: two nonstimulated RVR, 3: three nonstimulated RVR, 4: four to ten nonstimulated RVR, 5: more than ten nonstimulated RVR lasting less than 2 minutes, 6: sustained ventricular tachycar…

Echocardiography in assessing acute pulmonary hypertension due to pulmonary embolism.

Eighteen patients with acute pulmonary embolism were studied with right heart catheterization and M mode echocardiography. No patient had evidence of preexisting cardiopulmonary disease; pulmonary embolism was documented with pulmonary angiography. The mean pulmonary arterial pressure correlated with the angiographic severity index of embolic obstruction (r = 0.61, p 2 , p 2 ) and in 5 patients with acute pulmonary embolism and a mean normal pulmonary arterial pressure (10.9 ± 0.4 mm/m 2 ). For all measurements the index size of the right pulmonary artery correlated with the mean pulmonary arterial pressure (r = 0.84, p

Efficacy of the long-acting nitro vasodilator pentaerithrityl tetranitrate in patients with chronic stable angina pectoris receiving anti-anginal background therapy with beta-blockers: a 12-week, randomized, double-blind, placebo-controlled trial.

Background The organic nitrate pentaerithrityl tetranitrate (PETN) has been shown to have ancillary properties that prevent the development of tolerance and endothelial dysfunction. This randomized, double-blind, placebo-controlled, multicentre study (‘CLEOPATRA’ study) was designed to investigate the anti-ischaemic efficacy of PETN 80 mg b.i.d. (morning and mid-day) over placebo in patients with chronic stable angina pectoris. Methods and results A total of 655 patients were evaluated in the intention-to-treat population, randomized to PETN (80 mg b.i.d., n = 328) or placebo ( n = 327) and completed the study. Patients underwent treadmill exercise tests at randomization, after 6 and 12 wee…

SATURABLE PRESYSTEMIC ELIMINATION OF THE ANTIARRHYTHMIC DRUG LORCAINIDE

NADPH Oxidase Accounts for Enhanced Superoxide Production and Impaired Endothelium-Dependent Smooth Muscle Relaxation in BKβ1 −/− Mice

Objective— Nitric oxide (NO)-induced vasorelaxation involves activation of large conductance Ca 2+ -activated K + channels (BK). A regulatory BKβ1 subunit confers Ca 2+ , voltage, and NO/cGMP sensitivity to the BK channel. We investigated whether endothelial function and NO/cGMP signaling is affected by a deletion of the β1-subunit. Methods and Results— Vascular superoxide in BKβ1 −/− was measured using the fluorescent dye hydroethidine and lucigenin-enhanced chemiluminescence. Vascular NO formation was analyzed using electron paramagnetic resonance (EPR), expression of NADPH oxidase subunits, the endothelial NO synthase (eNOS), the soluble guanylyl cyclase (sGC), as well as the activity a…

Experience in the long term use of new antiarrhythmic drugs.

Meinertz et a1. (1984) investigated the long term efficacy and tolerability of flecainide in patients with ventricular arrhythmias. 15 patients were studied, 8 women and 7 men, aged 19 to 74 (mean 58.7) years, with more than 30 ventricular premature complexes (VPCs) per hour, and ventricular arrhythmias of Lown grade IVA or IVB. 11 had coronary artery disease and 2 had idiopathic dilated cardiomyopathy. Patients were excluded on the basis of sustained ventricular tachycardia (VT) [defined as ~ 3 consecutive beats at a rate of> 100 beats/min]; myocardial infarction within the last 6 months; unstable angina; severe congestive heart failure; or conduction abnormalities. Previously unsuccessful…

Autonome Blockade: Bedeutung in der elektrophysiologischen Diagnostik des kranken Sinusknotens

Die normale Sinusknotenfunktion ist von einer komplexen und ausgewogenen Interaktion zwischen intrinsischen elektrophysiologischen Eigenschaften des Sinusknotens und der sinuatrialen Leitung einerseits sowie von extrinsischen Faktoren andererseits abhangig [1]. Unter letzteren spielt das autonome Nervensystem die wichtigste Rolle. Vagale Stimulation oder Acetylcholin fuhren zu einer Senkung der Herzfrequenz und zu einer Verlangsamung der sinuatrialen Leitungszeit. Im Gegensatz dazu steigert Sympathikusstimulation oder Katecholamingabe die Herzfrequenz und verkurzt die sinuatriale Leitungszeit [2].

Klinische Pharmakologie II

1963 beschrieb Ommaya ein subkutanes Plastikreservoir, das nach Implantation unter die Kopfhaut einen direkten, sterilen, wiederholbaren Zugang zum Ventrikelliquor ermoglichte. Nach okzipitaler Bohrlochtrepanation des Schadels wurde ein Siliconkatheter in das Hinterhorn des Seitenventrikels eingefuhrt und an das Reservoir angeschlossen.

Lorcainide. I. Saturable presystemic elimination.