Relation of dose of carvedilol to reduction in QT dispersion in patients with mild to moderate heart failure secondary to ischemic or to idiopathic dilated cardiomyopathy.

Carvedilol has been shown to improve survival and morbidity in patients with heart failure. It has been demonstrated that carvedilol use is associated with dose-dependent reduction in QT dispersion (QTd) independent of the cause of heart failure, suggesting that reduction in QTd may be a mechanism by which carvedilol improves outcomes in heart failure.

Influence of pretreatment systolic blood pressure on the effect of carvedilol in patients with severe chronic heart failure: the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) study.

Objectives: We sought to evaluate the influence of pretreatment systolic blood pressure (SBP) on the efficacy and safety of carvedilol in patients with chronic heart failure (CHF).

Background: Although beta-blockers reduce the risk of death in CHF, there is little reported experience with these drugs in patients with a low pretreatment SBP, who may respond poorly to beta-blockade.

Methods: We studied 2,289 patients with severe CHF who participated in the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial.

Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study.

Background: Beta-blocking agents improve functional status and reduce morbidity in mild-to-moderate heart failure, but it is not known whether they produce such benefits in severe heart failure.

Methods And Results: We randomly assigned 2289 patients with symptoms of heart failure at rest or on minimal exertion and with an ejection fraction <25% (but not volume-overloaded) to double-blind treatment with either placebo (n=1133) or carvedilol (n=1156) for an average of 10.4 months.

Exacerbation of radiocontrast nephrotoxicity by endothelin receptor antagonism.

Background: Endothelin is a potent vasoconstrictor that has been implicated in the pathogenesis of radiocontrast nephrotoxicity. Endothelin antagonists may reduce the renal hemodynamic abnormalities following radiocontrast administration.

Methods: One hundred fifty-eight patients with chronic renal insufficiency [mean serum creatinine +/- SD = 2.

Safety and efficacy of carvedilol in severe heart failure. The U.S. Carvedilol Heart Failure Study Group.

Background: Many patients remain markedly symptomatic despite optimal current therapy for heart failure. Beta-blockers have often been viewed as contraindicated in this group because of their potential adverse short-term effects on cardiac function.

Methods And Results: One hundred thirty-one patients with severe congestive heart failure were enrolled into a double-blind, placebo-controlled study of the vasodilating beta-blocker carvedilol.

Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure. US Carvedilol Heart Failure Study Group.

Background: We tested the hypothesis that carvedilol inhibits clinical progression in patients with mildly symptomatic heart failure due to left ventricular (LV) systolic dysfunction.

Methods And Results: Patients (n = 366) who had mildly symptomatic heart failure with an LV ejection fraction (LVEF) < or = 0.35, had minimal functional impairment (defined as the ability to walk 450 to 550 m on a 6-minute walk test), and were receiving optimal standard therapy, including ACE inhibitors, were randomized double-blind to carvedilol (n = 232) or placebo (n = 134) and followed up for 12 months.

Randomized, prospective trial of fenoldopam vs sodium nitroprusside in the treatment of acute severe hypertension. Fenoldopam Study Group.

Objective: To compare the safeties and efficacies of IV fenoldopam (FNP) vs sodium nitroprusside (NTP) in severe acute hypertension.

Methods: A prospective, randomized, open-label, multicenter international trial, at 24 academic medical centers, was conducted. The participants were adult patients (21-80 years of age) who had supine diastolic blood pressures (DBPs) > or = 120 mm Hg, were capable of written informed consent, and did not have selected exclusion criteria.

Clinical experience with intravenous fenoldopam.

Fenoldopam (Corlopam), a new dopaminergic agent in clinical development by SmithKline Beecham Pharmaceuticals, is a dopamine-1 (DA1) agonist at post-synaptic dopamine receptors. Preclinical and clinical studies have demonstrated that it is a potent renal vasodilator as well as a peripheral vasodilator. In both normal volunteers and hypertensive patients intravenous fenoldopam causes dose-related decreases in blood pressure and important increases in renal hemodynamics and function including increased renal blood flow, diuresis and natriuresis.

Biochemical and functional effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the heart of female rats.

Biochemical, functional and morphologic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the hearts of female rats were examined. Six days after the treatment of rats with TCDD, the blood pressures and resting heart rates were significantly less than in control animals. Treated animals were also less responsive to the effects of the beta-1 agonist, (-)isoproterenol.

Evidence for presynaptic inhibitory histamine (H2) receptors in the rat hindquarter vasculature.

Histamine released within walls of resistance blood vessels is suggested to mediate an active portion of baroreceptor-mediated neurogenic vasodilatation in skeletal muscle vasculature. Studies were undertaken to examine the possibility that histamine-mediated active vasodilatation could be effected, in part, by an inhibitory presynaptic action of histamine on vascular sympathetic varicosities. All experiments were conducted in constant-flow autoperfused rat hindquarters in which vasoconstrictor responses were evoked by sympathetic chain (L2-4) stimulation at varying frequencies or intraarterial norepinephrine (0.

Antihistamine-sensitive active vasodilatation in the perfused hindquarters of the rat.

The innervated, constant flow perfused hindquarters of the rat have been used to evaluate post-stimulation vasodilatation, which is a model of active reflex vasodilatation in this species. The vasodilatation resulting from lumbar sympathetic stimulation was dependent on stimulation frequency and duration. Maximal vasodilatation (16 +/- 2%) was at 8 Hz for 15 s, while markedly reduced vasodilatation was seen after stimulation for longer than 30 s at all frequencies tested.

Studies on uptake and catabolism of vascular histamine in spontaneously hypertensive rats.

Reduced vascular histamine content is postulated to contribute to increased peripheral vascular resistance in experimental hypertension in rats. Experiments were conducted to examine histamine content, in vitro uptake ability and in vitro catabolism of histamine in blood vessels from 12-week-old spontaneously hypertensive rats (SHR) and age-matched normotensive controls. Histamine content of mesenteric artery and abdominal aorta from SHR was significantly reduced (P less than .

Alterations in hepatic microsomal drug metabolism and cytochrome P-450 proteins in spontaneously hypertensive rats.

Experiments were conducted to determine if substrate-specific changes in microsomal metabolism and liver proteins occurred in young (12-13 weeks) spontaneously hypertensive rats (SHR) fed ad libitum compared to age-matched normotensive Wistar Kyoto (WKY) control rats. The hepatic microsomal protein content in SHR rats was significantly increased compared to WKY rats while cytosolic and total liver protein levels did not differ between the two groups. Liver microsomal ethylmorphine-N-demethylase activity was substantially enhanced in SHR rats with only slight increases in cytochrome P-450 content and aniline hydroxylase activity compared to WKY rats.

Histamine uptake and metabolism in the blood vessels of rats.

In vitro radiolabeled histamine uptake and metabolism were investigated in abdominal aorta, iliac artery, mesenteric artery and hepatic portal vein of the rat. Histamine uptake was rapid and remained linear over the initial 10 min of the accumulation period. The uptake rate was temperature sensitive with marked reduction in rate at 0 degrees C.

Exposure of urban applicators to carbaryl.

Thirty-eight urban volunteers from the Lincoln and Omaha, Nebraska areas were monitored for carbaryl exposure during the summer of 1979. All volunteers were involved in the application of carbaryl incidental to their employment or leisure activities. The investigators made no attempt to affect the method of carbaryl application.

Exposure of professional pesticide applicators to carbaryl.

Dermal and respiratory exposure, and erythrocyte and serum acetylcholinesterase activity were monitored on two groups of professional pesticide applicators spraying trees with carbaryl. The mean dermal exposure to the first group was 128 mg hr-1 of carbaryl and the mean respiratory exposure was 0.1 mg hr-1.

Hemodynamic properties of a new quinidine analog, cupreidine (6'-hydroxycinchonine).

Cupreidine 96'-hydroxycinchonine) is a recently synthesized analog of quinidine (6'-methoxycinchonine). Previous studies in mice have shown that quinidine and cupreidine have equivalent antiarrhythmic potencies, whereas the acute toxicity of cupreidine is about 50% less than that of quinidine. Many of the serious adverse effects of quinidine are due to undesirable cardiovascular properties.

Direct vasodilator activity of atropine in the rat perfused hindlimb preparation.

1. The autoperfused hindlimb technique in the rat was used to determine the effects of atropine upon the peripheral vasculature. 2.

A comparative study on the antiarrhythmic activity and acute toxicity of quinidine and four new analogs in mice.

We have compared the ED50 value for antiarrhythmic activity and the acute toxicities in mice of quinidine and 4 recently synthesized analogs. For the ED50 studies, groups of mice were treated intravenously with equally spaced logarithmic doses of 6'-methoxycinchonine (quinidine), 6'-hydroxycinchonine (cupreidine), 6'-isovaleryloxycinchonine, 6'-acetyloxycinchonine and 6'-benzoyloxycinchonine. For the actue toxicity studies, mice were treated intraperitoneally with quinidine and the 4 analogs.

Quantitation of isoproterenol-induced myocardial necrosis with 3H-tetracycline.

Methods currently used to quantitate myocardial damage and necrosis produced by chemicals are usually time consuming and subjective. These studies were conducted to evaluate the utility of 3H-tetracycline as a means of quantitating myocardial necrosis produced by isoproterenol. Male, Sprague-Dawley derived rats (180-200 g) were treated with (+/-)-isoproterenol HCl (0.

Partial synthesis of 6'-hydroxycinchonine and its antiarrhythmic activity in mice.

The synthesis of 6'-hydroxycinchonine [8R,9S)-cinchonan-6',9-diol] was achieved by demethylating quinidine with boron tribromide in dichloromethane at -75 degrees C. The antiarrhythmic activities of 6'-hydroxycinchonine and quinidine were compared following the infusion of aconitine into the tail veins of mice to induce arrhythmias. Comparative ED50 and LD50 studies for quinidine and 6'-hydroxycinchonine revealed equivalent antiarrhythmic potencies for the two drugs but a smaller acute toxicity for 6'-hydroxycinchonine.

The effect of large doses of atropine sulfate on heart rate and blood pressure in rats.

Atropine sulfate causes bradycardia in doses which are greater than the usual anticholinergic doses producing tachycardia (Shucard and Andrew, 1977, Res. Comm. Chem.