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 = 2.7 +/- 1.0 mg/dL (242. 3 to +/- 92.8 micromol/L)] and undergoing cardiac angiography were randomized to receive either a mixed endothelin A and B receptor antagonist, SB 290670, or placebo. All patients received intravenous hydration with 0.45% saline before and after radiocontrast administration. Serum creatinine concentrations were measured at baseline, 24 hours, 48 hours, and 3 to 5 days after radiocontrast administration. The primary end point was the mean change in serum creatinine concentration from baseline at 48 hours; the secondary end point was the incidence of radiocontrast nephrotoxicity, defined as an increase in serum creatinine of > or =0.5 mg/dL (44 micromol/L) or > or = 25% from baseline within 48 hours of radiocontrast administration. RESULTS: The mean increase in serum creatinine 48 hours after angiography was higher in the SB 209670 group [0.7 +/- 0. 7 mg/dL (63.5 +/- 58.6 micromol/L)] than in the placebo group [0.4 +/- 0.6 mg/dL (33.6 +/- 55.1 micromol/L), P = 0.002]. The incidence of radiocontrast nephrotoxicity was also higher in the SB 209670 group (56%) compared with placebo (29%, P = 0.002). This negative effect of SB 209670 was apparent in both diabetic and nondiabetic patients. Adverse effects, especially hypotension or decreased blood pressure, were more common in the SB 209670 group. CONCLUSIONS: In patients with chronic renal insufficiency who were undergoing cardiac angiography, endothelin receptor antagonism with SB 209670 and intravenous hydration exacerbate radiocontrast nephrotoxicity compared with hydration alone.

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. All patients had symptomatic, advanced heart failure while on standard triple therapy, as evidenced by a mean ejection fraction of 0.22, marked reduction in distance traveled in a 6-minute corridor walk test, and severe impairment in quality of life measured by the Minnesota Living With Heart Failure Questionnaire. After a 2-week, open-label test of 6.25 mg twice daily carvedilol, 105 patients were randomized (2:1) to receive either carvedilol (up to 25 mg twice daily, n = 70) or matching placebo (n = 35) for 6 months while background therapy with digoxin, diuretics, and an angiotensin-converting enzyme inhibitor remained constant. Ten patients (8%) did not complete the open-label period because of adverse events and 11.4% in both the carvedilol and placebo groups dropped out in the double-blind phase. The study was terminated early by the Data Safety and Monitoring Board and follow-up evaluation was therefore aborted before the projected number of patients and follow-up time was achieved. Quality of life, which was the primary endpoint, improved similarly in the carvedilol and placebo groups, whereas the global assessment by the physicians and the patient exhibited a better response to carvedilol (P < .05). Hospitalization and mortality rate were too low to evaluate a difference, and exercise time and New York Heart Association classification did not change significantly in response to the drug. Left ventricular ejection fraction rose significantly (+0.09) in the carvedilol group compared with the placebo group (+0.02, P = .004). CONCLUSION: The beta-blocker carvedilol can be safely employed in patients with severe heart failure. Improved left ventricular function with a trend for some improvement in symptoms combined with the experience with the drug in the larger population of less severe patients in this multicenter trial suggests that carvedilol may have a favorable long-term effect in heart failure of diverse severity.

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. The primary end point was clinical progression, defined as death due to heart failure, hospitalization for heart failure, or a sustained increase in heart failure medications. Clinical progression of heart failure occurred in 21% of placebo patients and 11% of carvedilol patients, reflecting a 48% (P = .008) reduction in the primary end point of heart failure progression (relative risk, 0.52; CI, 0.32 to 0.85). This effect of carvedilol was not influenced by sex, age, race, cause of heart failure, or baseline LVEF. Carvedilol also significantly improved several secondary end points, including LVEF, heart failure score, NYHA functional class, and the physician and patient global assessments. Carvedilol reduced all-cause mortality but had no effects on the Minnesota Living With Heart Failure scale, the distance walked in 9 minutes on a self-powered treadmill, or cardiothoracic index. The drug was well tolerated. CONCLUSIONS: Carvedilol, when added to standard therapy, including an ACE inhibitor, reduces clinical progression in patients who are only mildly symptomatic with well-compensated heart failure.

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. The subjects were randomized to either FNP or NTP therapy; DBP was titrated to 95-110 mm Hg, or a maximum reduction of 40 mm Hg for very high pressures. Infusions were maintained for at least six hours, then the patients were weaned off the IV therapy and oral medication was started. Measurements included BP, heart rate, and duration of study drug infusion and frequency of side effects or complications. RESULTS: A total of 183 patients (90 FNP, 93 NTP) were enrolled. Fifteen patients from each arm were excluded from efficacy analysis due to protocol violation. There was no significant difference in baseline characteristics. The two antihypertensive agents were equivalent in controlling and maintaining DBP. Systolic blood pressure (SBP) was reduced to a slightly greater degree for the NTP-treated patients during the initial (0.5-1-hr) study period, and both SBP and DBP were reduced more for the FNP-treated patients in the subset receiving infusions during the 12-24-hour period. The adverse effect profiles of the drugs were similar, as were the times to achieve target pressure, with no clinically relevant difference. CONCLUSIONS: For patients who had acute severe hypertension, FNP and NTP were equivalent in terms of efficacy and acute adverse events. Because of a unique mechanism of action, FNP may have advantages in selected subsets of patients. Further studies may be indicated in patient populations with pure "hypertensive emergencies."

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. Fenoldopam does not alter glomerular filtration. Intravenous fenoldopam has been demonstrated to be efficacious in severe hypertensive patients in several multicenter, multinational trials. In severe hypertension efficacy trials fenoldopam was judged to be as effective as sodium nitroprusside and to produce less serious side effects. In patients with moderate to severe heart failure, fenoldopam has been demonstrated to produce dose-related acute increases in cardiac output, stroke volume and work index, decreased systemic vascular resistance but no important changes in pulmonary wedge pressure or right atrial pressure. In CHF patients fenoldopam has been demonstrated to be as efficacious as sodium nitroprusside. Fenoldopam, as a specific (DA1) agonist resulting in decreased peripheral and renal vascular resistance, diuresis, natriuresis and increases in cardiac hemodynamics on intravenous administration, appears to be an efficacious agent which offers a reasonable alternative in the treatment of severe hypertension and acute congestive heart failure.

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. No histopathologic changes were observed in the heart although extensive centrilobular necrosis occurred in the liver after TCDD administration. Serum levels of thyroxine were 66% less than in control animals. Marked lipid peroxidation was produced in the liver with small but significant increases occurring in the heart. TCDD administration had no effect on catalase activity in the heart, but produced a 20% decrease in superoxide dismutase activity relative to control animals. The effects of TCDD on cardiac function do not appear to be due to a direct action of the xenobiotic on the heart but possibly to a down-regulation of beta-receptors in the heart as a result of the hypothyroid state.

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 (0.5 microgram) administration. Intraarterial histamine infusion resulted in a significant inhibition of nerve-stimulated hindquarter vasoconstriction, with the greatest reduction (20%) occurring at the 82.5-ng/ml/min dose. The inhibitory effect of histamine was not stimulation frequency dependent, and occurred when the vasoconstrictor responses to intraarterial norepinephrine and dilator responses to intraarterial nitroglycerin (1 microgram) were unaltered by the histamine infusions. The H2 agonist impromidine produced a significant inhibition of nerve-stimulated hindquarter vasoconstrictor responses without altering perfusion pressure responsiveness to either intraarterial norepinephrine or nitroglycerin. The magnitude of this inhibition of nerve-stimulated vasoconstrictor response was equivalent to or greater than that produced by histamine. The alpha 2-agonist clonidine produced a significant inhibitory effect on neurogenic vasoconstrictor responses with a maximum of 54%. Cimetidine infusion (10 mg/kg i.a.) essentially abolished the inhibitory effect of histamine on nerve-stimulated hindquarter vasoconstriction. These results are consistent with the existence of inhibitory presynaptic histamine receptors on sympathetic varicosities in the hindquarter vascular bed. Furthermore, evidence supports these inhibitory receptors being of the H2 class and the possibility that histamine-mediated active vasodilatation in rat hindquarters involves inhibitory presynaptic histamine receptors.

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. The vasodilatation was transient. Atropine (2.0 mg kg-1 i.v.) failed to attenuate post-stimulation vasodilatation at a time when hindquarter vasodilatation to i.a. acetylcholine had been abolished. The H1 antihistamine, tripelennamine (2.5 mg kg-1 i.v.) significantly reduced (77%) post-stimulation vasodilatation relative to controls at a time when hindquarter vasodilatation due to i.a. histamine was essentially abolished. Reactive hyperaemia is an unlikely cause of vasodilatation since it is not blocked by H1 antihistamines; 60 s post-occlusion hyperaemia also, was not demonstrable. These data suggest that there is an active component of baroreceptor-mediated vasodilatation in the rat and that histamine, rather than acetylcholine, could be a mediator of this vasodilatation.

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 .05) when compared to Wistar-Kyoto normotensive controls. This finding confirms a similar observation of reduced vascular histamine content in deoxycorticosterone acetate salt hypertensive rats reported from our laboratory. This reduction in histamine content may be more prevalent in arteries because the decrease was not observed in the portal vein from SHR. Uptake of [14C]histamine into mesenteric artery and abdominal aorta was unchanged in SHR compared to Wistar-Kyoto controls. No significant differences between slopes for uptake regression lines were observed for either mesenteric artery or abdominal aorta. Mesenteric artery exhibited a greater capacity of [14C]histamine accumulation than aorta and significant reductions in accumulation of labeled histamine after 20 and 60 min were found in this vessel from SHR. Because metabolism of histamine was inhibited by aminoguanidine, this reduction may reflect diminished retention by histamine storage sites. In vitro I-[14C]histidine uptake was significantly increased in abdominal aorta and iliac artery but not mesenteric artery from SHR. These differences were also present at the later accumulation periods of 20 and 60 min.(ABSTRACT TRUNCATED AT 250 WORDS)

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. The substrate-specific increases in the microsomal drug metabolism in SHR rats were accompanied by an increase in the prominence of a protein with molecular weight 55,000 in the cytochrome P-450 region. These preliminary observations may be clinically relevant in that alterations in hepatic drug metabolism may be associated with endogenous biochemical processes underlying the hypertensive state.

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. The accumulation at 0 degrees C represents nonspecific uptake. The uptake of histamine was observed to be related to the amount of tissue stores of histamine as well as extracellular sodium ion concentration. The only histamine metabolite detected in the vasculature examined was imidazoleacetic acid representing almost 80% of the chromatogram radioactivity. This observation indicates the primary metabolic pathway for histamine in rat vasculature involves the enzyme, diamine oxidase.

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. The maximum percent (%) toxic dose received by the applicators was 0.12% hr-1. The mean exposure to the second group of applicators was 59.4 mg hr-1 dermal and 0.1 mg hr-1 respiratory, for a total of 0.02% toxic dose per hr. It was estimated that 86.9% of the dermal exposure was to the forearms and hands. The rate of exposure to pads placed under the applicators clothing was approximately 1/20 that of pads on the outside of the clothing. Of the body areas monitored, the back received the least rate of exposure. It was determined, in vitro, that 10(-3) M carbaryl would inhibit human serum (pseudocholinesterase) and erythrocyte acetylcholinesterase for at least 72 hr. There was no overall inhibition of acetylcholinesterase activity in the applicators.

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. The mean rates of carbaryl exposure were 3.85 and 0.26 microgram cm-2 hr-1, respectively, for the outside of the clothing and the skin beneath the clothing; clothing apparently provided an effective barrier to carbaryl penetration. The rate of carbaryl exposure to the hands of applicators was 2.36 and 24.96 micrograms cm-21 hr-1, respectively, for applicators with and without gloves. The maximum dermal exposure recorded in this study was 2.86 mg kg-1 hr-1 which is significantly less than the stimated dermal LD50 value for carbaryl (4000 mg kg-1). The maximum air concentration of carbaryl was 0.28 microgram L-1. Only a small mean decrease was found in the applicators serum (-1.01%) or erythrocyte (-1.39%) acetylcholinesterase activity. Although some applicators had decreases in either serum or erythrocyte acetylcholinesterase activity greater than 20%, an equal number had increases of the same magnitude. The mean total carbaryl exposure to the applicators, expressed as a percent of toxic dose per hr, was 0.01%, with a maximum estimated exposure of 0.08%.

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. We have, therefore, compared the effects of the two drugs on blood pressure, heart rate, and peripheral vasodilation in rats, and on myocardial contractility in isolated rabbit hearts at a series of comparable doses. Quinidine produces a more marked bradycardia and depression of blood pressure than does cupreidine. The vasodilation produced by intraarterial administration of quinidine was significantly greater than cupreidine. Furthermore, quinidine elicited a greater negative inotropic effect. Cupreidine exhibited a much more favorable hemodynamic profile than quinidine with regard to the properties that were examined. These results, coupled with the fact that cupreidine has significant antiarrhythmic activity and a lower acute toxicity profile, suggest that this drug may be useful in the therapy of cardiac arrhythmias.

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. Injection of atropine (0.1-0.8 mumoles) into the hindlimb perfusion circuit resulted in a dose-dependent decrease in perfusion pressure which was immediate in onset and always preceded systemic pressure changes. The duration of vasodilation lengthened with increasing doses of atropine and ranged from 1.5 to 9 min. 3. During atropine-induced vasodilation, challenging doses of acetylcholine did not alter the perfusion pressure. 4. These experiments suggest that atropine is capable of direct vasodilator activity upon the peripheral vasculature in which a muscarinic mechanism appears unlikely.

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. Mice were observed over a 24-h period, and thereafter for each additional 24-h period for a total of 120 h. Tests for parallelism of acute toxicity indicated that with the exception of the 6'-isovaleryloxy derivative the drug treatment regression lines were parallel to that of quinidine (P > 0.05). The results indicated decreases of 50% (843 mumol/kg), 52% (857 mumol/kg), and 61% (910 mumol/kg) in the acute toxicities of the 6'-acetyloxy, 6'-hydroxy, and 6'-benzoyloxycinchonine, respectively. The 6'-acetyloxy (18.5 mumol/kg) and 6'-benzoyloxy (14.6 mumol/kg) derivatives had significantly lower ED50 values than quinidine (60.1 mumol/kg). The results suggest that the 6'-acetyloxy and 6'-benzoyloxy derivatives may have much greater antiarrhythmic effectiveness than quinidine.

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 (0.1-100 mg/kg, s.c.) or equivalent volumes of saline. After 90 minutes, all rats received 50 uCi/kg of 3H-tetracycline. Rats were sacrificed 3 hours after 3H-tetracycline administration and the hearts were removed and rinsed free of blood. The degree of radioactivity of the heart as determined by liquid scintillation counting was directly proportional to the dose of isoproterenol. Propranolol pretreatment decreased the accumulation of radioactivity in a dose-dependent fashion. Determination of 3H-tetracycline accumulation appears to be a rapid and reliable method for quantitating isoproterenol-induced myocardial necrosis.