Beta blockers reduce myocardial oxygen demand and are therefore useful in ischemic states. They reduce angina pectoris and reduce the risk of death when administered long-term after acute myocardial infarction. Some studies suggest that when administered early after coronary occlusion they can reduce myocardial infarct size. Relative contraindications to beta blockers, such as a history of congestive heart failure, chronic obstructive lung disease, atrioventricular conduction defects and low blood pressure, limit their use. Conventional beta blockers have a relatively long duration of action and are either contraindicated or must be used with particular caution in patients with these contraindications. Esmolol is an ultrashort-acting beta blocker with a biologic half-life of 9 minutes. Therefore, such an agent may be useful in patients with ischemic heart disease in whom reducing heart rate would be beneficial but in whom there is concern that beta blockers might not be tolerated. Esmolol reduced myocardial infarct size in 2 experimental studies of coronary occlusion followed by reperfusion, and improved the recovery of the stunned myocardium when administered during experimental myocardial ischemia. Esmolol's brief duration of action may make it safer than conventional beta blockers for the management of patients with unstable angina or myocardial infarction.

Adrenergic beta-Antagonists↗

PubMed1985

Isolation and partial characterization of a rifampicin induced rabbit liver microsomal cytochrome P-450.

Rifampicin administration to New Zealand male rabbits increased the concentration of an LM3 form of cytochrome P-450 to up to 30% of the microsomal P-450 concentration. This enzyme was purified to electrophoretic homogeneity with a yield of 8% of the original total microsomal P-450 concentration. Isolated as a low spin hemoprotein in its substrate free oxidized form, it displays in its reduced CO-complexed form an absorption maximum at 449 nm. Immunological assays, as well as activity measurements, in particular its stereospecific progesterone hydroxylation in the 6 beta-position, show a relationship between LM3,Rif and LM3c (from untreated rabbits).

Animals↗

PubMed1985

Definition of a gastric emptying abnormality in patients with anorexia nervosa.

Upper gastrointestinal symptoms may be prominent in anorexia nervosa. This study is an investigation of the gastric emptying of solid and liquid meal components in 16 female patients (mean age 20.0 years, range 14-40 years) who met accepted psychiatric diagnostic criteria for anorexia nervosa. The results were compared with those of gastric emptying studies in 10 normal females of ideal body weight (mean age 25.4 years, range 20-35), 13 normal persons (12 males), and six patients (mean age 12 years, range 9-14 years) with weight loss (less than 90 percent ideal body weight) secondary to Crohn's disease with no psychiatric symptoms. A dual-isotope technique using chicken liver intracellularly labeled with technetium-99m (99mTc) bound to sulfur colloid as the solid-phase marker, and indium-111 (111In) -labeled water as the liquid-phase marker was used. Gastric emptying was monitored for 2 hr by gamma camera. In 13 of the 16 anorexia nervosa patients (80%), gastric emptying of solids was slower than the range in the two groups of normal subjects, and mean gastric emptying was significantly slower (P less than 0.05) than in the weight-loss patients. Liquid emptying (water) in anorexia nervosa was normal and similar to the control groups studied. In 11 of the anorexia nervosa patients with delayed gastric emptying, intramuscular metoclopramide, 10 mg, significantly (P less than 0.05) accelerated the mean gastric emptying from 60 through 120 min after the meal. We conclude that in anorexia nervosa patients who are symptomatic and seeking medical care: gastric emptying of solids is significantly delayed when compared with female subjects of similar age and normal body weight and with patients of less than 90% ideal body weight but without psychiatric disorder; these data are consistent with an antral motility disturbance, either primary or secondary; and metoclopramide, a gastric prokinetic agent, accelerates (delayed) gastric emptying.

Adolescent↗

PubMed1985

In vitro protection of amphibian gastric mucosa by nutrient HCO3- against aspirin injury.

The effects of luminal aspirin [acetylsalicylic acid (ASA)] at luminal pH 4.5 and pH 3.0 on Ussing chambered amphibian gastric fundic and antral mucosae were investigated using different concentrations of HCO3- ([HCO3-]) in the nutrient solution in histamine-stimulated or metiamide-treated tissues. The severe surface cell and oxyntic gland injury seen in histamine-stimulated tissues after a 3-h exposure to 20 mM ASA at luminal pH 4.5 in HCO3- -free nutrient solution (HEPES) was prevented by including 18 mM or 48 mM HCO3- in the nutrient solution. At luminal pH 3.0, 48 mM HCO3- in the nutrient solution delayed the histologic damage to the surface epithelium and oxyntic glands caused by a 30-min exposure to 20 mM luminal ASA, but it afforded no protection to a 60-min exposure. This protection of the gastric epithelium by a high nutrient [HCO3-] did not occur in metiamide-treated tissues at luminal pH 3.0. Although the injury to antral epithelial cells exposed to 20 mM luminal ASA at luminal pH 3.0 or 4.5 was less severe than that in fundic mucosae, 48 mM HCO3- in the nutrient solution also afforded clear protection in this tissue. A high nutrient [HCO3-] prevented the sharp fall in the potential difference observed in fundus exposed to ASA at luminal pH 4.5 and delayed the fall in potential difference observed in fundic and antral mucosae exposed to ASA at luminal pH 3.0. The high nutrient [HCO3-] did not prevent the increase in resistance observed in tissues during ASA exposure at luminal pH 4.5 and 3.0. The electrical data reflect not only the damaged surface and oxyntic cells caused by ASA, but also the complex effects of ASA on active and passive ion transport. We conclude the following: (a) The mucosal injury to the fundus and antrum caused by luminal ASA is prevented by 48 mM HCO3- in the nutrient solution when luminal pH is 3.0 and by 18 mM HCO3- when luminal pH is 4.5. Absence of nutrient HCO3- accentuates the injury caused by luminal ASA. (b) The luminal pH, concentration, and time of exposure influence the depth and severity of ASA injury to the fundic and antral mucosa. (c) The electrophysiologic and morphologic changes after ASA exposure are not interrelated, due to the complex effects of ASA on the ion transport and morphology of the gastric epithelium.

Animals↗

PubMed1985

Delayed gastric emptying in children with Crohn's disease.

To evaluate the role of delayed gastric emptying in the decreased nutritional intake and growth retardation of some patients with Crohn's disease, we looked at four groups: 1) Crohn's disease with growth retardation; 2) Crohn's disease with malnutrition or acute weight loss; 3) Crohn's disease without growth retardation or malnutrition; and 4) normal controls. Gastric emptying was measured by a test meal incorporating 99mTc sulfur colloid-labeled chicken liver as the solid phase marker and 111In-labeled water as the liquid phase marker. The percent of each isotope retained in the stomach over 120 minutes was compared among the groups and correlated with established nutritional parameters, caloric intake, and disease activity. Gastric emptying of the liquid component was the same in all groups, and emptying of solids in patients with Crohn's disease and growth retardation was not significantly different from controls. However, gastric emptying of solids was delayed in five of seven patients in the malnourished group; the mean emptying rate of all seven patients was significantly slower compared both to the normals (p less than 0.01) and the Crohn's patients without growth disturbances (p less than 0.05). This delay was correlated with caloric intake, but not with disease activity or any individual nutritional parameter except arm muscle area (p less than 0.01). Multiple regression analysis revealed that 54% of the variation in the emptying of solids could be accounted for by nutritional factors. Fifty-seven percent of patients with delayed gastric emptying had radiologic and/or endoscopic evidence of nonconstrictive involvement of the duodenum with Crohn's disease, while 80% of patients with such involvement had delayed gastric emptying. These results help explain the decreased caloric intake observed in Crohn's disease patients and support the role of liquid caloric supplements.

Adolescent↗

PubMed1985

Characteristics of sudden potential drop in bullfrog gastric mucosa.

An unusual sudden potential drop (SPD) has been described by Kidder in bullfrog gastric mucosa exposed to anoxia and a serosal pH less than or equal to 7.1. We found that anoxia was not a prerequisite, since under fully oxygenated conditions the SPD occurred reliably in metiamide-treated tissues when the pH of the nutrient solution (pHN) was below 7.1. The SPD was observed also in metiamide-treated tissues exposed to 20 mM luminal or nutrient acetylsalicylic acid (ASA) with pHN = 7.3, an effect that was abolished by increased nutrient HCO3- concentration. The SPD occurred when NO3- but not isethionate or acetate replaced Cl- in the bathing media. A marked increase in potential difference in response to changing luminal Cl- concentration was observed after the SPD, uptake of Cl- from the luminal solution into the tissue increased, but transmural fluxes of Cl- decreased bidirectionally. Permeability to H+ was unaltered in the post-SPD state. An SPD never occurred in antrum under conditions causing SPD in fundus, suggesting that oxyntic cells are prerequisite. We conclude that, under conditions which cause tissue or cellular acidosis and cessation of H+ secretion, fundic mucosae respond with an anion-selective increase in apical permeability manifest as the SPD.

Animals↗

PubMed1984

Inductive and repressive effects of rifampicin on rabbit liver microsomal cytochrome P-450.

New Zealand White rabbits were treated with rifampicin at a dose of 50 mg/kg for 4 days. The total amount of microsomal hepatic cytochrome P-450 was not modified in treated, with respect to control, animals. However, further studies involving SDS-PAGE analysis, monooxygenase activity measurements and radial immunodiffusion assays indicated that rifampicin strongly affects the level of two P-450 isoenzymes. An LM3 form was induced; this form, apparently associated with erythromycine demethylase activity and hydroxylation of progesterone preferentially in position 6 beta, was shown to be immunologically and functionally different from LM3a and LM3b. On the other hand, an LM4 form, typically induced by beta-naphthoflavone, was repressed. The concomitant inductive/repressive effect of rifampicine on two cytochrome P-450 isoenzymes makes this drug a very atypical inducer, at least in the rabbit.

Animals↗

PubMed1984

Correlates of reperfusion ventricular fibrillation in dogs.

To elucidate determinants of reperfusion ventricular fibrillation (VF), regional myocardial blood flow, ATP, creatine phosphate (CP), heart rate and blood pressure were compared in 2 groups of anesthetized dogs: those that fibrillated spontaneously upon release of a 15-minute coronary artery occlusion (VF group, n = 8) and those that did not fibrillate when reperfused (No VF group, n = 27). Arterial pressure and heart rate before and during coronary artery occlusion were similar in both groups. Ischemic endo- and epicardial ATP values, measured at the end of the occlusion period, were reduced approximately 20% of nonischemic values in both groups. In contrast, CP (nmol . mg protein-1) within the ischemic zone was significantly lower in the VF group in both the epicardium (14.3 +/- 1.6 in the VF group vs 22.8 +/- 2.5 in the No VF group, p less than 0.01) and the endocardium (9.0 +/- 2.0 in the VF group vs 18.7 +/- 1.8 in the No VF group, p less than 0.01). Furthermore, epi- and endocardial regional myocardial blood flow in the center of the ischemic zone during occlusion was significantly lower in VF dogs than in No VF dogs. Epicardial flow was 0.06 +/- 0.03 ml X min-1 X g-1 in VF dogs vs 0.44 +/- 0.06 in No VF dogs (p less than 0.001) and endocardial flow was 0.03 +/- 0.02 ml X min-1 X g-1 in VF dogs vs 0.23 +/- 0.04 ml X min-1 X g-1 in No VF dogs (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗

PubMed1984

Failure of pindolol and metoprolol to reduce the size of non-reperfused infarcts in dogs using area at risk techniques.

Recent studies have shown that long term mortality after acute myocardial infarction is reduced by chronic beta-blocker therapy, however, the mechanism is not well understood. Our objective was to determine whether the selective beta blocker, metoprolol, or the nonselective intrinsic sympathomimetic activity (ISA)-blocker pindolol, reduce infarct size as a function of an area at risk (AR) in a permanent infarction model in dogs and which blocker is preferable in regards to myocardial function. Dogs were instrumented with ultrasonic crystals to measure regional function in nonischaemic and infarct margin segments. Left ventricular (LV) pressures, LV dP/dt and heart rate (HR) were monitored. Dogs were subjected to a 6 h LAD coronary artery occlusion and were randomised to a control (n = 9), pindolol (n = 10), and metoprolol (n = 9) group. At 30 and 90 min post occlusion saline, pindolol (3 micrograms X kg-1 and 12 micrograms X kg-1) or metoprolol (12 micrograms X kg-1 and 48 micrograms X kg-1) were given intravenously. The in vivo AR was determined by autoradiography, the in vitro AR by postmortem dye infusion and the area of necrosis by tetrazolium staining. Pindolol and metoprolol decreased LV dP/dt by 20% (P less than 0.05). Metoprolol also decreased HR by 20% (P less than 0.05) and shortening of nonischaemic segments by 12% (P less than 0.05) following the 1st and 2nd dose. Function in infarct margin segments was not changed in either group. Blood flow, measured by microspheres, was similar in the three groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1984

Absence of a cumulative deterioration of regional function during three repeated 5 or 15 minute coronary occlusions.

Recurrent myocardial ischemia is commonly seen in patients with coronary artery disease, in patients undergoing cardiac surgery with intermittent cross-clamping, and experimentally when multiple occlusion preparations are used to test drugs. Our study was designated to investigate whether myocardial injury is cumulative after three sequential ischemic episodes. Sixteen dogs were instrumented with ultrasonic crystals to assess percentage of segmental shortening and percentage of wall thickening in ischemic and nonischemic regions. The left anterior descending coronary artery was occluded three times for 5 min in one group (n = 8) and three times for 15 min in another group of dogs (n = 8) and each occlusion was followed by 30 min of reflow. Blood flow was determined with microspheres before coronary artery occlusion in the 5 min group and during occlusion in the 15 min group and in all dogs 25 min into the first and third reperfusion periods. During the three reperfusion periods mean segmental shortening in the ischemic zone recovered to only 60.5 +/- 8.7% (+/- SEM) of the preocclusion level (p less than .003) in the 5 min occlusion group and to 36.9 +/- 17.7% in the 15 min occlusion group (p less than .01). Mean wall thickening recovered to 61.3 +/- 16.6% (p less than .06) in the 5 min group and to 48.6 +/- 11.8% in the 15 min group (p less than .004). There were no significant differences during the reperfusion phase when mean values for the ischemic segment after the second and third occlusion were compared with the data obtained after the first occlusion in either group.(ABSTRACT TRUNCATED AT 250 WORDS)

Angina Pectoris↗

PubMed1984

Preservation of high-energy phosphates by verapamil in reperfused myocardium.

To determine whether verapamil prevents depletion of adenine nucleotides during and after severe myocardial ischemia, dogs were subjected to 15 min occlusions of the left anterior descending coronary artery followed by 240 min of reperfusion. One hour before occlusion, dogs were randomly assigned to a treatment group (n = 10) to which an infusion of intravenous verapamil was given until the onset of reperfusion or to an untreated saline group (n = 9). Verapamil reduced mean aortic pressure and heart rate. After 15 min of ischemia, endocardial adenosine triphosphate (ATP) level, determined by needle biopsy, decreased in the untreated group from 34.7 +/- 2.0 to 24.4 +/- 2.7 nmol X mg protein-1 (p less than .005 vs preocclusion) and in the verapamil group from 32.8 +/- 1.5 to 30.3 +/- 1.5 nmol X mg protein-1 (NS vs preocclusion). Dogs receiving verapamil had significantly higher ATP levels than untreated animals after 90 and 240 min of reperfusion. In untreated animals the sum of inosine and hypoxanthine levels increased during occlusion from very low levels to 4.6 +/- 1.1 nmol X mg protein-1 in the epicardium and to 6.8 +/- 1.5 nmol X mg protein-1 in the endocardium (p less than .05 compared with preocclusion values). In verapamil-treated dogs inosine and hypoxanthine levels increased to only 1.2 +/- 0.3 (epicardium) and 1.9 +/- 0.6 nmol X mg protein-1 (endocardium) (both NS compared with preocclusion values). After 90 min of reperfusion the sum of ATP, adenosine diphosphate, adenosine monophosphate, inosine, and hypoxanthine levels was decreased in the endocardium by 10.2 nmol X mg protein-1 in the untreated group, but no change was observed in verapamil-treated animals. We conclude that breakdown of ATP to inosine and hypoxanthine during severe ischemia is reduced by verapamil, resulting in higher ATP concentrations during occlusion and reperfusion and decreased washout of the diffusible purines inosine and hypoxanthine during reperfusion.

Adenosine Diphosphate↗

PubMed1984

Improved intrinsic resolution: does it make a difference? Concise communication.

The purpose of this study was to determine what effect further improvement in an Anger camera's intrinsic resolution has on lesion detection. We studied 52 patients undergoing bone imaging and 58 undergoing liver imaging. All patients had images performed in rapid sequence on ZLC -75 and ZLC -37 Anger cameras, both by Siemens. The two imaging systems are virtually identical except for the number of photomultiplier tubes and crystal thickness; these resulted in differences in intrinsic resolution ( ZLC -75 less than 3.8 mm FWHM at 140 keV, ZLC -37 less than 4.9 mm) and sensitivity ( ZLC -75 approximately 0.91 of ZLC -37 at 140 keV). Observer performance, measured by ROC curves, for detection of abnormalities was virtually identical with the two instruments. Subjectively, there was a trend toward preference of the ZLC -75 images, but this was not associated with any significant improvement in lesion detectability even in the subgroup in which a preference for one or the other instrument was noted.

Bone and Bones↗