Myocardial glucose uptake is regulated by nitric oxide via endothelial nitric oxide synthase in Langendorff mouse heart

Although the role of nitric oxide (NO) in the modulation of vascular tone has been studied and well understood, its potential role in the control of myocardial metabolism is only recently evident. Several lines of evidence indicate that NO regulates myocardial glucose metabolism; however, the details and mechanisms responsible are still unknown. The aim of this study was to further define the role of NO in the control of myocardial glucose metabolism and the nitric oxide synthase (NOS) isoform responsible using transgenic animals lacking endothelial NOS (ecNOS). In the present study, we examined the regulation of myocardial glucose uptake using isometrically contracting Langendorff-perfused hearts from normal mice (C57BL/6J), mice with defects in the expression of ecNOS [ecNOS (-/-)], and its heterozygote [ecNOS (+/-)], and wild-type mice [ecNOS (+/+)] (n=6, respectively). In hearts from normal mice, little myocardial glucose uptake was observed. This myocardial glucose uptake increased significantly in the presence of N(omega)-nitro-L-arginine methyl ester (L-NAME). Similarly, in the hearts from ecNOS (-/-), glucose uptake was much greater than in normal mice, whereas myocardial glucose uptake of ecNOS (+/-) and ecNOS (+/+) mice was not different from normal mice. In addition, myocardial glucose uptake of ecNOS (+/-) and ecNOS (+/+) mice increased significantly in the presence of L-NAME. At a workload of 800 g. beats/min, L-NAME increased glucose uptake from 0.1+/-0.1 to 3+/-0.4 microg/min x mg in ecNOS (+/-) mice and from 0.2+/-0.1 to 2.7+/-0.7 microg/min x mg in ecNOS (+/+) mice. Furthermore, in the hearts from ecNOS (-/-) mice, 8-bromoguanosine 3':5'-cyclic monophosphate (8-Br-cGMP), a cGMP analog or S-nitroso-N-acetylpenicillamine (SNAP), a NO donor essentially shut off glucose uptake, and in hearts from ecNOS (+/-) mice, 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ), an inhibitor of cGMP, increased the glucose uptake significantly. These results indicate clearly that cardiac NO production regulates myocardial glucose uptake via a cGMP-dependent mechanism and strongly suggest that ecNOS plays a pivotal role in this regulation. These findings may be important in the understanding of the pathogenesis of the diseases such as ischemic heart disease, heart failure, diabetes mellitus, hypertension, and hypercholesterolemia, in which NO synthesis is altered and substrate utilization by the heart changes.     

Slow release theophylline in patients with airways obstruction with particular reference to the effects of food upon serum levels

Eighteen patients with airways obstruction were given slow release theophylline and were then investigated to determine the influence of a standard meal upon the serum levels achieved over the ensuing 12-hour period. After food the peak to trough differences were decreased and the serum levels were significantly lower over the first 6 hours. In this study, the patients were given 10 mg/kg/day of slow release theophylline and none subsequently was found to have toxic levels, therefore this was considered to be a reasonable dose with which to initiate therapy in adults with uncomplicated airflow limitation. However even under the strictly controlled conditions of the study there were wide variations between individuals in the blood levels achieved and serum monitoring is necessary to use theophylline in an optimal fashion.     

Divergent efficacy of antibody to tumor necrosis factor-alpha in intravascular and peritonitis models of sepsis

The role of tumor necrosis factor-alpha (TNF alpha) in the lethal consequences of intravascular lipopolysaccharide (LPS) or Escherichia coli sepsis was compared with that in bacterial peritonitis. Intravenous administration of E. coli LPS or E. coli (live or dead) resulted in large transient increases in serum TNF alpha levels, peaking at 90 min at 10,000-30,000 units/ml. In contrast, the serum TNF alpha response following the induction of bacterial peritonitis was substantially less, peaking at 200-500 units/ml. Sterile peritonitis (essentially nonlethal) and bacterial peritonitis (greater than 60% lethal) elevated TNF alpha levels to 1000-2000 units/lavage within the peritoneal cavity 2 h after challenge. Passive immunization with neutralizing goat anti-TNF alpha IgG improved survival from 8% to 75% in rats administered LPS intravenously but was completely ineffective in protecting rats from lethal E. coli peritonitis. Thus significant differences exist in the role TNF alpha plays in systemic intravascular models of sepsis and bacterial peritonitis.     

Selection of patients for bile diversion surgery: use of bile acid measurement in fasting gastric aspirates

Eighteen patients with dyspepsia and vomiting which followed surgery for peptic ulcer have completed a study to examine the role of diverting bile from the stomach by a Roux-en-Y procedure. Bile regurgitation and mild epigastric pain relieved by vomiting were abolished. Measurements of bile acids in the fasting gastric aspirate were useful in predicting the outcome of surgery; good results were obtained when initially there was reflex into the stomach of more than 120 mumol/hour of bile acids. A wider group of patients than those selected in previous series may benefit from this operation, as good results can be obtained in patients with dyspepsia relieved by alkali and without achlorhydria or gastritis. Endoscopy was repeated one year after Roux-en-Y operation. Erythema of the mucosa was improved, but gastritis did not improve.     

Irritant induced cough as a model of intrapulmonary airway reactivity

Theophylline, papaverine and isoprenaline produced dose-related inhibition of citric acid induced cough. In addition, cough susceptibility correlated well with the susceptibility of intrapulmonary airways to constrict whether aerosolised citric acid or intravenous histamine were used as the agonists. The anti tussive activity of isoprenaline could be inhibited with propranolol whereas that of theophylline was unaffected. Atropine and propranolol alone failed to modify citric acid induced cough. We suggest that the reactivity of intrapulmonary airway smooth muscle dictates the cough response following inhalation of a citric acid mist.     

The role of transesophageal echocardiography in the diagnosis and management of patients with aortic perivalvular abscesses

Aortic valve abscesses (AVAs) are a devastating complication of aortic valve endocarditis. Over 8 years, 25 patients were diagnosed with AVA by transesophageal echo (TEE). Management and outcomes were then analyzed. Eleven (44%) AVAs involved prosthetic valves, and 6 (24%) occurred in congenitally malformed valves. Twenty patients (80%) underwent surgical intervention; the rest were treated medically. Eleven (44%) of the patients died [6 (30%) surgery patients and all the medical patients]. Eight of 11 (73%) patients who died were culture positive for Staphylococcus aureus. All patients with congenitally malformed aortic valves underwent surgical intervention and survived. We conclude that: (1) despite advances in therapy and diagnosis, patients with AVAs have a high mortality rate; (2) prognosis with AVA is especially poor when S aureus is the infectious organism; (3) patients with AVAs in congenitally malformed valves have a great outcome with surgery; (4) patients treated medically have a very poor prognosis; earlier identification by TEE may be critical to improving survival.     

Effects of verapamil on haemodynamic function and myocardial metabolism in patients with hypertrophic cardiomyopathy

The effect of 20 mg dose of intravenous verapamil was studied over a range of heart rates in 12 patients with hypertrophic cardiomyopathy. Six patients had an appreciable left ventricular outflow tract gradient and six did not. The drug reduced myocardial oxygen consumption in proportion to a reduction in the development of left ventricular pressure. The negative inotropic effect of verapamil was counteracted by the drug's non-specific vasodilator activity, so that cardiac index was unaltered at any heart rate and as a result myocardial efficiency was unaffected by the drug. Verapamil did not consistently alter myocardial metabolism. Some patients showed improvement in anaerobic myocardial metabolism after verapamil but an equal number showed impairment of lactate metabolism. It was not possible to predict from clinical features, echocardiographic findings, or haemodynamic variables measured before administration of verapamil which patients would demonstrate haemodynamic or metabolic improvement after the drug. In this short term study no mechanism was demonstrated by which patients with hypertrophic cardiomyopathy might obtain a consistent improvement from treatment with verapamil.     

Reduction of blood viscosity following plasma exchange.

The effect of plasma exchange with plasma protein fraction on blood viscosity was determined in seven hyperlipoproteinaemic patients with coronary or peripheral vascular disease. This resulted in decreases in whole blood viscosity of 83% and 30% respectively at the lowest and highest shear rates studied, and decreases of 21% and 59% in plasma viscosity and fibrinogen. Serum cholesterol and triglyceride were reduced by 66% and 48% respectively. Sequential studies in two patients showed that blood viscosity returned to near-basal values by the 6th day. These findings suggest that plasma exchange may result in short-term enhancement of blood flow in vessels where low shear rates predominate.