William A. Speir

Apparent irrelevance of cyclic nucleotides to the relaxation of tracheal smooth muscle induced by theophylline

The mechanism of action of the negative inotropic (relaxing) effect of the methylxanthine theophylline on respiratory smooth muscle is generally assumed to involve inhibition of cyclic nucleotide phosphodiesterase. When guinea pig tracheal rings or dog tracheal muscle strips were incubated with low concentrations of theophylline capable of producing a significant negative inotropic effect in vivo and in vitro, there was no alteration of cyclic 3′,5′-adenosine monophosphate (cAMP) or cyclic 3′,5′-guanosine monophosphate (cGMP) levels.45Ca uptake increased however, and there was a subcellular redistribution of elemental calcium consistent with a sequestration of calcium in mitochondria and a decrease of myoplasmic calcium ion (Ca++) concentration.

Studies of mediator involvement in cooling-induced alterations of guinea pig tracheal smooth muscle contractility.

Abstract Heat loss from airway smooth muscle is a potent stimulus which causes substantial, but poorly understood, alterations in muscle tension. This study considered the involvement of endogenous mediators in cooling-induced tension changes in incubated guinea pig trachea. Smooth muscle tension was monitored in tracheal cylinders which were carefully cooled from 37 to 30°C in the presence or absence of various inotropic mediators. In our study, cooling alone, at a rate of 1 °C/min, was associated with an average loss of smooth muscle tension of 88.2 mg. Cooling tracheal tissue that had been previously exposed to 3 × 10-6 M histamine, however, caused an additional increase in tracheal tension of 133 mg, over and above that caused by histamine alone. In the presence of 10-5 M prostaglandin F2α, or 10-5 M thromboxane B2, cooling was associated with respective losses of smooth muscle tension of 211.4 and 211.2 mg, as compared to the tension associated with these mediators when they were used alone under control conditions. When the speed of tracheal cooling was increased to 40°C/min, there was a slight increase in tension for 20 sec followed by a pronounced and sustained relaxation. The mechanisms involved in the response of airway smooth muscle to cooling are complex. The results of our study, however, suggest that mediators may play a role in the cooling-induced alterations of airway smooth muscle tension.

Alkalotic disequilibrium in patients with solid tumors: Rediscovery of an old finding

Abstract Acid-base equilibrium in two groups of cancer patients, one with newly diagnosed bronchogenic cancer and one with various solid tumors, was compared to that of a group of normal volunteers and a group of hospitalized patients with diverse diseases. A consistent tendency toward alkalosis was found in both groups of cancer patients. Similar findings reported in the literature of 40–70 years ago are discussed and the possible biochemical implications of these findings considered. It is our hope that this report of findings obtained with modern technology will encourage studies of the effects of alkalinity in the pathogenesis and progression of cancer.

Crown ethers which influence cardiac and respiratory muscle contractility

Guinea-pig tracheal smooth muscle and heart muscle demonstrated a variety of in vitro positive and negative inotropic responses to concentrations of crown ethers in the nmole/l to μmole/l range. It is suggested that these ionophoretic compounds have potential as therapeutic agents.

Facilitation of isoproterenol induced airway smooth muscle relaxation by nifedipine

The facilitating effect of nifedipine on isoproterenol induced airway smooth muscle relaxation was studied in guinea pig tracheas. For isometric force measurement, 4 mm tracheal cylinders were suspended in incubation chambers in oxygenated physiologic medium. After 90 minutes of equilibration under 2 grams resting tension, at a temperature of 37 degrees C and pH of 7.4, concentration response curves for isoproterenol were performed with and without the addition of a 1 X 10(-5)M nifedipine dose. The experiments were then repeated using tissues precontracted with histamine. Our data show that in the nifedipine pretreated tissues, the EC50 of isoproterenol is shifted to the left (p less than 0.05) probably due to further reduction in cytosolic calcium by nifedipine. Our findings suggest that nifedipine might have a role in the treatment of asthma and obstructive airway disease.

The influence of lanthanum on the subcellular distribution of calcium in the perfused dog heart

A newly developed method was used to make a direct study of the influence of lanthanum on the subcellular distribution of isotopic and elemental calcium in the isolated perfused dog heart. The trivalent cation was introduced into the heart for the last 5 min of a 60 min perfusion period. Developed pressure and dP/dt were monitored continually from a fluid filled balloon positioned within the left ventricular chamber. At the end of the perfusion period, calcium was fixed within the myocardium by rapid freezing followed by vacuum desiccation at -60 degrees C. Enriched populations of sarcolemma and mitochondria were then obtained utilizing a newly developed nonpolar density gradient ultracentrifugation technique. Lanthanum was found to decrease dP/dt by 82.5% without significant changes in contractile rate. Atomic absorption spectrophotometric analysis revealed that lanthanum was associated with a 48.8% decrease in sarcolemmal calcium and a 159.6% increase in mitochondrial calcium. Lanthanum caused a 40.2% increase in the mitochondrial tissue/medium 45Ca ratio without significantly altering the isotropic activity of the sarcolemma. The results confirm that lanthanum-induced negative inotropy is associated with a displacement of sarcolemma-associated calcium. Surprisingly, the diminished contractility occurs with an increase in mitochondrial-associated calcium.

SLEEP APNEA, PULMONARY HYPERTENSION AND NEPHROTIC SYNDROME *

DOI: http://dx.doi.org/10.5915/16-1-12440 Many cardiopulmonary abnormalities have been described in patients with sleep apnea syndrome. We are reporting a patient with severe obstructive sleep apnea who had severe episodic pulmonary hypertension, hypoxemia, and nephrotic syndrome. We are postulating that nephrotic syndrome was causally related to sleep apneas. Presented at the 16th Annual Meeting: of the Islamic Medical Association (September 1983), Oakbrook, Illinois, United States of America

Temporal relationship of cyclic nucleotide levels and calcium exchange to histamine-induced tension development.

Abstract The purpose of these experiments was to study the temporal relationship between tension development in incubated guinea pig tracheal smooth muscle and changes in tissue levels of cAMP and cGMP, and isotopic Ca. Dose–response studies were performed with increasing concentrations of histamine both in the absence and presence of H1 receptor blockade using 10-5 M diphenhydramine. The time course of tension development was subsequently determined in the presence of three concentrations of histamine shown to cause 50% (3 × 10-6 M), 85% (9 × 10-6 M), and 100% (5 × 10-5 M) of maximal contraction. Tissue cyclic nucleotide and 45Ca levels were measured 20 sec, 1 min, and 6 min after the onset of contraction. For comparison, the influence of carbachol was also studied. Our findings demonstrate that there were no detectable alterations in tissue cAMP or cGMP levels during the initial phases of contractile change. In contrast, tissue isotopic Ca uptake increased early in histamine-induced contraction and was blocked by the H1 antagonist.

Health Effects of Smokeless Tobacco

DOI: http://dx.doi.org/10.5915/19-1-12833 Smokeless tobacco is used all over the world. It is usually used orally either as chewing tobacco or as snuff. In 1985, 12 million persons in the United States used smokeless tobacco and the trend is increasing among young males. There is strong association between smokeless tobacco use and cancers of the oral cavity. There may be a fifty-fold increased risk of oral cancers among long term snuff dippers. Potent carcinogens including nitrosamines, aromatic hydrocarbons and radiation-emitting polonium are found in tobacco. Smokeless tobacco is associated with oral leukoplakia at the site of tobacco placement. Some leukoplakias undergo dysplastic changes and may become cancerous. Nicotine dependency is very similar to other drugs such as morphine. The effects of nicotine from smokeless tobacco are similar to those as seen in cigarette smoking and are not discussed in this review.

Diagnostic Challenge Dyspnea and Abdominal Pain in an Alcoholic

History A 42 year old black male presented with the complaints of upper abdominal pain and shortness of breath. He had previous hospitalizations for alcoholism and pancreatitis. Physical examination revealed a cachectic man with BP 110170 mm Hg; temperature 37 .2 °C; respiration 18/min; and pulse 80/min. Lung fields were clear except for diminished breath sounds in the right base. Abdominal examination was unremarkable. White blood ceU count was 8200/cu mm with 680Jo