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Biomedical subjects

R A Roth

Publications and source records attributed to R A Roth.

At least 343 records · Page 19Linked to original sources
PubMed1980

Disposition of biogenic amines and angiotensin I by lungs of spontaneously hypertensive rats.

Recent studies have suggested that the lung plays an important role in modifying concentrations of circulating vasoactive compounds. Isolated lungs of spontaneously hypertensive rats (SHR) were examined for their ability to modify concentrations of perfused norepinephrine, 5-hydroxytryptamine, or angiotensin I. Lungs from 4- or 14-wk-old SHR removed significantly more perfused 0.1 microM norepinephrine (NE) than lungs of normotensive controls (Wistar-Kyoto rats, WKY) of the same age. For example, lungs of 14-wk-old WKY removed 18.5 +/- 1.8% of perfused NE in a single pass through the pulmonary vasculature, whereas lungs from SHR removed 31.7 +/- 1.0%. Lungs of 14-wk-old SHR also produced more O-methylated NE metabolite than did lungs of WKY. Conversely, lungs of 14-wk-old SHR removed slightly less perfused 5-hydroxytryptamine and produced less 5-hydroxyindoleacetic acid metabolite than those of WKY. Monoamine oxidase activity, determined in 600 g supernatant fractions of lung homogenates, was the same in SHR and WKY. In addition, no difference in the ability of lungs of WKY and SHR to remove perfused angiotensin I was found either in animals 4 or 14 wk of age. These results suggest that lung may contribute to differences in concentrations of circulating biogenic amines observed in SHR and WKY.

Angiotensin I↗
PubMed1980

Age-related differences in angiotensin I metabolism by isolated perfused rat lungs.

The pulmonary vasculature has been implicated in the clearance of several vasoactive substances from the circulation including angiotensin I (AI). In view of the previously reported age-related differences in angiotensin-converting enzyme (ACE) activity of lung homogenates, it was of interest to examine the ability of intact perfused lungs to metabolize AI. Lungs from newborn and adult rats were perfused with Krebs bicarbonate buffer containing 1.0 ng/ml AI in a single-pass, nonrecirculating system. The rate of perfusion was normalized to lung mass. Removal of AI was determined from the transpulmonary difference in radioimmunoassayable AI. Lungs from 7-day-old rats removed a smaller fraction of AI from the circulation than did adult lungs. The age-related increase in AI clearance was accompanied by an increase in pulmonary ACE content; however, enzyme content alone could not account for the observed differences. The increased metabolism of AI by the pulmonary vasculature during development may contribute to the age-related increase in circulating angiotensin II concentrations.

Aging↗
PubMed1980

Disposition of 5-hydroxytryptamine in lungs of developing rats.

The pulmonary vasculature has been implicated in the clearance of several vasoactive peptides, prostaglandins, and biogenic amines from the circulation. In view of the age-related differences in the metabolism of angiotensin by intact lungs, it was of interest to examine the maturation of 5-hydroxytryptamine (5-HT) disposition by isolated perfused lungs. Lungs from newborn and adult rats were perfused with Krebs bicarbonate buffer containing 0.1 microM 5-[14C]HT and samples of the effluent medium collected and analyzed for 5-HT and metabolite. Adult lungs removed and a greater fraction of perfused 5-HT than did lungs from 7-day-old rats. No age-related difference in monoamine oxidase (MAO) activity was observed; however, lung slices from adult rats incubated with 5-[14C]HT accumulated radiolabel at a greater rate than did slices from lungs of 7-day-old rats. The age-related difference in 5-HT clearance by intact lungs may be attributable to a relative deficiency in the facilitated transport process for 5-HT in newborns and may reflect a general functional maturation of processes associated with pulmonary endothelial cell membranes.

Aging↗
PubMed1980

Clearance of 5-hydroxytryptamine by rat lung and liver: the importance of relative perfusion and intrinsic clearance.

Since it is replete with degradative enzymes, the liver is commonly viewed as the organ primarily responsible for clearing circulating substances which are eliminated by metabolism. However, the enzyme content of an organ is not the only determinant of clearance. The relative tissue perfusion, a determinant of substrate delivery, is also an important factor. On the basis of enzyme content, clearance of 5-hydroxytryptamine (5-HT) by rat liver would be predicted to be greater than that by rat lung, since liver contains more than 10 times as much monoamine oxidase. However, pulmonary blood flow and, hence, substrate delivery is greater than that of liver. To examine the effect of tissue perfusion, the clearance of [14C]5-HT was studied in isolated, perfused rat lung and liver at several flows. The clearance of 5-HT was found to increase, while the extraction ratio decreased, with increasing flow in both organs. At normal (i.e., in vivo) organ flows, hepatic 5-HT clearance was only one-third of that observed in lung. The pulmonary 5-HT extraction ratio was greater than 0.90 at low flows, but was only 0.43 at normal flow. Attempts to predict the clearance of 5-HT from monoamine oxidase enzyme kinetic parameters determined in organ homogenates were successful for liver, but underestimated the observed pulmonary clearance. These results suggest that, despite its relative deficiency in degradative enzyme, the rat lung plays a major role in the total body clearance of circulating 5-HT.

Animals↗
PubMed1978

Effects of monocrotaline pretreatment of rats on removal of 5-hydroxytryptamine and noradrenaline by perfused lung.

1 The alkaloid, monocrotaline, causes significant pulmonary damage in many species, including the rat. We, therefore, determined whether the inactivation of biogenic amines by perfused lungs of rats was modified by prior treatment of the animals with monocrotaline.2 Young rats (45 to 50 g) treated for 21 days with monocrotaline (22 mug/ml) in their drinking water developed right ventricular hypertrophy. Treated animals gained weight more slowly and consumed less food and water than control rats that drank tap water. Lungs from monocrotaline-treated animals were heavier and had a higher protein content than control lungs.3 Isolated lungs from treated animals removed and metabolized 50% less perfused 5-hydroxytryptamine than did controls.4 The diminished 5-hydroxytryptamine metabolism was probably due to impaired delivery of substrate to intrapulmonary monoamine oxidase (MAO) since MAO activity in 600 g supernatant fractions of homogenates of lungs from monocrotaline-treated rats was not different from control values.5 Pulmonary removal of perfused noradrenaline was decreased about 60% by the 21-day treatment, suggesting that the effects of monocrotaline were somewhat nonspecific.6 These effects were not caused by monocrotaline directly, since perfusion of lungs from untreated animals with this drug did not alter removal of co-perfused 5-hydroxytryptamine.7 Reduced pulmonary removal of circulating biogenic amines following pretreatment with monocrotaline may reflect damage to capillary endothelium, which could also affect other metabolic functions of lung.

Animals↗
PubMed1977

Disposition of 14C-mescaline by rabbit lung.

Metabolism of mescaline by several rabbit tissues was examined in vitro. Mescaline-oxidizing activity (micromoles per milligram of protein/15 min) of lung homogenates was 4 times greater than that of either liver or kidney. Brain and plasma each had comparatively little capacity to metabolize mescaline. Mescaline metabolism in vitro was sensitive to inhibition by semicarbazide. Removal of mescaline from the medium perfusing the isolated rabbit lung was explained by intrapulmonary metabolism. Semicarbazide (10(-3) M pargyline. Semicarbazide-treated lungs accumulated more mescaline than did untreated lungs. Mescaline efflux from lung was slower than that of its metabolite. These results indicate that the intact lung removes perfused mescaline and may be important in the disposition of circulating mescaline in vivo.

Animals↗
PubMed1976

Systematic evaluation of cellular radiosensitivity parameters.

Cellular radiosensitivity parameters of the track structure theory of Katz and co-workers are evaluated from a sum of squares minimizing computer program for nonlinear models. Based on these observations, suggestions are presented for efficient experiment design for the determination of these parameters from track-segment bombardments of high LET radiations.

Cell Survival↗
PubMed1976

Comparison of the effect of carbon monoxide and of hypoxic hypoxia. I. In vivo metabolism, distribution and action of hexobarbital.

Previous experiments had shown that carbon monoxide inhalation prolonged the in vivo response zoxazolamine. However, CO was clearly less potent than an equivalent level of hypoxia induced by inhalation of lowered O2 content (hypoxic hypoxia). The present study revealed that both CO and hypoxic hypoxia also prolonged the pharmacologic response to a drug of vastly different structure and site of action, i.e., hexobarbital. In this case, CO was approximately equipotent to hypoxic hypoxia in prolonging sleeping time. In spite of a number of significant effects of the two types of hypoxia on factors such as rate of peritoneal absorption, distribution into the brain and brain sensitivity to the drug, their relative potencies in prolonging sleeping time appeared to reflect adequately their relative effects on in vivo rate of metabolism. This conclusion was based on their equipotencies in decreasing the rate of disappearance of hexobarbital from the blood. The observation that hypoxia induced by CO had no greater effect on hexobarbital metabolism than hypoxia induced by oxygen deprivation suggests that the binding of CO to cytochrome P-450 is not important in drug metabolism in vivo. CO would appear to act solely by inducing tissue hypoxia.

Animals↗
PubMed1976

Comparison of the effect of carbon monoxide and of hypoxic hypoxia. II. Hexobarbital metabolism in the isolated, perfused rat liver.

Rat livers were perfused with a red blood cell-containing perfusion medium. The rate of metabolism of hexobarbital was determined in this system as the recirculating perfusion fluid was made hypoxic by exposure to either CO or lowered oxygen tension. It was found that 7.6% of the total oxygen consumed by the liver was utilized to metabolize hexobarbital regardless of the severity of the hypoxia, which suggests that the liver does not shunt O2 to more preferential pathways as O2 availability becomes limited. When oxygen delivery was lowered below 0.3 ml of O2 per min per g of liver by either type of hypoxia, the rate of hexobarbital metabolism decreased. However, based on the rate of oxygen delivery, CO was more potent than hypoxic hypoxia in inhibiting drug metabolism. On the other hand, the two types of hypoxia were equipotent when compared on the basis of alterations in oxygen consumption. These results are consistent with the known effect of CO in decreasing the availability of hemoglobin-bound O2 and further argue against the direct inhibition of drug metabolism by the binding of CO to cytochrome P-450 in the isolated liver. They also suggest that the lack of a greater potency of CO relative to hypoxic hypoxia in vivo might be related to alterations in hepatic blood flow.

Animals↗