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Biomedical subjects

F R Goodman

Publications and source records attributed to F R Goodman.

At least 37 records · Page 2Linked to original sources
PubMed1988

Effects of two nonsulfhydryl angiotensin-converting enzyme inhibitors, CGS 14831 and CGS 16617, on myocardial damage and left-ventricular hypertrophy following coronary artery occlusion in the rat.

The present study was designed to examine the effects of two new angiotensin-converting enzyme (ACE) inhibitors, CGS 14831 and CGS 16617 (3 mg/kg i. v. 1 min prior to occlusion and 4 and 24 h after occlusion), on myocardial ischemic (MI) damage and left-ventricular hypertrophy in rats. Administration of CGS 14831 or CGS 16617 inhibited angio-tensin-I-induced pressor responses by 40-100% for 4 h after each dose. Myocardial creatine phosphokinase (CK) levels were 10.6 +/- 0.6 U/mg protein in sham-MI animals, and following coronary artery occlusion for 48 h were decreased to 4.1 +/- 0.2 U/mg protein in MI + vehicle animals (p less than 0.01). CGS 14831 and CGS 16617 attenuated the decrease in CK content and resulted in 47 and 40% sparing, respectively, of the left-ventricular free wall. Neither agent attenuated the left-ventricular hypertrophy which developed following coronary artery occlusion. These data indicate that the nonsulfhydryl ACE inhibitors CGS 14831 and CGS 16617 have a significant cardioprotective effect in rats surviving 48 h, and suggest a potential therapeutic usefulness of these agents for the treatment of ischemia-induced heart failure.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1987

Differential calcium movements induced by agonists in guinea pig tracheal muscle.

The effects of high potassium, carbachol and histamine on tension responses and 45Ca fluxes in tracheal smooth muscle were examined. Calcium depletion or nitrendipine (10(-8) M) inhibited potassium-induced contractile responses more than those obtained with either histamine or carbachol, whereas Sr2+ inhibited mainly responses to histamine or carbachol. The Ca2+ entry facilitator, CGP 28392 (3 X 10(-6) M), potentiated contractions induced only by potassium. Uptake of 45Ca in guinea pig tracheal muscle can be separated into high and low affinity components. The 45Ca efflux rate from tracheal muscle into a La3+-substituted solution was over four-fold higher than in other smooth muscles. Potassium, carbachol and histamine induced sustained increases in 45Ca efflux into solutions containing 1.5 mM Ca2+; only transient increases in 45Ca efflux with carbachol and histamine were obtained after Ca2+ depletion. These agonists elicit contractile responses in tracheal muscle by selectively mobilizing different cellular and extracellular Ca2+ components.

Animals↗
PubMed1987

Central and peripheral inhibition of angiotensin converting enzyme (ACE) in the SHR: correlation with the antihypertensive activity of ACE inhibitors.

A series of five structurally distinct ACE inhibitors were evaluated for their ability to inhibit tissue ACE activity in the SHR after oral administration. In the first series of experiments, the ACE inhibitors captopril, enalapril, pentopril, CGS 14824A and CGS 16617 were given to groups of SHR at doses that produced a 15 to 20 mm Hg reduction in blood pressure within 1 hour. Under these conditions of dose and time, only captopril significantly inhibited brain ACE activity (43%), whereas inhibition of serum ACE activity ranged from 72% to 99% with these agents. Inhibition of aortic ACE activity ranged from 54% to 87%, and lung ACE inhibition varied from 50% to 83%. In the second series of experiments, SHR were administered higher doses of each ACE inhibitor such that these compounds produced peak reductions in blood pressure (-25 mm Hg to -33 mm Hg) within a range of 2 to 6 hours. When tissue ACE activity was measured at the time corresponding to peak reduction in blood pressure, all five ACE inhibitors produced a significant inhibition of brain ACE activity ranging from 21% to 76%. Serum ACE activity was almost completely inhibited by these agents, with the exception of captopril (62% inhibition). The inhibition of aortic ACE activity ranged from 79% to 99%, while the inhibition of lung ACE activity did not increase under these conditions. These data suggest that ACE inhibitors may exert their maximal antihypertensive effects by inhibiting ACE in vascular tissues and brain.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1987

Pharmacological characterization of CGS 15943A: a novel nonxanthine adenosine antagonist.

CGS 15943A is a potent adenosine receptor antagonist with a novel nonxanthine heterocyclic ring structure. In vitro, CGS 15943A competitively inhibited the 2-chloroadenosine-induced A2 receptor-mediated relaxation of dog coronary artery strips contracted with KCl (25 mM). Similarly, CGS 15943A blocked 2-chloroadenosine- and N-ethylcarboxamideadenosine-induced A2 receptor-mediated relaxation of histamine-contracted guinea pig tracheal strips. Schild analysis of these results yielded pA2 values of 10.8 and 10.1 for the coronary arteries and the tracheal smooth muscle strips, respectively. In comparison, 8-phenyltheophylline blocked 2-chloroadenosine-induced tracheal response with a pA2 value of 7.0. CGS 15943A was devoid of intrinsic activity, and did not affect either histamine- or KCl-induced contractions of the smooth muscle strips. In the electrically stimulated guinea pig left atrial preparation, CGS 15943A antagonized the A1 receptor-mediated negative inotropic effects of R-phenylisopropyladenosine with a pA2 value of 7.4. In vivo, i.v. administration of CGS 15943A blocked the vasodepressor response to 2-chloradenosine in anesthetized normotensive rats with an ID50 of 0.024 mg/kg. In addition, p.o. administration of CGS 15943A (4.0 mg/kg) to conscious rats inhibited 2-chloroadenosine-induced decreases in diastolic blood pressure; maximal effects were observed 30 min after dosing, with a T1/2 of approximately 103 min. Therefore suggesting that CGS 15943A is an orally active antagonist of adenosine receptors. These results indicate that CGS 15943A antagonized both A1 and A2 receptor-mediated responses with a greater affinity toward the A2 than the A1 receptor subtype.

2-Chloroadenosine↗
PubMed1985

Relationship between 45Ca movements, different calcium components and responses to acetylcholine and potassium in tracheal smooth muscle.

Correlations between tension responses elicited with acetylcholine (ACh) and high K+ and corresponding alterations in Ca++ mobilization were obtained in rabbit and canine tracheal smooth muscle. Removal of Ca++ or preincubation with D-600 (50 microM) inhibited responses to K+ (50 or 80 mM) and low ACh (89 nM) and had only a small effect on responses to high ACh (8.9 microM). Conversely, solutions containing Sr++ instead of Ca++ inhibited responses to both concentrations of ACh to a greater degree than were those to K+. Washout of slow component 45Ca into a O-Ca solution was more rapid in rabbit trachea than reported previously for rabbit aorta. Washout of tracheal smooth muscle into an 80.8 mM La -substituted solution at 0.5 degrees C removed superficial (La -accessible) 45Ca and blocked both 45Ca uptake and most 45Ca efflux. D-600, which had no significant effect on control 45Ca uptake in rabbit aortic smooth muscle, decreased 45Ca uptake by 33% in rabbit tracheal smooth muscle. The uptake of 45Ca from the Ca++ binding sites with low affinity for Ca++ was increased by 80 mM K+, 50 mM K+ or 8.9 microM ACh, and the accumulation of Ca++ from the Ca++ binding sites with high affinity for 45Ca was inhibited by Sr++. The stronger effect of either Ca++ removal or D-600 on responses to K+ and the correspondingly greater effect of Sr++ on responses to ACh indicate that different Ca++ stores are present in tracheal smooth muscle. These Ca++ components appear to be qualitatively similar to those present in aortic smooth muscle but they differ quantitatively and are not as readily dissociated as are aortic Ca++ components.

Acetylcholine↗
PubMed1981

Respiratory responses to Ascaris antigen in rhesus and cynomolgus monkeys.

Responses to Ascaris antigen were evaluated in rhesus and cynomolgus monkeys. Of 19 cynomolgus monkeys tested, 15 were found to have cutaneous reactivity to Ascaris: 13 of these responded to Ascaris aerosols with changes in respiratory function including an increase in respiration rate, decrease in tidal volume and peak expiratory flow rate, decrease in dynamic compliance, and an increase in resistance. Four of the six rhesus monkeys studied with cutaneous reactivity to Ascaris responded to Ascaris aerosols: the changes in respiratory function observed after the Ascaris challenge in these monkeys were similar to those observed in the cynomolgus monkeys. Responses to repetitive Ascaris challenges were obtained in monkeys of both species with a recovery period of 30 to 60 min between challenges. In monkeys of both species that reacted to Ascaris aerosols, blood pressure was elevated transiently; changes in heart rate were variable. Changes in cardiovascular measurements were not observed in monkeys that did not respond to Ascaris aerosols. Thus, it appears that the cynomolgus monkey responds to an aerosol Ascaris challenge in a manner similar to the rhesus monkey and is an additional suitable model for the study of allergic respiratory responses.

Animals↗
PubMed1981

A comparative study of the respiratory responses to bronchoactive agents in rhesus and cynomolgus monkeys.

Respiratory responses to a variety of known bronchoactive agents were compared in anesthetized rhesus (Macaca mulatta) and cynomolgus (Macaca fascicularis) monkeys. Administration of 0.1 to 1.0% histamine aerosols resulted in an increase in airway resistance of 50 to 200% and a decrease in lung compliance of 30 to 80%. Aerosols of prostaglandin E2 (1 mg/ml), terbutaline (10 mg/ml), and isoproterenol (10 mg/ml) or iv aminophylline (up to 7.0 mg/kg) administered concomitantly with histamine produced a transient reversal of the histamine-induced changes in both species. Since the rhesus and cynomolgus monkeys responded in a comparable manner to these bronchodilator agents, the cynomolgus monkey appears to be an additional valuable model for the evaluation of potential bronchoactive compounds.

Airway Resistance↗
PubMed1980

Evaluation of rotenone and related compounds as antagonists of slow-reacting substance of anaphylaxis.

Rotenone (1), dihydrorotenone (2), isorotenone (3), mutarotenone (4), and deguelin (12) were found to be potent antagonists of slow-reacting substance of anaphylaxis (SRS-A) in vitro. However, these compounds were also shown to inhibit histamine, serotonin, and acetylcholine at only ten times their IC50 concentrations for SRS-A antagonism. Rotenone (1) and several related compounds were also evaluated in an in vivo guinea pig anaphylaxis model. Several of these compounds and FPL 55712 (I) were effective in prolonging collapse times of animals which received an aerosol challenge of an antigen to which they had been sensitized.

Acetylcholine↗
PubMed1980

Delta-9-tetrahydrocannabinol on isolated human bronchioles.

Experiments were conducted to investigate the bronchodilating action of delta-9-tetrahydrocannabinol (THC) using normal human lung tissue obtained post mortem. Isolated rings of human bronchioles contracted to histamine, carbachol, and prostaglandin F(2a)(PGF(2a)) and relaxed to isoproterenol. THC (5 X 10(-4)M) did not alter the responses of the bronchial rings to histamine, whereas methapyrilene (10(-6)M) antagonized these responses. Atropine (2 X 10(-6)M) had a highly significant effect on the responses of the bronchioles to carbachol: there was also a significant effect of THC (5 X 10(-4)M), but to a much lesser extent than atropine. Propranolol (10(-6)M) pretreatment significantly antagonized the relaxant responses of the bronchioles to isoproternol: THC antagonized these responses to a smaller degree. Incubation with THC did not cause relaxation of resting tissues or tissues in which a spasm had been induced. These data suggest that THC does not have significant direct effects in human bronchial smooth muscle and that bronchoactivity observed in vivo is likely to be of a nondirect or central origin.

Adolescent↗
PubMed1978

Calcium incorporation by canine aortic smooth muscle microsomes.

The accumulation of calcium (Ca2+) and factors influencing Ca2+ incorporation in vascular smooth muscle were examined in a microsomal fraction prepared from canine aortae. The accumulation of Ca2+ required the presence of ATP and increased over time. Furthermore, the incorporation of 45Ca into the microsomal preparation was stimulated both in the presence of oxalate and when the Ca2+ concentration of the bathing media was elevated from 20 micron to 40 micron. Calcium uptake (with oxalate) was temperature-dependent; uptake was unaffected by azide. Both lanthanum (La3+) and phosphatidyl serine (PS) inhibited ATP-dependent uptake in a concentration-dependent manner. In the presence of ATP, calcium binding (without oxalate) was slightly inhibited by La3+, whereas PS had no effect under these conditions. When ATP was removed from the incubation medium, the presence of PS stimulated both the uptake and binding of 45Ca, whereas La3+ decreased both uptake and binding. These findings support the idea that La3+ binds on the surface of the vesicles and, in this manner, decreases available Ca2+ sites, whereas PS appears to increase the number of Ca2+ sites by either entering the membranes or adsorbing on it.

Adenosine Triphosphate↗
PubMed1977

Effect of pulmonary edema on drug transport and binding in rat lung.

The pulmonary absorption and uptake of (35S)phenol red ((35S)PR was measured in anesthetized rats with alpha-naphthylthiourea- (ANTU) induced lung edema. When (35S)PR solution was injected through a tracheal cannula in control animals and the percentage of the tracheal cannula in control animals and the percentage of the dose unabsorbed plotted semilogarithmically against time, an apparent first-order absorption rate was obtained. In contrast, in rats with ANTU-induced edema, the absorption time curve showed at least two different first-order components. Increasing the concentration of (35S)PR from 0.01 to 3 mM resulted in a decrease in the percentage absorption of the compound in controls compared with a relatively constant percentage absorption in edematous lungs. (35S)PR uptake by lung slices from ANTU-treated rats was decreased in the presence of IAA and a N2 atmosphere, and the dye accumulated at a faster rate and to a greater extent than in controls. The results suggest that although energy-dependent drug transport mechanisms remain intact, the porosity of the absorbing membranes and the extent of drug binding in the lung are increased markedly in the presence of edema.

Animals↗
PubMed1977

Characteristics of 45Ca uptake and efflux in rat lung slices.

The distribution and movements of 45Ca were investigated in lung slice preparations obtained from rats. The accumulation of 45Ca was measured in either 5.0 mM Ca2+, 0.5 mM Ca2+ or 0-Ca solutions. The 45Ca tissue to medium ratio was greatest in the 0-Ca solution; the presence of either 5.0 mM Ca2+ or 0.5 mM Ca2+ reduced this ratio 8- and 5-fold, respectively. Efflux of 45Ca indicated that there are at least two washout components. Exposure to either La3+ or Sr2+ (0.5 mM) during the washout resulted in a transient increase in 45Ca efflux (Sr2+ greater than La3+), whereas 0 degrees C slowed the loss of 45Ca. Uptake of 45Ca was increased by the metabolic inhibitor iodoacetic acid and inhibited in the presence of either La3+ or Sr2+. These findings indicate that the 45Ca accumulated within the lung is not readily depleted and a portion appears to accumulate at intracellular or less superficial sites or stores.

Animals↗
PubMed1976

Contractile function and 45Ca movements in vascular smooth muscle of nonhuman primates: effects of aminoglycoside antibiotics.

1. The effects of 7mM neomycin, 10 mM kanamycin and 5 mM gentamicin on vascular smooth muscle contractile responses and 45Ca movements were examined in arterial preparations isolated from nonhuman primates (squirrel monkeys, capuchin monkeys and baboons). 2. Present findings demonstrate that these antibiotics inhibit contractile responses and alter 45Ca movements in monkey blood vessels, and suggest that the manner in which these agents affect vascular smooth muscle from nonhuman primates does not differ qualitatively from their effects in canine and rabbit vascular preparations.

Aminoglycosides↗
PubMed1976

Comparison of uptake and binding of disodium cromoglycate and phenol red in rat lung.

In rat lung slices 3H-disodium cromoglycate (3H-DSCG) (0.001 mM) was taken up rapidly and 3H-DSCG tissue spaces, which equilibrated by 30 minutes, remained constant over a 4-hour incubation period. In contrast, 35S-phenol red (0.001 mM) accumulated in lung slices to a much greater extent than did DSCG, and the measured tissue spaces continued to increase over a 3-hour incubation period. In the presence of either phenol red (1 mM) or the metabolic inhibitors, iodoacetic acid (10(-4) M) and dinitrophenol (10(-4) M), 3H-DSCG uptake was significantly decreased. Accumulation of 3H-DSCG in lung slices and binding to tissue homogenates (pH 7.4) was also decreased when Ca and Mg ions were omitted from the bathing solution. Although DSCG and phenol red mutually inhibited the accumulation of one another over time in lung slices and 3H-DSCG (0.001 mM) binding to lung homogenates was decreased in the presence of 1 mM phenol red, 35S-phenol red efflux was not altered by the addition of 1 mM DSCG during the washout. Thus, it appears that, in rat lung, DSCG and phenol red share a common binding site(s) for uptake, possible on the transport "carrier." Also, there appear to be additional pulmonary binding sites for phenol red. These sites are not occupied by DSCG and their presence could account for the differences observed in the extent of accumulation of the two compounds in lung slices.

Animals↗
PubMed1976

Distribution of a lanthanide (147 Pm) in vascular smooth muscle.

In order to ascertain whether trivalent rare earth ions such as lanthanum (La+++) penetrate the cell membrane under physiological conditions, the extracellular and cellular distribution of promethium (147 Pm), a carrier-free rare earth radioisotope, was examined in rabbit aortic smooth muscle. As the duration of incubation was lengthened, uptake of 147Pm continued to increase; it was inhibited by La+++ and other rare earth ions (Nd+++, Lu+++) only when the 147 Pm/rare earth concentration ratio exceeded 1:10(6). However, equally high concentrations of Ca++ had no effect on 147Pm uptake. Efflux of 147Pm was only transiently increased by 1.5 mM La+++, and exposure to 0.05 mM EDTA elicited an increased 147Pm efflux with both transient and maintained components. The magnitude of the EDTA-induced increase in 147 Pm efflux was similar over a 30-fold range of EDTA concentration (0.05-1.5 mM); the limiting factor for 147Pm efflux is the rate of 147Pm desorption from the tissue rather than the extracellular concentration of EDTA. Loss of 147Pm in the presence of 0.05 mM EDTA could be described in terms of two specific washout components (the more rapid of which included 147Pm within the extracellular space and the slower of which had half-times of washout of approximately 7-10 minutes). Uptake of 147Pm was inhibited by lowering the incubation solution temperature to 0 degrees C or by procaine. However, concentrations of metabolic inhibitors (iodoacetate and dinitrophenol) which diminish loss of Ca++ from the cell did not decrease either the uptake or efflux of 147Pm. Thus, significant quantities of 147Pm do not appear to be accumulated within the cell or transported out of the cell; distribution of 147Pm can be most simply described in terms of a binding at and desorption from surface acessible fiber sites.

Animals↗