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Biomedical subjects

J Pitha

Publications and source records attributed to J Pitha.

At least 91 records · Page 5Linked to original sources
PubMed1985

Peripheral nerve changes following epineurial injection of saline and blood in rat sciatic nerve.

The effects of warm saline and heparinized autogeneic blood injection on a rat sciatic nerve were observed by histologic, histochemic, and CT planimetry. Demonstrable intraneural degenerative changes and epineurial cellular proliferation were present in both groups. Hemosiderin deposits were present in the epineurium and intraneurally only in the blood group. Epineurial saline injection produces nerve damage; therefore, its use for the purpose of neurolysis is not recommended. Further investigations are needed to study the effect of nonheparinized blood injection. The use of computerized planimetry in assessing quantitative nerve damage proved to be feasible.

Animals↗
PubMed1985

Relation of the hepatic and splenic microcirculations to the development of lesions in experimental amyloidosis.

By the use of a perfusion technique for identifying blood vessels, it was found that amyloid lesions in mice have a close relation to the underlying microcirculation. The earliest lesions develop about arteriolar capillaries. With the onset of the lesions, circulation of plasma not only continues through the affected vessels but also extends into the entire volume of the surrounding lesions. Progression of the lesions follows the underlying microcirculation, and there is a continuing presence of circulating proteins. Other observations, from tracer studies using labeled plasma proteins and studies of unfixed, frozen, tissue sections following saline extraction, indicate that much of the early amyloid lesions in these animals is circulating plasma. It would appear that the onset and site of formation of the lesions is determined by arteriolar capillary injury rather than by polymorphism of SAA proteins. Structural amyloid fibril proteins may gain access to the lesions by either entry from the circulation or local formation.

Amyloidosis↗
PubMed1984

The effect of bromoacetylalprenololmentane on rat atrial tension development and beta-adrenoreceptors.

In isolated rat atria, 1 microM bromoacetylalprenololmentane shifted the tension development curve for isoproterenol to the right of the control curve. After a 2 h washout period, no significant recovery of the isoproterenol concentration-response curve had occurred. Pretreatment of rat atrial membranes with 1 microM bromoacetylalprenololmentane resulted in an 83% decrease in the concentration of beta-adrenoceptors with no change in the KD value for [125I]iodocyanopindolol binding to the receptors left. The results indicated that bromoacetylalprenololmentane was an irreversible beta-blocker.

Alprenolol↗
PubMed1984

Digitonin derivatives of low toxicity: potential solubilizers for lipophilic compounds.

Digitoxin was modified by condensation with propylene oxide or with 1,4-butanediol diglycidyl ether in aqueous alkali, yielding products in which some of the CH2OH groups of digitonin were converted to CH2OCH2CHOHCH3 or to CH2OCH2CHOHCH2O(CH2)4OCH2CHOHCH2OH groups, respectively. These modified digitonins were very soluble in water and chloroform and effectively solubilized lipophilic compounds into aqueous solutions; e.g., 2 mg of vitamin A or 0.6 mg of cholecalciferol could be dissolved per 1 mL of 5% aqueous solutions of modified digitonins. Compared with the toxicity of digitonin (LD50 4 mg/kg iv), the toxicity of modified digitonin was greatly reduced: doses of 500 mg/kg by intravenous infusion were not lethal for mice.

Adjuvants, Pharmaceutic↗
PubMed1983

Decreased response with age of the cardiac catecholamine sensitive adenylate cyclase system.

The cardiac beta-adrenergic coupled adenylate cyclase system was examined in young and old male Wistar rats. The concentration of binding sites for (-)3H-DHA in membranes prepared from cardiac ventricles was 21.1 +/- 2.78 (SD) fmoles/mg protein in 3-4 month old rats (young rats) and 31.2 +/- 2.20 fmoles/mg protein in 24 month old rats (old rats). The dissociation constant, KD was 4.3 +/- 1.8 nM and 6.7 +/- 1.7 nM for young and old rats, respectively. Various compounds were used to study the characteristics of activation of adenylate cyclase in homogenates from cardiac ventricles. Basal adenylate cyclase was reduced 30% in old animals compared to young (6.1 pmoles/min/mg protein in 24 month vs. 8.6 pmoles/min/mg protein in 3-4 month). (-)Isoproterenol (10(-5) M) alone stimulated adenylate cyclase greater than two-fold in young rats (10.6 pmoles/min/mg protein above basal) and this stimulation was 34% lower in old animals. GppNHp (100 microM), fluoride (10 mM), and forskolin (100 microM) activation of adenylate cyclase above basal was reduced 38, 37, and 34%, respectively, in the old animals. No significant changes between the two groups were noted in the apparent affinity of GppNHp either alone or in the presence of (-)isoproterenol nor in the affinities of catecholamine agonists for activation of cyclase. These results suggest a reduction in the amount of functional regulatory protein or possibly cyclase in 24 month old rat ventricular tissue compared to 3-4 month old tissue. However, this data does not rule out the possibility of altered molecular interactions of a full complement of regulatory protein(s) with beta-adrenergic receptor and/or catalytic adenylate cyclase.

Adenylyl Cyclases↗
PubMed1983

Poly-L-methionine sulfoxide: a biologically inert analogue of dimethyl sulfoxide with solubilizing potency.

Poly-L-methionine sulfoxide is a water-soluble polymer containing the sulfoxide moiety. The preparation and radiolabeling of this polymer is described and its bioeffects are compared with those of dimethyl sulfoxide. Poly-L-methionine sulfoxide is similar to dimethyl sulfoxide in that it is a potent solubilizer of lipophilic compounds in water. Although the partition coefficient of poly-L-methionine sulfoxide in 1-octanol-water is only 20 times lower than that of dimethyl sulfoxide, it was found not to penetrate into intracellular spaces. In contrast to dimethyl sulfoxide, poly-L-methionine sulfoxide and L-methionine sulfoxide were found to be ineffective in inducing differentiation in murine erythroleukemia cells and inhibiting differentiation of avian neural crest cells, suggesting that compounds effective in these processes must have the ability to penetrate into cells or membrane proteins. Overall lack of bioactivity of poly-L-methionine sulfoxide, combined with low toxicity (2 g/kg, iv, in the mouse with no effect), makes this compound a suitable inert solubilizer and carrier for lipophilic drugs.

Animals↗
PubMed1983

Effect of a beta-adrenergic antagonist on blood pressure, heart rate and beta-adrenoceptors in turkey poults.

An irreversible beta-adrenergic blocker, bromoacetylalprenololmenthane (BAAM), was administered both peripherally and centrally to turkey poults, Meleagris gallopavo. Peripheral administration of BAAM (60 mg/kg body weight) effected a significant reduction in blood pressure and heart rate. Twenty minutes postinjection, mean blood pressure and heart rate were reduced 34.5 and 24.2%, respectively. Two days later, mean blood pressure values remained significantly depressed at 17.3% below preinjection determinations. Biochemical analysis of heart tissue following peripheral (intraperitoneal) injections of BAAM (60 mg/kg body weight) showed a significant decrease in beta-adrenergic receptors (BAR). Little or no change in the number of BAR in brain tissue was observed. Central (intraventricular) administration of BAAM (0.72 mg/g brain weight) resulted in no change in mean blood pressure or heart rate during a 20 min postinjection period. Biochemical analysis of heart tissue following central injections of BAAM showed little or no change in the number of BAR. There was, however, a significant decrease in the number of BAR in brain tissue.

Adrenergic beta-Antagonists↗
PubMed1983

beta-Adrenergic antagonists with multiple pharmacophores: persistent blockade of receptors.

beta-Adrenergic antagonists containing from one to four identical pharmacophores were prepared and studied. These compounds had the general structure R2NCH(CH3)CH2[-OCH2CH(CH3)-]2-8NR2, where R is either H or an aryl-OCH2CHOHCH2 group. Synthesis was achieved by reaction of aryl glycidyl ethers with Jeffamines, which are primary diamines used in the manufacture of plastics. The following aryl groups were used: 2-allyphenyl, 4-(2-methoxyethyl)phenyl, 1-naphthyl, and 4-methoxyphenyl. The first three correspond to moieties of the established drugs alprenolol, metoprolol, and propranolol, respectively. The affinities of these compounds for beta-adrenergic receptors of rat heart and lung were estimated by measuring their ability to compete with the specific binding of (-)-[3H]-dihydroalprenolol. Compounds containing one pharmacophore bound to the receptors with affinities comparable to those of the parent drugs and the blockade of receptors could be dissociated by successive washes as easily as were those of the parent drugs. Compounds containing two or three pharmacophores had somewhat lower affinities for receptors, but the resulting blockade was persistent even after successive washing.

Adrenergic beta-Antagonists↗
PubMed1983

Beta-adrenoreceptor antagonists with multiple pharmacophores: persistent inhibition of rat heart adenylate cyclase.

beta-Adrenoreceptor antagonists containing several pharmacophores, so called alprenolol-Jeffamines, were studied. These compounds are derived from Jeffamine NH2-CH-(CH3)-CH2-[-O-CH2-CH(CH3)-]n-NH2, n = 2.6 ave. by substitution of nitrogen with 3-(2-allylphenoxy)-2-hydroxypropyl groups, which are part of the Alprenolol pharmacophore. Alprenolol-Jeffamines inhibited (-)isoprenaline stimulated adenylate cyclase activity; the derivative with one pharmacophore was about 4-fold and the derivative with two pharmacophores was about 17-fold less potent than (+/-)alprenolol; the trisubstituted derivative which has one complete and two partial pharmacophores was ineffective. The ratio of Ki's for inhibition of (-)3H-DHA binding and for inhibition of adenylate cyclase were approximately one for each derivative. When (+/-)alprenolol and alprenolol-Jeffamine derivatives were injected intraperitoneally into rats and heart membranes or homogenates were prepared 18-20 h afterwards, the mono, di, and trisubstituted derivatives, but not (+/-)alprenolol, inhibited binding of (-)3H-DHA. This persistency pattern is different from that observed in vitro, where only di and trisubstituted derivatives are persistent. Slow metabolism/slow excretion of the monosubstituted derivative may be a source of the increased persistency in vivo. In similarly prepared animals, the dose-response curve for (-)isoprenaline stimulated adenylate cyclase was shifted to the right 3-to-4 fold for mono and disubstituted derivatives but was unaffected by (+/-)alprenolol and the trisubstituted derivative. The results suggest that these derivatives interact with physiologically important beta-adrenoreceptors in vitro, and that, in vivo, they persistently block beta-adrenoreceptors and inhibit isoprenaline stimulated adenylate cyclase.

Adenylyl Cyclase Inhibitors↗
PubMed1983

Bromoacetylalprenololmenthane: a potent irreversible antagonist of beta adrenergic elicited protein exocytosis in rat parotid cells.

The interaction of bromoacetylalprenololmenthane (BrAlpM), an irreversible beta adrenergic receptor antagonist, with rat parotid acinar cells was studied in vitro. In the presence of BrAlpM, the rate of (-)-isoproterenol-induced exocrine secretion from cells, measured as percentage of amylase release, was markedly reduced. The concentration of (-)-isoproterenol required to elicit half-maximal protein secretion was about 100 times greater (5 microM) in the presence of 1 microM BrAlpM than in control incubations (0.05 microM). BrAlpM and propranolol were similar in their ability to inhibit parotid protein release (IC50 approximately 10(-7) M). To demonstrate that BrAlpM functioned as an irreversible beta adrenergic antagonist, cells were preincubated with BrAlpM for varying amounts of time and then washed three to six times before adding (-)-isoproterenol. At least 10 min preincubation was required to show irreversibility. Alprenolol, under the same preincubation conditions, was unable to inhibit amylase release. BrAlpM inhibited the binding of [3H]dihydroalprenolol to parotid beta adrenoreceptors over a concentration range similar to that required for inhibition of protein secretion. Cells incubated in the absence or presence of BrAlpM displayed a comparable morphologic appearance when viewed by light and electron microscopy. The degree of inhibition of isoproterenol-induced exocytosis of secretory granules by BrAlpM appeared to vary from cell to cell. These findings suggest that BrAlpM should be a useful probe to study beta adrenoreceptor function and metabolism in rat parotid acinar cells.

Adrenergic beta-Antagonists↗
PubMed1982

Mapping of mammalian beta-adrenoreceptors by use of macromolecular alprenolol derivatives. A comparison with amphibian erythrocyte receptors.

THe interaction of macromolecular alprenolol derivatives with beta-adrenoreceptors of rat heart, lung, and erythrocytes and frog erythrocytes has been studied. Macromolecular derivatives were prepared by covalently coupling alprenolol to dextrans containing a homologous series of spacer arms of various lengths. The affinity of these macromolecules for frog erythrocyte membranes increased with increasing length of spacer arm. In contrast, the affinity of these macromolecules for all mammalian membrane preparations was weak and insensitive to the length of the spacer arm. The inhibition of [3H]dihydroalprenolol binding to rat heart, lung, and erythrocyte membrane preparations by these macromolecular derivatives was more than 1000-fold less potent than inhibition by alprenolol. The results suggest different structural characteristics between mammalian and amphibian beta-adrenoreceptors; however, apparently only small differences between mammalian receptors could be distinguished with these probes.

Alprenolol↗
PubMed1982

Muir-Torre syndrome: report of a case and reevaluation of the dermatopathologic features.

Muir-Torre syndrome patients have multiple internal malignancies along with cutaneous sebaceous proliferations and keratoacanthomas. We describe a 62-year-old male with nine primarily internal malignancies who survived eight years after his initial tumor was identified. His sebaceous lesions ranged from innocuous adenomas to an anaplastic carcinoma of the chin which recurred and spread locally to involve the mandible and the right parotid region.

Humans↗
PubMed1982

Probe for polyanionic regions on the cell surface.

The binding of polyuridylate to cells in the presence of proflavine may be used as a probe to provide relative estimates of exposed polyanionic regions on the external surface of the cell. This probe binds preferably to hydrophilic, polyanionic regions, and soluble polysaccharides containing either carboxylate or sulfate groups compete with the binding of this probe. Binding of the probe to protein and lipid regions is considerably weaker. Virus-transformed human fibroblasts bind 10 times less of the probe than nontransformed cells when confluent monolayers are compared. However, as the cell density is decreased, the amount of probe bound per cell increases dramatically both for transformed as well as for normal cells. In fact, human fibroblasts (a) derived from normal donors, (b) from donors with different metabolic disorders, and (c) transformed by simian virus 40, all bind about the same amount of probe when compared at the same density. Populations of human fibroblasts aged in vitro, which contain high proportions of large cells and grow only to relatively low densities in monolayers, bind disproportionately large amounts of the complex.

Cell Line↗
PubMed1982

Regeneration of beta-adrenergic receptors in senescent rats: a study using an irreversible binding antagonist.

The drug used in this study, bromoacetylalprenololmenthane, has the ability to bind and block irreversibly beta-adrenergic receptors. The drug was bound to membranes prepared from hearts, lungs, and brains of both senescent and young rats with a similar affinity. When this drug was injected into rats in nontoxic doses (up to 70 mg/kg), up to 90% of beta-adrenergic receptors were irreversibly blocked 4 hr after injection, whereas the injection of similar amounts of (+/-)-alprenolol was without effect on receptor number. In senescent animals this blockade lasted considerably longer than in young animals; receptor numbers in hearts and lungs of senescent rats returned to control levels only 1 month after injection. The number of beta-adrenergic receptors in brains of senescent rats was unaffected by this drug. Thus, based upon the long-lasting blockade of beta-adrenergic receptors in therapeutically important organs, it appears that irreversible binding blockers may have potential in the treatments of senescent organisms.

Adrenergic beta-Antagonists↗
PubMed1982

Irreversible blockade of beta adrenoreceptors and their recovery in the rat heart and lung in vivo.

The interaction of a bromoacetylated derivative of alprenolol (Alm-CO-CH2Br) with cardiac and lung beta adrenoreceptors was partially characterized. After a short incubation period, the concentration of Alm-CO-CH2Br that inhibited specific [3H]dihydroalprenolol binding by 50% in cardiac and lung membranes was 0.5 and 0.11 microM, respectively. The blockade was time-dependent and Scatchard analysis showed no change in the KD value for specific (-)-[3H]dihydroalprenolol binding but a loss of beta adrenoreceptor content after membrane pretreatment with Alm-CO-CH2Br. The blockade was not reversed by extensive membrane washing, although concurrent treatment with alprenolol fully protected whereas phentolamine had no protective effect. Alm-CO-CH2Br produced a dose-dependent blockade of heart and lung beta adrenoreceptors in vivo and the compound had little or no effect on the growth rate of the rat. Four hours after a single i.p. injection of Alm-CO-CH2Br at 35 mg/kg, the heart and lung beta adrenoreceptor content was decreased by 88 and 90%, respectively. The time required for complete recovery from irreversible beta adrenoreceptor blockade was about 200 hr in the heart and 650 hr in the lung. These results suggest that Alm-CO-CH2Br may be a useful probe for the beta adrenoreceptor both in vitro and for recovery studies in vivo.

Adrenergic beta-Antagonists↗