Stability of terbutaline sulfate admixtures stored in polyvinyl chloride bags.
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Chemistry, Pharmaceutical↗
Biomedical subjects
J Mehta
Publications and source records attributed to J Mehta.
Studies of cell death (apoptosis) and cell division in leprosy granulomas.
We have studied the histological changes across leprosy lesions by taking biopsies from the center and edge of the lesions and from the clinically uninvolved skin outside the lesions. A comparison of the granuloma fraction (GF) between biopsies from the center and edge of lesions and the adjacent unremarkable skin shows that the greatest GF is found at the edge of lesions, except in early tuberculoid (BT) cases when biopsies from the center have the greatest GF. Central healing of leprosy lesions occurs without tissue necrosis or appreciable fibrosis. Apoptosis, a form of individual cell death in living tissues, is known to be the mechanism of cell loss in a variety of situations, and we have found it to occur in leprosy lesions. Apoptotic activity is greatest at the edge of established tuberculoid lesions, but can be found in the center of the lesion in early cases. We, therefore, suggest that apoptosis is the mechanism by which epithelioid cells are lost during central healing in tuberculoid leprosy lesions. In the small number of multibacillary cases studied, apoptosis were found in biopsies from both the center and edge of the lesions. Mitoses can be found in biopsies from both lepromatous and tuberculoid lesions. However, the degree of mitotic activity does not appear to be related to the position of the biopsy within the lesion, and immigration of monocytes into the granulomas may be of greater importance than cell division in maintaining the numbers of epithelioid cells or macrophages present.
Cell Division↗
Fibrin(ogen)-derived peptide B beta 30-43 increases coronary blood flow in the anesthetized dog.
The hemodynamic effects of intracoronary administration of a fibrin (ogen)-derived peptide B beta 30-43 (Arg-Pro-Ala-Pro-Pro-Pro-Ile-Ser-Gly-Gly-Gly-Tyr-Arg-Ala) were evaluated in open-chest anesthetized dogs. Coronary blood flow (CBF) increased and coronary vascular resistance (CVR) decreased with intracoronary administration of peptide B beta 30-43. These changes were dependent on the amount of the peptide B beta 30-43 administered. There were no significant effects of peptide B beta 30-43 on aortic & left ventricular end-diastolic pressures. Plasma 6-keto-PGF1 alpha (stable hydrolysis product of PGI2) concentrations increased in coronary sinus blood samples in conjunction with increase in CBF. Intravenous administration of indomethacin (5 mg/kg) inhibited the release of PGI2 and almost completely abolished the effects of the fibrin(ogen)-derived peptide on CBF. This study suggests that this fibrin (ogen)-derived peptide has potent effects on the coronary vascular bed of the dog, and that these effects are in large part mediated through PGI2 release. These coronary hemodynamic effects of fibrin(ogen)-derived products may have important autoregulatory effects in atheromatous coronary circulation, wherein thrombi may form spontaneously.
Animals↗
Analytical errors in measuring radioactivity in cell proteins and their effect on estimates of protein turnover in L cells.
Previous studies from this laboratory on protein turnover in 3H-labelled L-cell cultures have shown recovery of total 3H at the end of a 3-day experiment to be always significantly in excess of the 3H recovered at the beginning of the experiment. In this study we have critically reviewed a number of possible sources for this error in measuring radioactivity in cell proteins. 3H-labelled proteins, when dissolved in 0.3 M-NaOH and counted for radioactivity in a liquid-scintillation spectrometer, showed losses of 30-40% of the radioactivity; neither external or internal standardization compensated for this loss. Hydrolysis of these proteins with either Pronase or concentrated HCl significantly increased the measured radioactivity. In addition, approx. 5-10% of the cell protein is left on the plastic culture dish when cells are recovered in phosphate-buffered saline. To aggravate this latter loss further, this surface-adherent protein, after pulse labelling, contains proteins of high radioactivity that turn over rapidly and make a major contribution to the accumulating radioactivity in the medium. These combined errors can account for up to 60% of the total radioactivity in the cell culture. Similar analytical errors have been found in studies of other cell cultures. The effect of these analytical errors on estimates of protein turnover in cell cultures is discussed.
Animals↗
Lack of efficacy of nafazatrom, a novel anti-thrombotic compound, in patients with coronary artery disease.
Nafazatrom (Bay G 6575) is a novel antithrombotic compound, which acts by stimulation of prostacyclin as well as by inhibition of lipoxygenase enzymes. To determine its effects on exercise performance in coronary artery disease patients, a double-blind study was conducted. Twenty patients with coronary artery disease underwent an exercise stress test before and 2 hours after administration of placebo or nafazatrom (1.2 gm). Before the drug administration, there was evidence of enhanced platelet activity, as reflected by elevated resting plasma beta thromboglobulin and thromboxane B2 concentrations. Plasma 6-keto-PGF1 alpha levels were undetectable in most patients. All coagulation tests were in the normal range. None of these parameters changed with exercise. Administration of placebo or nafazatrom before the exercise stress test did not significantly influence any of the coagulation or platelet function parameters or plasma concentrations of thromboxane B2 and 6-keto-PGF1 alpha. This lack of effect was evident both at rest and upon exercise. Compared to placebo, nafazatrom did not significantly increase exercise tolerance time or exercise-induced symptoms. In conclusion, nafazatrom did not influence exercise performance in patients with coronary disease.
6-Ketoprostaglandin F1 alpha↗
Prostacyclin and thromboxane A2 production by human cardiac atrial tissues.
We examined the generation of prostacyclin and thromboxane A2 in the right atrial tissues obtained from patients undergoing coronary bypass surgery. In all instances, the capability of atrial tissues to produce these potent prostaglandins was identified. The identity of prostacyclin and thromboxane A2 was confirmed by use of specific radioimmunoassays of stable metabolites and by use of specific thromboxane A2 synthetase and cyclo-oxygenase inhibitors.
6-Ketoprostaglandin F1 alpha↗
Arachidonic acid and isolated human umbilical vein: concentration-limited prostacyclin generation and absence of direct toxic effects on endothelial integrity.
Previous studies show that administration of high doses of arachidonic acid to rabbits causes disruption of vascular integrity. To examine if similar changes would occur in isolated human vascular tissue, we treated human umbilical veins with arachidonic acid (0, 0.01, 0.1, 1.0 mM). Prostacyclin biosynthesis was quantitated in the supernatants and the endothelial integrity was evaluated by scanning electron microscopy. Prostacyclin synthesis was maximum at low concentrations (0.01-0.1 mM) with no additional increase with higher concentrations of arachidonic acid (1mM) confirming previous observations. There was no evidence for endothelial disruption with any concentration of arachidonic acid. This study shows that arachidonic acid has no direct effects on the vascular lining of isolated human umbilical vein, arachidonic acid-induced sudden death in experimental animals is not due to limitation of prostacyclin synthesis.
Arachidonic Acid↗
Reduction in blood flow in normal and narrowed coronary arteries of dogs by leukotriene C4.
The hemodynamic effects of intracoronary leukotriene C4 (0.3 to 10.0 micrograms) in seven anesthetized dogs with normal and severely narrowed coronary arteries were examined. Intracoronary leukotriene C4 caused a significant dose-related reduction in coronary blood flow in both normal and narrowed coronary arteries with no effect on heart rate or mean arterial pressure. However, left ventricular end-diastolic pressure increased at the 10.0 micrograms dose. The reduction of blood flow in normal and narrowed coronary arteries in response to leukotriene C4 was similar. At the peak effects of leukotriene C4, there was evidence of intracoronary thromboxane A2 release. To examine the contribution of thromboxane A2 release to the coronary vasoconstrictor effects of leukotriene C4, dogs were administered leukotriene C4 after indomethacin pretreatment. The decrease in coronary blood flow was not significantly affected by pretreatment of the animals with indomethacin. However, indomethacin lowered baseline levels of thromboxane B2 and blocked the release of thromboxane A2 after leukotriene C4 administration. Thus, intracoronary leukotriene C4 causes direct dose-dependent decrease in coronary blood flow of similar magnitude in both normal and narrowed coronary arteries. These coronary hemodynamic effects of leukotriene C4 in dogs are not mediated by release of thromboxane A2. Leukotriene C4 released from activated leukocyte in the intracoronary thrombus or in the injured myocardium may reduce coronary blood flow and adversely influence the fate of the affected myocardial tissue.
Animals↗
Peptide 6A, a fibrin(ogen) degradation product, increases coronary blood flow.
The coronary hemodynamic effects of intracoronary administration of a fibrin(ogen)-derived pentapeptide, Ala-Arg-Pro-Ala-Lys (peptide 6A), were evaluated in open-chest anesthetized dogs. With administration of peptide 6A (2.5-30 mumol), coronary blood flow increased and coronary vascular resistance decreased promptly in a dose-related manner. Increase in coronary blood flow was independent of any change in indexes of myocardial O2 demand, indicating the peptide 6A exerts direct effects on coronary arterial tone. Systemic arterial and left ventricular end-diastolic pressures remained unchanged with smaller doses but decreased when higher doses of peptide 6A (greater than or equal to 20 mumol) were administered. Plasma concentrations of 6-ketoprostaglandin F1 alpha, stable hydrolysis product of prostacyclin, increased in coronary sinus blood samples in conjunction with increase in coronary blood flow. Administration of indomethacin (5 mg/kg iv) inhibited peptide 6A-induced release of prostacyclin and significantly attenuated the effects of peptide 6A on coronary hemodynamics. Pretreatment of animals with H2-receptor blocker cimetidine (500 mg iv) or with H1-and H2-receptor blocker diphenhydramine (50 mg iv) had no significant effects on peptide 6A-induced increase in coronary blood flow. This study suggests that this fibrin(ogen)-derived peptide has potent vasodilator effects on the coronary vascular bed of the dog, and these effects are in part mediated by stimulation of prostacyclin release.
6-Ketoprostaglandin F1 alpha↗
Increase in human platelet alpha 2-adrenergic receptor affinity for agonist in unstable angina.
Spontaneous increase in platelet activity and change in coronary vasomotor tone have been implicated in the pathogenesis of acute myocardial ischemia. To define the mechanism of platelet "hypersensitivity" in acute myocardial ischemia, we examined the status of platelet alpha 2-adrenergic receptors in patients hospitalized with severe unstable angina. With the use of the specific alpha 2-receptor antagonist 3H-yohimbine, we identified a 26% decrease in the receptor binding sites on platelet membranes from patients with unstable angina compared with controls (155 +/- 32 vs. 210 +/- 29 fmol/mg protein, P less than or equal to 0.005). The dissociation constants of 3H-yohimbine binding to platelet alpha 2-receptors were similar in both groups (3.3 +/- 1.1 and 4.1 +/- 1.6 nmol/L, P not significant). To study the alterations in the affinity of platelet alpha 2-receptors for the agonists, effects of 1-epinephrine on specific binding of 3H-yohimbine were examined. We observed a marked reduction in 1-epinephrine concentration for inhibition of antagonist binding by 50% in acute myocardial ischemia (IC50: 4.2 +/- 3.9 X 10(-8) vs. 6.7 +/- 3.4 X 10(-7) mol/L, P less than or equal to 0.01), indicating increase in platelet alpha 2-receptor affinity for the agonist. Platelet aggregation and thromboxane A2 generation in response to epinephrine were also significantly increased in the acute phase of myocardial ischemia. This study suggests enhanced affinity of platelet alpha 2-receptors to the agonist 1-epinephrine as a possible mechanism of platelet hypersensitivity in acute myocardial ischemia.
Acute Disease↗
Platelets and prostaglandins in sudden death: therapeutic implications.
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Adrenergic beta-Antagonists↗
Deactivation of guinea pig pulmonary alveolar macrophage responses to N-formyl-methionyl-leucyl-phenylalanine: chemotaxis, superoxide generation, and binding.
Incubation of pulmonary alveolar macrophages (PAM) with the synthetic chemotactic tripeptide, N-formyl-methionyl-leucyl-phenylalanine (FMLP) results in deactivation of PAM chemotaxis. The chemotactic response to 10(-8) M FMLP was inhibited 85% after 30 min of preincubation with 10(-6) M FMLP and 48% by 10(-8) M FMLP. Only the higher dose of FMLP (10(-6) M) caused deactivation of the chemotactic response to C5a (20%). Preincubation with partially purified C5a at a concentration of 100 microliter/ml produced a 32% inhibition of the PAM response to 10(-8) M FMLP. In contrast, preincubation with FMLP had no significant effect on superoxide generation, either at baseline or after stimulation. Levels of intracellular cyclic adenosine-3',5'-monophosphate (cAMP) increased in response to PGE1 in the presence of 3-isobutyl-1-methylxanthine (IBMX), a phosphodiesterase inhibitor, but FMLP failed to induce a change in cAMP levels. Studies of 3H-FMLP binding were consistent with two populations of membrane receptors with different affinities. Preincubation of PAM with FMLP did not result in a reduction of maximal binding. We conclude that FMLP induces deactivation of PAM chemotaxis, but cross-deactivation occurs only after high dose treatment. Unlike the PMN, macrophage chemotactic activation is not accompanied by an elevation in cAMP levels. These observations suggest that PAM chemotaxis is influenced by prior exposure to chemotactic stimuli, but other aspects of the PAM response diverge from that of PMN. The mechanism of deactivation of PAM does not appear to result from a shift in the dose-response curve or decreased availability of membrane receptors, but may involve uncoupling of post-receptor cellular responses.
Animals↗
Contributory role of platelets in various manifestations of ischemic heart disease.
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Angina Pectoris↗
Influence of selective thromboxane synthetase blocker CGS-13080 on thromboxane and prostacyclin biosynthesis in whole blood: evidence for synthesis of prostacyclin by leukocytes from platelet-derived endoperoxides.
Increase in thromboxane A2 (TXA2) generation has been proposed as a mechanism of dynamic vaso-occlusion and in vivo platelet thrombus formation. We have examined the effects of CGS-13080, an imidazole derivative, on rabbit and human TXA2-prostacyclin (PGI2) "balance." In rabbits given CGS-13080, serum levels of TXB2 (stable metabolite of TXA2) were inhibited 81% at 2 hours and 56% at 24 hours (both P less than or equal to 0.01). Collagen-induced platelet aggregation was inhibited at 2 hours after CGS-13080 administration. In contrast, serum levels of 6-keto-PGF1 alpha (stable hydrolysis product of PGI2) increased 587% compared with control values at 2 hours (P less than or equal to 0.01). Platelet and white blood cell counts were not significantly altered. In human blood incubated in vitro with CGS-13080, serum TXB2 was completely inhibited, whereas PGI2 generation was stimulated (both P less than or equal to 0.001). In other experiments, we demonstrated uptake of platelet-generated cyclic endoperoxides by leukocytes and generation of PGI2 in the presence of CGS-13080 but not indomethacin. Thus, CGS-13080 inhibits TXA2 and stimulates PGI2 production in rabbit and human blood. Increase in PGI2 generation with TXA2 inhibition may be of potential benefit in conditions characterized by platelet hyperactivity.
6-Ketoprostaglandin F1 alpha↗
Decreased platelet aggregation but increased thromboxane A2 generation in polycythemia vera.
Patients with polycythemia vera have been described to have hemorrhagic as well as thrombotic tendencies. In a patient with polycythemia vera and angina pectoris, we observed markedly decreased platelet aggregation response to epinephrine but increased platelet and whole-blood thromboxane A2 generation compared with normal subjects. Electron microscopy mostly showed partially activated forms of platelets, which may account for decreased aggregation response in vitro and hemorrhagic tendencies. Young and large platelets found in this disease, however, can generate large amounts of vasoconstrictor and platelet proaggregatory prostanoid thromboxane A2 in response to endogenous thrombin, which may be a basis for thrombotic tendencies.
Angina Pectoris↗
Sulfasalazine inhibition of binding of N-formyl-methionyl-leucyl-phenylalanine (FMLP) to its receptor on human neutrophils.
Sulfasalazine, a drug useful in the therapy of inflammatory bowel disease, was found to block N-formyl-methionyl-leucyl-phenylalanine (FMLP)-induced arthritis in rabbits as well as FMLP-induced superoxide production and chemotaxis in human neutrophils in vitro. Sulfasalazine was also found to block FMLP binding to human neutrophils with an I50 of 10 microM. The dose-response curve for the inhibition of binding was very similar to the dose-response curves for the inhibition of FMLP-induced neutrophil activation.
Animals↗
Receptor blockade as a mechanism of deactivation of human neutrophils by pepstatin and formyl-Met-Leu-Phe.
The pentapeptide pepstatin was shown to be chemotactic for human neutrophils by two techniques: ED50 for chemotaxis was found to be 3 microM by the agarose method and 0.2 microM by the Boyden chamber technique. Pepstatin also induced superoxide radical generation, release of lysosomal enzymes, and a transient increase in intercellular adenosine-3',5'-cyclic monophosphate (cAMP) levels in a dose-dependent manner. Carbobenzoxy-phenylalanyl-methionine (CBZ-PM), which competitively inhibits formyl-methionyl-leucyl-phenylalanine (FMLP) -induced neutrophil functions, also inhibited pepstatin-induced neutrophil function of superoxide generation in a dose-dependent fashion. Likewise, pepstatin inhibited the binding of [3H]FMLP to the cells. Furthermore, preincubation of neutrophils with suboptimal concentrations of FMLP or pepstatin diminished the cellular response toward either factor when tested for their chemotactic activity and for their ability to induce superoxide generation, to release granule enzymes, and to induce a transient increase in intracellular cAMP levels. The concentrations of pepstatin or FMLP tested had no effect on superoxide generation, granule enzyme release, or intracellular levels of cAMP on subsequent challenge with C5a; both of these factors, however, cross-deactivated the chemotactic response of the cells towards C5a. Similar results were observed when cells were preincubated with C5a and subsequently challenged with pepstatin or FMLP. These results suggest that FMLP and pepstatin interact with the same receptor molecules to activate human neutrophil functions. Furthermore, our data indicate that the deactivation of the neutrophil functions of superoxide production and granule enzyme release are receptor specific, but the heterologous deactivation of chemotaxis involves a postreceptor mechanism(s).
Binding, Competitive↗
Role of platelet antagonists in coronary artery disease: implications in coronary artery bypass surgery and balloon-catheter dilatation.
Platelets play an important role in regulation of hemostasis and maintenance of vascular tone. Endothelial disruption occurring during coronary artery bypass surgery and balloon-catheter dilatation may promote platelet adhesion, aggregation, and thrombus formation. Recent studies suggest that platelet-endothelial interaction is mediated in part through products of arachidonic acid metabolism. Understanding of the platelet interaction with blood vessels is important in pharmacologic interventions directed at prevention of thrombus formation in bypass grafts. Although it remains to be proved, use of platelet-suppressive drugs may also improve patency of coronary arteries after balloon-catheter dilatation.
Angioplasty, Balloon↗