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Biomedical subjects

J L Mehta

Publications and source records attributed to J L Mehta.

At least 217 records · Page 12Linked to original sources
PubMed1988

Modulation of human neutrophil superoxide production by selective thromboxane synthetase inhibitor U63,557A.

Prostaglandin I2 and prostaglandins of E series have been known to inhibit human neutrophil superoxide production. To examine the effects of selective thromboxane synthetase inhibition on human neutrophil superoxide production (with or without platelets), neutrophils were incubated with U63,557A and stimulated with f-MLP, serum-activated zymosan or calcium ionophore A23187. U63,557A had no significant direct inhibitory effect on neutrophil superoxide production. On the other hand, in the presence of platelets in neutrophil suspension, U63,557A significantly reduced neutrophil superoxide production and increased prostaglandin I2 release. These data suggest that selective thromboxane synthetase inhibition may reduce neutrophil superoxide generation, most likely via increase in prostaglandin I2.

Benzofurans↗
PubMed1988

Neutrophils as potential participants in acute myocardial ischemia: relevance to reperfusion.

An interaction among leukocytes, platelets and endothelial cells is important in atherogenesis and in maintenance of blood flow and vascular tone. These complex cell-cell interactions are mediated by release of such metabolic substances as arachidonic acid metabolites, growth factors, oxygen free radicals and endothelium-derived relaxing factor. These substances participate in the regulation of blood flow in health and disease, and perturbation in the delicate equilibrium among various cellular elements may lead to evolution and propagation of myocardial ischemia. During reperfusion of ischemic myocardium, neutrophils together with platelets cause capillary plugging in the coronary microcirculation and exert detrimental effects on endothelial function resulting in the "no reflow" phenomenon, ventricular arrythmias, loss of coronary vascular reserve and, perhaps, extension of cellular injury. This review addresses the mechanisms of cell-cell interactions with special reference to myocardial ischemia and the potential for development of improved therapy to protect and preserve ischemic myocardium.

Arachidonic Acids↗
PubMed1988

Reduction in coronary vasodilator reserve following coronary occlusion and reperfusion in anesthetized dog: role of endothelium-derived relaxing factor, myocardial neutrophil infiltration and prostaglandins.

To examine the effects of acute myocardial ischemia and reperfusion on regional coronary vasodilator (or flow) reserve, peak reactive hyperemic blood flow following a 10 s occlusion was obtained in dogs subjected to circumflex (Cx) coronary artery occlusion for 1 h followed by reperfusion for 1 h. Acute myocardial ischemia resulting from Cx artery occlusion-reperfusion caused an attenuation in peak reactive hyperemic Cx flow (mean +/- S.E., from 215 +/- 29% to 87 +/- 17%, P less than or equal to 0.001). Acetylcholine-induced increase in Cx flow was also significantly (P less than or equal to 0.01) attenuated following Cx occlusion-reperfusion. These alterations were not observed in the left anterior descending (LAD) coronary artery, which was not subjected to occlusion. Pre-treatment of four dogs with indomethacin inhibited prostaglandin release (P less than or equal to 0.01), but did not affect peak reactive hyperemic coronary flow or acetylcholine-induced increase in coronary flow before or after occlusion-reperfusion. Histopathology revealed extensive myocardial neutrophil infiltration in the Cx-supplied region compared to the LAD-supplied region. Myocardial myeloperoxidase activity, an index of neutrophil infiltration, was also increased in the Cx compared to the LAD region (P less than or equal to 0.02). Myocardial neutrophil accumulation and myeloperoxidase activity were similar in the control and indomethacin-treated animals. These observations suggest that acute myocardial ischemia resulting from coronary artery occlusion-reperfusion impairs coronary vasodilator reserve in anesthetized dogs. This impairment, which was not modified by prostaglandin inhibition, may be related to the loss of endothelium-derived relaxing factor and/or decreased microvascular cross-sectional area resulting from capillary plugging by neutrophils.

Acetylcholine↗
PubMed1988

Increased prostacyclin and thromboxane A2 biosynthesis in atherosclerosis.

It has been proposed that atherosclerotic arteries produce less prostacyclin (PGI2) than nonatherosclerotic arteries do, thereby predisposing arteries to vasospasm and thrombosis in vivo. We reexamined this concept by measuring spontaneous as well as arachidonate-induced PGI2 biosynthesis in aortic segments from nonatherosclerotic and cholesterol-fed atherosclerotic New Zealand White rabbits. Thromboxane A2 (TXA2) generation was also measured. Formation of PGI2, as well as TXA2, as measured by radioimmunoassay (RIA) of their metabolites, was increased in atherosclerotic aortic segments relative to nonatherosclerotic segments (P less than or equal to 0.05) at 0, 5, 10, 15, and 30 min of incubation with arachidonate. Pretreatment of arterial segments with indomethacin inhibited PGI2 as well as TXA2 formation, whereas pretreatment with the selective TXA2 inhibitor OKY-046 inhibited only TXA2 release, thus confirming the identity of icosanoids. To confirm the RIA data, aortic segments were incubated with [14C]arachidonate prior to stimulation with unlabeled arachidonate. The uptake of arachidonate was similar, but the release of incorporated [14C]arachidonate was significantly (P less than or equal to 0.05) greater in atherosclerotic segments than in nonatherosclerotic ones. Conversions of released [14C]arachidonate to 6-keto[14C]prostaglandin F1 alpha and [14C]thromboxane B2 were similar in the two types of aortic segments. Thus, synthesis of PGI2 as well as TXA2 is increased in atherosclerosis, and this alteration in arachidonate metabolism is related to increased release of arachidonate.

Animals↗
PubMed1988

Systemic and coronary hemodynamic effects of prostacyclin and nitroprusside in conscious dogs.

In order to simulate physiologic conditions and eliminate the influence of anesthesia on the cardiovascular responses to prostacyclin (PGI2) and nitroprusside, hemodynamic parameters were monitored in conscious dogs prior to and during infusion of the two agents at equally hypotensive concentrations. Heart rate was significantly increased with nitroprusside (p less than or equal to 0.05) and decreased with PGI2 (p less than or equal to 0.01), while mean ascending aortic blood flow or cardiac output increased (p less than or equal to 0.05) in response to both PGI2 and nitroprusside, more with nitroprusside than with PGI2 (p less than or equal to 0.05). Stroke volume increased with PGI2 only (p less than or equal to 0.05 vs. control, p less than or equal to 0.05 vs. nitroprusside). Both systemic and coronary (circumflex) vascular resistances decreased more with nitroprusside than with PGI2 (p less than or equal to 0.05); however, characteristic impedance (index of aortic elasticity) decreased similarly with PGI2 and nitroprusside. Circumflex coronary blood flow increased (p less than or equal to 0.05) only with nitroprusside. These results indicate that in conscious dogs (a) nitroprusside causes a greater decrease in vascular (systemic and coronary) resistance compared to PGI2, but the effects of the two vasodilators on arterial distensibility are similar; (b) nitroprusside, but not PGI2, causes a marked increase in coronary blood flow; and (c) the major distinguishing hemodynamic response to these vasodilators relates to marked bradycardia with PGI2 and tachycardia with nitroprusside, which may account for the observed differences in aortic blood flow and stroke volume.

Animals↗
PubMed1988

Cimetidine does not increase alpha 1-acid glycoprotein serum concentrations.

Serum concentrations of alpha 1-acid glycoprotein (AAG) were studied in six healthy, male volunteers before and after administration of cimetidine, 300 mg by mouth every 6 h for 2 days. Serum AAG concentrations were measured at three different times during the first day, i.e. before cimetidine administration, and on the fourth and sixth days, after commencing cimetidine administration. Neither cimetidine treatment nor time of day contributed significantly to differences in serum AAG concentration, and no interaction of these factors was observed. It is concluded that altered drug-AAG binding as a result of cimetidine therapy is not likely to be an important mechanism contributing to cimetidine drug interactions.

Adult↗
PubMed1988

Synergistic effects of LTC4 and TxA2 on coronary flow and myocardial function.

Accumulation of leukocytes and platelets in the injured myocardium may influence coronary arteriolar resistance via release of peptidoleukotrienes and thromboxane A2 (TxA2). Although leukotriene C4 (LTC4) and TxA2 individually reduce coronary blood flow, the effects of their simultaneous administration are not known. Accordingly, the combined effects of intracoronary administration of synthetic LTC4 and thromboxane "mimic" U 46619 on coronary blood flow in patent and severely narrowed coronary arteries and myocardial segmental function were examined in eight anesthetized dogs. Administration of LTC4 and U 46619 (0.3-3 micrograms) showed concentration-dependent reductions in coronary blood flow and myocardial segment shortening. When these eicosanoids (3 micrograms each) were administered in close sequence, coronary blood flow decreased 33% in the patent artery and 47% in the narrowed artery. This reduction in coronary blood flow in the narrowed coronary artery produced a 26% decrease in myocardial segment shortening. Reductions in narrowed coronary artery blood flow and myocardial segment shortening were greater than the sum of changes caused by LTC4 and U 46619 administered separately (P less than 0.05). The histopathology of the narrowed coronary artery revealed endothelial disruption at the site of occlusion and an in vivo thrombus just distal to the site of occlusion. These data suggest marked synergism between the actions of LTC4 and TxA2, which may be released locally at the site of coronary thrombus, on blood flow in a severely narrowed coronary artery, and on segmental function in the region supplied by this vessel.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1988

Leukotriene D4 potentiates the contractile effects of epinephrine and norepinephrine on rat aortic rings.

Previous studies have demonstrated a cooperative interaction between peptido-leukotrienes (LTs) and epinephrine (EPI) relative to induction of platelet aggregation and thromboxane formation. To examine if a similar interaction occurs in arteries, we studied the effects of LTD4 and EPI as well as norepinephrine (NOREPI) on isolated rat aortic rings. LTD4 alone (mean concentration 2 x 10(-7) M) induced contraction in 10 of 15 rings examined (mean peak tension 0.31 +/- 0.27 g/mg of tissue). However, pretreatment of aortic rings with LTD4 (10(-7) M) consistently and significantly enhanced the contractile effects of EPI and NOREPI and lowered the threshold concentration of these agonists required to evoke contraction from 4 x 10(-9) to 3 x 10(-10) M (P less than .05). This enhancement of the sensitivity of aortic rings by LTD4 was not observed when KCl or 5-hydroxytryptamine was used as agonists. Furthermore, the LTD4-induced potentiation of effects of EPI or NOREPI on aortic contraction was blocked by the LT-receptor antagonist FPL-55712, but not by indomethacin. These data suggest a specific cooperative contractile effect of LTD4 and alpha adrenergic agonists on rat aortic rings. This LTD4 potentiation of vascular contraction is mediated through LT-receptor stimulation and not through release of cyclooxygenase metabolites.

Animals↗
PubMed1987

Inhibition of human platelet and neutrophil function by piriprost (U-60,257).

Platelets and neutrophils are important in determining the extent of myocardial injury following coronary occlusion. The detrimental effects of these blood elements are mediated in part via release of arachidonate metabolites and oxidative species. A new selective inhibitor of leukotriene formation, piriprost (U-60,257), has been observed to decrease both neutrophil accumulation in the myocardium and infarct size following coronary ligation in experimental animals. Since piriprost may have clinical use, we examined its effects on human platelet and neutrophil functions. This compound was found to exert potent inhibitory effects on epinephrine-induced human platelet aggregation and TXA2 biosynthesis (IC50 0.04 microM). Piriprost also inhibited human neutrophil chemotaxis, oxidative species release, aggregation, and LTB4 synthesis with IC50 of 0.1, 0.04, 10 and 14 microM, respectively. Thus, piriprost inhibits a variety of human platelet and neutrophil functions. Because of its suppressive effects on human platelet and neutrophil functions and protective effects in experimental myocardial infarction, this agent may have clinical applications.

Blood Platelets↗
PubMed1987

Serum lidocaine concentrations following application to the oropharynx: effects of cimetidine.

Solutions of lidocaine hydrochloride are widely used for anesthesia of the oropharynx and respiratory tract prior to endoscopic procedures. It is commonly believed that this route of administration is not associated with clinically significant systemic absorption of the drug, and large doses of topical lidocaine are routinely used in this setting. Serious adverse effects, including seizures, occasionally occur. The extent of absorption of lidocaine from the oropharynx was studied in eight healthy volunteers. Wide variation in serum lidocaine concentrations was observed. A 14-fold range of peak lidocaine concentrations occurred following identical, accurately metered doses of a lidocaine aerosol spray preparation. The effects of cimetidine on lidocaine pharmacokinetics were also studied. Therapeutic doses of oral cimetidine significantly increased the area under the lidocaine time-concentration curve (p = 0.019), but no effect on the terminal-phase elimination rate constant was observed. Serum concentrations of alpha 1-acid glycoprotein, a major binding protein of lidocaine, were significantly elevated following cimetidine (p = 0.030). Maximum lidocaine concentration, time to reach maximum concentration, and mean residence time of lidocaine were unchanged following cimetidine. These observations suggest an effect of cimetidine on the volume of distribution of lidocaine. Because of the wide variability in lidocaine pharmacokinetics and the potentially serious nature of adverse reactions, caution is advised in the use of topical lidocaine solutions in "standard" doses.

Administration, Topical↗
PubMed1987

The argon contact laser scalpel: a study of its effect on atherosclerosis.

A new argon laser scalpel (ALS) that delivers radiation to tissue by direct contact was used to perform endarterectomies on atherosclerotic rabbit aortas in vivo. The resultant effects were compared to those induced by CO2 laser (CO2) and conventional surgical endarterectomy (END) to determine whether this instrument might be useful in the treatment of occlusive cerebrovascular disease. Light microscopy of the treated aortic segments revealed significantly more atheroma removed and less damage to the underlying media in the ALS segments compared to the CO2 segments. Electron microscopy showed that the ALS surface and distal intima-media interface were smoother and more even than those of the CO2 or END groups. Prostacyclin synthesis, as measured by 6-keto-prostaglandin F1a levels, was significantly reduced in the ALS compared to the END and control segments. These results indicate that the ALS is superior to CO2 in performing open laser endarterectomies, but such treatment places the atherosclerotic blood vessel at greater risk for thrombotic complications during the early postoperative period that does surgical endarterectomy. It is conceivable that a contact laser may be useful in the smooth welding of the distal edge of an atheroma (i.e., during carotid endarterectomy) and for the transcatheter ablation of surgically inaccessible obstructions of the cerebral circulation.

Animals↗
PubMed1987

Platelets and arachidonic acid derivatives in myocardial ischemia in animal models.

The accumulated evidence indicates that myocardial ischemia is a complex process involving dysfunction of various cellular elements as well as coronary narrowing. A homeostatic imbalance of endogenously produced vasoactive compounds, released locally as a result of intricate platelet, neutrophil, and endothelial cell-cell interactions, participates in the eventual outcome of tissue ischemia. This imbalance is frequently caused by the formation of an intracoronary platelet thrombus. Therapeutic strategy aimed to modulate intrinsic eicosanoid biosynthesis and neutrophil platelet function may reduce ischemia and benefit patients with ischemic heart disease.

Animals↗
PubMed1987

Acute myocardial ischemia: role of atherosclerosis, thrombosis, platelet activation, coronary vasospasm, and altered arachidonic acid metabolism.

Potential causes for the development of acute myocardial ischemia include extracardiac factors, rapid progression of atherosclerosis, dynamic coronary artery thrombosis, platelet activation in diseased vessels, abnormal constriction of a coronary artery, and abnormal arachidonic acid metabolism. It is entirely possible that all or many of these potential causes may be occurring in the individual patient.

Acute Disease↗
PubMed1987

Rebound hypertension following abrupt cessation of clonidine and metoprolol. Treatment with labetalol.

Abrupt withdrawal of adrenergic blockers in a hypertensive subject may result in acute hypertensive crisis. This crisis results from marked increase in adrenergic discharge and upregulation of adrenoceptors. In a patient with hypertensive crisis following abrupt cessation of clonidine hydrochloride and metoprolol tartrate, intravenous administration of labetalol hydrochloride rapidly reduced blood pressure and heart rate to precrisis levels. The patient was subsequently maintained in a normotensive state by continued oral use of labetalol. This case study demonstrates that alpha- and beta-blocking activities of labetalol may be particularly beneficial in a hyperadrenergic state following abrupt withdrawal of adrenergic blockers.

Aged↗