Biomedical subjects

P Mehta

Publications and source records attributed to P Mehta.

At least 145 records · Page 8Linked to original sources

PubMed1990

Effects of calcium channel-blocking agents on platelet-osteogenic sarcoma interaction: platelet aggregation and electron microscopic findings.

A variety of tumors stimulate platelet activation. Because platelet activation may, in part, require calcium channel mobilization, we evaluated whether calcium channel blocking agents inhibit osteogenic sarcoma induced platelet aggregation. Platelet rich plasma (PRP) from normal subjects was incubated with one of four calcium channel-blocking agents: nifedipine, diltiazem, verapamil, or amlodopine, all 0-25 micrograms/ml, or diluent. Osteogenic sarcoma cells (2 or 4 x 10(6)/ml) were then added. Platelet aggregation was monitored by light transmission through PRP, and residual PRP was processed for electron microscopy. MG63 cells caused aggregation of PRP in most subjects (mean, 36 +/- 3%). Calcium channel-blocking agents (nifedipine greater than diltiazem greater than amlodopine greater than verapamil) caused partial inhibition of osteogenic sarcoma-induced platelet aggregation, at high concentrations only. Electron microscopy showed platelets aggregating to each other and to tumor cell membranes within 1-5 minutes. Changes in pattern of platelet clumping around tumor cells occurred when PRP was incubated with high concentration of diltiazem (50 micrograms). This study shows that calcium channel-blocking agents inhibit osteogenic sarcoma-induced platelet aggregation when used in high doses.

Blood Platelets↗

PubMed1990

Characterization of butyrate-dependent electroneutral Na-Cl absorption in the rat distal colon.

Recent studies have established that mucosal butyrate stimulates electroneutral sodium-chloride (Na-Cl) absorption in the distal colon of the rat and a model in which Na-hydrogen (H) and Cl-butyrate exchanges are coupled has been proposed as the mechanism of butyrate-dependent electroneutral Na-Cl absorption. These studies were designed to examine butyrate-dependent electroneutral Na-Cl absorption in experimental conditions in which HCO3-dependent electroneutral Na-Cl absorption is inhibited: in Na-depleted (aldosterone-treated) animals and in the presence of increased mucosal cyclic adenosine monophosphate (AMP). Butyrate-dependent electroneutral Na-Cl absorption was markedly reduced in Na-depleted rats. In contrast, the inhibition of both net Na and net Cl absorption by 5 mM serosal theophylline was significantly less in butyrate-containing, HCO3-free Ringer solution than in butyrate-free- HCO3-containing Ringer solution. These studies indicate that cyclic AMP does not inhibit butyrate-dependent electroneutral Na-Cl absorption and we propose that the mechanism of cyclic AMP inhibition of HCO3-dependent electroneutral Na-Cl absorption may be a result of its inhibition of Cl-HCO3, not Na-H exchange.

Aldosterone↗

PubMed1990

Computer-analyzed EEG (CEEG) and dynamic brain mapping in AIDS and HIV related syndrome: a pilot study.

In a group of HIV positive young male patients without any significant neuropsychiatric signs, computer-analyzed EEG (CEEG) and Dynamic Brain Mapping evaluations were conducted. These patients, who only had micro-neuropsychiatric symptoms, demonstrated CEEG profiles that more closely resemble those of patients diagnosed as suffering from mild dementia than age-related normals from our CEEG data base. The CEEGs of patients diagnosed as having Acquired Immune Deficiency Syndrome (AIDS), compared to patients with HIV positive, showed greater similarity in CEEG patterns to severely demented patients than to normal control groups. The findings of this pilot study suggest that CEEG may be useful for early determination of the Central Nervous System's (CNS) involvement with the AIDS virus and monitoring the progress of the illness.

AIDS Dementia Complex↗

PubMed1990

Superoxide radical-mediated endothelial injury and vasoconstriction of rat thoracic aortic rings.

Endothelium regulates smooth muscle tone in response to various agonists and antagonists by release of vasorelaxing and vasoconstricting factors. It also has been postulated that superoxide radicals, which degrade endothelium-derived relaxing factor, exert smooth muscle-constrictor effects. To determine the role of superoxide radicals on vasomotor tone, we exposed rat thoracic aortic rings in vitro to a superoxide radical-generating system of xanthine and xanthine oxidase (X + XO). In rings with intact endothelium, X + XO caused modest smooth muscle contraction and increased vascular sensitivity to both l-epinephrine and thromboxane A2 (TxA2) "mimic" U46619. These vascular contractile effects were more pronounced in rings without intact endothelium. In the supernates of vascular rings with intact endothelium, TxA2 and prostacyclin metabolites were identified on exposure of vascular rings to X + XO, indicating stimulation of the cyclooxygenase pathway. Although both superoxide radical scavenger superoxide dismutase and cyclooxygenase inhibitor indomethacin blocked release of TxA2 and prostacyclin, only superoxide dismutase blocked the contractile effects of superoxide radicals (p less than 0.05). Neither catalase nor mannitol had any effect on X + XO mediated vasoconstriction, suggesting that hydrogen peroxide and hydroxyl radicals did not participate in the observed effects of X + XO. Exposure of vascular rings to X + XO revealed extensive endothelial disruption as determined by scanning electron microscopy. Thus superoxide radicals exert procontractile effects on vascular smooth muscle and enhance its response to l-epinephrine and TxA2 mimic. These effects are probably exerted by injury to the endothelial barrier.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Comparative platelet inhibitory effects of human neutrophils and lymphocytes.

The effects of isolated leukocytes (polymorphonuclear leukocytes [PMNLs] or neutrophils and lymphocytes) on platelet aggregation in platelet-rich plasma (PRP) were examined. Both PMNLs and lymphocytes decreased platelet aggregation in a concentration-dependent fashion. PMNL-induced, but not lymphocyte-induced, inhibition of platelet aggregation was more pronounced as the incubation time of PRP with PMNLs was prolonged. The platelet-inhibitory effect of PMNLs was enhanced by superoxide dismutase (SOD) and was attenuated by oxyhemoglobin and methylene blue. These agents, in contrast, had no effect on lymphocyte-mediated inhibition of platelet aggregation. Adenosine deaminase did not modulate the platelet inhibitory effects of either PMNLs or lymphocytes. The incubation of PMNLs with PRP was associated with an increase in cyclic guanine 5' monophosphate (cGMP) levels in PRP. Incubation of lymphocytes, however, did not result in an increase in cGMP levels in PRP. Neither PMNLs nor lymphocytes in PRP caused a reduction in thromboxane B2 (TXB2) or an increase in 6-keto-PGF1 alpha. Thus this study shows potent inhibitory effects of isolated PMNLs mediated by a substance with biologic characteristics of nitric oxide. However, the mechanism of lymphocyte-induced inhibition of platelets appears to be independent of prostaglandins, nitric oxide, or adenosine.

6-Ketoprostaglandin F1 alpha↗

PubMed1990

The checkerboard tissue block. An improved multitissue control block.

We describe an improved method of embedding a large number of tissue samples in a single, normal-sized paraffin block. Because the tissues are evenly distributed in a checkerboard arrangement, they can be readily identified by their position in the resulting sections. This device permits rapid and inexpensive screening of new histologic reagents, and facilitates intra- and interlaboratory quality control.

Fixatives↗

PubMed1989

Differential brain expression of the Alzheimer's amyloid precursor protein.

The expression of the Alzheimer amyloid protein precursor (AAPP) was examined in human, monkey, dog and rat brains. Two proteins, one identified as AAPP695 and the other as AAPP751, were immunoprecipitated from the in vitro translation of human, dog and rat brain polysomes. The AAPP751 to AAPP695 ratio was highest in human, intermediate in dog and lowest in rat brain polysomes. Human cerebral cortex contained higher levels of the AAPP751 mRNA than either dog or rat cortex. AAPP695 was detected in both cerebral cortex and cerebellum of all species examined. In contrast, AAPP751 was detected predominantly in the cortex of human, monkey and to a lesser extent dog brains while it was not detected in rat brain. These findings indicate that the amyloid precursors are differentially expressed in different mammalian brains and suggest that AAPP751 is mainly expressed in the brain regions involved in plaque formation.

Aged↗

PubMed1989

Nerve and epidermal growth factors induce the release of the Alzheimer amyloid precursor from PC 12 cell cultures.

Antisera against specific sites of the Alzheimer beta Amyloid protein precursor (beta APP) were used to study the effects of nerve and epidermal growth factors on the expression and processing of this protein in PC12 cell cultures. Two major beta APP proteins (140 and 105 kDa) both containing the Kunitz-protease inhibitor insert (KPI), were detected in cell extracts of naive PC12 cells. Treatment of these cultures with nerve growth factor (NGF) induced the release of two beta APP species 125 and 120 kDa, both of which contained the KPI domain and lacked the carboxy-terminal portion of the precursor. The released beta APP contained O-linked sugars. Only one of the released beta APP proteins bound to the lectin Concanavalin A indicating that they differ in their glycosylation. Epidermal growth factor (EGF) also induced the release of beta APP proteins into the culture medium with similar electrophoretic mobilities as those released by NGF.

Adrenal Gland Neoplasms↗

PubMed1989

Activation of K+ channels in renal medullary vesicles by cAMP-dependent protein kinase.

ADH, acting through cAMP, increases the potassium conductance of apical membranes of mouse medullary thick ascending limbs of Henle. The present studies tested whether exposure of renal medullary apical membranes in vitro to the catalytic subunit of cAMP-dependent protein kinase resulted in an increase in potassium conductance. Apical membrane vesicles prepared from rabbit outer renal medulla demonstrated bumetanide- and chloride-sensitive 22Na+ uptake and barium-sensitive, voltage-dependent 86Rb+ influx. When vesicles were loaded with purified catalytic subunit of cAMP-dependent protein kinase (150 mU/ml), 1 mM ATP, and 50 mM KCl, the barium-sensitive 86Rb+ influx increased from 361 +/- 138 to 528 +/- 120 pM/mg prot.30 sec (P less than 0.01). This increase was inhibited completely when heat-stable protein kinase inhibitor (1 microgram/ml) was also present in the vesicle solutions. The stimulation of 86Rb+ uptake by protein kinase required ATP rather than ADP. It also required opening of the vesicles by hypotonic shock, presumably to allow the kinase free access to the cytoplasmic face of the membranes. We conclude that cAMP-dependent protein kinase-mediated phosphorylation of apical membranes from the renal medulla increases the potassium conductance of these membranes. This mechanism may account for the ADH-mediated increase in potassium conductance in the mouse mTALH.

Adenosine Triphosphate↗

PubMed1989

Short-chain fatty acids stimulate active sodium and chloride absorption in vitro in the rat distal colon.

Studies were performed to determine the mechanism by which short-chain fatty acids increase colonic Na and Cl absorption by determining unidirectional 22Na and 36Cl fluxes across isolated stripped mucosa from the rat distal colon under voltage clamp conditions. Mucosal butyrate (25 mM, in the absence of bicarbonate) significantly enhanced both net Na and net Cl absorption by 7.0 +/- 1.3 and 6.9 +/- 1.0 microEq/h.cm2, respectively, without increasing the short-circuit current. Net Na and Cl absorption in butyrate-Ringer's solution and HCO3-Ringer's solution were identical. Butyrate stimulation of Na (and Cl) absorption was Cl-dependent and prevented by 1 mM mucosal amiloride, an inhibitor of Na-H exchange, but was HCO3-independent and not inhibited by acetazolamide, a carbonic anhydrase inhibitor. In contrast, bicarbonate-stimulated Na (and Cl) absorption was also Cl-dependent and amiloride-sensitive, but was significantly inhibited by acetazolamide. The effect of mucosal butyrate on net Na and Cl absorption was substantially greater than serosal butyrate, which in the presence of bicarbonate did not alter ion transport. The stimulation of Na and Cl absorption by mucosal butyrate was significantly greater than by propionate and acetate, whereas mucosal formate did not alter Na transport. The results of this study permit the following model: short-chain fatty acid stimulation of active Na and Cl absorption involves uptake of the nonionized form of butyrate and the coupling of Na-H and Cl-butyrate exchanges.

Acetazolamide↗

PubMed1989

Tissue plasminogen activator and plasmin independently decrease human neutrophil activation.

Tissue-plasminogen activator (t-PA) and plasmin both decrease platelet aggregation, which may contribute to thrombolysis and tissue salvage. Since neutrophils may contribute to reperfusion injury, we examined the effects of t-PA and plasmin on human neutrophil function. t-PA (1 to 100 micrograms/ml) decreased f-MLP-induced chemotaxis and ionophore A23187-induced superoxide and LTB4 release in isolated neutrophils, and these effects were not blocked by the plasmin-inhibitor epsilon-aminocaproic acid (epsilon-ACA). On the other hand, plasmin (0.05 to 0.5 units/ml) also decreased these neutrophil functions but its effects were blocked in the presence of epsilon-ACA. Thus, while both t-PA and plasmin decrease neutrophil functions, effects of t-PA are independent of plasmin generation. Cumulative effects of t-PA and plasmin on neutrophil functions may relate to the overall efficacy of t-PA in thrombotic disorders.

Calcimycin↗

PubMed1989

Modulation of vascular tone by neutrophils: dependence on endothelial integrity.

To determine the influence of polymorphonuclear leukocytes (PMNLs) on vascular smooth muscle tone, isolated human PMNLs (10(4)-10(7) cells/ml) were suspended in a tissue bath with precontracted rat aortic rings with or without endothelium. PMNLs in low concentrations (10(4) and 10(5) cells/ml) caused a mild contraction, and in higher concentrations (10(6) and 10(7) cells/ml) caused a modest relaxation of aortic rings with intact endothelium. In contrast, PMNLs caused a potent concentration-dependent relaxation of deendothelialized rings (P less than 0.01 compared with rings with intact endothelium). The PMNL-induced vascular smooth muscle relaxation was abolished by both hemoglobin and methylene blue and potentiated by both superoxide dismutase and captopril. Although suspension of PMNLs caused release of eicosanoids, thromboxane A2 and prostacyclin, from rings with intact endothelium, neither indomethacin nor the TxA2-endoperoxide receptor antagonist SQ 29548 modified the effects of PMNLs on vascular smooth muscle tone. These observations suggest that unstimulated PMNLs generate a smooth muscle relaxant, which has biological characteristics similar to the endothelium-derived relaxing factor. Since the activity of this PMNL-derived smooth muscle relaxant is more pronounced in deendothelialized vascular segments, it appears that endothelium provides a barrier against vasorelaxation by high concentrations of PMNLs.

6-Ketoprostaglandin F1 alpha↗

PubMed1989

Neutrophil function in ischemic heart disease.

Neutrophils contribute to the healing of and scar formation in myocardium after ischemic injury. Many recent studies indicate that neutrophils may be involved in the genesis and propagation of myocardial ischemia. To characterize neutrophil function in ischemic heart disease, neutrophil chemotaxis, leukotriene B4 (LTB4) generation, and elastase release in plasma were measured in 20 patients with stable angina, 17 patients with unstable angina or acute myocardial infarction (AMI), and 20 age-matched control subjects. Neutrophils from patients with stable angina exhibited markedly increased chemotactic activity and LTB4 generation as compared with the age-matched control subjects (p less than 0.01). Neutrophils of nine of 17 patients with unstable angina or AMI clumped spontaneously ex vivo and exhibited marked pseudopod formation and granule extrusion on electron microscopy. Subsequent chemotactic activity and LTB4 generation by neutrophils from these patients was less than in patients with stable angina, suggesting previous in vivo activation. Plasma levels of peptide B beta, a product of fibrin degradation by human neutrophil elastase, were approximately 15-fold higher (p less than 0.001) in patients with unstable angina or AMI (588 +/- 171 pmol/l, mean +/- SEM) compared with those in patients with stable angina (37 +/- 25 pmol/l) or control subjects (40 +/- 22 pmol/l), confirming intense in vivo neutrophil activation. Our study shows enhanced neutrophil function in patients with ischemic heart disease. The increased neutrophil chemotactic activity and LTB4 generation may be markers of stable angina pectoris. Intense neutrophil activation in unstable angina or AMI, as manifested by morphologic changes in neutrophils and elastase release, may relate to ongoing in vivo cellular activation.

Chemotaxis, Leukocyte↗

PubMed1989

Depressor and natriuretic effects of M&B 22,948, a guanosine cyclic 3',5'-monophosphate-selective phosphodiesterase inhibitor.

We examined the effects of an acute infusion of M&B 22,948 (2-o-propoxyphenyl-8-azapurin-6-one), a (cGMP)-selective phosphodiesterase inhibitor, on mean arterial pressure (MAP) and urinary sodium excretion in anesthetized rats. M&B 22,948 (at doses of 0.34-2.72 mg/kg/min for 30 min) lowered MAP in a dose-dependent manner, with a 60 mm Hg fall in pressure produced at the highest dose. Despite large decreases in MAP, a profound natriuresis was observed at all doses. Plasma concentrations of cGMP increased in parallel with the depressor action of M&B 22,948, whereas increases in the urinary excretion of cGMP temporally correlated with the natriuresis. The concentration of cyclic AMP in plasma increased transiently in rats treated with M&B 22,948 but the urinary excretion of cyclic AMP was not elevated in these animals. Because changes in cGMP correlated with the physiological effects of M&B 22,948, and the increase in cyclic AMP did not, it is likely that the depressor and natriuretic actions of M&B 22,948 are mediated by increases in cGMP. M&B 22,948 administered chronically at an oral dose of 200 mg/kg/day normalized MAP in spontaneously hypertensive rats; whereas MAP in vehicle-treated spontaneously hypertensive rats remained at hypertensive levels. cGMP-selective phosphodiesterase inhibitors (like M&B 22,948) could be more effective antihypertensive drugs than currently available vasodilators because, when administered acutely, M&B 22,948 simultaneously lowers blood pressure and promotes sodium excretion in the anesthetized rat.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed1989

Endothelium-dependent relaxation of rat aortic rings by leukotriene D4: importance of the magnitude of preload.

Leukotriene D4 (LTD4) generally constricts vascular smooth muscle resulting in reduction in blood flow in a variety of blood vessels which can be blocked by specific LT-receptor antagonists. LTD4 has also been shown to cause vasodilation in some animal species. To examine the basis of vasodilation, we evaluated the effects of LTD4 (10(-9) to 2 X 10(-6) M) on precontracted rat thoracic aortic rings in a tissue bath. LTD4 caused relaxation of the rat thoracic rings in a concentration-dependent fashion. This relaxant effect of LTD4 on rat aortic rings was observed regardless of the stimulus used for precontraction, such as l-epinephrine, l-norepinephrine, KCl, 5-hydroxy-tryptamine, or non-pharmacologic manual stretch. This relaxant effect of LTD4 was not blocked by inhibition of vascular eicosanoid synthesis with indomethacin or LT-receptor blockade with two different agents FPL-55712 or LY171883. However, de-endothelialization of rat thoracic aortic rings or treatment of aortic rings with the 5-lipoxygenase inhibitor nordihydroguaiaretic acid abolished the relaxant effect of LTD4. In addition, pretreatment of rings with an inhibitor of endothelium-derived relaxing factor (EDRF), free hemoglobin, also resulted in inhibition of LTD4-induced vascular relaxation. These observations suggest that the rat aortic ring relaxation by LTD4 is endothelium-dependent and is probably related to the release of EDRF.

Acetophenones↗

PubMed1989

Comparative effects of mezlocillin and carbenicillin on platelet function and thromboxane generation in patients with cancer.

Carbenicillin and mezlocillin are widely used for treatment of Pseudomonas infections in patients with cancer. Carbenicillin has been reported to cause platelet dysfunction and bleeding diathesis in some individuals. We evaluated whether carbenicillin causes deterioration of platelet function in patients with cancer and whether mezlocillin causes similar effects on platelets from normal subjects or from patients with cancer. In these in vitro studies, carbenicillin and mezlocillin decreased ADP and epinephrine-induced platelet aggregation and thromboxane A2 generation similarly, but only in concentrations of 3.2 mg/ml or higher. In contrast, carbenicillin was more potent than mezlocillin in decreasing ristocetin-induced platelet aggregation. We also evaluated effects of these antibiotics on platelet function in 19 patients with cancer who developed fever and neutropenia. These patients received either mezlocillin (10 patients) or carbenicillin (nine patients) in combination with nafcillin and gentamycin. Neither carbenicillin nor mezlocillin had any significant effect on platelet aggregation or thromboxane A2 generation. Lack of effects in vivo was due to defective platelet function in these patients prior to any antibiotics. These defects were most probably related to underlying disease and/or prior chemotherapy. Thus, carbenicillin and mezlocillin can both safely be used in patients with cancer who develop fever and neutropenia, and neither seems to have advantage over the other in terms of platelet function.

Adolescent↗

PubMed1988

Enhancement of human neutrophil function by platelets: effects of indomethacin.

To characterize the influence of presence of platelets on human neutrophil function, neutrophil oxidative burst, chemotaxis, leukotriene B4 and prostacyclin generation were examined in the presence of physiologic concentration of platelets (40: 1). Presence of platelets significantly (P less than or equal to 0.05) increased all these neutrophil functions. To determine if cyclooxygenase products are involved in platelet-neutrophil interaction, neutrophils (+/- platelets) were incubated with indomethacin. Although high concentrations of indomethacin (10 microM) inhibited neutrophil (no platelets) chemotaxis and leukotriene B4 generation, these inhibitory effects of indomethacin were attenuated in the presence of platelets. Thus presence of platelets enhances neutrophil activity and overcomes the inhibitory effects of indomethacin on neutrophils.

Blood Platelets↗

PubMed1988

The primary wave of epinephrine-induced platelet aggregation represents alpha 2-adrenoceptor status.

We examined relationships between epinephrine-induced slope of primary wave of aggregation and the alpha 2-adrenoceptor status on platelets. A concentration (10(-9) to 10(-6]-dependent increase in slope of primary wave with EC50 of epinephrine at 4.5 +/- 0.4 x 10(-7) was observed. In studies on epinephrine binding to alpha 2-adrenoceptors in competition with 3H-yohimbine to platelets, (IC50) of epinephrine was 4.8 +/- 3.4 x 10(-7) M. There was a significant (P less than or equal to 0.02) correlation between EC50 of epinephrine to evoke biological response and IC50 of epinephrine to bind to alpha 2-adrenoceptors (r-0.75). There was no relationship between number of receptor sites or dissociation constant of 3H-yohimbine binding and primary wave of platelet aggregation. These data show that the slope of primary wave in response to epinephrine reflects alpha 2-adrenoceptor binding of the agonist.

Adolescent↗