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Biomedical subjects

J L Mehta

Publications and source records attributed to J L Mehta.

At least 19 recordsLinked to original sources
PubMed1995

Reduction of nitric oxide synthase activity in human neutrophils by oxidized low-density lipoproteins. Reversal of the effect of oxidized low-density lipoproteins by high-density lipoproteins and L-arginine.

Oxidized low-density lipoproteins (ox-LDL) inhibit vascular relaxation by decreasing the synthesis or rapid degradation of endothelium-derived relaxing factor (EDRF), now identified to be nitric oxide (NO). We examined the regulation of NO synthase activity in human neutrophils, which also generate NO, by lipoproteins. Isolated human neutrophils were incubated with native-LDL, ox-LDL (10-50 micrograms protein/mL), high-density lipoproteins (HDL, 100 micrograms protein/mL) or HDL+ox-LDL, and NO synthase activity was measured as conversion of [3H]L-arginine to [3H]L-citrulline. Ox-LDL, but not native-LDL or HDL, significantly decreased NO synthase activity in human neutrophils. This effect of ox-LDL was incubation time and concentration dependent. The incubation of cells with HDL or L-arginine diminished the effects of ox-LDL on NO synthase activity. Thus, ox-LDL decreases the activity of NO synthase enzyme, and this effect of ox-LDL can be modified by HDL and L-arginine.

Arginine↗
PubMed1995

Decrease in hematocrit after coronary stent placement and dextran therapy.

In summary, dextran 40, when given after coronary stent placement, results in a marked decrease in hematocrit within 24 hours. Hematocrit often returns to near baseline levels within 48 hours of stopping dextran. This phenomenon most likely reflects dextran-related hemodilution. This hemodilutional decrease in hematocrit is often misinterpreted as acute blood loss and may result in blood transfusion in patients with low baseline hematocrit. However, far less aggressive anticoagulation regimens, which do not include dextran, are under investigation in patients undergoing coronary stent placement.

Angioplasty, Balloon, Coronary↗
PubMed1995

Recombinant lys-plasminogen, but not glu-plasminogen, improves recombinant tissue-type plasminogen activator-induced coronary thrombolysis in dogs.

OBJECTIVES: This study examined the modification of recombinant tissue-type plasminogen activator (rt-PA)-induced thrombolysis by recombinant lys-plasminogen. BACKGROUND: Recombinant tissue-type plasminogen activator restores flow in the thrombosed coronary artery, but the artery often reoccludes. The rt-PA-induced thrombolysis is a result of activation of plasminogen bound to fibrin in the thrombus and results in generation of the fibrinolytic enzyme plasmin. Small amounts of lys-plasminogen are formed when rt-PA is used. Lys-plasminogen binds to fibrin with a 10-fold greater affinity than the predominant native glu-plasminogen, leading to a loose fibrin structure. METHODS: Dogs with electrically induced occlusive intracoronary thrombus were treated with saline solution (n = 9), glu-plasminogen (2 mg/kg body weight, n = 5) or lys-plasminogen (2 mg/kg, n = 5), followed by infusion of rt-PA (1 mg/kg over 20 min) 10 min later. RESULTS: Reperfusion rates were similar in all groups of dogs, but the time to reflow was lowest in dogs given lys-plasminogen compared with those given saline solution or glu-plasminogen before rt-PA (mean [+/- SE] 14 +/- 2 vs. 22 +/- 2 and 23 +/- 3 min, respectively, p < 0.05). None of the reperfused coronary arteries reoccluded in the lys-plasminogen plus rt-PA group, whereas 75% reoccluded in dogs given saline solution plus rt-PA, and 50% reoccluded in those given glu-plasminogen plus rt-PA. Accordingly, duration of reflow was greater in the lys-plasminogen plus rt-PA group (> 120 vs. 39 +/- 7 and 82 +/- 21 min, respectively, p < 0.05). Plasminogen activator inhibitor-1 activity decreased during rt-PA infusion and thereafter increased in all dogs, but less so in dogs given lys-plasminogen (p < 0.05 vs. those given saline solution before rt-PA). CONCLUSIONS: Treatment with recombinant lys-plasminogen before rt-PA reduces time to reflow and sustains reflow after thrombolysis, whereas glu-plasminogen has no such effect.

Animals↗
PubMed1995

Myocardial neutrophil infiltration, lipid peroxidation, and antioxidant activity after coronary artery thrombosis and thrombolysis.

Neutrophil accumulation and free radical release are implicated in the genesis of reperfusion injury. However, little is known about the changes in myocardial lipid peroxidation and antioxidant activity in relation to coronary artery thrombosis and thrombolysis. To investigate this issue, 18 dogs with electrically induced occlusive thrombus in the left anterior descending (LAD) coronary artery were given tissue-type plasminogen activator (TPA). Sustained reflow (lasting > 120 min) occurred in 4 dogs, reocclusion after initial thrombolysis (transient reflow, duration of reflow 5 to 25 min) occurred in 7 dogs, and no reperfusion was evident in 7 dogs. Myocardial neutrophil infiltration was determined by measuring myeloperoxidase (MPO) activity, lipid peroxidation by malondialdehyde (MDA) levels and antioxidant activity by superoxide dismutase (SOD) activity in the myocardial regions supplied by the nonischemic left circumflex (Cx) and the ischemic LAD coronary arteries. In dogs with ischemia alone (no reperfusion), MPO activity and MDA levels in the LAD-supplied myocardium were modestly higher and SOD activity modestly lower than in the corresponding Cx-supplied myocardium. In dogs with sustained reperfusion there was a marked increase in MPO and MDA and a marked reduction in SOD activity in the reperfused myocardium. The MPO and MDA values in the myocardium of dogs with transient reperfusion, although much higher than the corresponding normal myocardial values, were less marked than in the myocardium of dogs with sustained reperfusion, and the SOD activity was preserved in the transiently reperfused regions. Myocardial shortening fraction in the LAD region was worse in dogs with sustained reperfusion than in those with sustained ischemia or transient reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Endothelium, coronary vasodilation, and organic nitrates.

Recent investigations have suggested that the vascular endothelium is an active participant in the regulation of arterial tone and blood flow. In a state of health, the endothelium contributes to hemodynamic equilibrium; however, it rapidly becomes dysfunctional in hypercholesterolemia and diabetes mellitus or with exposure to the stress of hypertension or long-term smoking. Among the deficits observed during endothelial dysfunction is a reduction in the synthesis and release or an excessive degradation of EDRF. This potent vasorelaxant is derived from the amino acid L-arginine and has been characterized as NO or a closely related substance. EDRF relaxes vascular smooth muscle by activating guanylate cyclase. A deficiency in the activity of EDRF may be the mechanism of diminished coronary vasodilation in patients with ischemic heart disease. Organic nitrates, which are metabolized to NO or S-nitrosothiol at the cellular level, are often used in the management of myocardial ischemia; they also induce vasodilation by activating guanylate cyclase. The similarities between organic nitrates and endogenous EDRF and their interactions are discussed in this review.

Coronary Vessels↗
PubMed1995

Amlodipine in chronic stable angina: results of a multicenter double-blind crossover trial.

The efficacy and safety of amlodipine, 10 mg, a new long-acting calcium antagonist, was compared with placebo in 103 patients with stable angina pectoris in a multicenter double-blind crossover study. The trial consisted of an initial 2-week single-blind placebo period followed by a first period of 4 weeks of double-blind therapy, which was followed by a 1 week washout period and then a second 4-week double-blind period after treatments were crossed over. Twenty-four-hour Holter electrocardiographic monitoring was carried out in 12 patients at three centers. In the first double-blind period amlodipine produced a significantly greater increase in symptom-limited exercise duration (amlodipine 478.5 to 520.6 vs placebo 484.6 to 485.2 seconds; change +8.8% vs +0.1%, respectively; p = 0.0004) and total work (amldipine 2426 to 2984 vs placebo 2505 to 2548 kilopondmeters; change +24% vs +1.7%, respectively; p = 0.0006) and a decrease in angina attack frequency (from 3 to 1 per week; p = 0.016) and nitroglycerin consumption (from 2 to 0.5 tablets/wk; p = 0.01) compared with placebo. Holter monitoring revealed significant reductions in numbers (amlodipine 4.65 to 2.22 vs placebo 1.84 to 1.54; change -52% vs +84%, respectively; p = 0.06), absolute total area (amlodipine 87.66 to 11.43 vs placebo 5.76 to 35.24; change -87% vs +513%, respectively; p = 0.02), and duration (amlodipine 12.29 to 2.95 vs 1.66 to 7.74 seconds; change -76% vs +367%, respectively; p = 0.008) of ST-segment depressions after treatment with amlodipine compared with placebo. After the treatments were crossed over changes continued to favor amlodipine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Critical role of endothelium in sustained arterial contraction during prolonged hypoxia.

Acute anoxia or severe hypoxia causes an initial transient contraction followed by marked relaxation of vascular tissues. We observed a spontaneous gradual sustained contraction of rat aortic rings following relaxation when hypoxia was prolonged. Deendothelialization as well as treatment of the endothelium-intact rings with nitric oxide synthase inhibitors or oxyhemoglobin abolished the late hypoxic contraction despite prolonged hypoxia. The prolonged hypoxia-induced sustained contraction was not affected by adenosine receptor blockade, cyclooxygenase inhibition, free radical scavengers, or the endothelin receptor antagonists. The ATP-sensitive K+ channel blocker glibenclamide abbreviated the duration of hypoxic relaxation and potentiated the magnitude of late hypoxic contraction. These data suggest that the late-sustained hypoxic contraction of arterial tissues is dependent on the presence of intact functional endothelium. Activation of ATP-sensitive K+ channels may participate in the genesis of hypoxic relaxation. However, cyclooxygenase products, free oxygen radicals, adenosine, and endothelin are not involved in the regulation of hypoxia-mediated events in rat aortic rings.

Adenosine Triphosphate↗
PubMed1995

Alterations in pulmonary artery tone during repeated episodes of hypoxia.

To examine the basis of pulmonary constriction during chronic hypoxia, rat pulmonary artery rings were precontracted and exposed to multiple episodes of hypoxia. The first hypoxic episode resulted in a transient contraction, followed by potent relaxation, and then a slow sustained contraction. Repeated hypoxic exposure resulted in stronger initial contraction and attenuated relaxation. Prolongation of the normoxic interval between hypoxic episodes reversed the attenuation of hypoxic relaxation. Pulmonary artery rings that were deendothelialized or treated with the nitric oxide synthesis inhibitor N omega-nitro-L-arginine methyl ester or oxyhemoglobin displayed only hypoxic relaxation without initial or late contractions and no attenuation of relaxation during repeated hypoxia. Pretreatment of rings with indomethacin or adenosine or endothelin receptor antagonists had no effect on the hypoxia-mediated alterations. Thus repetitive exposure to hypoxia results in an increase in initial contraction and a decrease in relaxation of pulmonary artery rings. Frequency of hypoxic episodes and endothelial integrity determine pulmonary tone during repeated hypoxia. However, cyclooxygenase products, adenosine, or endothelin do not play a role in hypoxia-mediated changes in rat pulmonary artery tone.

Animals↗
PubMed1995

Oxidized low-density lipoproteins facilitate leukocyte adhesion to aortic intima without affecting endothelium-dependent relaxation. Role of P-selectin.

Inflammatory cell deposition in atherosclerotic blood vessels has been thought to relate to loss of endothelium-derived nitric oxide (NO). To examine whether cell deposition correlates temporally with the loss of NO activity, rat aortic rings were incubated with buffer, native LDL (n-LDL), oxidized LDL (ox-LDL), or the endothelium-derived relaxing factor synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) for 2 hours, and vascular contractile response to norepinephrine and relaxant response to acetylcholine, thrombin, and calcium ionophore A23,187 were examined. Thereafter, the rings were exposed to biotin-fluorescein isothiocyanate-labeled fluorescent or unlabeled leukocytes for 30 minutes. Cell adhesion was quantitated by fluorescent microscopy as well as by scanning electron microscopy. Incubation with n-LDL or ox-LDL did not affect either the contractile or the relaxant response of rings. However, leukocyte adhesion increased markedly in all ox-LDL-treated rings but not in those treated with n-LDL. Thus, leukocyte adhesion occurred independent of NO activity. In keeping with this concept, pretreatment of rings with the NO precursor L-arginine failed to influence leukocyte adhesion to rings incubated with ox-LDL. Treatment of rings with L-NAME also resulted in adhesion of a large number of leukocytes. Furthermore, all rings treated with ox-LDL or L-NAME demonstrated marked expression of P-selectin leukocyte adhesion molecules, determined by immunohistochemistry. Pretreatment of rings with the P-selectin blocking antibody PB1.3 markedly decreased deposition of leukocytes in rings exposed to ox-LDL.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Identification of constitutive and inducible forms of nitric oxide synthase in human platelets.

A number of cell types possess an L-arginine-nitric oxide (NO) pathway. We studied the presence of constitutive and inducible forms of NO synthase in human platelets. N omega-nitro-L-arginine, an inhibitor of NO synthase, potentiated thrombin-induced aggregation of washed human platelets, whereas L-arginine inhibited it. The direct evidence for the presence of constitutive form of NO synthase came from the observation of conversion of tritium-labeled L-arginine to tritium-labeled L-citrulline by washed platelets suspended in Ca(++)-rich but not in Ca(++)-free buffer. Incubation of washed platelets in Ca(++)-free buffer with cytokines (tumor necrosis factor-alpha and interferon-gamma) or cytokines plus lipopolysaccharide caused a marked increase in the conversion of [3H]L-arginine to [3H]L-citrulline, suggesting the presence of inducible form of NO synthase. Gel electrophoresis identified an approximately 130 kd protein band with NO synthase in the platelet cytosol, which on isolation converted [3H]L-arginine to [3H]L-citrulline. This 130 kd protein required the presence of Ca++, reduced nicotinamide adenine dinucleotide phosphate tetrahydro-L-biopterin, and flavin adenine dinucleotide for expression of NO synthase activity. Platelet sonicates demonstrated presence of nitrite, and its concentrations were lowered by preincubation of platelets with NG-nitro-L-arginine methyl ester and enhanced in cytokine-treated platelets. Reverse-transcription polymerase chain reaction demonstrated messenger RNA expression of the constitutive endothelial (but not brain) and inducible isoforms of NO synthase in platelets. These observations indicate that human platelet cytosol possesses both constitutive and inducible forms of NO synthase.

Amino Acid Oxidoreductases↗
PubMed1994

Reduction in human neutrophil superoxide anion generation by n-3 polyunsaturated fatty acids: role of cyclooxygenase products and endothelium-derived relaxing factor.

Dietary supplementation with n-3 polyunsaturated acids (PUFAs) results in augumented vasorelaxation and reduction in superoxide anion generation. Augmented vasorelaxation may be mediated by enhanced generation of vasodilator prostaglandins and/or endothelium-derived relaxing factor (EDRF), now thought to be nitric oxide (NO). To determine the importance of enhanced vasodilator prostaglandins or EDRF-NO in reduction in superoxide anion generation during n-3 PUFAs intake, human polymorphonuclear leukocytes (PMNs) were incubated with n-6 PUFA arachidonic acid (AA), or n-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (each 10(-7) M) for 1 hr at 37 degrees C. Parallel sets of PMNs were treated with the cyclooxygenase inhibitors indomethacin (10(-5) M), or aspirin (10(-5) M), or the EDRF-NO synthase inhibitor L-NMMA (10(-3) M) prior to incubation with PUFAs. Superoxide anion generation by PMNs was determined by measuring the superoxide dismutase (SOD) inhibitable reduction of ferricytochrome C. PMNs incubated with EPA or DHA, but not AA, demonstrated marked reduction in superoxide anion generation. This reduction in superoxide anion generation by n-3 PUFAs was abolished by treatment of PMNs with indomethacin or aspirin, but not by L-NMMA. These observations suggest that n-3 PUFAs decrease superoxide anion generation primarily by a prostaglandin-dependent pathway.

Arachidonic Acid↗
PubMed1994

Alterations in nitric oxide synthase activity, superoxide anion generation, and platelet aggregation in systemic hypertension, and effects of celiprolol.

A decrease in endothelium-derived relaxing factor or nitric oxide has been proposed as a potential mechanism of increased vascular resistance in hypertension. An increase in the generation of superoxide anions, which degrade nitric oxide and induce platelet aggregation, may also compromise regional blood flow in hypertension. Recent studies show that human neutrophils generate nitric oxide, which has a similar biologic profile to the endothelium-derived relaxing factor. This study measured nitric oxide synthase activity and superoxide generation in human neutrophils and platelet aggregation in patients with essential hypertension. Nitric oxide synthase activity, measured as conversion of 3H-L-arginine to 3H-L-citrulline, in peripheral blood neutrophils was decreased in hypertensive subjects (percent conversion of 3H-L-arginine: 4.2 +/- 0.5 vs 9.0 +/- 3.0 in control subjects; p < 0.01). Neutrophil superoxide anion generation, measured as conversion of ferricytochrome C to ferrocytochrome C, in response to phorbol-12-myristate 13-acetate (100 ng/ml) was higher in hypertensive subjects (17.5 +/- 8.1 vs 13.2 +/- 3.0 nmoles/10(6) cells/10 minutes in control subjects; p < 0.05). Patients were treated with a selective beta blocker, celiprolol, for 8 weeks. Supine blood pressure decreased from 177/103 mm Hg (mean +/- SD 18/7) to 160/92 mm Hg (mean +/- 10/5; p < 0.02), while heart rate was unchanged (73 +/- 11 vs 69 +/- 10 beats/min). Epinphrine and adenosine diphosphate-induced platelet aggregation was also increased in hypertensive subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1994

Concurrent nitroglycerin therapy impairs tissue-type plasminogen activator-induced thrombolysis in patients with acute myocardial infarction.

Nitroglycerin given with tissue-type plasminogen activator (t-PA) has been shown to decrease the thrombolytic effect of t-PA in animal models of coronary artery thrombosis. The present study was conducted to determine whether such an interaction between nitroglycerin and t-PA occurs in patients with acute myocardial infarction undergoing thrombolytic treatment. Patients with acute myocardial infarction were treated with t-PA plus saline solution (group 1; n = 11) or t-PA plus nitroglycerin (group 2; n = 36). Stable coronary artery reperfusion assessed by continuous ST-segment monitoring in 2 electrocardiographic leads, and release of creatine kinase occurred in 91% of group 1 patients and in 44% of group 2 patients (95% confidence interval, 14% to 82%; p < 0.02). Plasma levels of t-PA antigen were consistently (p < 0.005) higher in group 1 than in group 2 patients up to 6 hours after t-PA infusion. Conversely, plasminogen activator inhibitor-1 (PAI-1) levels were slightly higher in group 2 than in group 1 patients. These observations indicate that nitroglycerin given with t-PA significantly decreases the plasma t-PA antigen concentrations and impairs the thrombolytic effect of t-PA in patients with acute myocardial infarction.

Aged↗
PubMed1994

Lys- and glu-plasminogen potentiate the inhibitory effect of recombinant tissue plasminogen activator on human platelet aggregation.

To examine the basis of enhanced thrombolytic effect of tissue-type plasminogen activator (t-PA) in the presence of lys- or glu-plasminogen, studies were performed with human platelet-rich plasma (PRP) and washed platelets (WP). t-PA inhibited platelet aggregation in PRP and this effect was potentiated by lys-plasminogen as well as glu-plasminogen. t-PA inhibited WP aggregation only in the presence of lys- or glu-plasminogen. The potentiation of the effects of t-PA was greater (P < 0.05) with lys-plasminogen than with glu-plasminogen. t-PA alone also decreased 14C-serotonin release from WP, and lys- as well as glu-plasminogen reversed this effect of low concentrations of t-PA in WP. Aggregation of WP was also inhibited by plasmin, a proteolytic product of plasminogen. Low, but not high concentrations, of plasmin increased the release of 14C-serotonin. Anti-aggregatory effects of plasmin and lys-plasminogen plus t-PA on platelets were attenuated by preincubation of PRP or WP suspension with aprotinin. These observations suggest enhanced inhibitory effect of t-PA on platelet function in the presence of lys-plasminogen as potential basis of salutary interaction in models of arterial thrombosis.

Drug Synergism↗
PubMed1994

Emerging options in the management of myocardial ischemia.

Improved understanding of the pathogenesis of symptomatic and silent myocardial ischemia has led to important advances in the prevention and treatment of these syndromes. For example, recognition of the role of platelets in the atherogenic process and of thrombosis in acute myocardial ischemia has led to extensive use of aspirin and thrombolytic therapy, with resultant decreases in mortality. Both nitrates and beta-adrenergic blockers effectively alleviate myocardial ischemia. However, long-term nitrate use is limited by the occurrence of tolerance. beta blockers have been shown to decrease subsequent cardiovascular events in patients with acute myocardial infarction; however, adverse effects are often associated with their use. Calcium antagonists have been shown to be effective in the treatment of stable and vasospastic angina. In patients with coronary artery disease and symptoms resulting from either fixed obstruction or vasospasm, these agents decrease the frequency of angina episodes. The 3 types of calcium antagonists currently available--phenylalkylamine, benzothiazepine, and dihydropyridine derivatives--while chemically a heterogeneous group, share the common property of decreasing depolarization of smooth muscle, albeit to varying degrees. Nonetheless, other characteristics, including varying electrophysiologic effects, distinguish these groups. The novel calcium antagonist amlodipine is effective and well tolerated as an antianginal agent, and offers the advantage of once-daily dosing. Calcium antagonists appear to be well tolerated in patients with concomitant conditions such as diabetes and are effective in commonly coexistent cardiovascular disorders such as hypertension.

Adrenergic beta-Antagonists↗
PubMed1994

Adenosine protects against attenuation of flow reserve and myocardial function after coronary occlusion and reperfusion.

Total coronary artery occlusion and reperfusion result in attenuation of coronary blood flow reserve, regional myocardial dysfunction, and myocardial leukocyte infiltration. To examine the effects of intracoronary adenosine on these occlusion and reperfusion-induced perturbations, we subjected 14 dogs to total left anterior descending (LAD) coronary artery occlusion (1 hour) and reperfusion (1 hour). Seven dogs received adenosine (3.75 mg/min into the LAD distal to the occlusion) over a 1-hour period starting 5 minutes before reperfusion, and the remaining seven dogs received saline solution. One dog in each group died of ventricular fibrillation during coronary artery occlusion. Coronary flow reserve, measured as peak reactive hyperemia (10 and 20 seconds of total coronary artery occlusion) and peak coronary blood flow response to acetylcholine (0.01 to 1.0 micrograms) and nitroglycerin (5 to 25 micrograms), was impaired in the LAD region after LAD occlusion and reperfusion in the saline-treated dogs (all p < 0.01 vs before occlusion and reperfusion); LAD regional myocardial shortening fraction measured by ultrasonic crystals was also diminished after occlusion and reperfusion in saline-treated dogs (-5% +/- 1% vs 12% +/- 2%; p < 0.02). The adenosine-treated dogs showed total protection against loss of coronary flow reserve (peak reactive hyperemia and blood flow increase in response to acetylcholine and nitroglycerin; all p values not significant vs before LAD occlusion and reperfusion). LAD regional myocardial shortening fraction was also preserved in adenosine-treated dogs (9% +/- 2% vs 14% +/- 2%; p not significant). Myocardial myeloperoxidase activity, measured as an index of myocardial leukocyte infiltration, was greater (p < 0.02) in the LAD ischemic-reperfused regions than in nonischemic circumflex regions in the saline-treated dogs. A similar difference in myeloperoxidase activities in the reperfused and control regions was not observed in the adenosine-treated dogs. Thus adenosine protects against loss of coronary flow reserve and regional myocardial function in dogs subjected to coronary artery occlusion and reperfusion.

Acetylcholine↗