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Biomedical subjects

J L Mehta

Publications and source records attributed to J L Mehta.

At least 181 records · Page 10Linked to original sources
PubMed1991

Pathological basis of failure of concurrent glyceryl trinitrate therapy to improve efficacy of tissue type plasminogen activator in coronary thrombosis.

STUDY OBJECTIVE: The aim was to examine the effect of glyceryl trinitrate, a potent coronary vasodilator, on the thrombolytic effects of tissue type plasminogen inhibitor (t-PA) in dogs with coronary thrombosis. DESIGN: The thrombus was formed by delivery of anodal direct current into the left anterior descending coronary artery. Fourteen dogs were randomly given t-PA alone (0.75 mg.kg-1 over 20 min) or t-PA with glyceryl trinitrate (125 micrograms.min-1 for 40 min). In four other dogs, glyceryl trinitrate was given after t-PA induced thrombolysis. Its effect on t-PA induced thrombolysis, in terms of reperfusion rate, time to thrombolysis, peak coronary blood flow, and reocclusion rate, was quantitated. Peripheral blood platelet counts and whole blood platelet aggregation were measured in all dogs. The thrombosed left anterior descending artery and normal circumflex coronary artery segments were examined by scanning electron microscopy at the end of the experiment. MEASUREMENTS AND MAIN RESULTS: The reperfusion rate in the t-PA plus glyceryl trinitrate (t-PA + GTN) group was 57% (4/7 dogs) and with t-PA alone, 71% (5/7 dogs). The time to thrombolysis in the t-PA + GTN group was greater than with t-PA alone, at 30(SD 10) v 18(7) min, p less than 0.02, and the duration of reperfusion much shorter, at 11(17) v 48(15) min, p less than 0.02. Peak coronary blood flow in the t-PA + GTN group following reperfusion was less compared with t-PA alone, at 36(52) v 53(18) ml.min-1, p less than 0.02. Reocclusion rates in the two groups were similar. Peripheral blood platelet counts decreased during thrombus formation in all dogs; this decrease stabilised when t-PA was given alone but not when it was given with glyceryl trinitrate [mean platelet count at the end of t-PA infusion 7.23(1.68) and 4.78(3.00) X 10(8).ml-1 respectively, p less than 0.02], suggesting continued sequestration of platelets in the intracoronary thrombus in the latter group. Whole blood platelet aggregation decreased significantly with t-PA alone, but less so with t-PA + GTN [magnitude of platelet aggregation 0.23(0.57) and 5.67(6.23) ohms, respectively, p less than 0.02], suggesting lower plasma concentrations of t-PA when given with glyceryl trinitrate. Glyceryl trinitrate given after thrombolysis induced by t-PA failed to sustain reperfusion. Scanning electron microscopy of occluded left anterior descending artery showed extensive endothelial injury and a thrombus composed of platelet--red blood cells--fibrin mesh. The reperfused left anterior descending artery showed extensive endothelial injury and residual thrombus consisting mostly of fibrin and red blood cells with some platelets. CONCLUSION: Glyceryl trinitrate given concurrently with t-PA or after t-PA induced thrombolysis does not modify the thrombolytic potential of t-PA. The potentially "detrimental" effects of glyceryl trinitrate may be due to increase in hepatic blood flow and subsequent enhanced catabolism of t-PA. Lack of any significant effect of therapeutic dosage of glyceryl trinitrate on platelet--fibrin rich thrombus may explain the absence of a salutary action of this agent. Dynamic coronary vasoconstriction does not play an important role in coronary reocclusion after initial thrombolysis.

Animals↗
PubMed1991

Captopril-induced reversal of nitroglycerin tolerance: role of sulfhydryl group vs. ACE-inhibitory activity.

The angiotensin-converting enzyme (ACE) inhibitor captopril has been shown to reverse vascular tolerance to nitroglycerin (NTG). Whether captopril reverses NTG tolerance by providing sulfhydryl (SH) groups or by inhibiting ACE is not clear. To examine this issue, we treated rat aortic rings with buffer, captopril (SH +, ACE inhibitory activity +), enalaprilat (SH-, ACE inhibitory activity +), or N-acetylcysteine (NAC, SH+, ACE inhibitory activity-) prior to their contraction with epinephrine and subsequent relaxation with NTG. Previous exposure of NTG-treated rings resulted in marked resistance to the vasorelaxant effect of a subsequent exposure to NTG in buffer-treated rings. Both NAC and captopril, but not enalaprilat, potentiated the vasorelaxant effects of NTG during the first exposure of vascular rings to NTG and also prevented the development of tolerance to NTG during a second exposure. Buffer-treated rings showed an inability to accumulate cyclic guanosine monophosphate (GMP) in response to a second exposure to NTG. In contrast, both NAC and captopril-pretreated rings demonstrated a persistence of cyclic GMP accumulation during the second NTG exposure. The endothelium-dependent vasodilator acetylcholine (ACh) caused relaxation of the NTG-tolerant rings and also induced cyclic GMP accumulation in these rings. In other experiments, we found that prior exposure of vascular rings to ACh did not cause resistance to the subsequent vasorelaxant effects of ACh. NAC, captopril, and enalaprilat did not modulate the effects of ACh during either the first or subsequent exposures to ACh. In addition, indomethacin did not influence the "protective" effects of NAC or captopril against NTG tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1991

Combined thrombolytic effects of tissue-plasminogen activator and a fibrinogen-degradation product peptide 6A or iloprost.

Thrombolytic effects of tissue-type plasminogen activator (t-PA) are limited by in vivo platelet activation and dynamic coronary vasoconstriction. To examine if the concurrent administration of a fibrin(ogen)-degradation product, pentapeptide 6A (Ala-Arg-Pro-Ala-Lys) with t-PA would improve the thrombolytic effects of t-PA, dogs with electrically induced coronary thrombus were given t-PA alone or with peptide 6A. In dogs given t-PA alone (0.75 mg/kg over 20 min), coronary blood flow was restored in 69% of animals (9 of 13 dogs), with a mean time to reflow of 21 +/- 10 min and duration of reflow of 35 +/- 18 min. Reocclusion occurred in 77% of dogs (7 of 9 dogs). With concurrent administration of peptide 6A (200 mumol), coronary venous 6-keto-PGF1 alpha concentrations increased from 221 +/- 71 to 422 +/- 161 pg/ml (p less than 0.05), but not with t-PA given alone. Coronary blood flow was restored in 7 of 11 dogs (reperfusion rate 64%), with mean time to reflow of 17 +/- 7 min and duration of reflow of 35 +/- 15 min. The coronary reocclusion rate was 86%. All these indices of thrombolysis were similar to those in dogs given t-PA alone. In ex vivo experiments, we also demonstrated release of endothelium-derived relaxing factor from canine coronary artery rings in response to peptide 6A. To further examine the role of prostacyclin (PGI2) in thrombolytic response to t-PA, eight other dogs were given t-PA with a PGI2 analog iloprost (100 ng/kg/min for 40 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Interactions between nitroglycerin and endothelium in vascular smooth muscle relaxation.

To evaluate the role of endothelium in nitroglycerin (NTG)-mediated vascular relaxation, epinephrine-contracted rat thoracic aortic segments with and without intact endothelium were exposed to NTG (10(-10) to 10(-5) M). Aortic segments with intact (endo+, n = 15) and denuded endothelium (endo-, n = 9) exhibited typical NTG-induced relaxation. However, the mean effective concentration of NTG was lower for endo- than for endo+ segments (P less than 0.001). To determine if this phenomenon related to nitric oxide (NO) generation by endothelium, six endo+ segments were treated with NG-monomethyl-L-arginine (L-NMMA), an inhibitor of NO production. These endo+ segments exhibited greater (P less than 0.001) relaxation in response to NTG than the untreated endo+ segments. Oxyhemoglobin, an inhibitor of guanylate cyclase activation, greatly diminished NTG-mediated relaxation of all aortic segments. To determine if the enhanced NTG-mediated relaxation of endo- segments was unique to the guanosine 3',5'-cyclic monophosphate-dependent vasodilator NTG, other endo+ and endo- segments were exposed to adenosine 3',5'-cyclic monophosphate-dependent vasodilator papaverine (10(-8) to 10(-4) M), and no difference in EC50 was noted between endo+ and endo- segments. Thus endothelium attenuates NTG-mediated vasorelaxation, and this attenuation is abolished by inhibition of endothelial NO production with L-NMMA. These observations indicate that endothelium is a dynamic modulator of vascular smooth muscle relaxant effects of NTG. This modulation appears to result from a competitive interaction between endothelial NO and NTG.

Animals↗
PubMed1991

Effects of activated polymorphonuclear leukocytes on vascular smooth muscle tone.

Unstimulated polymorphonuclear leukocytes (PMNLs) release nitric oxide or a like material that relaxes vascular tissues. To determine the effects of activated PMNLs on vascular tone, precontracted rat aortic rings were exposed to ionophore A23187-treated PMNLs. Whereas "unstimulated" PMNLs caused 29 +/- 4% relaxation, "stimulated" PMNLs caused initial contraction followed by 90 +/- 7% relaxation of aortic rings. Indomethacin or the 5-lipoxygenase blocker piriprost had no effect on PMNL-induced initial contraction or subsequent relaxation. However, initial contraction was abolished and the subsequent vasorelaxation attenuated (22 +/- 5%) by the superoxide radical scavenger superoxide dismutase (SOD), suggesting that release of superoxide radicals may have induced vascular contraction and caused endothelial damage that would permit unopposed vasorelaxant effect of PMNLs. To examine this hypothesis, aortic rings were exposed to superoxide radicals (generated by xanthine plus xanthine oxidase, X + XO) or manually deendothelialized. These rings revealed marked relaxation (78 +/- 6 and 85 +/- 6%, respectively) in response to unstimulated PMNLs. These observations suggest that stimulated PMNLs exert an initial vasoconstrictor effect and a subsequent vasorelaxant effect in response to release of superoxide radicals and nitric oxide, respectively. Arachidonate metabolites or 5-lipoxygenase products do not appear to be important in the actions of PMNLs on vascular smooth muscle.

Animals↗
PubMed1991

Omega-3 polyunsaturated fatty acids augment endothelium-dependent vasorelaxation by enhanced release of EDRF and vasodilator prostaglandins.

Dietary supplementation with fish oil results in augmentation of endothelium-dependent vasorelaxation in experimental animals. The present study was designed to evaluate the direct in vitro effects of omega-3 polyunsaturated fatty acids (omega-3 PUFAs) on vascular reactivity in isolated rat aortic rings. Aortic rings were incubated with the omega-6PUFA arachidonic acid (AA, 10(-7) M) or the omega-3 PUFAs eicosapentaenoic acid (EPA, 10(-7) M) and docosahexaenoic acid (DHA, 10(-7) M) in an organ bath at 37 degrees C. Following contraction with norepinephrine, changes in isometric force were measured in response to the endothelium-dependent vasodilators acetylcholine (ACh, 10(-10) to 10(-5) M) or the calcium ionophore A23187 (10(-10) to 10(-5) M). Parallel sets of vascular rings were pretreated with the cyclooxygenase inhibitor indomethacin (10(-5) M) or the inhibitor of nitric oxide synthesis NG-monomethyl L-arginine (L-NMMA 5 x 10(-5) M) prior to treatment with AA or EPA. Treatment of rings with EPA resulted in an increase (P less than 0.05) in ACh-mediated vasorelaxation compared both to AA-treated and buffer-treated rings (maximum relaxation 83 +/- 5% vs 46 +/- 5% and 63 +/- 4%, respectively). A similar augmentation was observed in DHA-treated rings. Pretreatment of rings with indomethacin or I-NMMA decreased (P less than 0.05) the ACh-mediated vasorelaxation, although EPA-treated rings showed less (P less than 0.05) attenuation of ACh response compared to AA-treated or untreated control rings.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1991

Response of rat thoracic aortic rings to thromboxane mimetic U-46,619: roles of endothelium-derived relaxing factor and thromboxane A2 release.

Studies were designed to test the role of the endothelium and endogenous release of thromboxane (Tx) A2 in the contractile response of rat thoracic aortic rings to the TxA2/prostaglandin (PG) H2 mimetic, U-46,619. U-46,619 caused a dose-dependent contraction of rings with endothelium (mean ED50 = 6.54 +/- 3.02 x 10(-9) M; n = 13) which was abolished by the TxA2/PGH2 receptor antagonist, SQ-29,548. Removal of endothelium greatly potentiated (P less than .05) the contractile response to U-46,619 (ED50 = 4.78 +/- 2.14 x 10(-10) M; n = 14). On addition to the organ bath, oxyhemoglobin (10(-6) M), an inhibitor of endothelium-derived relaxing factor, increased vascular smooth muscle contraction in response to U-46,619 and abolished the difference in response between rings with endothelium (ED50 = 6.63 +/- 0.38 x 10(-11) M) and those without (ED50 = 5.13 +/- 0.18 x 10(-11) M). Vascular contraction with U-46,619 (10(-7] was associated with release of immunoreactive TxB2 and 6-keto PGF1 alpha as well as increased conversion of [14C]arachidonate to [14C]TxB2 and 6-keto-[14C]PGF1 alpha. To test the role of endogenous TxA2 in response to U-46,619, the TxA2 synthetase inhibitor UK-38,485 (10(-6) M) was added directly to the organ bath; this diminished (P less than .05) the contractile responses to U-46,619 of rings with and without endothelium.(ABSTRACT TRUNCATED AT 250 WORDS)

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1990

Iloprost and tissue-type plasminogen activator differentially affect platelet aggregation in platelet-rich plasma and in whole blood.

Platelet aggregation in platelet-rich plasma (PRP) is more sensitive to agonists and more resistant to antagonists than that in whole blood. In this study, we show that the presence of neutrophils in whole blood accounts at least in part for diminished platelet aggregation in whole blood. The platelet-inhibitory effect of neutrophils relates to the release of nitric oxide and not to elastase or adenosine. Furthermore, two unrelated platelet inhibitors, iloprost and tissue-type plasminogen inhibitor, decrease platelet aggregation to a greater extent in whole blood than in PRP. However, these agents exert cumulative or synergistic inhibitory effects with neutrophils on platelet aggregation in PRP. Thus, the inhibition of platelet aggregation in vivo may relate to the interaction between neutrophils and platelet-inhibitory agents.

Blood Physiological Phenomena↗
PubMed1990

Evidence for generation of a large amount of nitric oxide-like vascular smooth muscle relaxant by cholesterol-rich neutrophils.

To determine the effect of cholesterol incorporation on the ability of neutrophils to generate superoxide radicals and nitric oxide-like vasorelaxant material, isolated human neutrophils were incubated with cholesterol-rich liposomes, which increased total cholesterol content by 141% and esterified cholesterol content by 523%. Cholesterol loading resulted in 5 to 7 fold increase in cytosolic calcium in resting as well as in PMA or f-MLP-stimulated cells, but a marked (P less than 0.01) reduction in both PMA- and f-MLP-stimulated superoxide radical generation by these cells. Nitric oxide-like activity measured as relaxation of rat aortic rings was more pronounced (P less than 0.02) in cholesterol-rich than in cholesterol-poor cells. The greater relaxation of aortic rings in response to cholesterol-rich neutrophils was observed in rings with or without intact endothelium, and was potentiated by superoxide dismutase and inhibited by oxyhemoglobin as well as L-NMMA, thus suggesting that the vasorelaxant material was nitric oxide. The greater generation of nitric oxide by cholesterol-rich neutrophils occurs perhaps in response to increased cytosolic calcium.

Animals↗
PubMed1990

Inhibitory effect of unstimulated neutrophils on platelet aggregation by release of a factor similar to endothelium-derived relaxing factor (EDRF).

Previous studies have indicated a possible role for polymorphonuclear leukocytes (PMNLs) in the maintenance of hemostasis and vascular tone. We now demonstrate that unstimulated isolated PMNLs maintained at 37 degrees inhibited human platelet aggregation in a concentration- and time-dependent fashion. In addition, PMNLs increased platelet cyclic GMP concentrations. The platelet aggregation inhibitory effect of PMNLs was potentiated by superoxide dismutase and attenuated by hemoglobin and methylene blue. This inhibitory effect of PMNLs was not observed in 48-hr-old killed cells and was not modulated by aspirin treatment or by adenosine deaminase. These observations suggest that human PMNLs maintained at 37 degrees produce a substance with biological characteristics similar to those of the endothelium-derived relaxing factor.

Hemoglobins↗
PubMed1990

Leukotriene-receptor antagonist FPL-55712 and t-PA-induced thrombolysis in canine coronary thrombosis.

Leukocyte-derived arachidonate products peptido-leukotrienes have been shown to induce coronary constriction and platelet aggregation. As such, leukocytes may have a role in coronary thrombosis and coronary re-occlusion following thrombolysis. In the present study, we examined the effects of tissue-plasminogen activator (t-PA, 0.75 mg/kg over 20 minutes) given after either saline or FPL-55712 (2 mg/kg), a peptido-leukotriene receptor antagonist, in dogs with electrically-induced coronary thrombosis. Peripheral blood neutrophil number and superoxide anion generation increased (P less than 0.01) during formation of thrombus and subsequent t-PA administration in saline-treated dogs. FPL-55712 pretreatment attenuated (P less than 0.05) the increase in number of and superoxide anion generation by neutrophils. However, frequency of thrombolysis, duration of restored flow and re-occlusion rates were similar (P-NS) in both groups of dogs. This study shows that FPL-55712 does not modulate the thrombolytic potential of t-PA even though it decreases neutrophil activation in response to myocardial ischemia.

Animals↗
PubMed1990

Endothelial, platelet and leukocyte interactions in ischemic heart disease: insights into potential mechanisms and their clinical relevance.

Recent investigations of the complex interactions among vascular endothelium, platelets and leukocytes have relevance to the pathogenesis of atherosclerosis and ischemic heart disease. Perturbations in the hemodynamic equilibrium maintained by these cellular elements may lead to vasospasm, in vivo thrombosis and a reduction in blood flow. Recent advances in the understanding of these interactions in health and disease states are summarized. The effect of pharmacologic agents on these cell-cell interactions are discussed to provide the reader with a general understanding of the relevance of these interactions in cardiovascular disease.

Animals↗
PubMed1990

Increased neutrophil elastase release in unstable angina pectoris and acute myocardial infarction.

Neutrophils, a source of proteolytic enzymes and oxygen free radicals, have been shown to participate in animal models of myocardial ischemic injury. To characterize neutrophil activation in human ischemic heart disease, a specific neutrophil elastase-derived fibrinopeptide in plasma was measured in 25 patients with stable angina pectoris, 29 patients with unstable angina pectoris, 17 patients with acute myocardial infarction and 22 control subjects. Mean plasma levels (+/- standard error) of a neutrophil elastase-derived fibrinopeptide (B beta 30-43) measured by a specific radioimmunoassay were fivefold higher in patients with acute myocardial infarction (877 +/- 337 pmol/liter, p less than 0.02) and 13-fold higher in patients with unstable angina (2,277 +/- 613 pmol/liter, p less than 0.006) as compared with control subjects (172 +/- 74 pmol/liter). Mean plasma levels of peptide B beta 30-43 in patients with stable angina (676 +/- 334 pmol/liter), although higher than in control subjects, were not significantly increased (p = 0.64). Total leukocyte counts were 11.0 +/- 0.6 x 10(6)/ml in those with acute myocardial infarction, 9.2 +/- 0.7 x 10(6)/ml in those with unstable angina, 7.1 +/- 0.3 x 10(6)/ml in those with stable angina and 7.7 +/- 0.4 x 10(6)/ml in control subjects. Although total leukocyte counts in patients with unstable angina pectoris and acute myocardial infarction were higher (p less than 0.01) than in patients with stable angina or in control subjects, elevations in peptide B beta 30-43 levels were independent of the differences in both leukocyte count and absolute neutrophil count as well as in history of smoking, hypertension, diabetes mellitus or treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Angina Pectoris↗
PubMed1990

Coronary reperfusion in dogs inhibits endothelium-dependent relaxation: role of superoxide radicals.

Previous studies indicate that release of superoxide radicals during coronary reperfusion following occlusion may relate to the loss of endothelium-dependent coronary arterial relaxation. We examined coronary arterial ring relaxation in dogs subjected to temporary circumflex (Cx) coronary artery occlusion and treated with saline or the superoxide radical scavenger superoxide dismutase (SOD). In dogs treated with saline, Cx coronary ring relaxation in response to leukotriene D4 (LTD4) and acetylcholine (ACh) was attenuated (p less than 0.01), but coronary relaxation in response to nitroglycerin was preserved, suggesting loss of endothelium-dependent relaxation following coronary reperfusion. In contrast, Cx coronary relaxation in response to LTD4 and ACh was preserved in the SOD-treated dogs (p less than 0.01 compared to saline-treated dogs). To further examine the role of superoxide radicals in the loss of endothelium-dependent relaxation, normal nonischemic canine coronary artery and rat aortic rings were exposed to a superoxide radical generating system of xanthine and xanthine oxidase in vitro. Xanthine plus xanthine oxidase treatment caused a significant (p less than 0.01) decrease in the relaxant effects of ACh. Pretreatment of rat aortic rings with SOD protected against the loss of ACh-induced relaxation. These observations suggest that release of superoxide radicals during reperfusion is the basis of loss of endothelium-dependent coronary arterial relaxation. Treatment with superoxide radical scavengers prior to coronary reperfusion protects against this loss.

Acetylcholine↗