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Biomedical subjects

J Mehta

Publications and source records attributed to J Mehta.

At least 289 records · Page 16Linked to original sources
PubMed1983

Comparative effects of nitroglycerin and nitroprusside on prostacyclin generation in adult human vessel wall.

The precise mechanism of vasodilatory actions of nitroso-compounds is not clear. It has been suggested that these drugs might modulate release of the vasodilator, prostacyclin, from cultured endothelial cells and bovine arteries or potentiate actions of prostacyclin. This study was designed to examine the effects of nitroglycerin and nitroprusside on prostacyclin release from adult human vasculature. Saphenous vein ring preparations were incubated with nitroglycerin or nitroprusside and arachidonic acid, the substrate for prostacyclin. Vascular rings incubated with nitroglycerin released significantly more prostacyclin (measured as 6-keto-prostaglandin F1 alpha, a stable hydrolysis product of prostacyclin by radioimmunoassay) compared with the control vascular rings (p less than 0.02). This increase was observed at the therapeutic concentrations of nitroglycerin (5 to 10 ng/ml). However, incubation of saphenous vein rings with nitroprusside in concentrations as high as 1 microgram/ml was not associated with any increase in prostacyclin release. Prior incubation of vascular rings with the cyclooxygenase blocker, indomethacin, inhibited nitroglycerin-induced prostacyclin release. Incubation of vascular rings with the selective thromboxane A2 blocker, OKY 1581, resulted in additional prostacyclin release with nitroglycerin treatment, presumably by inhibiting vessel wall-generated thromboxane A2. Nitroprusside had no significant effect on prostacyclin release from indomethacin-treated or OKY 1581-treated vascular rings. This study suggests significant stimulatory effects of nitroglycerin, but not of nitroprusside, on prostacyclin release from human saphenous vein. Nitroglycerin-induced prostacyclin release may be an important mechanism of its antiischemic actions in human subjects.

6-Ketoprostaglandin F1 alpha↗
PubMed1983

Influence of propranolol and 4-hydroxypropranolol on platelet aggregation and thromboxane A2 generation.

We examined in vitro effects of propranolol and its major metabolite, 4-hydroxypropranolol, on human platelets. Both propranolol and its 4-hydroxy metabolite had no significant direct effect on either platelet aggregation or TXA2 generation in therapeutic concentrations. Higher concentrations (greater than or equal to 10 micrograms/ml), however, reduced both parameters of platelet function. When propranolol and 4-hydroxypropranolol were incubated in combination with platelets in equal concentrations, there were synergistic effects on platelet aggregation and TXA2 generation. Neither propranolol nor 4-hydroxypropranolol inhibited platelet aggregation or TXA2 synthesis in sonicated platelets at any concentration, indicating that intact platelet membrane is necessary for their action.

Adenosine Diphosphate↗
PubMed1983

Human vascular tissues produce thromboxane as well as prostacyclin.

Four different types of human blood vessels were examined for spontaneous and arachidonate-stimulated release of prostacyclin (PGI2) and thromboxane A2 (TXA2). Spontaneous PGI2 release was umbilical veins greater than umbilical arteries greater than saphenous veins greater than internal mammary arteries. With stimulation, PGI2 release by all four different vessels increased significantly (P less than 0.001) and was similar. Spontaneous release of TXA2 was also identified from all vessels examined and was similar. With stimulation, TXA2 release from all vessels increased significantly (P less than 0.001). Internal mammary artery released more TXA2 than other vessels on stimulation. The identity of TXA2 was confirmed by similar displacement of TXB2 antibody by TXB2 standards and by multiple dilutions of supernates. Treatment of vessels with aspirin inhibited PGI2 as well as TXA2 release, whereas treatment with OKY 1581 (TXA2 synthetase inhibitor) inhibited TXA2 release only. Two-dimensional thin-layer chromatography showed [14C]arachidonate conversion to PGI2 and TXA2 similar to that measured by radioimmunoassay. These data suggest that TXA2 is synthesized by human vessels. In older vessels when PGI2 generation is decreased, TXA2 production may by of pathophysiological significance.

Adult↗
PubMed1983

Effects of nitroglycerin on human vascular prostacyclin and thromboxane A2 generation.

We examined the effects of NTG on human saphenous and umbilical vein PGI2 and TXA2 generation. Vascular rings from both types of vessels generated TXA2 in addition to PGI2. The treatment of vascular rings with NTG in concentrations of 5 to 1000 ng/ml and subsequent incubation with AA caused a significant increase in PGI2 in the supernatants, as identified by bioassay (platelet aggregation inhibition) and by measurement of 6-keto-PGF1 alpha (stable hydrolysis product of PGI2). The maximum increase in PGI2 was observed with therapeutic concentrations of NTG, i.e., 5 to 10 ng/ml. The levels of vessel wall-generated TXB2 (stable metabolite of TXA2) were not affected by NTG treatment. A prior incubation of vascular rings with indomethacin abolished the increase in PGI2 after NTG treatment. In contrast, incubation of vascular rings with OKY 1581 (selective TXA2 inhibitor) resulted in a significant additional increase in PGI2 release but no change in TXB2 levels after NTG treatment. These studies indicate important effects of NTG on vascular PGI2 generation but not on TXA2 generation.

Epoprostenol↗
PubMed1983

Inhibitory effects of diltiazem on platelet activation caused by ionophore A23187 plus ADP or epinephrine in subthreshold concentrations.

We examined the effects of the slow channel Ca++ blocker diltiazem on human platelet aggregation and TXA2 generation. Diltiazem inhibited platelet aggregation induced by 2 microM ADP or 5.5 microM epinephrine alone at 5 and 50 micrograms/ml (11.1 and 111 microM), respectively, and that induced by threshold concentrations of ADP or epinephrine at 0.2 to 1.0 micrograms/ml (0.4 to 2.2 microM). Platelet TXA2 generation stimulated by either ADP or epinephrine alone was inhibited by diltiazem in concentrations above the clinically achieved range (0.05 to 0.2 micrograms/ml, 0.1 to 0.4 microM). When PRP was stimulated with subthreshold concentrations of the Ca++ ionophore A23187 followed by subthreshold concentrations of ADP or epinephrine, a marked potentiation of platelet aggregation and TXA2 generation was observed. Incubation of PRP with diltiazem in a pharmacologic range resulted in marked reduction in ionophore A23187-induced potentiation of platelet activity caused by ADP or epinephrine. In other experiments, diltiazem was found to have no effects on PGI2-induced platelet aggregation inhibition. On the basis of these data, we conclude that (1) Ca++ flux across the platelet membrane stimulates platelet activity of subthreshold concentrations of ADP or epinephrine and (2) diltiazem in therapeutic concentrations reduces platelet activation induced by ionophore A23187 plus ADP or epinephrine, most likely by inhibiting Ca++ flux. These effects of diltiazem may not be observed in the therapeutic range if aggregatory concentrations of ADP or epinephrine alone are used.

Adenosine Diphosphate↗
PubMed1983

Pharmacokinetics of verapamil and norverapamil during long-term oral therapy.

Serum concentrations of verapamil and its pharmacologically-active metabolite, norverapamil, were measured in six patients with angina at rest after six to fifteen months of therapy. Optimal daily doses were selected during a previous in-hospital titration period and ranged from 240 to 640 mg per day. There was no significant relationship between dose, corrected for body weight, and area under the verapamil serum concentration-time curve (AUC). The mean apparent oral clearance of verapamil was highly variable with a mean of 21.9 +/- 9.1 ml/min/kg and a range of 7.7 to 32.0 ml/min/kg. The ratio of verapamil AUC to norverapamil AUC, used to assess accumulation kinetics of parent drug and metabolite, was less than 1.0 in five of six patient (mean 0.93). However, one patient with verapamil concentrations ranging from 300 to 900 ng/ml had a ratio of 1.37 suggesting saturation of the enzymes that convert verapamil to norverapamil. When the relationship between serum concentration at the end of the dosing interval and angina frequency was studied, it was observed that patients in whom angina was completely suppressed had concentrations greater than 160 ng/ml and patients with poor control (greater than 5 anginal episodes per week) had concentrations less than 60 ng/ml. The findings suggest that the oral clearance of verapamil following long-term (greater than 6 mo.) administration may be different than after short-term therapy and that it is difficult to predict verapamil serum concentrations and antianginal effect during long-term oral therapy. Individualizing verapamil therapy to maintain serum concentrations greater than 100 ng/ml may improve therapeutic response and appears to more reliably predict response than daily dose.

Aged↗
PubMed1982

Mexiletine, a new antiarrhythmic agent, for treatment of premature ventricular complexes.

This double-blind crossover study was designed to compare the safety and efficacy or mexiletine, a new class I antiarrhythmic agent, with those of a placebo in reducing premature ventricular complexes. Twelve patients who had a median of 294 such complexes/hour were admitted to the study. Eleven completed 4 weeks of trial with mexiletine and placebo with ambulatory electrocardiographic (Holter) recordings taken at the end of each treatment period. The doses given were designed to reduce the frequency of premature ventricular complexes by 50 percent or more from the baseline value. Mexiletine significantly reduced the rate of premature ventricular complexes by comparison with placebo (-66 percent versus 3 percent, p = 0.032). In addition, mexiletine reduced the median number/hour of ventricular couplets observed. After 4 weeks of therapy, 2, 2, 1 and 6 patients, respectively, were taking 100, 200, 300 and 400 mg of mexiletine every 8 hours. Mexiletine produced no significant change in baseline values including electrocardiographic intervals, blood pressure or heart rate. The most frequently observed adverse effects were digestive difficulties (eight patients taking mexiletine, four taking placebo) and central nervous system effects (seven taking mexiletine, five taking placebo). These data show the efficacy and safety of mexiletine in the treatment of premature ventricular complexes in a majority of patients.

Aged↗
PubMed1982

Comparison of platelet function during exercise in normal subjects and coronary artery disease patients: Potential role of platelet activation in myocardial ischemia.

Platelet function parameters as influenced by exercise stress were evaluated in 22 patients with coronary artery disease (CAD) and in 13 normal subjects. Upon exercise stress, 14 CAD patients exhibited positive tests and eight exhibited negative tests. Platelet counts during exercise increased similarly in normal and CAD patients. Platelet aggregation response to ADP was unaffected by exercise both in normal and CAD patients. Platelets from 7 of the 14 CAD patients with positive stress tests had increased sensitivity to endoperoxide analog (U-46619) defined as less than 200 ng/ml U-46619 required for 50% platelet aggregation. Resting plasma beta-thromboglobulin (B-TG) levels, an index of in vivo platelet activation, were significantly higher in CAD patients compared to normal subjects (74 +/- 7 and 41 +/- 5 ng/ml, respectively; p less than 0.02). During exercise plasma B-TG levels increased in normal subjects to 60 +/- 5 ng/ml. In contrast, B-TG levels increased to 102 +/- 14 ng/ml in CAD patients (p less than 0.01 compared to normal subjects). These increases were transient and B-TG declined to preexercise values soon after exercise. Eleven of the 12 CAD patients with positive exercise stress tests had increases in plasma B-TG levels, whereas only three of the eight CAD patients with negative stress tests had any increase. These observations of increased platelet activation in certain CAD patients during exercise may be related to exercise-induced myocardial ischemia.

Adult↗
PubMed1982

Long-term effectiveness of verapamil in stable and unstable angina pectoris. One-year follow-up of patients treated in placebo-controlled double-blind randomized clinical trials.

The clinical responses to 12 months' treatment with verapamil were evaluated in 63 patients with stable and unstable angina pectoris in whom the effectiveness of verapamil had been established in short-term double-blind placebo-controlled randomized clinical trials. In 41 patients with effort-related angina, long-term responses were sustained for periods exceeding 1 year. Twenty patients were evaluated by clinical history and showed a sustained reduction in frequency of anginal attacks and consumption of nitroglycerin with verapamil compared with the initial placebo control periods; the magnitude of this benefit was similar to that observed during double-blind treatment with the drug. Twenty-one patients were evaluated by serial treadmill exercise testing and showed a sustained improvement in exercise duration after 4, 8, 16, 24, and 52 weeks of verapamil treatment; withdrawal of the drug resulted in a deterioration of exercise performance to levels similar to those seen before initiation of therapy. In 22 patients with unstable angina at rest, verapamil produced an amelioration of anginal symptoms that was sustained in most patients for longer than 1 year. However, these patients continued to have a high incidence of death and myocardial infarction in a frequency similar to that previously reported in large clinical studies using either combinations of verapamil and nitrates, nifedipine and propranolol, or propranolol and nitrates. Calcium-channel antagonists may decrease the number of patients requiring coronary artery bypass surgery for relief of refractory angina, but they do not appear to alter the natural history of the disease.

Adult↗
PubMed1982

Verapamil therapy for unstable angina pectoris: review of double-blind placebo-controlled randomized clinical trials.

The effectiveness of verapamil in the management of patients with unstable angina pectoris associated with obstructive coronary artery disease was evaluated in 2 double-blind placebo-controlled randomized clinical trials. In the 1st study, verapamil was compared with placebo using alternating 48 hour treatment periods in a multiple cross-over protocol. Verapamil was superior to placebo in abolishing symptomatic and asymptomatic ischemic episodes; there were 127 ischemic events during treatment with placebo but only 27 episodes during therapy with verapamil (p less than 0.006). In the 2nd study, verapamil and placebo were compared using a double-blind randomized parallel design in which the choice of drug was altered and the doses administered were increased according to the individual responses. Verapamil reduced anginal attacks in 12 of 13 patients, but placebo was effective in only 1 of 6 (p less than 0.025); verapamil reduced daily anginal attacks from 3.2 to 0.6/day (p less than 0.01). Thus, verapamil is highly effective in the short-term management of patients with unstable angina secondary to coronary artery disease.

Adult↗
PubMed1982

Comparison of umbilical vein models for measurement of relative prostacyclin and thromboxane production.

There is growing evidence that blood vessels generate TXA2 in addition to PGI2. We examined effluents from continuously perfused human umbilical vein and supernatants from umbilical vein rings for TXB2 and 6-keto-PGF1 alpha measurements (stable metabolites of TXA2 and PGI2, respectively). TXB2 and 6-keto-PGF1 alpha were identified in all samples. 6-keto-PGF1 alpha to TXB2 ratio was higher in intact vein effluents than in the venous ring supernatants (112:1 and 28:1, respectively, P less than 0.01). Arachidonate stimulation increased 6-keto-PGF1 alpha and TXB2 levels similarly in the intact vein effluent. In contrast, stimulation of the venous rings resulted in a relatively larger increase in TXB2 than in 6-keto-PGF1 alpha. This caused 6-keto-PGF1 alpha to TXB2 ratio to decline (p less than 0.01). The identity of TXB2 was confirmed in several different ways. These data suggest that 1) human umbilical veins produce TXA2 in addition to PGI2, 2) TXA2 release is more by venous rings than by the intact vein probably reflecting contribution from non-endothelial layers, and 3) arachidonate stimulation causes relatively greater release of TXA2 than of PGI2 from the venous rings, whereas release of PGI2 and TXA2 is similar from the intact vein.

6-Ketoprostaglandin F1 alpha↗
PubMed1982

Effect of dipyridamole on prostaglandin generation by human platelets and vessel walls.

These experiments were conducted to determine the effects of dipyridamole on human platelet aggregation, platelet thromboxane A2 (TXA2) and human vessel wall prostacyclin (PGI2) generation. Dipyridamole in varying concentrations (5 to 50 micrograms/ml) had no direct effect on ADP-induced platelet aggregation in vitro, but it potentiated PGI2-induced platelet aggregation inhibition at these concentrations. Dipyridamole also inhibited arachidonic acid-induced platelet TXA2 generation at these concentrations. In continuously perfused umbilical vein segments, dipyridamole treatment resulted in stimulation of PGI2 release determined by bioassay and by measurement of its stable metabolite 6-keto-PGF1 alpha. Minimum concentration of dipyridamole causing PGI2 release was 50 micrograms/ml. These in vitro studies suggest that anti-thrombotic effects of dipyridamole in man are mediated mainly by potentiation of PGI2 activity and to some extent by TXA2 suppression. Stimulation of PGI2 release by human vessels may not be seen in usual therapeutic concentrations.

Arachidonic Acid↗
PubMed1982

5,8,11,14-Eicosatetraynoic acid (ETYA) inhibits binding of N-formyl-methionyl-leucyl-phenylalanine (FLMP) to its receptor on human granulocytes. A note of caution.

Binding of two biochemically chemotactic factors, FMLP and C5a, to their respective receptors on human granulocytes produces a transient several-fold increase in cAMP. To determine if arachidonic acid metabolites were responsible for the increased cAMP concentrations, two inhibitors of arachidonic acid metabolism, indomethacin and ETYA, were incubated with granulocytes prior to FMLP or C5A. ETYA, but not indomethacin, inhibited both the cAMP and superoxide responses to a similar degree. However, the mechanism of this effect was found to be through inhibition of the binding of FMLP to its receptor rather than through inhibition of arachidonate metabolism.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1982

Effects of smoking on platelets and on plasma thromboxane-prostacyclin balance in man.

To determine the influence of brief period of smoking on platelet release and platelet-vessel wall prostaglandins, we studied 13 non-smokers and 15 habitual smokers. Blood samples were collected before and immediately after smoking. Before smoking plasma beta-thromboglobulin levels were similar in the two groups. Plasma levels of thromboxane B2 (TXB2), stable metabolite of TXA2 were slightly higher (124 +/- 43 vs 101 +/- 36 pg/ml) and of 6-keto-PGF1 alpha (stable metabolite of PGI2) lower (39 +/- 23 vs 63 +/- 23 pg/ml) in smokers compared to non-smokers. Immediately after smoking, plasma TXB2 levels increased 197% (P less than 0.05) and plasma 6-keto-PGF1 alpha 44% (P-NS) in non-smokers. Similar increases were not observed in the smoker population, although plasma beta-thromboglobulin levels increased 40%. Platelet TXA2 generations induced by arachidonic acid and thrombin were similar in the two groups. These data show that brief period of smoking stimulates both TXA2 and PGI2 release in the non-smokers. Increase in TXA2 is more than in PGI2. Episodic increase in TXA2 may be a mechanism of vascular injury. Absence of increase in TXA2 and PGI2 with smoking in habitual smokers may reflect tolerance to effects of smoking.

6-Ketoprostaglandin F1 alpha↗
PubMed1982

Thromboxane and prostacyclin generation by intact human vessels in response to balloon catheter trauma.

Recent description of thromboxane (TXA2) synthesis by endothelial cells in addition to prostacyclin (PGI2) has stimulated interest in the significance of TXA2 generation by vessel walls. We studied TXA2 and PGI2 release from human umbilical veins with intact and continuous endothelium. Resting TXB2 (stable metabolite of TXA2) concentrations in umbilical vein effluent (mean 0.45 +/- 0.07 ng/ml) were lower than those of 6-keto-PGF1 alpha (stable metabolite of PGI2) (mean 92 +/- 26 ng/ml). Following mechanical trauma to the umbilical veins with a balloon catheter, documented by adherence of indium111-labeled platelets, both TXA2 and PGI2 increased in the venous effluent. Increase in TXB2 (65%) was less than that in 6-keto-PGF1 alpha (199%). These data show that a) human vessel walls generate both TXA2 and PGI2, b) both TXA2 and PGI2 increase following mechanical trauma, the former less than the latter. Vessel wall TXA2 generation may become pathologically relevant in conditions of decreased PGI2 generation.

6-Ketoprostaglandin F1 alpha↗
PubMed1982

A review of the haemodynamic effects of labetalol in man.

1 Labetalol at a dose of 800 to 1600 mg daily inhibited isoprenaline-induced tachycardia and phenylephrine-induced elevation in arterial pressure in hypertensive subjects. The beta-adrenoreceptor effect was four times more potent than the alpha-adrenoreceptor effect. 2 Isoprenaline-induced tachycardia was more effectively blocked than isoprenaline-induced inotropism, thereby raising the possibility of a subselective effect on cardiac beta-adrenoceptors. 3 Labetalol reduced blood pressure in hypertensive subjects with no change in cardiac output in the supine or upright position and with marked inhibition of the heart rate and blood pressure response to treadmill exercise. 4 Labetalol administered in single doses to patients with stable, treated congestive heart failure impaired blood pressure support during exercise. 5 The unique adrenoceptor and haemodynamic effects of labetalol make it a potentially attractive drug for management of hypertension and other cardiovascular disorders.

Blood Pressure↗
PubMed1982

Effects of propranolol therapy on platelet release and prostaglandin generation in patients with coronary heart disease.

Suppression of platelet function is thought to be a mechanism of propranolol's beneficial action in angina pectoris. To study the effects of propranolol on platelets, we measured plasma beta thromboglobulin and plasma thromboxane B2 (TXB2, stable metabolite of TXA2) levels by radioimmunoassay as indexes of platelet alpha-granule and TXA2 release, respectively. Platelet TXA2 generation in vitro in response to arachidonate and thrombin was also quantitated. Twenty-nine patients with coronary disease -- 15 not taking propranolol (group A) and 14 taking propranolol (group B) -- and 15 normal subjects were studied. Plasma beta-thromboglobulin levels were increased in group A and B patients (mean 63 +/- 8 and 96 +/- 14 ng/ml, respectively) compared with normal subjects (mean 46 +/- 6 ng/ml). Plasma TXB2 levels were similar in group A and B patients and in normal subjects (mean 148 +/- 41, 149 +/- 36 and 216 +/- 39 pg/ml). Arachidonate-induced platelet TXA2 generation was significantly higher in group A patients than in normal subjects (725 +/- 393 vs 82 +/- 25 pg TXB2/10(8) platelets, p less than 0.001). In contrast, platelets from group B patients had very low TXA2 generation (mean 21 +/- 18 pg) compared with platelets from group A patients or normal subjects (p less than 0.001). Similar results were obtained using thrombin. These data show that propranolol therapy does not affect platelet-released beta thromboglobulin or TXA2 at rest, but significantly reduces the capability of platelets to generate TXA2 in vitro. Reduction in platelet TXA2 generation may be an important mechanism of action of propranolol in patients with coronary artery disease.

Adult↗