David Ezra

Coronary constriction by leukotriene C4, D4, and E4 in the intact pig heart.

Leukotrienes are naturally occurring vasoactive metabolites of arachidonic acid that increase during inflammatory reactions and anaphylaxis. Coronary constriction and reduced myocardial contractility after leukotriene C4 and D4 administration were demonstrated in the isolated guinea pig heart. To explore the effects of leukotrienes in the in situ, blood-perfused heart, we administered leukotrienes C4, D4, and E4 into the coronary artery of the domestic pig. Increasing doses (0.1, 0.3, 1.0, and 3.0 micrograms) of leukotrienes C4, D4, and E4 were injected into the left anterior descending coronary artery of 8 open-chest domestic pigs. Significant dose-related reduction in coronary blood flow was observed after each leukotriene administration. Three micrograms of each leukotriene produced the following maximal decreases (mean +/- standard error); C4 = 80 +/- 9%, p less than 0.001; D4 = 81 +/- 3%, p less than 0.001; E4 = 64 +/- 12%, p less than 0.005. In several instances, surface electrograms recorded from the myocardial region exposed to leukotrienes showed signs of focal myocardial ischemia, sometimes accompanied by ventricular arrhythmia. Significant elevation of left ventricular end-diastolic pressure was observed after large doses (1 or 3 micrograms) of leukotrienes C4 and D4. Minimal (5 to 10%) decreases in mean arterial pressure and no change in heart rate were observed after leukotriene injection. We conclude that leukotrienes C4, D4, and E4 are extremely potent coronary constrictors in the in situ heart. The intensity of response and associated electrocardiographic signs of ischemia suggest that constriction is mainly due to a primary effect on vascular smooth muscle. However, coronary flow reduction may also reflect consequences of a primary negative inotropic action. Leukotrienes may play a significant role in the pathogenesis of a variety of cardiac disorders, particularly those associated with extensive inflammatory changes.

Calcitonin-gene-related peptide: a potent modulator of coronary flow

Calcitonin gene-related peptide (CGRP) has been identified in nerve fibers innervating cardiovascular elements and particularly in coronary arteries (CA). To investigate its potential role in modulating coronary blood flow, we injected rat-CGRP into the CA of pentobarbital anesthetized, open chest pigs. Significant dose-related increments in coronary flow were observed. The rise in coronary flow was characterized by unusually, slow onset, late peak and prolonged duration. Arterial pressure, heart rate (HR) and myocardial contractility were unchanged, except at the highest dose (3.0 nmol), which produced mild systemic hypotension and sinus tachycardia. Coronary levels of catecholamines and 6-keto-PGF1 alpha were unchanged by CGRP. The direct, sustained, and potent dilatory activity of CGRP, in coronary arteries of the pig together with anatomical CGRP localization in this site suggest a role for this neuropeptide in hemodynamic regulation.

Cardiac and coronary consequences of intracoronary platelet activating factor infusion in the domestic pig

In previous studies we have shown that platelet-activating factor (PAF) is a potent vasoactive substance with deleterious effects on coronary blood flow (CBF) and myocardial performance. The present study further investigates the effects of PAF during its sustained intracoronary infusion in the blood-perfused domestic pig (n = 16). PAF infusion (1-9 nmol/min) produced triphasic changes in CBF (n = 7): an initial brief phase of coronary dilation (14 +/- 2% above baseline), followed by severe reduction in CBF due to increase in coronary vascular resistance and a third phase of escape that was characterized by return of CBF towards baseline in spite of continuing PAF infusion. In 9 remaining pigs PAF infusion had a biphasic response: the first phase of coronary dilation rapidly turned into severe coronary constriction accompanied by severe systemic hypotension and death within a few min. PAF infusion caused a profound rise in systemic arterial and coronary venous thromboxane B2 levels, while 6-keto-PGF1 alpha and leukotriene C4-immunoreactivity levels were not changed. Indomethacin completely blocked the rise in thromboxane level during PAF infusion and abolished the constrictor effect of PAF on the coronary vessels. These data suggest that PAF might play a detrimental role on the coronary circulation and cardiac function, primarily through thromboxane A2 mediated mechanism.

Thyrotropin-releasing hormone blocks the hypotensive effects of platelet-activating factor in the unanesthetized guinea pig.

Platelet-activating factor (PAF) and leukotrienes, newly described classes of vasoactive lipids, may play a role in anaphylaxis. It has recently been suggested that the vasoconstrictor effects of PAF in isolated rat lung are related to release of leukotrienes C4 and D4. Thyrotropin-releasing hormone (TRH), a tripeptide, has potent antihypotensive activity in experimental shock, including that resulting from either leukotriene D4 administration or antigen-induced anaphylaxis. We utilized an unanesthetized guinea pig model to study the relationships among PAF, leukotrienes, and TRH and their potential interactions on the cardiovascular system. PAF (1 nmol/600 g body weight i.v.) produced profound hypotension which was completely blocked by TRH (2 mg/kg i.v.). Nafazatrom or FPL 55712, a presumed receptor antagonist of leukotrienes, was ineffective, whereas U-60257, a leukotriene synthesis inhibitor, displayed incomplete blockade. Moreover, leukotriene-like immunoreactivity in plasma did not increase following PAF administration. Thus, hypotension produced by PAF does not appear to result secondarily from release of cysteinyl leukotrienes. Moreover, the ability of TRH to block the hypotensive effects of PAF may partially account for its beneficial effects in experimental anaphylaxis and provides further rationale for the therapeutic evaluation of this peptide in anaphylactic shock.

Effects of FPL-55712 or indomethacin on leukotriene-induced coronary constriction in the intact pig heart

Intracoronary leukotriene D4, 0.1-3.0 micrograms (0.2-6.0 nmol), produced dose-dependent decreases in coronary flow of anesthetized pigs. Pretreatment with intracoronary FPL-55712 (0.1, 0.3 and 1.0 mg) reduced coronary constriction due to 1.0 micrograms leukotriene D4 by up to 77%. FPL-55712 did not produce sustained alterations in coronary flow, left ventricular end-diastolic pressure, systemic arterial pressure, or heart rate. Indomethacin pretreatment (6 mg/kg i.v.) had no effect on leukotriene-induced coronary constriction. Inhibition produced by FPL-55712 may be useful in disease states involving leukotriene-mediated coronary constriction.

Tachykinin modulation of coronary blood flow.

In pentobarbital anesthetized, open chest pigs, coronary blood flow (CBF), myocardial contractility and systemic hemodynamic variables were monitored during intracoronary injections of substance P (SP), neurokinin A (NA) or neurokinin B (NB). SP was most potent in increasing CBF although NA was also active in high doses while NB had absolutely no effect. SP was also more potent than NA in producing systemic hypotension. The data suggests that SP and its receptors might be potentially important modulators of CBF.

Clinical pharmacodynamics of theophylline.

The clinical pharmacodynamics of theophylline, which concerns the correlation between the serum theophylline concentration ([TH]) attained during therapy for asthma and improved pulmonary function or unwanted side effects, serves to link the pharmacokinetics of theophylline with the time course of clinical outcome. Although the minimum effective and maximum safe [TH]s have been known for some years, it was only recently shown that maximal improvement in pulmonary function lags behind rapidly changing [TH]s and that improved pulmonary function relates to increasing [TH]s within the therapeutic range. While much is known about the determinants of theophylline disposition in patients with asthma, enabling individualized pharmacokinetically based therapy, it is difficult to predict the clinical pharmacodynamic outcome. Investigation of the effects of age, cardiopulmonary disease, concurrent drugs, diet, circadian rhythms, and other patient features on theophylline clinical pharmacodynamics may provide a basis for prediction of individual patient responsiveness to theophylline and lead to further optimization of theophylline therapy in asthma.

Outward transcutaneous chemical migration: implications for diagnostics and dosimetry.

Chemical substances migrate outwards from within the body to the skin surface by diffusion from cutaneous capillaries across the epidermis. Heretofore, study of transepidermal chemical emissions have been restricted to substances which are in the vapor phase at skin surface temperature. We have investigated outward transcutaneous chemical migration of nongaseous chemicals by devising an occlusive transcutaneous chemical collection system, consisting of a tape-encased plug of gelled saline in which activated carbon is dispersed. Investigations of nine chemicals in fuzzy rats, rhesus monkeys, and man provide data which are consistent with a general theory of outward transcutaneous chemical migration. This noninvasive continuous transcutaneous sampling technique provides a new method for investigating skin permeability in vivo and may provide a basis for convenient diagnosis and monitoring of chemical exposure.

Reversal of leukotriene D4 hypotension by thyrotropin-releasing hormone.

Thyrotropin-releasing hormone (TRH) reversed the hypotension produced by leukotriene D4 (LTD4) (5 micrograms/kg, i.v.) in conscious guinea pigs in a dose-dependent fashion at intravenous doses between 0.2 and 2.0 mg/kg. LTD4 hypotension was also reversed by the synthetic TRH analog MK771 (0.2 or 2 mg/kg, i.v.), suggesting a possible receptor-mediated mechanism. Since LTD4 has been implicated as a mediator of anaphylaxis, these results provide a basis for further evaluation of TRH and its analogs in the treatment of anaphylactic shock.

Inhibition of eicosanoid-mediated coronary constriction during myocardial ischemia.

Thromboxane A2 and cysteinyl leukotrienes are highly effective microvessel constrictors in normally perfused myocardium. Their release during acute coronary thrombosis might augment myocardial underperfusion. The constrictor action of these substances could be modified substantially, however, by concomitant myocardial ischemia. We compared the effects of the two eicosanoid constrictors in normally perfused and ischemic myocardium of 24 open‐chest, pentobarbital‐anesthetized pigs. Left anterior descending coronary flow was measured after intracoronary bolus injections of the stable thromboxane A2 analog U46619 (1‐10 μg) or leukotriene D4 (LTD4, 1‐10 μg). Each dose was given before and during myocardial ischemia induced by a snare adjusted to produce 63 ± 2% decrease in coronary flow for 10 min. Marked dose‐independent inhibition of eicosanoid‐induced coronary flow decrease occurred during ischemia. With 10 μg U46619, coronary flow decrease in the unoccluded state (25 ± 2 from 55 ± 4 ml/min pretreatment baseline) was virtually eliminated during snare occlusion (1 ± 1 from 21 ± 3 ml/min pretreatment baseline, P < 0.001). Similar results occurred with LTD4. Distal coronary pressure during ischemia indicated a lack of microvessel responsiveness to the eicosanoids rather than a buffering of resistance change by the snare. U46619 and LTD4 did induce transient, small reductions in regional shortening fraction during ischemia. Our data suggest that eicosanoid‐induced constriction of myocardial resistance vessels is not a likely complication of acute coronary thrombosis. However, eicosanoids could depress residual contractility in moderately ischemic regions.— Laurindo, F. R. M.; Finton, C. K.; Ezra, D; Czaja, J. F.; Feuerstein, G. Z.; Goldstein, R. E. Inhibition of eicosanoid‐mediated coronary constriction during myocardial ischemia. FASEB J. 2: 2479‐2486; 1988.