A pharmacological approach to thromboxane receptor antagonism.

Thromboxane A2 (TxA2) appears to be an important mediator of ischemia and hypoxia. Despite its short half-life and the fact that it may not circulate in the blood until its values become quite high, TxA2 contributes to the pathogenesis of cardiopulmonary diseases (e.g.

Mechanisms of platelet-activating factor-induced cardiac depression in the isolated perfused rat heart.

A potent phospholipid (platelet-activating factor, PAF) has been implicated in a variety of inflammatory and ischemic responses (eg, myocardial ischemia and anaphylactic shock). In isolated rat hearts perfused at constant flow, PAF produced a dose-dependent increase in coronary perfusion pressure (CPP) and a decrease in contractile force (CF). At 20 nM, PAF increased CCP by 21 +/- 1 mm Hg and decreased CF by 31 +/- 3% in nine hearts.

Cardioprotective actions of specific thromboxane receptor antagonist in acute myocardial ischemia.

Thromboxane A2 (TxA2) has been implicated as a potential mediator of myocardial damage during acute ischemia. A potent and specific TxA2 receptor antagonist, SQ-29,548 (2 mg/kg bolus + 2 mg/kg/h) was tested in a cat acute coronary ligation model of myocardial ischemia over a 5-h observation period. Those cats given the TxA2 receptor antagonist had a significant reduction in elevated S-T segment from 0.

Anti-shock properties of the prostacyclin analog, iloprost, in traumatic shock.

The effects of iloprost, a synthetic carbacyclin derivative of prostacyclin (PGI2) was studied in a standardized model of traumatic shock. Pentobarbital anesthetized rats (35 mg/kg) subjected to Noble-Collip drum trauma were characterized by a 84 +/- 10 minute survival time, a 16-fold increase in plasma cathepsin D activity, and a 5-fold increase in plasma myocardial depressant factor (MDF) activity. Iloprost significantly attenuated the accumulation of MDF activity in the plasma (69 +/- 14 vs.

Coronary vasoactivity of four 7,13-bridged analogs of arachidonic acid.

Four newly synthesized 7,13-bridged arachidonic acid analogs which have been shown to exert 5-lipoxygenase inhibitory activity were studied in isolated perfused cat coronary arteries. The two dehydro analogs constricted and the two non-dehydro analogs dilated the coronary arteries. None antagonized LTD4 induced constriction.

Beneficial effects of tissue-type plasminogen activator in acute myocardial ischemia in cats.

Tissue-type plasminogen activator is a new thrombolytic agent that dissolves intravascular thrombi in coronary and peripheral vessels with less pronounced systemic lysis than that produced by streptokinase. Plasminogen activator was shown to induce reperfusion, and to salvage ischemic myocardium, by lysing experimentally induced coronary artery thrombi. The effect of a melanoma cell-derived tissue-type plasminogen activator was studied in cat myocardium rendered ischemic by coronary artery ligation for 2 hours and reperfused for another 4 hours.

Significance of production of peptide leukotrienes in murine traumatic shock.

We studied the formation of a leukotriene metabolite in plasma and bile during traumatic shock. Anesthetized rats subjected to Noble-Collip drum trauma developed a lethal shock state characterized by a survival time of 1.9 +/- 0.

Inhibition of leukotriene actions by the calcium channel blocker, nisoldipine.

Nisoldipine, a calcium channel blocker having a highly potent effect on vascular smooth muscle relative to cardiac muscle, was tested to determine its anti-leukotriene properties. Nisoldipine, at concentrations from 1 to 300 ng/ml, significantly attenuated the vasoconstrictor effects of both LTC4 and LTD4 in isolated perfused cat coronary arteries and in isolated Langendorff perfused cat hearts. In isolated perfused coronary arteries, nisoldipine exerted a greater percentage inhibition of LTC4- and LTD4-induced constriction than of the constriction induced by the thromboxane analog, carbocyclic thromboxane A2 (CTA2).

Antagonism of thromboxane actions in the isolated perfused rat heart.

The effects of SQ-29,548, a novel thromboxane A2 (TxA2) receptor antagonist, were studied in the isolated perfused rat heart. SQ-29,548 at concentrations of 2.5 to 50 ng/ml antagonized the increase in coronary perfusion pressure (CPP) in response to the thromboxane agonist, 9,11-methanoepoxy PGH2.

CGS-12970, a thromboxane synthetase inhibitor, limits ischemic damage following coronary artery occlusion.

A new thromboxane synthetase inhibitor, CGS-12970, was evaluated for its ability to reduce the extension of myocardial infarct size in rats. CGS-12970 was given at either 4 or 8 mg/kg following acute coronary artery ligation. Both myocardial creatine kinase (CK) and amino-nitrogen loss from the left ventricular free wall (LVFW) were used as indices of ischemic damage at 48 hours.

Synthesis and vascular actions of an arachidonic acid ethylene-diamino-triethyl-ester (AA-EDTA) derivative.

An ethylene-diamino-triethyl-ester derivative of arachidonic acid (AA-EDTA) was newly synthesized and tested for its coronary vasoactivity in isolated perfused cat coronary arteries. This arachidonic acid analog exerted a coronary vasodilator effect and significantly antagonized the coronary vasoconstrictor effect of LTD4. The constrictor response to the thromboxane analog carbocyclic thromboxane A2 was unaffected by AA-EDTA.

Effects of lisinopril, a new angiotensin converting enzyme inhibitor in a cryo-injury model of chronic left ventricular failure.

The angiotensin converting enzyme inhibitor, lisinopril, was studied in a cryo-injury model of chronic heart failure. This model is characterized by a progressive decrease in cardiac output starting six weeks after cryo-injury to a 30% decrease in cardiac output 10 weeks after injury. Although histological damage to the myocardial tissue, particularly in the epicardial area, was observed, no significant changes occurred in body weight, mean arterial blood pressure, heart rate or central venous pressure.

Anti-shock actions of the pyrimido-pyrimidine derivative, RA-642.

The anti-shock actions of RA-642 were studied in traumatic shock in rats. The shock state was characterized by a significantly reduced mean arterial blood pressure (MABP), a five-fold increase in plasma cathepsin D activity, a three-fold increase in plasma myocardial depressant factor (MDF) activity, and a mean survival time of 1.6 +/- 0.

In vivo anti-platelet properties of anipamil, a calcium channel blocker, in the rabbit.

The anti-platelet actions of anipamil, a new calcium channel blocker were studied in anesthetized rabbits using continuous on-line techniques to measure platelet count and platelet secretion by ATP release. Anipamil, at a dose of 0.5 mg/kg twice daily for three days, prior to challenge with collagen (100 micrograms/kg) or arachidonic acid (1.

Role of platelet-activating factor-acether in mediating guinea pig anaphylaxis.

The pathophysiology of anaphylaxis is very complex, and the sequelae of events are not fully explained in terms of the effects of histamine and peptide leukotrienes alone. Platelet-activating factor (1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine, PAF-acether) has been detected in animals undergoing anaphylaxis. Injection of synthetic PAF-acether induces similar effects, including bronchoconstriction, respiratory arrest, systemic hypotension, neutropenia, and thrombocytopenia.

Anti-ischemic actions of a new thromboxane receptor antagonist, SQ-29,548, in acute myocardial ischemia.

Thromboxane A2 (TxA2) has been implicated as a mediator of ischemic damage to the myocardium. A new, selective thromboxane receptor antagonist, SQ-29,548 (2 mg/kg bolus + 2 mg/kg per h infusion) was studied for its effects on the extension of ischemic damage following acute myocardial ischemia (MI) in the rat. Administration of SQ-29,548 to sham MI rats had no significant effect on mean arterial blood pressure or heart rate over the 6 h experimental protocol.

Cardioprotective actions of a new calcium channel blocker in acute myocardial ischemia.

The ability of anipamil, a calcium channel blocker, to protect ischemic myocardial tissue was investigated in pentobarbital anesthetized cats. Two bolus injections of anipamil (1.0 mg/kg i.

Leukotrienes as mediators of ischemia and shock.

Leukotrienes have been implicated as mediators of ischemia and shock. Recent evidence has been obtained supporting the four major criteria of acceptance of leukotrienes as mediators of shock, namely (a) increased concentration in body fluids during shock states, (b) ability to exert significant pathophysiologic effects which aggravate ischemia and shock, (c) amelioration of the shock state by leukotriene synthesis inhibitors and leukotriene receptor antagonists, and (d) production of a shock-like state by exogenous administration of leukotrienes. In conclusion, both LTB4 and the peptide leukotrienes (e.

Modulation of receptor mediated leukotriene release in the perfused heart.

The chemotactic peptide n-formyl-methionyl-leucyl-phenylalanine (FMLP) induces peptide leukotriene release at concentrations of 20-25 pmol/ml 3 min after the start of FMLP infusion. FMLP-induced leukotriene release in rabbit hearts is not blocked by the leukotriene receptor antagonist FPL-55712 at concentrations that totally antagonize the hemodynamic effects of exogenously infused peptide leukotrienes. Moreover, propyl gallate, a lipoxygenase inhibitor, does not block FMLP-induced leukotriene release.

Inhibition of the platelet activating factor mediated component of guinea pig anaphylaxis by receptor antagonists.

The role of platelet activating factor (PAF) and its inhibition by specific receptor antagonists was studied in hypersensitivity reactions in guinea pig lung parenchymal strips and in guinea pigs in vivo. Immunological challenge of isolated lung parenchymal strips with ovalbumin resulted in a contractile response of 184 +/- 16 mg (n = 38). Pretreatment of the strips with a combination of the antihistamine diphenhydramine, the dual lipoxygenase and cyclooxygenase product synthesis inhibitor BW-755C, and the PAF receptor antagonist kadsurenone totally inhibited the increase in tension.

Beneficial actions of thromboxane receptor antagonism in hemorrhagic shock.

The new specific thromboxane receptor antagonist, BM-13505, was infused intravenously (1 mg/kg bolus and 1 mg/kg hr continuous infusion) to determine its effect in a feline model of hemorrhagic shock. Hemorrhaged cats treated with BM-13505 maintained post-reinfusion mean arterial blood pressure and superior mesenteric artery flow at significantly higher values compared to cats receiving only the vehicle. BM-13505 was also found to attenuate the increase in plasma cathepsin D activity in hemorrhaged cats as well as to curtail plasma proteolysis to values not significantly different from sham shock animals at the end of the post-reinfusion period.

Mechanism of the pressor effect of the calcium agonist, BAY k 8644, in the intact rat.

The purported calcium agonist BAY k 8644 was tested as a pressor agent in pentobarbital anesthetized and conscious Sprague-Dawley rats. A dose of 10 micrograms/kg increased mean arterial blood pressure (MABP) by 47 +/- 3 mm Hg in anesthetized and 39 +/- 3 mm Hg in conscious rats. The calcium channel blockers nitrendipine or nisoldipine (180 micrograms/kg/h) blocked 62-84% of the pressor response of BAY k 8644 (p less than 0.

Anti-ischemic actions of a new thromboxane receptor antagonist during acute myocardial ischemia in cats.

Thromboxane A2 (TxA2) production increases significantly during acute myocardial ischemia. Since TxA2 induces platelet aggregation, coronary vasoconstriction, and has a direct cytolytic effect, thromboxane receptor antagonism would be expected to be beneficial in acute myocardial ischemia. Thirty minutes after ligation of the left anterior descending coronary artery (LAD) in anesthetized cats, the TxA2 receptor antagonist BM-13,177 or its vehicle was given as a bolus injection at 20 mg/kg, followed by continuous infusion of 20 mg/kg/hr for 4.

Antiaggregatory effects of thromboxane receptor antagonists in vivo.

The antiaggregatory and antisecretory effects of two newly developed thromboxane receptor antagonists, BM-13,177 and SQ-29,548, were studied in an in vivo model of platelet activation. Arterial platelet count and whole blood ATP concentrations were measured continuously on-line in the arterial blood of anesthetized rabbits. Injections of collagen decreased peripheral platelet count by 25% of initial value.