Reduction of myocardial reperfusion injury with human soluble complement receptor type 1 (BRL 55730).

This study was designed to evaluate the cardioprotective effects of a solubilized human complement receptor, sCR1, in the rat subjected to myocardial infarction. Following coronary artery occlusion for 0.5 h and reperfusion for 24 h (MI/R group), myocardial infarct size (determined by planimetric analysis) was 18.3 +/- 2.1% of the left ventricle (n = 16), while myeloperoxidase activity (a biochemical marker of neutrophil activation) was increased from 0.94 +/- 0.09 U/g tissue in the sham occluded + vehicle group to 2.96 +/- 0.17 U/g tissue in the MI/R + vehicle treated group (P < 0.01). Injection of sCR1 (5 mg/kg i.v., 5 min prior to coronary artery occlusion) produced plasma concentrations of 154 +/- 4 microgram/ml 1 min prior to coronary artery occlusion, and concentrations of 86 +/- 2 and 58 +/- 3 micrograms/ml at 40 min and 125 min after dosing (n = 6). sCR1 reduced myocardial infarct size to 11.3 +/- 2.2% of the left ventricle, and attenuated the increase in myeloperoxidase activity to 2.11 +/- 0.20 U/g tissue (n = 18; P < 0.01, compared to the MI/R + vehicle group). Administration of sCR1 5 min prior to reperfusion afforded a 25.3% non-significant reduction in myocardial injury. These results suggest a beneficial effect of sCR1 in myocardial ischemia/reperfusion injury by reducing the infiltration of neutrophils and attenuating the extent of myocardial injury.

Identification of cardiac endothelin binding sites in rats: downregulation of left atrial endothelin binding sites in response to myocardial infarction.

Endothelin-1 (ET-1) is a recently described potent vasoconstrictor peptide. Plasma and myocardial tissue levels of ET-1 are increased following myocardial ischemia, however, the factors which regulate ET-1 binding sites in vivo are not well understood. ET-1 binding sites were measured by Scatchard analysis of [125I]ET-1 binding to membranes of rat myocardium. The highest number of ET-1 binding sites (2,951 fmol/mg protein) were found in right atrial tissue, and followed the rank order of right atrium greater than left atrium (2,157 fmol/mg protein), greater than right ventricle (835 fmol/mg protein), greater than septum (609 fmol/mg protein) = left ventricle (498 fmol/mg protein). Following coronary artery occlusion for 24 h, ET-1 binding sites of left atrium were decreased by 35% (p less than 0.01), without a change in the Kd (i.e., 98 pM). Other regions of the myocardium did not exhibit any change in the number of ET-1 binding sites. Similarly, no change in ET-1 binding sites were observed following coronary artery occlusion for 0.5 h followed by 24 h reperfusion. These data indicate that there exists considerable regional differences in the density of ET-1 binding sites in the myocardium, and that ET-1 sites are selectively reduced in left atrial tissue following myocardial infarction.

ICI 198615 is an antagonist of leukotriene C4, leukotriene D4 and leukotriene E4 vasopressor responses in the conscious rat.

The purpose of these studies was to evaluate the effects of the peptidoleukotriene (LT) receptor antagonist, ICI 198615, on the vasopressor responses produced by LTC4, LTD4 and LTE4. Conscious, normotensive rats were prepared with arterial and venous catheters for measurement of changes in arterial blood pressure and administration of drugs, respectively. Complete dose-response curves were first generated to LTC4, LTD4 and LTE4: those agents produced dose-dependent increases in arterial blood pressure, with ED20 values (i.e. dose to increase blood pressure 20 mm Hg) of 1.7 +/- 0.2, 2.1 +/- 0.2 and 19.8 +/- 3.7 nmol/kg i.v., respectively. ICI 198615 (intravenous bolus followed by a continuous infusion) produced dose-dependent, parallel shifts to the right in the LTC4 dose-response curve. At doses of 0.2 mg/kg + 1 mg/kg/h, 1 mg/kg + 3 mg/kg/h or 2 mg/kg + 10 mg/kg/h, ICI 198615 produced dose ratios of 4.5, 17.1 and 50.0, respectively. Against LTD4 responses, ICI 198615 at a dose of 0.1 mg/kg + 0.3 mg/kg/h produced a dose ratio of 3.4, whereas at doses of 0.2 mg/kg + 1 mg/kg/h, 1 mg/kg + 3 mg/kg/h or 2 mg/kg + 10 mg/kg/h ICI 198615 produced dose ratios of 16.3, 24.9 and 16.2, respectively. The difference in the dose ratios between these three groups was not statistically significant (p greater than 0.05). However, a dose of 10 mg/kg + 30 mg/kg/h produced a dose ratio of greater than 100. Against LTE4 responses, ICI 198615 at doses of 0.2 mg/kg + 1 mg/kg/h or 1 mg/kg + 3 mg/kg/h produced dose ratios of 4.1 and 11.3, respectively. The similarity in the LTD4 dose ratios despite a 3- or 10-fold increase in the dose of ICI 198615 suggests the existence of high- and low-affinity LTD4 receptor sites, whereas the responses to LTC4 and LTE4 appeared to be mediated via a single receptor population. These results indicate that ICI 198615 is a potent and competitive antagonist of LTC4, LTD4 and LTE4 vascular responses in the rat.

Effect of propranolol on ischemic myocardial damage and left ventricular hypertrophy following permanent coronary artery occlusion or occlusion followed by reperfusion.

This study was designed to assess the effect of propranolol for limiting myocardial damage and hypertrophy in rats with permanent coronary artery occlusion or occlusion followed by reperfusion. Rats were subjected to occlusion of the left main coronary artery for 48 h (MI) or 0.5 h of occlusion followed by reperfusion for 47.5 h (MI/R). Myocardial injury was determined by measuring the depletion of creatine phosphokinase (CK) levels from the left ventricular free wall. In comparison to sham-occluded animals, myocardial CK levels were significantly decreased by 40% in MI + vehicle animals and 30% in MI/R + vehicle animals. Propranolol (0.3 mg/kg 1 min before occlusion followed by 1 mg/kg at 4 and 24 h after occlusion) significantly reduced the loss of myocardial CK-specific activity in MI animals, but failed to prevent the loss of CK-specific activity in animals subjected to coronary artery reperfusion. Left ventricular hypertrophy developed to a similar extent in both vehicle-treated MI and MI/R groups. Propranolol had no effect on the myocardial hypertrophy in MI or MI/R animals. Likewise, in MI/R animals no diminution of polymorphonuclear leukocyte infiltration was seen with propranolol. These data indicate that propranolol had a significant cardioprotective effect in rats with permanent coronary artery occlusion but failed to salvage ischemic tissue, reduce myocardial hypertrophy or mitigate neutrophil infiltration in animals with early reperfusion of the ischemic myocardium. These results suggest that propranolol may afford a significant protection of the ischemic myocardium, but the combination of reperfusion and propranolol may not result in any greater reduction in infarct size than reperfusion alone.

Protective effects of the thromboxane receptor antagonists BM 13.177 and BM 13.505 against U 46619-induced sudden death in rats.

The purpose of this study was to evaluate the pharmacology and pharmacodynamics of the thromboxane receptor antagonists, BM 13.177 and BM 13.505, for prevention of U 46619-induced sudden death in anesthetized male Sprague-Dawley rats. The injection of U 46619 (100 micrograms/kg i.v.) produced sudden death typically between 5 and 15 min. Administration of 0.01 mg/kg BM 13.505 (i.v.) 0.1 h prior to the U 46619 challenge did not protect against sudden death, while doses of 0.03 mg/kg or greater protected completely (100% survival). A dose of 1 mg/kg BM 13.505 afforded protection to 2 h but not to 24 h, while a single dose of 30 mg/kg administered 24 h prior to the U 46619 challenge provided complete protection against the lethal event. Administration of BM 13.177 (30 mg/kg, i.v. or i.p.) blocked the effects of U 46619 when administered 0.1 h before the challenge, but not when given 2 or 3 h prior to the challenge with U 46619. Pretreatment with indomethacin did not block the effects of U 46619, indicating that formation of endogenous thromboxane does not play a major role in the lethal effects of U 46619, and that blockade of the lethal effects of U 46619 was specific for thromboxane receptor antagonists. These data demonstrate that BM 13.177 and BM 13.505 prevented sudden death produced by the injection of U 46619. At comparable doses of 30 mg/kg, the duration of action for BM 13.505 was was significantly greater than for BM 13.177. These data suggest that BM 13.177 and BM 13.505 may be useful for the investigation of diseases where thromboxane is involved.