Keiji Nishiyama

Effects of thromboxane A2 injection on the rabbit coronary artery: II. The production of infarcts in cholesterol-fed animals

Abstract The role of thromboxane A 2 (TXA 2 ) in ischemic heart disease was studied using atherosclerotic rabbits fed a diet of pellets containing 1% cholesterol for 3 months, with agematched rabbits as controls. Various combinations of 15–30 μg of prostaglandin H 2 (PGH 2 ) and 1–5 mg of microsome protein obtained from cow platelets were injected at the origin of the aortic arch through an indwelling catheter. With this method, plasma levels of thromboxane B 2 of femoral arterial blood were over 1000 pg/ml immediately after injection of 30 μg of PGH 2 and 5 mg of microsome. The normal control groups showed no ECG changes related to myocardial damage. On the contrary, all of the cholesterol-fed rabbits exhibited a typical ST elevation in II, III, a Vf , and/or precordial leads at 3–5 min after injection of the TXA 2 -generating mixture, as well as a decrease in blood pressure and heart rate. All of these rabbits died within 40 hr except one given a mixture of minimum doses of PGH 2 (15 μg) and cow platelet microsome (1 mg protein). In two rabbits, the Q wave was observed. Various irregular-sized ischemic areas were frequently noted in the left ventricle and/or septal walls of the heart in these cholesterol-fed rabbits, using hematoxylin-basic fuchsin-picric acid stain and stains for detection of phosphorylase, LDH, and SDH activities. Microthrombi were frequently detected in the small coronary vessels, mainly at the subendocardial area of the myocardium. Such findings were not evident in the control group. These data suggest a role for thromboxane A 2 in the damaged myocardium and an association with coronary atherosclerosis.

Cyclic AMP accumulation in rabbit aorta smooth muscle cells altered in the presence of hyperlipidemic serum

We investigated the effect of hyperlipidemic serum on cAMP accumulation in cultured smooth muscle cells from the rabbit aorta. The cells were grown to confluence, then cultured for 24 h in hyperlipidemic medium (total cholesterol: 2.2 mmol/l). cAMP accumulation was enhanced in response to isoproterenol 10(-6) M, as compared to control cells, and this enhancement was still detectable in the presence of IBMX 10(-3) M, a potent inhibitor of phosphodiesterase. Application of propranolol 10(-4) M at 5 min after isoproterenol showed a similar time course for cAMP disappearance. The phosphodiesterase activity in the 40 000 g supernatant of the Triton X-100 solubilized homogenates of the cells in hyperlipidemic medium remained unchanged. Beta-receptor assays showed an increased Bmax with a similar Kd, and such may contribute, at least in part, to the increased adenylate cyclase activity. An extended incubation in the presence of hyperlipidemic medium attenuated the cAMP accumulation, possibly due to excessive increases in the total cholesterol content.

Protective Effects of Iloprost Against Thromboxane-Induced Myocardial Infarction

The discovery of thromboxane A2 (TXA2) and prostacyclin, and the elucidation of their physiologic roles have brought new insights into atherogenesis and thrombogenesis [1–3]. In particular, the roles of these prostanoids in the pathogenesis of ischemic heart disease have recently been highlighted in relation to coronary thrombosis, vasospasm, and microcirculatory disturbances [4–7], and there has been much discussion regarding whether or not antiplatelet agents such as prostacyclin have preventive or curative effects in these conditions [8–11].