The cardiovascular effects of CGS 21680, an adenosine A(2A) receptor agonist and 17beta-estradiol in rats with impaired cardiac function

The first part of this thesis examined the acute cardiovascular effects of CGS 21680, a selective adenosine A2A receptor agonist, relative to those of sodium nitroprusside (SNP) and vehicle (normal saline) in male Sprague-Dawley rats with or without acute occlusion or chronic ligation of the left main coronary artery. Rats with chronic coronary ligation were studied 8 weeks after the operation. The second part examined the chronic effects of 17beta-estradiol, the most abundant naturally-occurring estrogen, relative to those of vehicle on in vivo cardiovascular function and response to vasoactive drugs in ovariectomised rats at 7 weeks after ligation of the left coronary artery. It also examined the effects of 17beta-estradiol on ex vivo contractile and relaxant responses of aortic rings, pulmonary artery rings and portal vein strips to vasoactive drugs. The ovariectomised rats were implanted with 60 days sustained-release pellets containing 17beta-estradiol (1.5 mg) or vehicle one week prior to coronary ligation. The vasoactive drugs studied include noradrenaline, phenylephrine, NG-intro-L-arginine methyl ester (L-NAME), acetylcholine and SNP.; Cardiovascular assessments included measurements of mean arterial pressure (MAP), central venous pressure (CVP), left ventricular end-diastolic pressure (LVEDP), heart rate (HR), cardiac output (CO), coronary arterial flow and conductance, mean circulatory filling pressure (MCFP), arterial resistance (RA) and venous resistance (RV).; These results indicate that rats with acute occlusion as well as chronic ligation of the coronary artery have signs of impaired cardiac function, namely reduced CO and left ventricular +dP/dt as well as increased LVEDP, R V and MCFP. Acute administration of CGS 21680 increased CO and HR, dilated arterial and venous resistance vessels, as well as reduced LVEDP and MCFP in rats with acute or chronic heart failure. Chronic treatment of 17beta-estradiol in ovariectomized rats with chronic heart failure also increased CO, elicited dilatation of arterial and venous resistance vessels, and reduced LVEDP as well as MCFP. The reductions of arterial resistance and LVEDP by CGS 21680 or 17beta-estradiol reflect the reductions of cardiac afterload and preload, respectively. Chronic 17beta-estradiol also increased in vivo pressor and ex vivo contractile responses of blood vessels to L-NAME indicating restoration of the vasodilator activity of basal nitric oxide in rats with chronic heart failure. CGS 21680 and 17beta-estradiol, by virtue of their vasodilator properties, improved cardiac function in rat model of acute or chronic heart failure. (Abstract shortened by UMI.)...