The cardiovascular effects of CGS 21680, an adenosine A2A receptor agonist and 17b-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 17β-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 17β-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 17β-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. In both parts of the studies, sham-operated rats with normal cardiovascular function were also prepared to facilitate the evaluation of changes elicited by CGS 21680 or 17β-estradiol. In vivo studies were performed under sodium pentobarbitone or thiobutabarbital (Inactin) anaesthesia. 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). MAP, CVP and LVEDP were measured with catheters inserted into the femoral artery, inferior vena cava and left ventricle, respectively. HR was counted from the upstroke of the arterial pulse pressure or a tachograph. CO and coronary arterial flow were measured using radioactively-labelled microspheres. MCFP was measured by transiently stopping the circulation via the inflation of a saline-filled balloon placed in the right atrium, and was calculated as VPP + (FAP - VPP)/60, where FAP and VPP represent the final arterial pressure and venous plateau pressure, respectively, at 5-7 sec following circulatory arrest, and 60 is the ratio of venous to arterial compliance. RA and Rv were calculated as follows: RA = MAP/CO and Rv = (MCFP - CVP)/CO. Coronary arterial conductance was calculated as coronary arterial flow/MAP. In rats without coronary artery occlusion or ligation, CGS 21680 (0.1, 0.3 and 1.0 μg/kg.min, i.v. infusion) decreased MAP and RA, and increased CO, HR as well as coronary arterial flow and conductance. Ganglionic blockade with hexamethonium (200 μg/kg.min, i.v. infusion) decreased MAP, CO and HR, but did not alter coronary arterial flow or conductance. In the presence of hexamethonium,. CGS 21680 decreased MAP and RA , increased coronary arterial flow and conductance, but did not change CO or HR. The effects of CGS 21680 on CO and HR were, therefore, mediated via the alteration of baroreflex activity. Phenylephrine (7 μg/kg.min, i.v. infusion) increased MAP and RA, reduced CO, HR and coronary arterial conductance, but did not alter coronary arterial flow. In the presence of phenylephrine, CGS 21680 reduced MAP, RA , and increased CO, HR, as well as coronary arterial flow and conductance. Relative to sham-operation, acute occlusion as well as chronic ligation of the coronary artery reduced MAP, CO and rate of rise of left ventricular pressure (+dP/dt), and increased LVEDP, MCFP and Rv at 90 min and 8 weeks after the operation, respectively. CGS 21680 at 1.0 μg/kg.min in rats with acutely-occluded coronary arteries, and at 0.3 and 1.0 μg/kg/min in rats with chronically-ligated coronary arteries, increased CO and HR, and reduced MAP, RA, MCFP, Rv and LVEDP. SNP at a dose (4 μg/kg.min), which reduced MAP similar to CGS 21680 (0.3 μg/kg.min), caused similar reductions in RA, LVEDP or Rv, and a similar increase in CO. However, SNP caused a greater decrease in MCFP but less tachycardia than CGS 21680. Ovariectomised rats with chronic ligation of the coronary artery had lower MAP, CO and left ventricular +dP/dt, but higher RA , LVEDP, MCFP and Rv relative to sham-operated rats at 7 weeks post-ligation. Chronic ligation of the coronary artery reduced MAP-responses to i.v. bolus injections of L-NAME, acetylcholine and SNP, but not to i.v. bolus or i.v. infusion of noradrenaline. Chronic coronary ligation also attenuated the relaxation response to acetylcholine in the portal vein, but. not aorta or pulmonary artery, in ex vivo studies. Moreover, it reduced contractile responses to L-NAME, which reached statistical significance in the aorta and portal vein, but not pulmonary artery. However, it did not alter the contractile responses to phenylephrine or relaxation responses to SNP in any of these vessels. 17β-Estradiol increased CO, and augmented the MAP, RA , MCFP and Rv responses to i.v. infusion of noradrenaline as well as the MAP response to i.v. bolus of L-NAME. It also decreased RA , Rv as well as the. MAP response to i.v. bolus of acetylcholine, but did not alter the MAP responses to i.v. bolus of SNP or noradrenaline. In ex vivo studies, 17β-estradiol increased contractile responses to phenylephrine in the aorta, decreased the response in the portal vein, and did not change it in the pulmonary artery. 17β-Estradiol also reduced the maximal relaxation responses (Emax) to acetylcholine in the aorta, increased the response in the portal vein, and did not change it in the pulmonary artery. As well, it enhanced the contractile responses to L-NAME in all types of vessels, but did not alter the relaxation responses to SNP in any of the vessels. 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, Rv and MCFP suggesting the development of acute and chronic heart failure. 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 17β-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 17β-estradiol reflect the reductions of cardiac afterload and preload, respectively. Chronic 17β-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. The findings of the present thesis suggest that CGS 21680 and 17β-estradiol, by virtue of their vasodilator properties, improved cardiac function in rat model of acute or chronic heart failure. [Scientific formulae used in this abstract could not be reproduced.]Medicine, Faculty ofAnesthesiology, Pharmacology and Therapeutics, Department ofGraduat