Effects of CGS 21680, a selective A_2A adenosine receptor agonist, on cardiac output and vascular resistance in acute heart failure in the anaesthetized rat

Abstract

1 The e ects of CGS 21680, a selective A 2A adenosine receptor agonist, on cardiac output, blood pressure, mean circulatory ®lling pressure (P mcf ), arterial and venous resistances, heart rate and left ventricular end-diastolic pressure were assessed in rats with acute heart failure by means of coronary artery occlusion. 2 Animals (n=6 in each group) were divided into ®ve groups: group I, sham-operated vehicle-treated (0.9% saline; 0.018 mL min 71 ); groups II-V, subject to coronary artery occlusion and treated with vehicle (0.9% saline; 0.018 ml min 71 ) and CGS 21680 (0.1, 0.3 and 1.0 mg kg 71 min 71 ), respectively. Haemodynamic measurements were taken one hour after completion of surgery, ninety minutes after coronary artery occlusion (except in group I), and ®fteen minutes after infusion of saline or CGS 21680. 3 Baseline haemodynamic measurements before occlusion were found not to di er signi®cantly between the di erent groups of animals. However, after occlusion, cardiac output, rate of rise in left ventricular pressure (+dP/dt) and blood pressure were signi®cantly reduced when compared to corresponding values in sham-operated animals. In addition, occlusion of the coronary artery resulted in a signi®cant elevation in venous resistance, P mcf and left ventricular end-diastolic pressure as compared to corresponding values in sham-operated animals. 4 Infusion with CGS 21680 at the highest dose signi®cantly reduced blood pressure, arterial resistance and left ventricular end-diastolic pressure when compared to occluded vehicle-treated animals (group II). Administration of CGS 21680 at the highest dose also signi®cantly increased cardiac output (28%) and heart rate (10%) in comparison to occluded vehicle-treated animals. In addition, the highest dose of CGS 21680 signi®cantly reduced P mcf (9%) and venous resistance (62%) in comparison to occluded vehicle-treated animals. Administration of CGS 21680 did not signi®cantly a ect +dP/dt when compared to occluded vehicle-treated animals. 5 The results from the present investigation indicate that occlusion of the coronary artery in rats results in a state of heart failure characterized by reduced arterial pressure and cardiac output, and increased venous resistance, P mcf and left ventricular end-diastolic pressure. Administration of CGS 21680 to animals with acute heart failure resulted in increased cardiac output which was due to reduced venous resistance, as well as increased heart rate.

Haemodynamic effects of a selective adenosine A2A receptor agonist, CGS 21680, in chronic heart failure in anaesthetized rats

“…Unlike our previous observations in anaesthetized rats in a state of acute heart failure in which the administration of CGS 21680, only at the highest dose, significantly reduced venous resistance and left ventricular end‐diastolic pressure (Nekooeian & Tabrizchi, 1998), in the present investigation, administration of CGS 21680 significantly decreased venous resistance and left ventricular end‐diastolic pressure at the two higher dose levels. It is recognized that a decrease in Pmcf and an increase in venous capacitance can result in a reduction of cardiac loading.…”

“…It is evident that the influence of CGS 21680 on venous circulation in normal animals not treated with ganglion‐blockers is in contrast to our observations in animals with either acute or chronic heart failure. It seems that under pathophysiological situations, such as acute heart failure, in which Pmcf and venous resistance are elevated due to activation of the sympathetic nervous system, administration of CGS 21680 reduces both Pmcf and venous resistance (Nekooeian & Tabrizchi, 1998). Moreover, in the present investigation, administration of CGS 21680 to animals with established chronic heart failure resulted in reduced Pmcf and venous resistance.…”

“…Moreover, we also recently demonstrated that the administration of CGS 21680 to rats in a state of acute heart failure (1 h post‐coronary artery ligation) resulted in an increase in cardiac output. This increase in cardiac output was predominantly due to reduced resistance to venous return and, thus, reduced preload (Nekooeian & Tabrizchi, 1998). In the present investigation, we have attempted to further examine the influence of CGS 21680 on cardiac output, vascular resistance (arterial & venous), heart rate, cardiac contractility and left ventricular end‐diastolic pressure in animals with chronic heart failure (8 weeks post‐coronary artery ligation).…”

“…The many differences between animals with acute versus chronic heart failure are, in part, the result of changes in neurohormal factors (due to increased activity of the sympathetic nervous system and renin‐angiotensin system) that ultimately result in cardiac hypertrophy, left ventricular dilatation, alteration of responses to vasoactive substances and pulmonary congestion (van Wijngaarden et al , 1991; Thuillez et al , 1995; Ganguly et al , 1997; Mulder et al , 1997). Therefore, the primary goals of our present investigation were (a) to examine the effects of CGS 21680 in an established chronic heart failure model (Pfeffer et al , 1979), and (b) to compare the haemodynamic effects of CGS 21680 in chronic heart failure to that of acute heart failure from our previous study (Nekooeian & Tabrizchi, 1998).…”

Adenosine A2Areceptor activation attenuates tubuloglomerular feedback responses by stimulation of endothelial nitric oxide synthase

“…1063), is a potent and highly selective adenosine A 2A agonist and is active in vivo. It has binding affinities of 290, 27, 88,800, and 67 nM for A1, A2A, A2B, and A3 receptors, respectively (20,27,28,34). CGS-21680 therefore exhibits ϳ10-fold, 3,300-fold, and 2.5-fold selectivity for the A 2A receptor vs. A1, A2B, and A3 receptors, respectively.…”