Mechanism and Pressor Relevance of the Short-Term Cardiovascular and Renin Excitatory Actions of the Selective A2A-Adenosine Receptor Agonists

Abstract

Selective A2A adenosine receptor agonists are potent vasodilators that reduce blood pressure and induce marked increments in heart rate and plasma renin activity (PRA). To examine the mechanisms and pressor relevance of these cardiac and renin responses, we measured blood pressure and heart rate by telemetry and PRA in separate sets of spontaneously hypertensive rats (SHRs), which were given i.p. 2-hexynyl-5-methylcarboxamidoadenosine (2HE-NECA, 0.01 mg/kg) and 2-[4-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosin e (CGS 21680, 0.1 mg/kg) alone and after pretreatment with the beta 1-adrenoceptor blocking agent atenolol (100 mg/kg). The effects of 2HE-NECA (0.003 mg/kg) also were examined after pretreatment with the angiotensin-converting enzyme (ACE) inhibitor spirapril (3 mg/kg). Both A2A agonists induced marked reductions in blood pressure, associated with significant increments in heart rate and in PRA. Atenolol reduced blood pressure to the same extent as did the A2A agonists and markedly decreased heart rate and PRA. Pretreatment with atenolol entirely prevented the increase in heart rate and in PRA induced by the two A2A agonists but potentiated only slightly their antihypertensive effect. Spirapril alone reduced blood pressure and increased PRA and when given before 2HE-NECA potentiated its depressor and renin-stimulating effects by 44% and 69%, respectively. These results suggest that the increase in heart rate and in PRA induced by A2A agonists is the result of a reflex increase in sympathetic activity triggered by the decrease in blood pressure rather than of a direct stimulating effect on cardiac and renal A2A-adenosine receptors; the reactive activation of the renin-angiotensin system elicited by these compounds may contribute to blunting their antihypertensive effect.

Tachycardia Caused by A2A Adenosine Receptor Agonists Is Mediated by Direct Sympathoexcitation in Awake Rats

“…However, studies showed that adenosine could stimulate isolated arterial chemoreceptors (McQueen and Ribeiro, 1981) and studies using selective agonists suggested that this effect was mediated by A 2A receptors Ribeiro, 1983, 1986). In animals as well as humans, adenosine and its analogs cause sinus tachycardia and lower systemic blood pressure (Biaggioni et al, 1987;Lappe et al, 1992;Bonizzoni et al, 1995;Alberti et al, 1997;Koos and Chau, 1998;Barrett et al, 2005;Hendel et al, 2005;Schindler et al, 2005). The sinus tachycardia has been attributed to the baroreceptor reflex caused by the decrease in arterial pressure (Webb et al, 1990(Webb et al, , 1991Nekooeian and Tabrizchi, 1996;Alberti et al, 1997).…”

“…In animals as well as humans, adenosine and its analogs cause sinus tachycardia and lower systemic blood pressure (Biaggioni et al, 1987;Lappe et al, 1992;Bonizzoni et al, 1995;Alberti et al, 1997;Koos and Chau, 1998;Barrett et al, 2005;Hendel et al, 2005;Schindler et al, 2005). The sinus tachycardia has been attributed to the baroreceptor reflex caused by the decrease in arterial pressure (Webb et al, 1990(Webb et al, , 1991Nekooeian and Tabrizchi, 1996;Alberti et al, 1997). However, there is also evidence that adenosine-mediated tachycardia can occur independent of a decrease in MAP (Lappe et al, 1992;Mathot et al, 1995;Koos and Chau, 1998;Schindler et al, 2005).…”

“…Myocardial perfusion imaging using adenosine or A 2A receptor agonists as coronary vasodilators is accompanied by a significant sinus tachycardia (Johnston et al, 1995;Udelson et al, 2004;Hendel et al, 2005). The adenosine receptor subtype responsible for the tachycardia has been proposed to be the A 2A receptor (Koos et al, 1993;Alberti et al, 1997); however, this remains to be conclusively established, as well as the mechanism of the acceleration of the heart rate.…”

“…The peripheral vasodilation causes a decrease in arterial pressure, which in turn elicits a baroreflex-mediated activation of the sympathetic nervous system (SNS) and thereby an increase in heart rate. This has been proposed to be the mechanism underlying the increase in heart rate (HR) caused by adenosine and A 2A receptor agonists (Nekooeian and Tabrizchi, 1996;Alberti et al, 1997). However, it has been shown that adenosine elicits a direct positive chronotropic effect (Koos et al, 1993) and that activation of A 2A receptors leads to direct stimulation of the autonomic nervous system (Koos and Chau, 1998).…”

Heart rate response during vasodilator stress myocardial perfusion imaging: Mechanisms and implications

“…The increase in HR has been traditionally attributed to a reflex response to the vasodilatory effect on the systemic circulation and the resultant increase in sympathetic discharge. 5,6 The true mechanism of HR increase, however, is more complicated and involves direct stimulation of the sympathetic nervous system. 7 The administration of adenosine as a bolus, as done for the interruption of supra-ventricular tachycardias, has a negative chronotropic effect on the atrio-ventricular node via stimulation of the A1 receptor.…”