Because the sympathetic nervous system has a major role in controlling heart rate, the present study was designed to evaluate the effect of capadenoson on the sympathetic tone in detail in an animal model of increased sympathetic activity. An established model in which an activated sympathetic tone plays a major role is the SHR strain, which develops hypertensive blood pressure levels at 5 to 6 weeks of age, followed by cardiac and vascular hypertrophy and ultimately end-organ failure later in life, if the hypertension remains untreated. In SHR, an increased NE overflow from postganglionic nerve terminals has already been shown before. Thus, we chose SHR to study the effects of the novel adenosine-A1 agonist on the regulation of the sympathetic tone, and compared them to the effects in Wistar rats. We hypothesized,Estradiol Benzoate that activation of the cardiac adenosine-A1 receptor by capadenoson would reduce stimulation-induced NE release and consequently blunt the heart rate response during physical stress particularly in SHR. As hypothesized, the stress-induced increase of the heart rate was significantly blunted by capadenoson in SHR. This in vivo effect of capadenoson was paralleled by a significant reduction of NE release upon stimulation in isolated hearts of SHR. The effects of adenosine agonists on norepinephrine release in Wistar rats have been characterized Escitalopram Oxalate before. Burgdorf et al. showed that activation of adenosine-A1 receptors by CCPA or the non-selective adenosine analogue RN-adenosine decrease stimulation-induced NE release by about 50%, similar to the effect of CCPA we observed in the present study. Besides an activation of presynaptic A1-receptors, the attenuation of stimulation-induced norepinephrine release in the presence of desipramine as an uptake-1 inhibitor may also be explained by an activated extraneuronal uptake in SHR. However, there is no evidence that capadenosone activates this extraneuronal uptake, whereas the presence of A1-receptors presynaptically is well described. It has been described that the mean concentration of norepinephrine is higher in the right ventricle and ventricular septum of SHR hearts compared with hearts of Wistar rats. However, the functional meaning of the tissue concentration of norepinephrine is not clear, since the adrenergic activation may be more dependent on the release and turnover of norepinephrine as well as on the postsynaptic receptors than on the total amount of norepinephrine in the heart. Agonists of adenosine A2- and A3- receptor subtype seem to play no role in the modulation of cardiac NE release. Adenosine has been shown to exert protective effects during ischemia and reperfusion through its potential to limit the release of norepinephrine, and is beneficial in preventing hypertrophic changes under catecholamine stimulation in vitro. Thus, interventions aimed at a specific modulation of cardiac NE release would be highly promising in the treatment of various cardiac diseases, e.g. tachycardia-associated myocardial ischemia. Compared to a selective b1-blockade, a modulation of NE release would avoid the negative inotropic effects on the cardiomyocyte. In the present study we could demonstrate that capadenoson modulates NE release and stress-induced heart rate changes especially in SHR as a model for a high sympathetic tone, while heart rate in Wistar rats was not affected by capadenoson. Heart rate at rest was not affected in either strain. Such a selective attenuation of sympathetic activity as observed in the present study might be explained by the partial agonism of capadenoson on the adenosine-A1 receptor.