Selective Attenuation of Norepinephrine Release and Stress-Induced Heart Rate Increase by Partial Adenosine A1 Agonism

Abstract

The release of the neurotransmitter norepinephrine (NE) is modulated by presynaptic adenosine receptors. In the present study we investigated the effect of a partial activation of this feedback mechanism. We hypothesized that partial agonism would have differential effects on NE release in isolated hearts as well as on heart rate in vivo depending on the genetic background and baseline sympathetic activity. In isolated perfused hearts of Wistar and Spontaneously Hypertensive Rats (SHR), NE release was induced by electrical stimulation under control conditions (S1), and with capadenoson 6 · 10−8 M (30 µg/l), 6 · 10−7 M (300 µg/l) or 2-chloro-N6-cyclopentyladenosine (CCPA) 10−6 M (S2). Under control conditions (S1), NE release was significantly higher in SHR hearts compared to Wistar (766+/−87 pmol/g vs. 173+/−18 pmol/g, p<0.01). Capadenoson led to a concentration-dependent decrease of the stimulation–induced NE release in SHR (S2/S1 = 0.90±0.08 with capadenoson 6 · 10−8 M, 0.54±0.02 with 6 · 10−7 M), but not in Wistar hearts (S2/S1 = 1.05±0.12 with 6 · 10−8 M, 1.03±0.09 with 6 · 10−7 M). CCPA reduced NE release to a similar degree in hearts from both strains. In vivo capadenoson did not alter resting heart rate in Wistar rats or SHR. Restraint stress induced a significantly greater increase of heart rate in SHR than in Wistar rats. Capadenoson blunted this stress-induced tachycardia by 45% in SHR, but not in Wistar rats. Using a [35S]GTPγS assay we demonstrated that capadenoson is a partial agonist compared to the full agonist CCPA (74+/−2% A1-receptor stimulation). These results suggest that partial adenosine A1-agonism dampens stress-induced tachycardia selectively in rats susceptible to strong increases in sympathetic activity, most likely due to a presynaptic attenuation of NE release.

Chronic Therapy With a Partial Adenosine A1-Receptor Agonist Improves Left Ventricular Function and Remodeling in Dogs With Advanced Heart Failure

“…These observations support the concept that adenosine serves an important anti-adrenergic role in the heart to protect it from over-responding both mechanically and metabolically to excessive catecholamine stimulation. Adenosine acting through its A1 receptors has also been shown to inhibit norepinephrine release viewed as a protective mechanism in myocardial ischemia (23, 24). In the present study, CAP significantly decreased plasma levels of norepinephrine early and late during the course of therapy.…”

Super, Red Palm and Palm Oleins Improve the Blood Pressure, Heart Size, Aortic Media Thickness and Lipid Profile in Spontaneously Hypertensive Rats

“…The bradycardia observed in the SO and PO treated SHR may be attributable to a reduction in the sympathetic tone [40]. The SHR strain is a hypertensive rat model with increased sympathetic tone [41] and the increased sympathetic activity in the SHR is associated with increased HR in these animals [42]. There is increasing evidence that many forms of human hypertension are initiated and maintained by an elevated sympathetic tone [43], [44].Both the SBP (Fig.…”

The novel chromogranin A‐derived serpinin and pyroglutaminated serpinin peptides are positive cardiac β‐adrenergic‐like inotropes

“…To exclude the possibility that serpinin could act indirectly by eliciting NE efflux from intracardiac sympathetic nerve endings, the hearts were pretreated with tyramine alone (1 mM) for 30 min (for details, see ref. 20) and subsequently exposed to pGlu‐serpinin (1‐165 nM). Additional experiments were performed on isolated rat hearts exposed to pGlu‐serpinin (165 nM), in which NE concentrations were determined both in the perfusates and in cardiac tissue homogenates using HPLC with electrochemical detection, as described previously (20).…”