Abstract
α2-Adrenoceptors lower central sympathetic output and peripheral catecholamine release, and thus may prevent sympathetic hyperactivity and hypertension. α2AR also influence vascular tension. These α2AR are malfunctioning in spontaneously hypertensive rats (SHR). Here I tested if an interaction between α2AR subtypes and the angiotensin AT1 receptor (AT1R) precipitated these disorders. Blood pressure was monitored through a femoral artery catheter and cardiac output by ascending aorta flow in anesthetized rats. Catecholamine concentrations were determined in plasma collected at the end of a 15-min tyramine-infusion. Tyramine stimulates norepinephrine release through the re-uptake transporter, thus preventing re-uptake. Presynaptic control of vesicular release is therefore reflected as differences in overflow to plasma. Previous experiments showed surgical stress to activate some secretion of epinephrine, also subjected to α2AR-auto-inhibition. Normotensive rats (WKY) and SHR were pre-treated with (1) vehicle or α2AR-antagonist (L-659,066), followed by fadolmidine (α2C>B>A + α1AR-agonist), ST-91 (α2non-A-selective agonist), or m-nitrobiphenyline (α2CAR-agonist + α2A+B-antagonist), or (2) AT1R-antagonist losartan, losartan + L-659,066, or losartan + clonidine. In WKY, L-659,066 alone, L-659,066 + agonist or losartan + L-659,066 increased catecholamine overflow to plasma after tyramine and eliminated the norepinephrine-induced rise in total peripheral vascular resistance (TPR). In SHR, L-659,066 + fadolmidine/ST-91/m-nitrobiphenyline and losartan + L-659,066 greatly increased, and losartan + clonidine reduced, catecholamine concentrations, and L-659,066 + ST-91, losartan + L-659,066 and losartan + clonidine eliminated the tyramine-induced rise in TPR. Separately, these drugs had no effect in SHR. In conclusion, peripheral α2CAR-stimulation or AT1R-inhibition restored failing α2AAR-mediated auto-inhibition of norepinephrine and epinephrine release and control of TPR in SHR.
Highlights
Sympathetic hyperactivity is a major force in initiating and sustaining spontaneous hypertension (Guyenet, 2006; Esler, 2011). α2-adrenoceptors (AR) lower sympathetic output from the central nervous system (CNS), and inhibit release of norepinephrine from peripheral sympathetic nerves and catecholamines from the adrenal medulla (Starke, 2001)
We have recently demonstrated that during tyramine-stimulated norepinephrine release, α2AR failed to lower norepinephrine and epinephrine release in spontaneously hypertensive rat (SHR), and failed to control vascular tension (Berg and Jensen, 2013)
These malfunctions were not detected without activation of norepinephrine release (Berg et al, 2012), indicating that they resulted from the released catecholamine itself, or another agent released by, or co-released with norepinephrine or epinephrine
Summary
Sympathetic hyperactivity is a major force in initiating and sustaining spontaneous hypertension (Guyenet, 2006; Esler, 2011). α2-adrenoceptors (AR) lower sympathetic output from the central nervous system (CNS), and inhibit release of norepinephrine from peripheral sympathetic nerves and catecholamines from the adrenal medulla (Starke, 2001). Α2-adrenoceptors (AR) lower sympathetic output from the central nervous system (CNS), and inhibit release of norepinephrine from peripheral sympathetic nerves and catecholamines from the adrenal medulla (Starke, 2001) Their activation is tonic, and they hamper release even in the anesthetized rat without stimulation of norepinephrine release (Berg et al, 2012). Most likely by engaging NET in release, preventing re-uptake, presynaptic α2AR modulation altered tyramine-induced norepinephrine overflow to plasma, similar to that after desipramine in notstimulated rats (Berg and Jensen, 2013). The results will show that the failing α2AR control of norepinephrine and epinephrine release and modulation of the norepinephrine-induced rise in TPR in SHR was restored by stimulation of peripheral α2CAR or inhibition of the AT1R
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