Abstract
α2-adrenoceptors (AR) lower central sympathetic output and peripheral catecholamine release, thereby protecting against sympathetic hyperactivity and hypertension. Norepinephrine re-uptake–transporter effectively (NET) removes norepinephrine from the synapse. Overflow to plasma will therefore not reflect release. Here we tested if inhibition of re-uptake allowed presynaptic α2AR release control to be reflected as differences in norepinephrine overflow in anesthetized hypertensive spontaneously hypertensive rats (SHR) and normotensive rats (WKY). We also tested if α2AR modulated the experiment-induced epinephrine secretion, and a phenylephrine-induced, α1-adrenergic vasoconstriction. Blood pressure was recorded through a femoral artery catheter, and cardiac output by ascending aorta flow. After pre-treatment with NET inhibitor (desipramine), and/or α2AR antagonist (yohimbine, L-659,066) or agonist (clonidine, ST-91), we injected phenylephrine. Arterial blood was sampled 15 min later. Plasma catecholamine concentrations were not influenced by phenylephrine, and therefore reflected effects of pre-treatment. Desipramine and α2AR antagonist separately had little effect on norepinephrine overflow. Combined, they increased norepinephrine overflow, particularly in SHR. Clonidine, but not ST-91, reduced, and pertussis toxin increased norepinephrine overflow in SHR and epinephrine secretion in both strains. L-659,066 + clonidine (central α2AR-stimulation) normalized the high blood pressure, heart rate, and vascular tension in SHR. α2AR antagonists reduced phenylephrine-induced vasoconstriction equally in WKY and SHR. Conclusions: α2AAR inhibition increased norepinephrine overflow only when re-uptake was blocked, and then with particular efficacy in SHR, possibly due to their high sympathetic tone. α2AAR inhibited epinephrine secretion, particularly in SHR. α2AAR supported α1AR-induced vasoconstriction equally in the two strains. α2AR malfunctions were therefore not detected in SHR under this basal condition.
Highlights
INTRODUCTION α2-adrenoceptors (AR) are divided into three subtypes, i.e., α2A, α2B, and α2CAR
The results will demonstrate that presynaptic α2AR release inhibition was reflected as differences in the plasma norepinephrine concentration only when re-uptake was blocked, and release inhibition was demonstrated to be far greater in spontaneously hypertensive rat (SHR) than in WKY. α2AR inhibited adrenal epinephrine secretion, with greater efficacy in SHR, and stimulation of central α2AR lowered the elevated sympathetic tone and blood pressure (BP) in this strain only
AND IMPLICATIONS α2AR antagonist did not increase norepinephrine overflow to plasma unless re-uptake through norepinephrine transporter (NET) was blocked
Summary
INTRODUCTION α2-adrenoceptors (AR) are divided into three subtypes, i.e., α2A-, α2B-, and α2CAR. Α2AR in vascular smooth muscle cells (VSMC) promote vasoconstriction, whereas endothelial α2AR stimulate nitric oxide synthesis and vasodilatation (Shafaroudi et al, 2005) These functions have been shown to be failing in SHR (Feres et al, 1998; Berg and Jensen, 2011). We tested if α2AR activity modulated adrenal epinephrine release and a provoked α1-adrenergic vascular tension-response, and if these functions differed in SHR and their normotensive controls (WKY). The results will demonstrate that presynaptic α2AR release inhibition was reflected as differences in the plasma norepinephrine concentration only when re-uptake was blocked, and release inhibition was demonstrated to be far greater in SHR than in WKY. The results will demonstrate that presynaptic α2AR release inhibition was reflected as differences in the plasma norepinephrine concentration only when re-uptake was blocked, and release inhibition was demonstrated to be far greater in SHR than in WKY. α2AR inhibited adrenal epinephrine secretion, with greater efficacy in SHR, and stimulation of central α2AR lowered the elevated sympathetic tone and BP in this strain only
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