Altered β1-3-adrenoceptor influence on α2-adrenoceptor-mediated control of catecholamine release and vascular tension in hypertensive rats.

Torill Berg

doi:10.3389/fphys.2015.00120

Abstract

α2- and β-adrenoceptors (AR) reciprocally control catecholamine release and vascular tension. Disorders in these functions are present in spontaneously hypertensive rats (SHR). The present study tested if α2AR dysfunctions resulted from altered α2AR/βAR interaction. Blood pressure (BP) was recorded through a femoral artery catheter and cardiac output by an ascending aorta flow probe. Total peripheral vascular resistance (TPR) was calculated. Norepinephrine release was stimulated by a 15-min tyramine-infusion, which allows presynaptic release-control to be reflected as differences in overflow to plasma. Surgical stress activated some secretion of epinephrine. L-659,066 (α2AR-antagonist) enhanced norepinephrine overflow in normotensive controls (WKY) but not SHR. Nadolol (β1+2) and ICI-118551 (β2), but not atenolol (β1) or SR59230A [β(3)/1L] prevented this increase. All βAR antagonists allowed L-659,066 to augment tyramine-induced norepinephrine overflow in SHR and epinephrine secretion in both strains. Inhibition of cAMP-degradation with milrinone and β3AR agonist (BRL37344) enhanced the effect of L-659,066 on release of both catecholamines in SHR and epinephrine in WKY. β1/2AR antagonists and BRL37344 opposed the L-659,066-dependent elimination of the TPR-response to tyramine in WKY. α2AR/βAR antagonists had little influence on the TPR-response in SHR. Milrinone potentiated the L-659,066-dependent reduction of the TPR-response to tyramine. Conclusions: β2AR activity was a required substrate for α2AR auto inhibition of norepinephrine release in WKY. β1+2AR opposed α2AR inhibition of norepinephrine release in SHR and epinephrine secretion in both strains. βAR-α2AR reciprocal control of vascular tension was absent in SHR. Selective agonist provoked β3AR-Gi signaling and influenced the tyramine-induced TPR-response in WKY and catecholamine release in SHR.

Highlights

Α2- and β-adrenoceptors (AR) comprise the α2A,B,and C and the β1,2,and 3 subtypes
The main results in the present study were: (1) The α2AR antagonist L-659,066 required the presence of β2AR activity to enhance tyramine-induced norepinephrine overflow in WKY but was independent of β1AR signaling. (2) α2AR-mediated auto inhibition of norepinephrine release in spontaneously hypertensive rats (SHR) and epinephrine secretion in both strains was opposed primarily by β1+1LAR and by β2AR activity. (3) α2AR and β1+2AR reciprocally modulated the Total peripheral vascular resistance (TPR)-response to the released norepinephrine in WKY but not in SHR. (4) In the presence of L-659,066, β3AR agonist stimulated vasoconstriction in WKY and α2AR auto inhibition in SHR during tyramine-induced norepinephrine release
The reduction in tyramine-induced norepinephrine overflow to plasma after the β1AR antagonist atenolol was eliminated by additional pre-treatment with L-659,066 in WKY

Summary

Introduction

Α2- and β-adrenoceptors (AR) comprise the α2A,B,and C and the β1,2,and 3 subtypes. By coupling to inhibitory (Gi) and stimulatory (Gs) G-proteins, respectively, α2A,B,C- and β1+2AR have opposite. Α2AR-mediated auto inhibition of neuronal and adrenal catecholamine release has been shown to be dysfunctional in the spontaneously hypertensive rat (SHR) (Berg and Jensen, 2013). The inhibitory effect of presynaptic α2AR on catecholamine release could be demonstrated by the ability of the non-selective, peripherally restricted, α2AR antagonist L659,066 to increase tyramine-induced norepinephrine overflow and epinephrine secretion (Berg and Jensen, 2013). The purpose of the present investigation was to gain a better understanding of the reason underlying the failing α2AR auto-inhibition of catecholamine release in SHR, i.e., to test if there was a difference in the interaction between the α2AR and the three βAR subtypes in this strain compared to that in their normotensive controls (WKY). A second goal was to test if a difference in β1−3AR activity was responsible for the failing α2AR influence on the TPR-response to the tyramine-stimulated norepinephrine release in SHR

Materials and Methods

Discussion

Findings

Conclusions