Angiotensin AT1 – α2C-Adrenoceptor Interaction Disturbs α2A-auto-Inhibition of Catecholamine Release in Hypertensive Rats

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.

β1-Blockers Lower Norepinephrine Release by Inhibiting Presynaptic, Facilitating β1-Adrenoceptors in Normotensive and Hypertensive Rats

“…The transient rise in TPR during tyramine-induced norepinephrine release was, as previously described (11), changed to vasodilatation during the late part of the tyramine infusion in losartan-treated WKY but not in SHR. This observation indicated, as expected, that angiotensin II-AT1R-activity may potentiate norepinephrine-induced vasoconstriction.…”

Specific Role of α2A‐ and α2B‐, but not α2C‐, Adrenoceptor Subtypes in the Inhibition of the Vasopressor Sympathetic Out‐flow in Diabetic Pithed Rats

“…Admittedly, we did not measure blood pressure in conscious diabetic rats, but others have already shown a significant increase in blood pressure , attributed to the sympatho‐inhibitory α 2 ‐adrenoceptor's diminished affinity and differential expression of each subtype . Moreover, any influence from the central nervous system can be excluded since pithed rats were used.…”

β- and α2-Adrenoceptor Control of Vascular Tension and Catecholamine Release in Female Normotensive and Spontaneously Hypertensive Rats

“…Estrogen has been shown to mobilize one of the three α 2 AR-subtypes, i.e., α 2C AR, to the surface in VSMC from human, cutaneous arterioles (26), and this may influence the response to NE. The rise in TPR in response to a α 2C AR-selective agonist was highly variable in female rats but not male rats (3, 11), possibly due to differences in the estrous cycle. It is therefore possible that a change in α 2 AR functionality is the primary change in the gender-dependent difference in the α 2 AR/βAR control of vascular tension.…”

“…This conclusion was based on the fact that L-659,066 increased the secretion of epinephrine in both strains, whereas the βAR-antagonists alone had no effect in WKY and slightly increased the concentration in SHR. In the male rats, a significant α 2 AR-auto-inhibition of epinephrine secretion was regularly seen in WKY and occasionally in SHR (4, 6, 11). However, atenolol, ICI-118551, and nadolol potentiated the effect of the α 2 AR-antagonist in the female SHR (present study) similar to that seen in male WKY and SHR (6), in general with a greater effect of the β 1 - than the β 2 AR-antagonist and with a greater increase in the plasma epinephrine concentration in SHR than in WKY.…”

“…The angiotensin AT1 receptor (AT1R) antagonist losartan lowered the TPR response to stimulated endogenous release of NE in male WKY but not SHR (11), suggesting that VSMC AT1R-signaling may depend on functional α 2 AR-G i and/or βAR-G s activation. Moreover, in male rats, losartan greatly increased the TPR and MBP responses to NE release when combined with atenolol, particularly in WKY (5).…”