Plasma Norepinephrine in Hypertensive Rats Reflects α2-Adrenoceptor Release Control Only When Re-Uptake is Inhibited

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.

M-currents (Kv7.2-7.3/KCNQ2-KCNQ3) Are Responsible for Dysfunctional Autonomic Control in Hypertensive Rats

“…The secretion of epinephrine was stimulated by the experiment itself (Berg et al, 2012), and the concentration of epinephrine in the 3,4-DAP controls did not differ from that previously observed in time-controls. The norepinephrine but not epinephrine concentration was higher in SHR than in WKY ( P ≤ 0.003).…”

“…In unstimulated rats, the plasma norepinephrine concentrations are low due to re-uptake through the norepinephrine re-uptake transporter, and differences in release are difficult to demonstrate (Berg et al, 2012; Berg and Jensen, 2013). Autonomic nerve transmitter release was therefore stimulated by depolarization, induced by inhibition of presynaptic Kv by 3,4-DAP.…”

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

“…Tyramine stimulates NE release by reversing the transport through the NE reuptake transporter (NET), consequently blocking reuptake (Figure 1). Activation of the presynaptic receptors by the released NE and/or other agonists/antagonists present will alter the vesicular release of NE, and this modification will be reflected as differences in the overflow of NE to plasma, as previously documented in detail (4, 13). The action of tyramine is peripherally restricted, i.e., tyramine does not cross the blood–brain barrier (14).…”

“…Tyramine does not stimulate the secretion of epinephrine from the adrenal glands. However, the trauma induced by the surgical procedure activated some secretion of epinephrine, also subjected to receptor-mediated release control (3, 4, 13). Removal of the adrenal glands did not alter the plasma NE concentration, indicating that tyramine stimulated the release of NE from sympathetic nerves rather than from NE-producing cells in the adrenal medulla (5).…”

“…To test the influence of β 1 AR and β 2 AR on α 2 AR-mediated inhibition of catecholamine release and TPR, the rats were pretreated with atenolol, ICI-118551, or nadolol as above, followed 10 min later by the non-selective α 2 AR-antagonist L-659,066, which does not cross the blood–brain barrier (4, 13, 16). …”