Tyramine Reveals Failing α2-Adrenoceptor Control of Catecholamine Release and Total Peripheral Vascular Resistance in Hypertensive Rats

Abstract

α2-Adrenoceptor-activation lowers central sympathetic output, peripheral, vesicular norepinephrine release, epinephrine secretion, and modulates vascular tension. We previously demonstrated that α2-adrenoceptor-mediated inhibition of basal norepinephrine release was not reflected in plasma unless re-uptake through the norepinephrine transporter (NET) was blocked. Tyramine activates reverse norepinephrine transport through NET. Here we tested the hypothesis that tyramine, by engaging NET in release, also blocks re-uptake, and therefore allows manipulation of pre-junctional α2-adrenoceptors to directly regulate norepinephrine overflow to plasma. We compared in anesthetized spontaneously hypertensive rats (SHRs) and normotensive controls (WKYs), the effect of α2-adrenoreceptor antagonist (L-659,066) and/or agonist (clonidine) on norepinephrine overflow and increase in total peripheral vascular resistance (TPR) evoked by tyramine-infusion (1.26 μmol/min/kg, 15 min) and epinephrine secretion activated by the surgical stress. TPR was computed as blood pressure divided by cardiac output, recorded as ascending aortic flow. Plasma catecholamine concentrations after tyramine were higher in SHRs than WKYs. Pre-treatment with L-659,066 increased the catecholamine concentrations in WKYs, but only if combined with clonidine in SHRs. Clonidine alone reduced tyramine-induced norepinephrine overflow in SHRs, and epinephrine in both strains. Tyramine-induced increase in TPR was not different after clonidine, eliminated after L-659,066 and L-659,066 + clonidine in WKYs, but only after L-659,066 + clonidine in SHRs. We conclude that tyramine-infusion does allow presynaptic regulation of vesicular release to be accurately assessed by measuring differences in plasma norepinephrine concentration. Our results indicate that presynaptic α2-adrenoceptor regulation of norepinephrine release from nerve vesicles and epinephrine secretion is dysfunctional in SHRs, but can be restored by clonidine.

Direct and indirect cardiovascular actions of cathinone and MDMA in the anaesthetized rat

“…We have previously show that cocaine (0.1 mg/kg), by blocking the transporter, significantly increases pressor responses to noradrenaline (Killian and Docherty, 2014), and cocaine (1 mg/kg) produces a marked potentiation. However, a high dose of desipramine (approximately 13 mg/kg) blocks the tachycardia and pressor response to tyramine (Berg and Jensen, 2013), and this may agree with the present findings for the interaction of cocaine and tyramine. McDaid and Docherty (2001) found a larger pressor response to MDMA (1 mg/ kg) and that cocaine (10 mg/kg) reduces the pressor response to MDMA (5 mg/kg), but this dose of cocaine also significantly reduced blood pressure, implying possible depressant actions at this high dose.…”

“…Cathinone and MDMA probably act at the noradrenaline transporter (NET) (Schmidt et al, 1987;Wang et al, 1987;Al-Sahli et al, 2001;Cleary and Docherty, 2003). Tyramine may act both on the noradrenaline transporter and the vesicular monoamine transporter (VMAT-2), but shows higher potency at the vesicular site (Partilla et al, 2006;Berg and Jensen, 2013). Cathinone has similar potency to MDMA, and indeed tyramine, at the noradrenaline transporter (approximately 1 μM) (Horn, 1973;Cleary and Docherty, 2003), and yet is more potent than MDMA and tyramine in the present study of heart rate responses.…”

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

“…The α 2 AR-mediated auto-inhibition of release of NE and also epinephrine was functional in male WKY but not in the male SHR (4, 5). However, α 2 AR clearly inhibited release of both catecholamines in the female SHR (3).…”

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

“…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.…”