Adrenal α2-adrenergic receptors in the aging normotensive and spontaneously hypertensive rat.
ABSTRACT This study investigates α(2)-adrenergic receptor (α(2)AR) mediated feedback inhibition of catecholamine release from the adrenal medulla of adult (52 weeks) and old (98 weeks) spontaneously hypertensive rats (SHR) and normotensive controls Wistar Kyoto (WKY) rats. Adrenal epinephrine content as well as the spontaneous and the nicotinic-evoked release of epinephrine were similar between adult SHR and WKY rats. Aging produced a significant reduction in epinephrine synthesis in WKY rats. In contrast, in SHR aging produced a significant increase in epinephrine release without significant changes in epinephrine synthesis. The α(2)AR agonist medetomidine abolished (80-90% inhibition) the nicotinic-evoked release of epinephrine in adult SHR and WKY rats. With aging, this effect was unaltered in WKY rats but was significantly decreased in SHR (30% inhibition). Adrenal α(2A)AR mRNA levels were significantly reduced in old SHR compared with age matched WKY rats. In conclusion, in aging the α(2)AR mediated feedback inhibition of epinephrine release from the adrenal medulla is preserved in WKY rats but compromised in SHR, resulting in increased epinephrine release.
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ABSTRACT: This study was carried out to elucidate which alpha(2)-adrenoceptor subtypes mediated the inhibition of noradrenaline and adrenaline release from the adrenal medulla of mice. Isolated adrenal medullae from wild-type and alpha(2A), alpha(2B) and alpha(2C)-adrenoceptor knockout (KO) mice were placed in superfusion chambers. Catecholamine overflow was evoked by 1,1-dimethyl-4-phenylpiperazinium (500 microM) in absence or in presence of the alpha(2)-adrenoceptor agonist medetomidine. The effect of medetomidine was tested in presence of the alpha-adrenoceptor antagonists rauwolscine, WB 4101, spiroxatrine, phentolamine and prazosin. In wild-type mice, medetomidine reduced noradrenaline and adrenaline overflow in a concentration-dependent manner (EC(50) in nM: 1.54 and 1.92; E(max) in % of inhibition: 91 and 94, for noradrenaline and adrenaline, respectively). The pK (D) values of the antagonists for noradrenaline overflow did not correlate with pK(D) values at alpha(2A), alpha(2B), or alpha(2C) binding sites. The pK (D) values of the antagonists for adrenaline overflow correlated positively with pK(D) values at alpha(2C) binding sites (opossum kidney cells). The effect of medetomidine (100 nM) on noradrenaline overflow was significantly reduced in all three alpha(2)KO mice (57, 54, 44 % inhibition, for alpha(2A), alpha(2B), and alpha(2C), respectively), whereas the effect of medetomidine on adrenaline overflow was greatly reduced in alpha(2C)KO mice (14 % inhibition). In the adrenal medulla of mice, all three alpha(2)-adrenoceptor subtypes (alpha(2A), alpha(2B), and alpha(2C)) play an equal role in the inhibition of noradrenaline overflow, whereas the alpha(2C)-adrenoceptor is the predominant alpha(2)-adrenoceptor subtype involved in the inhibitory mechanism controlling adrenaline overflow.British Journal of Pharmacology 01/2007; 149(8):1049-58. · 5.07 Impact Factor
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ABSTRACT: In this study we have looked at the effects of ageing on prejunctional control of noradrenergic neurotransmission in the cardiovascular system, in terms of alpha2-adrenoceptors, beta2-adrenoceptors and the noradrenaline re-uptake process. These studies show diminished prejunctional alpha2- and prejunctional beta-adrenoceptor-mediated responsiveness together with diminished noradrenaline re-uptake in rat tissues. The reduced prejunctional alpha2-inhibitory control and reduced re-uptake found in tissues from aged rats is more than likely to outweigh the effects of reduced beta-adrenoceptor facilitation, at least in normal conditions. Hence, assuming that such changes also occur in man, we might expect to find evidence of increased release of noradrenaline from noradrenergic nerves, and this could be reflected in plasma levels of noradrenaline.Autonomic Neuroscience 03/2002; 96(1):8-12. · 1.85 Impact Factor
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ABSTRACT: In the present study, we evaluated the effect of the alpha(2)-adrenoceptor agonist clonidine on tyrosine hydroxylase activity in adrenal medulla and brain of spontaneously hypertensive rats and Wistar Kyoto rats. Six-week-old animals were treated with clonidine (100 microg/kg body weight, daily, i.p.) for 4 weeks. Treatment with clonidine significantly reduced mean arterial blood pressure in spontaneously hypertensive rats to values similar to normotensive Wistar Kyoto rats. In the adrenal medulla of spontaneously hypertensive rats, clonidine treatment produced a significant increase in tyrosine hydroxylase activity with higher V(max) values and no changes in K(M) values. This effect was accompanied by a significant increase in tyrosine hydroxylase protein expression and of noradrenaline and adrenaline levels. In the brain of spontaneously hypertensive rats, treatment with clonidine produced a significant decrease in tyrosine hydroxylase activity with lower V(max) values and no changes in K(M) values accompanied by a significant decrease in tyrosine hydroxylase protein expression and of dopamine and noradrenaline levels. In Wistar Kyoto rats, clonidine treatment had no effect on tyrosine hydroxylase activity and protein expression or catecholamine levels in adrenal medulla or brain. Clonidine treatment significantly reduced noradrenaline and adrenaline plasma levels in spontaneously hypertensive rats and Wistar Kyoto rats. In conclusion, treatment with the alpha(2)-adrenoceptor agonist clonidine prevented the increase in mean arterial blood pressure in young spontaneously hypertensive rats. This effect was accompanied by opposite effects on tyrosine hydroxylase activity in spontaneously hypertensive rat adrenal medulla and brain: an increase in adrenal medulla and a decrease in brain, bringing sympathetic function to a similar profile found in normotensive Wistar Kyoto rats.Basic & Clinical Pharmacology & Toxicology 01/2009; 104(2):113-21. · 2.18 Impact Factor