Effect of Clonidine on Tyrosine Hydroxylase Activity in the Adrenal Medulla and Brain of Spontaneously Hypertensive Rats

Abstract

Abstract:In the present study, we evaluated the effect of the α 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 μ g/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 α 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.The endogenous catecholamines noradrenaline and adrenaline mediate sympathetic regulation of blood pressure [1]. These effectors of the sympathetic nervous system are synthesized within sympathetic neurons and chromaffin cells of the adrenal medulla by a well-defined series of reactions that start with the conversion of tyrosine to 3,4-dihydroxyphenylalanine mediated by tyrosine hydroxylase, the initial and rate-limiting enzyme of the pathway [2]. Noradrenaline is the principal neurotransmitter of sympathetic neurons, whereas adrenaline is secreted from the chromaffin cells of the adrenal medulla into the circulation. Whereas the actions of noradrenaline are mostly restricted to the sites of release from sympathetic nerves, adrenaline acts as a neurohormone to activate cardiovascular and metabolic responses via the blood stream.Increased sympathetic nervous system activity with higher tyrosine hydroxylase activity and catecholamine levels are common features of hypertension in human beings and in the spontaneously hypertensive rat [3,4], an animal model used to investigate the mechanisms of essential hypertension [5]. It is noteworthy that in spont...

α2-Adrenoceptor-Mediated Inhibition of Catecholamine Release from the Adrenal Medulla of Spontaneously Hypertensive Rats is Preserved in the Early Stages of Hypertension

“…In agreement with our previous reports on catecholamine levels in the adrenal of SHR [20,21], at the start of the collection period (t = 90 min. ), the content of noradrenaline and adrenaline in the adrenal gland was significantly lower in SHR compared with age-matched WKY rats in both ages studied, and there was an age-dependent increase in adrenal catecholamine content ( fig.…”

“…However, we have previously shown that in SHR before (6 weeks of age) and during the development of high blood pressure (12 and 22 weeks of age) not only are adrenal catecholamine content and synthesis reduced but also that adrenaline plasma levels are similar compared with those found in the normotensive control Wistar Kyoto (WKY) rats [20]. Moreover, treatment with the a 2 -adrenoceptor agonist clonidine produces a similar reduction in adrenaline plasma levels in SHR compared with WKY rats [21].Despite the importance of a 2 -adrenoceptors in the control of adrenaline release from the adrenal medulla, their role in the control of catecholamine release from the adrenal medulla of SHR during the development of high blood pressure has not been previously tested. Therefore, in this study, we evaluated adrenal a 2 -adrenoceptor function before (6 weeks) and after (16 weeks) the development of hypertension in SHR.…”

“…However, we have previously shown that in SHR before (6 weeks of age) and during the development of high blood pressure (12 and 22 weeks of age) not only are adrenal catecholamine content and synthesis reduced but also that adrenaline plasma levels are similar compared with those found in the normotensive control Wistar Kyoto (WKY) rats [20]. Moreover, treatment with the a 2 -adrenoceptor agonist clonidine produces a similar reduction in adrenaline plasma levels in SHR compared with WKY rats [21].…”

“…The preserved adrenal a 2 -adrenoceptor inhibitory feedback mechanism could account for the lack of difference in adrenal adrenaline release and the similarity in adrenaline plasma levels between WKY and SHR. In fact, in SHR, in contrast to the impaired response of presynaptic a 2A -adrenoceptors to antagonists such as yohimbine [41,42] and agonists such as clonidine [21], activation of adrenal a 2 -adrenoceptors by the agonist medetomidine produces a reduction in catecholamine overflow similar to normotensive rats. Moreover, clonidine reduces adrenaline plasma levels in SHR in a similar manner to that observed in WKY rats [21].…”

Effect of Clonidine on Renal Sodium Handling in Spontaneously Hypertensive Rats

“…Increased noradrenaline synthesis and release and decreased α 2A -adrenoceptor inhibitory function, reflected by elevated noradrenaline plasma levels, are prominent features of SHR hypertension (34 -36). We have recently shown that administration of clonidine to SHR in the pre-hypertensive phase not only reduced sympathetic activation, as evidenced by the reduction in noradrenaline and adrenaline plasma levels, but also completely prevented the rise in blood pressure in the early stages of the development of SHR hypertension (37). We have also previously shown that 12-week-old SHR have significantly higher noradrenaline plasma levels compared to age-matched WKY rats (23).…”