Comparison of renal sympathetic baroreflex effects of rilmenidine and alpha-methylnoradrenaline in the ventrolateral medulla of the rabbit (original) (raw)
Related papers
Journal of Hypertension, 2007
We determined whether the cardiovascular actions of central anti-hypertensive agents clonidine and moxonidine are dependent on noradrenergic or serotonergic innervation of the rostral ventrolateral medulla (RVLM) in conscious rabbits. 6-Hydroxydopamine (6-OHDA) or 5,6-dihydroxytriptamine (5,6-DHT) was injected into the RVLM to deplete noradrenergic and serotonergic terminals respectively. One, 2 and 4 weeks later, responses to fourth ventricular (4V) clonidine (0.65 g/kg) and moxonidine (0.44 g/kg) were examined. Destruction of noradrenergic pathways in the RVLM by 6-OHDA reduced the hypotensive response to 4V moxonidine to 62%, 47% and 60% of that observed in vehicle treated rabbits at weeks 1, 2 and 4 respectively. The moxonidine induced bradycardia was similarly attenuated (to 46% of vehicle). Conversely, 6-OHDA had no effect on the hypotensive or bradycardic effects of 4V clonidine. Efaroxan (I 1 -imidazoline receptor/␣ 2 -adrenoceptor antagonist; 3.5, 11, 35 g/kg) and 2-methoxyidazoxan (␣ 2 -adrenoceptor antagonist; 0.3, 0.9, 3 g/kg) equally reversed the hypotension to 4V clonidine, suggesting a mainly ␣ 2 -adrenoceptor mechanism. Efaroxan preferentially reversed responses to moxonidine in both vehicle and 5,6-DHT groups and in the 1st week after 6-OHDA, suggesting a mechanism involving mainly I 1imidazoline receptors. This selectivity was subsequently lost in the 2nd and 4th weeks when the remaining hypotension was mainly mediated by ␣ 2 -adrenoceptors. Depletion of serotonergic terminals did not alter the responses to either agonist nor did it change the relative effectiveness of the antagonists. Western blots of RVLM tissues probed with imidazoline and ␣ 2 -adrenoceptor antisera showed a pattern of bands close to that reported in other species. The main effect of 6-OHDA was an 18% lower level of the 42 kDa imidazoline protein (P<0.05). We conclude that the hypotensive and bradycardic actions of moxonidine but not clonidine are mediated through imidazoline receptors and are dependent on intact noradrenergic pathways within the RVLM. Furthermore, the norad-renergic innervation may be associated with a 42 kDa imidazoline receptor protein. © 2005 Published by Elsevier Ltd on behalf of IBRO. (G. A. Head).
Journal of Cardiovascular Pharmacology, 2001
The pressor region of the rostral ventrolateral medulla (RVLM) is a critical site in the sympathoinhibitory action of imidazoline receptor agonists as shown by studies in anesthetized animals. The aim of this study was to compare the importance of the RVLM in mediating the inhibitory action of rilmenidine on renal sympathetic nerve activity (RSNA) and arterial pressure in urethane-anesthetized rabbits (n ס 11) and in conscious, chronically instrumented rabbits (n ס 6). Bilateral microinjection of rilmenidine (4 nmol in 100 nl) into the RVLM caused a greater decrease in resting arterial pressure in anesthetized animals (−19 mm Hg) than in conscious animals (−8 mm Hg). By contrast, the decrease in resting RSNA evoked by rilmenidine was similar in conscious (−27%) and anesthetized (−36%) rabbits. Furthermore, rilmenidine microinjection into the RVLM was equally effective in inhibiting the RSNA baroreflex in both groups of animals. The upper plateau of the RSNA baroreflex decreased by 37% and 42%, and gain decreased by 41% and 44% after rilmenidine treatments in conscious and anesthetized rabbits, respectively. We conclude that the RVLM plays an equally important role in the inhibitory action of rilmenidine on RSNA in conscious and anesthetized rabbits either at rest or during baroreflex responses. A relatively moderate effect of rilmenidine on arterial pressure in conscious, chronically instrumented rabbits may relate to a lower level of sympathetic drive compared with anesthetized animals.
Central Imidazoline Receptors and Centrally Acting Anti-Hypertensive Agents
Clinical and Experimental Hypertension, 1997
We have examined the location and contribution of imidazoline receptors (IR) in mediating the hypotensive and sympatholytic actions of first and second generation anti-hypertensive agents in rabbits. We found that the hypotension produced by rilmenidine and moxonidine given intravenously (IV) or into the fourth ventricle (4V) was preferentially reversed by the IR antagonists idazoxan and efaroxan (compared to a selective R-adrenoceptor antagonist 2-methoxy-idazoxan), suggesting that IR are important in the sympatho-inhibition produced by these agents. Clonidine was not 591 Copyright 0 1997 by Marcel Dekker, Inc. Clin Exp Hypertens Downloaded from informahealthcare.com by Monash University on 02/14/13 For personal use only.
American journal of physiology. Renal physiology, 2002
Renal blood flow (RBF) is modulated by renal sympathetic nerve activity (RSNA). However, agents that are supposed to reduce sympathetic tone, such as rilmenidine and captopril, influence RBF also by direct arteriolar effects. The present study was designed to test to what extent the renal nerves contribute to the renal hemodynamic response to rilmenidine and captopril. We used a technique that allows simultaneous recording of RBF and RSNA to the same kidney in conscious rabbits. We compared the dose-dependent effects of rilmenidine (0.01-1 mg/kg) and captopril (0.03-3 mg/kg) on RBF and RSNA in intact and renal denervated (RNX) rabbits. Because rilmenidine and captopril lower blood pressure, studies were also performed in sinoaortically denervated (SAD) rabbits to determine the role of the baroreflex in the renal hemodynamic response. Rilmenidine reduced arterial pressure, RBF, and RSNA dose dependently. In intact rabbits (n = 10), renal conductance (RC) remained unaltered (3 +/- 5%)...
Journal of the Autonomic Nervous System, 1998
Since the first suggestion of the existence of imidazoline receptors, there has been a continuing and yet unresolved debate as to their contribution to the antihypertensive actions of clonidine-like agents. In this review we bring together a number of studies from our laboratory which have examined the importance and interdependence of imidazoline receptors and a -adrenoceptors in the mechanism of 2 action of centrally acting antihypertensive drugs. Using conscious rabbits and a range of imidazoline and specific a -adrenoceptor 2 antagonists we have consistently found that second generation agents rilmenidine and moxonidine preferentially act via imidazoline receptors but that a -adrenoceptors are important for the hypotension produced by clonidine and a-methyldopa. Despite this difference in 2 receptor mechanism, the hypotension produced by all these drugs is dependent on central noradrenergic pathways. In other studies using anaesthetised rabbits and direct measures of sympathetic nerve activity we confirmed the generally held view that the major site of sympatho-inhibitory actions and sympathetic baroreflex effects of centrally acting antihypertensive agents is the rostral ventrolateral Ž . medulla RVLM . We also found, using microinjection of specific antagonists, that a -adrenoceptors in this nucleus appear to be 2 activated as a consequence of imidazoline receptor activation. Thus, there appears to be a close relationship between imidazoline receptors and a -adrenoceptors located in the RVLM in mediating the hypotension and inhibition of renal sympathetic nerve activity.
Hypertension, 2004
We determined whether the sympathetic excitatory responses to environmental stressors and the sympathoinhibitory responses to rilmenidine are altered by renovascular hypertension. Rabbits were made hypertensive with a clip on the right renal artery, and a left renal nerve recording electrode was implanted. After 3 or 6 weeks, the animals were given air-jet stress and loud noise stress before and after intravenous rilmenidine. Three and 6 weeks after renal clipping, mean arterial pressure was 28% and 36% greater than preclip values. Air-jet stress elicited a marked increase in renal sympathetic nerve activity, mean arterial pressure, and heart rate. Renal sympathetic nerve activity responses were much greater in hypertensive rabbits, but the pressor responses were similar to those observed in normotensive animals. Acute administration of rilmenidine decreased blood pressure more in hypertensive animals but with a much lesser inhibition of sympathetic activity. Rilmenidine markedly reduced increased sympathetic activity during air-jet stress in 3-week clipped rabbits but to a lesser extent in the other groups. These studies show that while sympathetic responses to stress were markedly enhanced in renal clip hypertensive rabbits, they did not result in greater pressor responses, thus suggesting that vascular neuroeffector mechanisms were not altered. By contrast, the increased effects of rilmenidine suggest a much greater contribution to the hypertension by the sympathetic nervous system, but one that is caused by an enhanced "nonvascular" neuroeffector mechanism. As such, sympathoinhibitory agents such as rilmenidine are very suitable and very effective agents for the treatment of renovascular hypertension. (Hypertension. 2004;43:636-642.)