Influence of anaesthesia on the cardiovascular effects of rilmenidine and clonidine in spontaneously hypertensive rats

Abstract

1 The acute cardiovascular effects of two a2-adrenoceptor agonists, rilmenidine and clonidine, were studied in 15-week-old male spontaneously hypertensive rats (SHRs). The effects of these drugs were compared with intravenous (i.v.) and intracerebroventricular (i.c.v.) administration in conscious and pentobarbitone-anaesthetized SHRs, in which aortic blood pressure (BP) was continuously recorded.2 In conscious SHRs, i.v. doses of either rilmenidine (30, 100, 300pgkg-') or clonidine (3, 10, 30 pg kg-') induced dose-dependent short-lasting increases in BP followed by moderate decreases associated with bradycardia, while the same three doses of both drugs given i.c.v. were devoid of BP and heart rate (HR) effects. 3 Pentobarbitone-anaesthesia increased the sympathetic control of BP and suppressed the cardiac baroreflex sensitivity. 4 In anaesthetized SHRs, i.v. injections of the same 3 doses of rilmenidine and clonidine induced a slight increase in BP, rapidly followed by profound and long-lasting BP and HR decreases. Surprisingly, when given i.c.v., these 3 doses lowered BP and HR to the same extent but in a more progressive manner. 5 The lack of efficacy of both drugs in conscious SHRs after the i.c.v. administration of i.v. active doses and the lack of more marked and rapid effects in anaesthetized SHRs, after i.c.v. than after i.v. injections, question the involvement of a major central site of action for these antihypertensive a2-adrenoceptor agonists. Moreover, these results show that the cardiovascular effects of these drugs are profoundly influenced by baseline sympathetic nervous system activity which is enhanced by pentobarbitone-anaesthesia.

Sympathoinhibitory effects of rilmenidine may be mediated by sites located below the brainstem

“…Although the mechanism proposed for the antihypertensive action of rilmenidine in SHRs is a reduction in peripheral sympathetic tone (Van Zwieten, 1988), to our knowledge, no studies have demonstrated its direct action on the peripheral SNS activity in anaesthetized or conscious SHRs. Previous studies in conscious, unrestrained (Sannajust et al, 1989) and pentobarbitone-anaesthetized (Sannajust et al, 1992) SHRs have shown that the ability of rilmenidine and clonidine to lower BP could be related to the level of the sympathetic drive and conversely to the integrity of the cardiac baroreflex. The absence of antihypertensive effects of rilmenidine or clonidine administered by the i.c.v.…”

“…Then, under methohexitoneanaesthesia, the renal nerve bipolar electrode was implanted Assessment of the guide-cannula implantation and of spinal transection At the end of each experiment, the guide-cannula position was assessed as previously described in Sannajust et al (1992). The spinal transection was confirmed post-mortem by dissection of the site of lesion.…”

“…Moreover, although one mechanism proposed for the antihypertensive action of rilmenidine in spontaneously hypertensive rats (SHRs) has been a reduction in peripheral sympathetic tone (Van Zwieten, 1988), to our knowledge, no studies have been able to demonstrate the direct action of rilmenidine on the peripheral sympathetic nervous system activity in anaesthetized or conscious SHRs. Otherwise, previous studies in conscious unrestrained (Sannajust et al, 1989;1992) and pentobarbitone-anaesthetized (Sannajust et al, 1992) SHRs suggested that rilmenidine did not act primarily and exclusively on the central nervous system (forebrain/ brainstem) to lower arterial blood pressure (BP) and heart rate (HR).…”

Brainstem Adenosine A1 Receptor Signaling Masks Phosphorylated Extracellular Signal-Regulated Kinase 1/2-Dependent Hypotensive Action of Clonidine in Conscious Normotensive Rats

“…In contrast, central A 1 R blockade had no influence on the hypotensive response or the increase in RVLM pERK1/2 elicited by clonidine in ABD rats. These findings support the hypothesis that central adenosine A 1 R signaling opposes the adenosine A 2A R-mediated (pERK1/ 2-dependent) hypotensive response and yield insight into a cellular mechanism that explains the absence of clonidineevoked hypotension in conscious normotensive rats.Clonidine-evoked hypotension is minimal or absent in conscious normotensive rats (Abdel-Rahman, 1992;Ricci et al, 1992;Medvedev et al, 1998) in contrast to animal preparations that exhibit baroreflex dysfunction such as anesthetized (Borkowski and Finch, 1979;Sannajust et al, 1992;Su et al, 2002;Sato et al, 2005) and hypertensive (Judy et al, 1976Judy and Farrell, 1979;Prados et al, 1998) rats and after surgically induced baroreceptor dysfunction [aortic barodenervation (ABD)] (Abdel-Rahman, 1992; Nassar and Abdel-Rahman, 2006, 2008. However, the cellular mechanisms that explain these findings remain unclear.…”

“…Clonidine-evoked hypotension is minimal or absent in conscious normotensive rats (Abdel-Rahman, 1992;Ricci et al, 1992;Medvedev et al, 1998) in contrast to animal preparations that exhibit baroreflex dysfunction such as anesthetized (Borkowski and Finch, 1979;Sannajust et al, 1992;Su et al, 2002;Sato et al, 2005) and hypertensive (Judy et al, 1976Judy and Farrell, 1979;Prados et al, 1998) rats and after surgically induced baroreceptor dysfunction [aortic barodenervation (ABD)] (Abdel-Rahman, 1992; Abdel-Rahman, 2006, 2008). However, the cellular mechanisms that explain these findings remain unclear.…”