Effects of centrally acting antihypertensive drugs on the microcirculation of spontaneously hypertensive rats

Abstract

We investigated the acute effects of centrally acting antihypertensive drugs on the microcirculation of pentobarbital-anesthetized spontaneously hypertensive rats (SHR). The effects of the sympatho-inhibitory agents clonidine and rilmenidine, known to activate both α 2 -adrenoceptors and nonadrenergic I 1 -imidazoline binding sites (I 1 BS) in the central nervous system, were compared to those of dicyclopropylmethyl-(4,5-dimethyl-4,5-dihydro-3H-pyrrol-2-yl)-amine hydrochloride (LNP 509), which selectively binds to the I 1 BS. Terminal mesenteric arterioles were observed by intravital microscopy. Activation of the central sympathetic system with L-glutamate (125 µg, ic) induced marked vasoconstriction of the mesenteric microcirculation (27 ± 3%; N = 6, P < 0.05). In contrast, the marked hypotensive and bradycardic effects elicited by intracisternal injection of clonidine (1 µg), rilmenidine (7 µg) and LNP 509 (60 µg) were accompanied by significant increases in arteriolar diameter (12 ± 1, 25 ± 10 and 21 ± 4%, respectively; N = 6, P < 0.05). The vasodilating effects of rilmenidine and LNP 509 were two-fold higher than those of clonidine, although they induced an identical hypotensive effect. Central sympathetic inhibition elicited by baclofen (1 µg, ic), a GABA B receptor agonist, also resulted in vasodilation of the SHR microvessels. The acute administration of clonidine, rilmenidine and LNP 509 also induced a significant decrease of cardiac output, whereas a decrease in systemic vascular resistance was observed only after rilmenidine and LNP 509. We conclude that the normalization of blood pressure in SHR induced by centrally acting antihypertensive agents is paralleled by important vasodilation of the mesenteric microcirculation. This effect is more pronounced with substances acting preferentially (rilmenidine) or exclusively (LNP 509) upon I 1 BS than with those presenting important α 2 -adrenergic activity (clonidine).

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

“…As discussed above, the concomitantly enhanced A 2A R signaling in the RVLM of ABD rats (Nassar and Abdel-Rahman, 2008) makes it difficult to discern the role of A 1 R signaling in clonidine-evoked hypotension. Although no study has directly investigated the role for central A 1 R signaling in clonidine-evoked hypotension, our conclusion is strengthened by the findings that in the SHR, which exhibits attenuated pressor responses to intra-nucleus tractus solitarius adenosine (Abdel-Rahman and Tao, 1996), clonidine lowers blood pressure (Jastrzebski et al, 1995;Estato et al, 2004). It must be noted that the pressor response elicited by adenosine reflects A 1 R signaling (Scislo and O'Leary, 2002).…”

Central Adenosine Signaling Plays a Key Role in Centrally Mediated Hypotension in Conscious Aortic Barodenervated Rats

“…Whereas clonidine-evoked hypotension manifests in hypertensive rats, conscious or anesthetized (Jastrzebski et al, 1995;Estato et al, 2004), it only manifests in anesthetized, but not conscious, normotensive rats (El-Mas et al, 1994;Yang et al, 2005). Reported studies including ours have shown that partial or complete baroreceptor denervation unmasks the hypotensive effect of clonidine in conscious normotensive rats (Abdel-Rahman, 1992;El-Mas and AbdelRahman, 1997;Medvedev et al, 1998).…”

“…Although, clonidine is classified by Bousquet as an agonist at imidazoline-binding sites, it is still considered a mixed I 1 /␣ 2A agonist Estato et al, 2004). Therefore, it was difficult to ascertain the receptor, I 1 or ␣ 2A , whose activation triggers central adenosine signaling.…”

“…Interestingly, 8-SPT pretreatment attenuated the hypotensive response elicited by both drugs. It is imperative to note that although ␣-MNE is considered a "pure" ␣ 2A receptor agonist (Szabo, 2002), the selective I 1 agonist rilmenidine also exhibits ␣ 2A agonist activity (Szabo et al, 1999;Estato et al, 2004). Together, these findings raise the interesting possibility that the ␣ 2A receptor activation triggers central adenosine signaling.…”

Borne Identity: Leading Endogenous Suspects at Imidazoline Binding Sites

“…Functional studies demonstrated that administration of harmane into rat brain RVLM elicited a hypotensive response which was also observed with I 1 -BS ligands clonidine, rilmenidine, moxonidine and LNP 509 [101,102]. Furthermore, the central antihypertensive action of harmane and clonidine was reversed by the mixed α 2 -AR/I 1 -BS antagonist efaroxan.…”