Moxonidine: A Second‐generation Central Antihypertensive Agent

Abstract

Rational treatment of primary hypertension remains elusive, owing to a lack of knowledge about the pathogenesis of blood pressure elevation. Established hypertension is associated with well-described cardiovascular hemodynamic changes. Because the cardiovascular system is self-regulating, the action of an antihypertensive on one of the regulatory mechanisms induces changes in others. A drug-induced decrease of the elevated peripheral resistance leads to compensatory reflex mechanisms. The use of centrally acting drugs avoids compensatory neural reflexes. Furthermore, the participation of the central and autonomic nervous systems in the pathogenesis of hypertension is probable. The development of drugs aimed at controlling the central nervous system (CNS) would, therefore, be reasonable. The use of a,-adrenoceptor agonists, such as clonidine, as antihypertensive agents has declined. The mean reason being a high rate of side effects such as sedation, dry mouth with marked reduction in salivary flow, and other nonspecific effects. The mode of action was explained by stimulation of both pre-and postsynaptic a,-adrenoceptors within the CNS . However, recent investigations have clearly demonstrated that centrally acting drugs like clonidine and moxonidine induce their antihypertensive effects primarily by high affinity binding at the imidazoline receptors. Most of the side effects are induced by an action at aw,-receptors. The difference between clonidine and moxonidine is moxonidine's pronounced selectivity for imidazoline rather than ctzreceptors. Moxonidine and other related compounds may reestablish the use of centrally active drugs in antihypertensive therapy.~ ~~~

Imidazoleacetic acid-ribotide: An endogenous ligand that stimulates imidazol(in)e receptors

“…4), IAA-RP injection into the RVLM was expected to lower blood pressure, as has been observed with other I 1 agonists (48,50). Instead, as observed with CDS in normotensive rats (35), IAA-RP produced a rapid, transient increase in MAP (Fig.…”

“…In a follow-up study, SH rats (n ϭ 6) were given I-4-AA-RP then moxonidine. When used alone, the latter reduced MAP to normotensive levels (50). Fig.…”

Central blockade of nitric oxide synthesis reduces moxonidine‐induced hypotension

“…Moxonidine, an a 2 -adrenoceptor/imidazoline receptor agonist, is a centrally acting anti-hypertensive drug that reduces arterial pressure by inhibiting sympathetic activity (Ernsberger et al, 1993;1997). The RVLM that contains the sympathetic pre-motor neurons involved in cardiovascular regulation (Barman & Gebber, 1989;Guyenet et al, 1989) has been implicated as one of the most important central sites for the anti-hypertensive action of moxonidine.…”

“…Only the hypotensive responses induced by clonidine, a drug that binds equally to a 2 -adrenoceptors and imidazoline receptors, have been tested after L-NAME injections into the LV (Dobrucki et al, 2001). The possible role of central NO in the hypotensive response produced by moxonidine, that is suggested to depend on the activation of central imidazoline receptors located specially in the RVLM (Ernsberger et al, 1993;1997), remains unclear. Hence, in the present study we investigated the effects of L-NAME (injected into the 4th V) on the hypotension, bradycardia and vasodilatation induced by intraventricular moxonidine (injected into the 4th V) in normotensive rats.…”

Synthesis of triple [14C]‐labeled moxonidine

“…[1][2][3] It is marketed in Europe and is generally well tolerated by hypertensive patients with fewer adverse reactions compared to the first generation a 2 agonist, clonidine. [4][5][6] For metabolism and pharmacokinetics studies of moxonidine in humans 7 a high specific activity radiolabeled material was required.…”