Atrial Natriuretic Peptide Is Involved in Renal Actions of Moxonidine

Abstract

Abstract-Moxonidine, an antihypertensive imidazoline compound, reduces blood pressure by selective activation of central imidazoline I 1 -receptors and inhibition of sympathetic nerve activity and by direct actions on the kidney, with both mechanisms resulting in diuresis and natriuresis. We hypothesized that the hypotensive and renal actions of moxonidine may be mediated by atrial natriuretic peptide (ANP), a cardiac peptide involved in pressure and volume homeostasis through its vasodilatory, diuretic, and natriuretic actions. Renal parameters were measured on an hourly basis over a period of 4 hours in conscious rats that received bolus intravenous injections of moxonidine (1 to 150 g/300 L saline). During the first hour, moxonidine dose-dependently stimulated diuresis, natriuresis, kaliuresis, and urinary cGMP, the index of ANP activity. Moxonidine (50 g) significantly (PϽ0.001) stimulated urinary volume (0.35Ϯ0.04 versus 1.05Ϯ0.09 mL/h per 100 g), sodium (14.3Ϯ2.5 versus 51.8Ϯ6.5 mol/h per 100 g), potassium (10.5Ϯ2.3 versus 32.3Ϯ3.2 mol/h per 100 g), and cGMP (325Ϯ52 versus 744Ϯ120 pmol/h per 100 g). Pretreatment with a selective imidazoline receptor antagonist, efaroxan, dose-dependently inhibited moxonidine-stimulated renal parameters. Efaroxan (25 g per rat) significantly inhibited moxonidine-stimulated diuretic and natriuretic effects and urinary cGMP excretion (744Ϯ120 versus 381Ϯ137 pmol/h per 100 g, PϽ0.02). The ␣ 2 -adrenoceptor antagonist yohimbine (50 g per rat) partially yet significantly inhibited moxonidine-stimulated diuresis and natriuresis but not cGMP excretion. Plasma ANP was dose-dependently increased by moxonidine and was inhibited by pretreatment with efaroxan (220.8Ϯ36.9 versus 100.3Ϯ31.7 pg/mL, PϽ0.03) but not by yohimbine. In conclusion, selective in vivo activation of imidazoline receptors by moxonidine is associated with dose-dependent diuresis, natriuresis, and kaliuresis as well as stimulated plasma ANP and urinary cGMP excretion, thus implicating ANP in the renal actions of moxonidine. (Hypertension. 2000;35:1215-1220.)

Functional and molecular effects of imidazoline receptor activation in heart failure

“…One month treatment with moxonidine did not significantly affect blood pressure. These findings fully agree with the reported inability of moxonidine and other centrally acting drugs to produce hypotension, particularly in presence of low or normal blood pressure (Motz et al 1998; Mukaddam-Daher and Gutkowska 2000). It is imperative to note that, even in the absence of hypotension, centrally acting drugs cause significant suppression in cardiac sympathetic activity (Mobini et al 2006;Van Kerckhoven et al 2000).…”

Antagonistic Effects of Atipamezole and Yohimbine on Xylazine-Induced Diuresis in Healthy Dogs

“…Previous studies have suggested that the decrease in plasma AVP plays a partial role in the profound diuretic effect of xylazine through its action on  2 -adrenoceptors [3, 10, 11 17, 18]. In our recent study [16], we suggested that ANP might partially influence xylazine-induced diuresis in dogs because it exerts a diuretic and natriuretic action on the renal proximal tubules and inner medullary duct cells of the kidney in rats [12,13]. The regulation of water excretion has implications for a number of clinical situations.…”

“…However, the level of ANP stimulated by atipamezole at the tested doses is not considered to be enough to induce diuresis. Stimulation of plasma ANP release has been reported to be related to the atrial stretch due to hypertension [8,12,13]. Atipamezole produces stronger and relatively longer hypertension [4,8,20].…”

Imidazoline Receptors but Not α2-Adrenoceptors Are Regulated in Spontaneously Hypertensive Rat Heart by Chronic Moxonidine Treatment

“…In addition, we have recently identified I 1 -receptors in heart atria and ventricles and shown that atrial I 1 -receptors are up-regulated in rat hypertension and ventricular I 1 -receptors are up-regulated in human and hamster heart failure (El-Ayoubi et al, 2002a). In other studies, we demonstrated that acute injections of moxonidine, an imidazoline compound that shows 40 times higher affinity to I 1 -receptor versus ␣ 2 -adrenoceptors, are associated with enhanced release of atrial natriuretic peptide (Mukaddam-Daher and Gutkowska, 2000), a cardiac hormone involved in pressure and volume homeostasis. Together, these studies led us to suggest that heart I 1 -receptors are functional and may be involved in cardiovascular regulation.…”