Central Moxonidine Research Articles

Involvement of central α 1-adrenoceptors on renal responses to central moxonidine and α-methylnoradrenaline

Moxonidine (α 2-adrenoceptor/imidazoline receptor agonist) injected into the lateral ventricle induces diuresis, natriuresis and renal vasodilation. Moxonidine-induced diuresis and natriuresis depend on central imidazoline receptors, while central α 1-adrenoceptors are involved in renal vasodilation. However, the involvement of central α 1-adrenoceptors on diuresis and natriuresis to central moxonidine was not investigated yet. In the present study, the effects of moxonidine, α-methylnoradrenaline (α 2-adrenoceptor agonist) or phenylephrine (α 1-adrenoceptor agonist) alone or combined with previous injections of prazosin (α 1-adrenoceptor antagonist), yohimbine or RX 821002 (α 2-adrenoceptor antagonists) intracerebroventricularly (i.c.v.) on urinary sodium, potassium and volume were investigated. Male Holtzman rats ( n = 5–18/group) with stainless steel cannula implanted into the lateral ventricle and submitted to gastric water load (10% of body weight) were used. Injections of moxonidine (20 nmol) or α-methylnoradrenaline (80 nmol) i.c.v. induced natriuresis (196 ± 25 and 171 ± 30, respectively, vs. vehicle: 101 ± 9 µEq/2 h) and diuresis (9.0 ± 0.4 and 12.3 ± 1.6, respectively, vs. vehicle: 5.2 ± 0.5 ml/2 h). Pre-treatment with prazosin (320 nmol) i.c.v. abolished the natriuresis (23 ± 4 and 76 ± 11 µEq/2 h, respectively) and diuresis (5 ± 1 and 7.6 ± 0.8 ml/2 h, respectively) produced by i.c.v. moxonidine or α-methylnoradrenaline. RX 821002 (320 nmol) i.c.v. abolished the natriuretic effect of α-methylnoradrenaline, however, yohimbine (320 nmol) did not change renal responses to moxonidine. Phenylephrine (80 nmol) i.c.v. induced natriuresis and kaliuresis that were blocked by prazosin. Therefore, the present data suggest that moxonidine and α-methylnoradrenaline acting on central imidazoline receptors and α 2-adrenoceptors, respectively, activate central α 1-adrenergic mechanisms to increase renal excretion.

Cardiovascular effects evoked by central moxonidine in renovascular hypertensive (RH) rats.

Cardiovascular effects evoked by central moxonidine in renovascular hypertensive (RH) rats.

Antihypertensive Responses Elicited by Central Moxonidine in Rats: Possible Role of Nitric Oxide

In the present study, we investigated the effects of pretreatment with NG-nitro-L-arginine methyl ester (L-NAME) (nitric oxide synthase inhibitor) injected intravenously (IV) on the hypotension, bradycardia, and vasodilation produced by moxonidine (alpha2-adrenergic/imidazoline receptor agonist) injected into the fourth brain ventricle (4th V) in rats submitted to acute hypertension that results from baroreflex blockade by bilateral injections of kynurenic acid (kyn, glutamatergic receptor antagonist) into the nucleus of the solitary tract (NTS) or in normotensive rats. Male Wistar rats (n=5 to 7/group) anesthetized with IV urethane (1.0 g kg(-1) of body weight) and alpha-chloralose (60 mg kg(-1) of body weight) were used. Bilateral injections of kyn (2.7 nmol 100 nL(-1)) into the NTS increased baseline mean arterial pressure (148 +/- 11 mm Hg, vs. control: 102 +/- 4 mm Hg) and baseline heart rate (417 +/- 11 bpm, vs. control: 379 +/- 6 bpm). Moxonidine (20 nmol microL(-1)) into the 4th V reduced mean arterial pressure and heart rate to similar levels in rats treated with kyn into the NTS (68 +/- 9 mm Hg and 359 +/- 7 bpm) or in control normotensive rats (66 +/- 7 mm Hg and 362 +/- 8 bpm, respectively). The pretreatment with L-NAME (25 micromol kg, IV) attenuated the hypotension produced by moxonidine into the 4th V in rats treated with kyn (104 +/- 6 mm Hg) or in normotensive rats (95 +/- 8 mm Hg), without changing bradycardia. Moxonidine into the 4th V also reduced renal, mesenteric, and hindquarter vascular resistances in rats treated or not with kyn into the NTS and the pretreatment with L-NAME IV reduced these effects of moxonidine. Therefore, these data indicate that nitric oxide mechanisms are involved in hypotension and mesenteric, renal, and hindquarter vasodilation induced by central moxonidine in normotensive and in acute hypertensive rats.

Cardiovascular effects evoked by central moxonidine in L‐NAME hypertension model.

Central inhibition of the nitric oxide (NO) synthesis with L-NAME attenuates the hypotension elicited by central moxonidine in spontaneously hypertensive rats and DOCA-salt hypertensive rats. In this study, we investigated the cardiovascular effects produced by central moxonidine in L-NAME hypertension model. A stainless steel cannula was implanted into the 4th brain ventricle (4th V) 7 days prior to the experiments in adult male Wistar rats (300–350 g). Four days before the experiments, the rats were treated with L-NAME (20 mg/kg/day) or saline (vehicle, control rats) through an orogastric cannula over 4 days. Mean arterial pressure (MAP) and heart rate (HR) were recorded in conscious L-NAME hypertensive rats that had an arterial cannula inserted into the femoral artery one day prior to the experiments. In control normotensive rats (N=6), moxonidine into the 4th V elicited a greater decrease in MAP (-29±2 mmHg) compared to L-NAME hypertensive rats (-8±4 mmHg, N=6), even though the fall in HR elicited by moxonidine into the 4th V was greater in L-NAME hypertensive rats (−89±13 bpm) compared to control rats (−33±3 bpm). The findings suggest that central nitric oxide is involved in the hypotension, but not in the bradycardic response evoked by moxonidine into the 4thV in L-NAME hypertensive rats. Supported by FAPESP, CNPq-PRONEX and NEPAS.

Central blockade of nitric oxide synthesis reduces moxonidine-induced hypotension.

1. Nitric oxide (NO) and alpha(2)-adrenoceptor and imidazoline agonists such as moxonidine may act centrally to inhibit sympathetic activity and decrease arterial pressure. 2. In the present study, we investigated the effects of pretreatment with l-NAME (NO synthesis inhibitor), injected into the 4th ventricle (4th V) or intravenously (i.v.), on the hypotension, bradycardia and vasodilatation induced by moxonidine injected into the 4th V in normotensive rats. 3. Male Wistar rats with a stainless steel cannula implanted into the 4th V and anaesthetized with urethane were used. Blood flows were recorded by use of miniature pulsed Doppler flow probes implanted around the renal, superior mesenteric and low abdominal aorta. 4. Moxonidine (20 nmol), injected into the 4th V, reduced the mean arterial pressure (-42+/-3 mmHg), heart rate (-22+/-7 bpm) and renal (-62+/-15%), mesenteric (-41+/-8%) and hindquarter (-50+/-8%) vascular resistances. 5. Pretreatment with l-NAME (10 nmol into the 4th V) almost abolished central moxonidine-induced hypotension (-10+/-3 mmHg) and renal (-10+/-4%), mesenteric (-11+/-4%) and hindquarter (-13+/-6%) vascular resistance reduction, but did not affect the bradycardia (-18+/-8 bpm). 6. The results indicate that central NO mechanisms are involved in the vasodilatation and hypotension, but not in the bradycardia, induced by central moxonidine in normotensive rats.

Involvement of Forebrain Imidazoline and a2‐Adrenergic Receptors in the Antidipsogenic Response to Moxonidine

We investigated the participation of central alpha(2)-adrenoceptors and imidazoline receptors in the inhibition of water deprivation-induced water intake in rats. The alpha(2)-adrenoceptor and imidazoline antagonist idazoxan (320 nmol), but not the alpha(2)-adrenoceptor antagonist yohimbine, abolished the antidipsogenic effect of moxonidine (alpha(2)-adrenoceptor and imidazoline agonist, 20 nmol) microinjected into the medial septal area. Yohimbine abolished the antidipsogenic effect of moxonidine intracerebroventricularly. Therefore, central moxonidine may inhibit water intake acting independently on both imidazoline receptors and alpha(2)-adrenoceptors at different forebrain sites.

Moxonidine and central α 2 adrenergic receptors in sodium intake

Central injections of the α 2 adrenergic/imidazoline receptor agonist moxonidine inhibit water and NaCl intake in rats. In the present study, we investigated the possible involvement of central α 2 adrenergic receptors on the inhibitory effect of moxonidine in 0.3 M NaCl intake induced by 24 h sodium depletion. Male Holtzman rats with stainless-steel cannulas implanted into the lateral ventricle (LV) were used. Sodium depletion was produced by the treatment with the diuretic furosemide (20 mg/kg of body weight) injected subcutaneously +24 h of sodium-deficient diet. Intracerebroventricular (icv) injections of moxonidine (20 nmol/1 μl) reduced sodium depletion-induced 0.3 M NaCl intake (6.6±1.9 ml/120 min vs. vehicle: 12.7±1.7 ml/120 min). Pre-treatment with the α 2 adrenoreceptor antagonists RX 821002 (80 nmol/1 μl), SK&F 86466 (640 nmol/1 μl) and yohimbine (320 nmol/3 μl) injected icv abolished the inhibitory effect of icv moxonidine on sodium depletion-induced 0.3 M NaCl intake (13.3±1.4, 15.7±1.7 and 11.8±2.2 ml/120 min, respectively). The results show that the activation of α 2 adrenoreceptors is essential for the inhibitory effect of central moxonidine on sodium depletion-induced NaCl intake.

Central moxonidine on salivary gland blood flow and cardiovascular responses to pilocarpine

Peripheral treatment with the cholinergic agonist pilocarpine induces intense salivation that is inhibited by central injections of the α 2-adrenergic/imidazoline receptor agonist moxonidine. Salivary gland blood flow controlled by sympathetic and parasympathetic systems may affect salivation. We investigated the changes in mean arterial pressure (MAP) and in the vascular resistance in the submandibular/sublingual gland (SSG) artery, superior mesenteric (SM) artery and low abdominal aorta (hindlimb) in rats treated with intraperitoneal (i.p.) pilocarpine alone or combined with intracerebroventricular (i.c.v.) moxonidine. Male Holtzman rats with stainless steel cannula implanted into lateral ventricle (LV) and anesthetized with urethane were used. Pilocarpine (4 μmol/kg of body weight) i.p. reduced SSG vascular resistance (−50±13% vs. vehicle: 5±3%). Pilocarpine i.p. also increased mesenteric vascular resistance (15±5% vs. vehicle: 2±3%) and MAP (16±3 mmHg, vs. vehicle: 2±3 mmHg). Moxonidine (20 nmol) i.c.v. increased SSG vascular resistance (88±12% vs. vehicle: 7±4%). When injected 15 min following i.c.v. moxonidine, pilocarpine i.p. produced no change on SSG vascular resistance. Pilocarpine-induced pressor responses and increase in mesenteric vascular resistance were not modified by i.c.v. moxonidine. The treatments produced no change in heart rate (HR) and hindlimb vascular resistance. The results show that (1) i.p. pilocarpine increases mesenteric vascular resistance and MAP and reduces salivary gland vascular resistance and (2) central moxonidine increases salivary gland vascular resistance and impairs pilocarpine-induced salivary gland vasodilatation. Therefore, the increase in salivary gland vascular resistance may play a role in the anti-salivatory response to central moxonidine.

Central moxonidine on water and NaCl intake

In this study we investigated: (a) the effects of intracerebroventricular (i.c.v.) injections of moxonidine (an α 2-adrenergic and imidazoline receptor agonist) on the ingestion of water and NaCl induced by 24 h of water deprivation; (b) the effects of i.c.v. injection of moxonidine on central angiotensin II (ANG II)- and carbachol-induced water intake; (c) the effects of the pre-treatment with i.c.v. idazoxan (an α 2-adrenergic and imidazoline receptor antagonist) and RX 821002 (a selective α 2-adrenergic antagonist) on the antidipsogenic action of central moxonidine. Male Holtzman rats had stainless steel cannulas implanted in the lateral cerebral ventricle. Intracerebroventricular injection of moxonidine (5 and 20 nmol/1 μl) reduced the ingestion of 1.5% NaCl solution (4.1 ± 1.1 and 2.9 ± 2.5 ml/2 h, respectively vs. control = 7.4 ± 2.1 ml/2 h) and water intake (2.0 ± 0.6 and 0.3 ± 0.2 ml/h, respectively vs. control = 13.0 ± 1.4 ml/h) induced by water deprivation. Intracerebroventricular moxonidine (5 nmol/1 μl) also reduced i.c.v. ANG II-induced water intake (2.8 ± 0.9 vs. control = 7.9 ± 1.7 ml/1 h) and i.c.v. moxonidine (10 and 20 nmol/1 μl) reduced i.c.v. carbachol-induced water intake (4.3 ± 1.7 and 2.1 ± 0.9, respectively vs. control = 9.2 ± 1.0 ml/1 h). The pre-treatment with i.c.v. idazoxan (40 to 320 nmol/1 μl) abolished the inhibitory effect of i.c.v. moxonidine on carbachol-induced water intake. Intracerebroventricular idazoxan (320 nmol/1 μl) partially reduced the inhibitory effect of moxonidine on water deprivation-induced water intake and produced only a tendency to reduce the antidipsogenic effect of moxonidine on ANG II-induced water intake. RX 821002 (80 and 160 nmol/1 μl) completely abolished the antidipsogenic action of moxonidine on ANG II-induced water intake. The results show that central injections of moxonidine strongly inhibit water and NaCl ingestion. They also suggest the involvement of central α 2-adrenergic receptors in the antidipsogenic action of moxonidine.