Action Of Moxonidine Research Articles

Involvement of central α 1- and α 2-adrenoceptors on cardiovascular responses to moxonidine

In the present study we compared the effects produced by moxonidine (α 2-adrenoceptor/imidazoline agonist) injected into the 4th cerebral ventricle and into the lateral cerebral ventricle on mean arterial pressure, heart rate and on renal, mesenteric and hindquarter vascular resistances, as well as the possible action of moxonidine on central α 1- or α 2-adrenoceptors to produce cardiovascular responses. Male Holtzman rats ( n = 7–8) anesthetized with urethane (0.5 g/kg, intravenously — i.v.) and α-chloralose (60 mg/kg, i.v.) were used. Moxonidine (5, 10 and 20 nmol) injected into the 4th ventricle reduced arterial pressure (− 19 ± 5, − 30 ± 7 and − 43 ± 8 mmHg vs. vehicle: 2 ± 4 mmHg), heart rate (− 10 ± 6, − 16 ± 7 and − 27 ± 9 beats per minute — bpm, vs. vehicle: 4 ± 5 bpm), and renal, mesenteric and hindquarter vascular resistances. Moxonidine (5, 10 and 20 nmol) into the lateral ventricle only reduced renal vascular resistance (− 77 ± 17%, − 85 ± 13%, − 89 ± 10% vs. vehicle: 3 ± 4%), without changes on arterial pressure, heart rate and mesenteric and hindquarter vascular resistances. Pre-treatment with the selective α 2-adrenoceptor antagonist yohimbine (80, 160 and 320 nmol) injected into the 4th ventricle attenuated the hypotension (− 32 ± 5, − 25 ± 4 and − 12 ± 6 mmHg), bradycardia (− 26 ± 11, − 23 ± 5 and − 11 ±6 bpm) and the reduction in renal, mesenteric and hindquarter vascular resistances produced by moxonidine (20 nmol) into the 4th ventricle. Pre-treatment with yohimbine (320 nmol) into the lateral ventricle did not change the renal vasodilation produced by moxonidine (20 nmol) into the lateral ventricle. The α 1-adrenoceptor antagonist prazosin (320 nmol) injected into the 4th ventricle did not affect the cardiovascular effects of moxonidine. However, prazosin (80, 160 and 320 nmol) into the lateral ventricle abolished the renal vasodilation (− 17 ± 4, − 6 ± 9 and 2 ± 11%) produced by moxonidine. The results indicate that the decrease in renal vascular resistance due to moxonidine action in the forebrain is mediated by α 1-adrenoceptors, while the cardiovascular effects produced by moxonidine acting in the brainstem depend at least partially on the activation of α 2-adrenoceptors.

Imidazoline receptors in the heart: a novel target and a novel mechanism of action that involves atrial natriuretic peptides.

Chronic stimulation of sympathetic nervous activity contributes to the development and maintenance of hypertension, leading to left ventricular hypertrophy (LVH), arrhythmias and cardiac death. Moxonidine, an imidazoline antihypertensive compound that preferentially activates imidazoline receptors in brainstem rostroventrolateral medulla, suppresses sympathetic activation and reverses LVH. We have identified imidazoline receptors in the heart atria and ventricles, and shown that atrial I1-receptors are up-regulated in spontaneously hypertensive rats (SHR), and ventricular I1-receptors are up-regulated in hamster and human heart failure. Furthermore, cardiac I1-receptor binding decreased after chronic in vivo exposure to moxonidine. These studies implied that cardiac I1-receptors are involved in cardiovascular regulation. The presence of I1-receptors in the heart, the primary site of production of natriuretic peptides, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), cardiac hormones implicated in blood pressure control and cardioprotection, led us to propose that ANP may be involved in the actions of moxonidine. In fact, acute iv administration of moxonidine (50 to 150 microg/rat) dose-dependently decreased blood pressure, stimulated diuresis and natriuresis and increased plasma ANP and its second messenger, cGMP. Chronic SHR treatment with moxonidine (0, 60 and 120 microg kg(-1) h(-1), sc for 4 weeks) dose-dependently decreased blood pressure, resulted in reversal of LVH and decreased ventricular interleukin 1beta concentration after 4 weeks of treatment. These effects were associated with a further increase in already elevated ANP and BNP synthesis and release (after 1 week), and normalization by 4 weeks. In conclusion, cardiac imidazoline receptors and natriuretic peptides may be involved in the acute and chronic effects of moxonidine.

Pharmacological evidence of a role for prejunctionalimidazoline (I1) receptors in ocular function

Imidazoline and guanidiniun-substituted isoindoline compounds have been reported to demonstrate affinity for the putative imidazoline receptors (I 1) and alpha-2 (a 2) adrenoceptors. The purpose of this study was to determine the relative contribution of I 1 receptors to ocular actions of moxonidine (MOX) and brimonidine (BRIM) by utilizing relatively selective a 2 and I 1 antagonists. MOX, an a 2 /I 1 receptor agonist, BRIM, a selective a 2 agonist, efaroxan (EFA), an I 1 /a 2 antagonist and rauwolscine (RAU), a relatively selective a 2 antagonist, were utilized to study alterations in sympathetically evoked contractions of the cat nictitating membrane (CNM). MOX (1-10 µg) suppressed, dose dependently, contractions of the CNM elicited by electrically stimulating the cervical preganglionic sympathetic trunk. The suppressive effect of MOX was antagonized more effectively by EFA (333 µg) than by rauwolscine (333 µg). In contrast, RAU, but not EFA, completely reversed the suppressive effects of BRIM on electrically induced contractions of the CNM. In conclusion, these in vivo data suggest that I 1 receptors are involved in the pre-junctional (neuronal) modulation of contractions in the CNM (Supported by NIH grant EY06338).

Site of action of moxonidine in the rat nephron.

Moxonidine is a centrally acting antihypertensive agent which has been found to exert its blood pressure lowering effect by interaction with (alpha2-adrenoceptors and imidazoline receptors of the I(1)-type. These receptors have also been demonstrated to be present in the rat kidney. In the present study, clearance and micropuncture techniques were applied to anaesthetized rats to localize the site of action of moxonidine within the nephron. The clearance data show that moxonidine (0.25 mg/kg i.v., followed by a continuous i.v. infusion of 0.25 mg/h) induced a marked increase in urine flow and urinary excretion of sodium, chloride and potassium. The changes in urine flow and urinary solute excretion were accompanied by an enhanced glomerular filtration rate. The micropuncture experiments revealed that moxonidine significantly increased glomerular filtration rate of superficial nephrons, and significantly inhibited fractional reabsorption of fluid, sodium, potassium and chloride by similar amounts (by 9.0%-9.8%) in superficial proximal tubules. Regarding fluid and sodium reabsorption, the proximal effect of moxonidine was continuously weakened by a compensatory increase of reabsorption in the loop of Henle and the subsequent distal nephron segments. The inhibitory effect of moxonidine on fractional proximal potassium reabsorption was completely compensated in the loop of Henle, but the drug induced a net secretion of potassium into the segments lying beyond the early distal tubule, probably as a consequence of the increased tubule fluid and sodium load delivered to them. The experiments have identified the proximal tubule as the principal nephron site where the diuretic action of moxonidine arises. The proximal effect may be related to the increased glomerular filtration rate and to a direct inhibitory interaction of moxonidine with the proximal Na+/H+ exchanger.

The I1-imidazoline receptor in PC12 pheochromocytoma cells activates protein kinases C, extracellular signal-regulated kinase (ERK) and c-jun N-terminal kinase (JNK).

We sought to further elucidate signal transduction pathways for the I1-imidazoline receptor in PC12 cells by testing involvement of protein kinase C (PKC) isoforms (betaII, epsilon, zeta), and the mitogen-activated protein kinases (MAPK) ERK and JNK. Stimulation of I1-imidazoline receptor with moxonidine increased enzymatic activity of the classical betaII isoform in membranes by about 75% and redistributed the atypical isoform into membranes (40% increase in membrane-bound activity), but the novel isoform of PKC was unaffected. Moxonidine and clonidine also increased by greater than two-fold the proportion of ERK-1 and ERK-2 in the phosphorylated active form. In addition, JNK enzymatic activity was increased by exposure to moxonidine. Activation of ERK and JNK followed similar time courses with peaks at 90 min. The action of moxonidine on ERK activation was blocked by the I1-receptor antagonist efaroxan and by D609, an inhibitor of phosphatidylcholine-selective phospholipase C (PC-PLC), previously implicated as the initial event in I1-receptor signaling. Inhibition or depletion of PKC blocked activation of ERK by moxonidine. Two-day treatment of PC12 cells with the I1/alpha2-agonist clonidine increased cell number by up to 50% in a dose related manner. These data suggest that ERK and JNK, along with PKC, are signaling components of the I1-receptor pathway, and that this receptor may play a role in cell growth.

Central imidazoline (I1) receptors modulate aqueous hydrodynamics

The purpose of this work is to determine the relative contributions of central imidazoline (I 1) receptors to the ocular hydrodynamic action of moxonidine. Moxonidine (MOX), an a 2 and I 1 receptor agonist, and efaroxan (EFA), a relatively selective I 1 antagonist, were utilized to study alterations in intraocular pressure (IOP) and aqueous flow in New Zealand white rabbits subjected to intracerebroventricular (i.c.v.) cannulation and sympathectomy. Intracerebroventricular administration of MOX (0.033, 0.33 and 3.33 µg) to normal rabbits produced dose-dependent, bilateral IOP decreases of 3, 6, and 8 mmHg, respectively. The ocular hypotensive response to MOX was immediate (10 min. post drug), lasted for one hour, and was inhibited by prior administration of efaroxan (3.33 µg icv). In unilaterally sympathectomized (SX) rabbits, the ocular hypotensive response induced by i.c.v MOX in the denervated eye was attenuated approximately 50%, but the duration of ocular hypotension in the surgically altered eye was longer than that of the normal eye. MOX (0.33 µg icv), caused a statistically significant decrease (2.24 to 1.59 ml/min.) in aqueous flow in normal eyes. In SX eyes, there was no change in aqueous flow by MOX, suggesting that IOP effect in icv MOX observed in the SX eye might be mediated by changes in outflow resistance. Sedation was observed in all the rabbits treated with MOX (icv) and was dose-dependent. These in vivo data support the suggestion that centrally located I 1 receptors modulate the early contralateral response to topically administered MOX and are involved in lowering of IOP and aqueous flow in rabbit. In addition, expression of the full ocular hypotensive effect of centrally applied MOX depends on intact sympathetic innervation. Ocular hypotension induced by MOX in the SX eye may involve an effect on uveoscleral outflow.

Pharmacology of moxonidine: an I1-imidazoline receptor agonist.

The I1-imidazoline receptor is a novel neurotransmitter receptor found mainly in the brainstem, adrenal medulla and kidney. The actions of moxonidine are described at the level of individual biomolecules, cells, tissues, organs and finally with integrative functions. The receptor functions at the cellular level works through arachidonic acid and phospholipid signaling cascades in neuronal cells with the net result of inhibiting sympathetic premotor neurons.

Moxonidine-induced inhibition of norepinephrine release in monkey and rabbit ciliary bodies: role of cGMP.

This study was designed to determine whether in isolated rabbits iris-ciliary bodies and monkey ciliary bodies, cGMP plays a role in the action of moxonidine, an alpha 2- and imidazoline (I1) receptor agonist. In field-stimulated rabbit iris-ciliary bodies, dose-related inhibition of norepinephrine release was induced by 8-Br-cGMP, moxonidine or sodium nitroprusside; 8-Br-cGMP in combination with moxonidine did not enhance inhibition of norepinephrine release. Sodium nitroprusside at intermediate and high concentrations stimulated cGMP production in rabbit iris-ciliary bodies, whereas moxonidine stimulated cGMP production modestly only at a high concentration. When iris-ciliary bodies were pretreated with a low concentration of moxonidine, sodium nitroprusside-stimulated cGMP production was enhanced from 1.6 to 2.2 pmol/mg protein. In field-stimulated monkey ciliary bodies, both sodium nitroprusside and moxonidine inhibited norepinephrine release. Pretreatment of electrically stimulated monkey ciliary bodies with sodium nitroprusside enhanced the suppressive effect of moxonidine on norepinephrine release. In monkey ciliary bodies, moxonidine raised cGMP production more than sodium nitroprusside did, but there was no synergism in cGMP production by combined treatment with moxonidine and sodium nitroprusside. These results suggest that cGMP could play a role in the ocular action(s) of moxonidine in ciliary bodies; however, involvement of cGMP in the action of moxonidine in monkey ciliary bodies seems to be more pronounced than in rabbit iris-ciliary bodies.