Central blockade of nitric oxide synthesis reduces moxonidine-induced hypotension (original) (raw)
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Moxonidine centrally inhibits the sympathetic activity through the I 1-imidazoline receptor and nitric oxide. In addition, inhibits the peripheral cardiac sympathetic outflow by α 2-adrenoceptors/I 1-imida-zoline receptors, although the role of α 2-adrenoceptor subtypes or nitric oxide in the cardiac sympatho-inhibition induced by moxonidine are unknown. Therefore, the cardiac sympatho-inhibition induced by moxonidine (10 μg/kg min) was evaluated before and after of the treatment with the following an-tagonists/inhibitor: (1) BRL 44408, (300 μg/kg, α 2A), imiloxan, (3000 μg/kg, α 2B), and JP-1302, (300 μg/ kg, α 2C), in animals pretreated with AGN 192403 (3000 μg/kg, I 1 antagonist); (2) N ω-nitro-L-arginine methyl ester (L-NAME; 34, 100, and 340 μg/kg min); and (3) the combinations of the highest dose of L-NAME plus AGN 192403 or BRL 44408. Additionally, the expression of the neuronal (nNOS) and inducible (iNOS) nitric oxide synthase in the stellate ganglion was determined after treatment with moxonidine (i. p. 0.56 mg/kg daily, during one week). The cardiac sympatho-inhibition of 10 μg/kg min moxonidine was: (1) unaffected by imiloxan and JP-1302, under pretreatment with AGN 192403, or L-NAME (34, 100 and 340 μg/kg min) given alone; (2) partially antagonized by the combination of 340 μg/kg min L-NAME plus BRL 44408; and (3) abolished by BRL 44408 under treatment with AGN 192403. Furthermore, moxonidine did not modify the nNOS or iNOS protein expression in the stellate ganglion, the main source of postganglionic sympathetic neurons innervating the heart. In conclusion, our results suggest that the peripheral cardiac sympatho-inhibition induced by moxonidine is mediated by α 2A-adrenoceptor sub-type but not by nitric oxide.
British Journal of Pharmacology, 1993
The effects of acute inhibition of nitric oxide (NO) synthase on cardiovascular responses to vasodilator challenges have already been described. We now report the responses to vasodilators during and after chronic NO synthase inhibition. 2 In conscious Brattleboro rats, the regional haemodynamic effects of 3 min infusions of acetylcholine (4 g min-'), sodium nitroprusside (15 fg min ') or adrenaline (0.2 ig min-') were assessed (from areas under or over curves (AUC, AOC)) under control conditions, 6 and 72 h after the addition of the NO synthase inhibitor, N0-monomethyl-L-arginine (L-NMMA) to the drinking water (1 mg ml-'), and 6, 24 and 48 h after the withdrawal of L-NMMA. In a separate group of Brattleboro rats, responses to acetylcholine, sodium nitroprusside and adrenaline were assessed before and 6 h after the onset of oral ingestion of the more potent nitric oxide synthase inhibitor, N0-nitro-L-arginine methyl ester (L-NAME; 0.05 mg ml-1). 3 Acetylcholine caused renal vasodilatation (87 ± 11 units) and mesenteric vasoconstriction (-31 ± 5 units), sodium nitroprusside caused vasodilatation in renal (96 ± 12 units), mesenteric (222 ± 13 units) and hindquarters (49 ± 15 units) vascular beds, whereas adrenaline caused hindquarters vasodilatation (92 ± 8 units). Seventy two h after the onset of oral ingestion of L-NMMA, acetylcholine had a decreased renal vasodilator (59 ± 9 units) effect, sodium nitroprusside had an increased renal vasodilator (142 ± 23 units) action, while adrenaline had a decreased hindquarters vasodilator (55 ± 6 units) influence. Twenty four h after withdrawal of L-NMMA, the renal vasodilator effect of acetylcholine was greater than the control response (106 ± 14 units), but the regional haemodynamic effects of sodium nitroprusside and adrenaline were not different from those under control conditions. Hence, the increased renal vasodilator response to acetylcholine was probably due to changes in muscarinic receptor-mediated mechanisms rather than to any increase in guanylyl cyclase or its sensitivity to NO.
Involvement of central α 1- and α 2-adrenoceptors on cardiovascular responses to moxonidine
European Journal of Pharmacology, 2007
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, intravenouslyi.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 minutebpm, 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. Pretreatment 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 2adrenoceptors.
European Journal of Pharmacology, 2009
This study analysed the inhibition produced by the agonists moxonidine (imidazoline I 1 receptors N α 2adrenoceptors) and agmatine (endogenous ligand of imidazoline I 1 /I 2 receptors), using B-HT 933 (6-ethyl-5,6,7,8-tetrahydro-4H-oxazolo[4,5-d]azepin-2-amine dihydrochloride; α 2 -adrenoceptors) for comparison, on the rat cardioaccelerator sympathetic outflow. Male Wistar rats were pithed and prepared to stimulate the cardiac sympathetic outflow or to receive i.v. bolus of exogenous noradrenaline. Sympathetic stimulation or noradrenaline produced, respectively, frequency-dependent and dose-dependent tachycardic responses. I.v. continuous infusions of moxonidine (3 and 10 µg/kg min), agmatine (1000 and 3000 µg/kg min) and B-HT 933 (30 and 100 µg/kg min) inhibited the tachycardic responses to sympathetic stimulation, but not those to noradrenaline. The cardiac sympatho-inhibition by either moxonidine (3 µg/kg min) or B-HT 933 (30 µg/kg min) was not modified by i.v. injections of saline or the antagonists AGN192403 [(±)-2-endo-Amino-3-exoisopropylbicyclo[2.2.1]heptane hydrochloride; 3000 µg/kg; imidazoline I 1 receptors] or BU224 (2-(4,5dihydroimidazol-2-yl)quinoline hydrochloride; 300 µg/kg; imidazoline I 2 receptors) and abolished by rauwolscine (300 µg/kg; α 2 -adrenoceptors). At the same doses of these compounds, the sympathoinhibition to moxonidine (10 µg/kg min) and agmatine (1000 µg/kg min) was: (1) not modified by saline, AGN192403 or BU224; (2) partially blocked by rauwolscine or the combination of rauwolscine plus BU224; and (3) abolished by the combination of rauwolscine plus AGN192403. These results demonstrate that the cardiac sympatho-inhibition to: (1) 3 µg/kg min moxonidine or 30 µg/kg min B-HT 933 involves α 2adrenoceptors; and (2) 10 µg/kg min moxonidine or 1000 µg/kg min agmatine involves α 2 -adrenoceptors and imidazoline I 1 receptors.
This study shows that in spontaneously hypertensive rats (SHR) of 14-weeks-old, the sympathetically-induced, but not noradrenaline-induced tachycardic response are higher than age-matched Wistar normotensive rats. Furthermore, in SHR the sympathetically-induced tachycardic response was: (1) unaffected by moxonidine (3 μg/kg min); (2) partially inhibited by B-HT 933 (30 μg/kg min), both at the lowest doses; and (3) completely inhibited by the highest doses of B-HT 933 (100 μg/kg min), moxonidine (10 μg/kg min) or agmatine (1000 and 3000 μg/kg min) while the noradrenaline-induced tachycardic responses remained unaffected by the above compounds, except by 3000 μg/kg min agmatine. In SHR, 300 μg/kg rauwolscine failed to block the sympatho-inhibition to 100 μg/kg min B-HT 933 or 10 μg/kg min moxonidine, but 1000 μg/kg rauwolscine abolished, partially antagonized, and did not modify the sympatho-inhibition to the highest doses of B-HT 933, moxonidine, and agmatine, respectively, 3000 μg/kg AGN 192403 or 300 μg/kg BU224 given alone had no effect in the moxonidine- or agmatine-induced sympatho-inhibition, and the combination rauwolscine plus AGN 192403 but not plus BU224, abolished the sympatho-inhibition to the highest doses of moxonidine and agmatine. In conclusion, the sympathetically-induced tachycardic responses in SHR are inhibited by moxonidine and agmatine. The inhibition of moxonidine is mainly mediated by prejunctional α2-adrenoceptors and to a lesser extent by I1-imidazoline receptors, while the inhibition of agmatine is mediated by prejunctional α2-adrenoceptors and I1-imidazoline receptors at the same extent. Notwithstanding, the inhibitory function of α2-adrenoceptors seems to be altered in SHR compared with Wistar normotensive rats.
Journal of Pharmacy and Bioallied Sciences, 2013
Obesity accounts for around 70 % of the patients with primary hypertension. This association accentuates the risk of cardiovascular disease as it is frequently accompanied by the components of the metabolic syndrome. Clinical, epidemiological and experimental studies show an association between obesity-hypertension with insulin resistance and increased sympathetic nervous system activity. We conducted the present study to evaluate in forty obese hypertensives of both genders, aged 27 to 63 years old, the chronic effects of moxonidine-a selective imidazoline receptor agoniston blood pressure, plasma catecholamines, leptin, renin-angiotensin aldosterone system and components of the metabolic syndrome. It was a randomized parallel open study, amlodipine was used as the control drug. Our results show that moxonidine and amlodipine significantly reduced blood pressure without affecting heart rate when measured by the oscillometric method and with twenty-four-hour blood pressure monitoring. Moxonidine therapy decreased systolic blood pressure from 160.4 ± 2.4 to 142.1 ± 3.3 mmHg (p < 0.005) and diastolic blood pressure from 102.4 ± 1.3 to 89.7 ± 1.6 mmHg (p < 0.005) after 24 weeks of treatment. Neither moxonidine nor amlodipine affected normal circadian variations on blood pressure. There was a reduction of the supine arterial plasma levels adrenaline from 63.2 ± 6.6 to 49.0 ± 6.7 pg/ml (p < 0.005), supine arterial levels noradrenaline from 187.9 ± 10.7 to 149.7 ± 13.2 pg/ml (p < 0.01) and orthostatic venous levels of noradrenaline from 258.6 ± 25.0 to 190.3 ± 16.4 pg/ml (p = 0.03) after moxonidine. These variables were not changed by amlodipine. Plasma leptin levels and plasma insulin after 120 min glucose load decreased after moxonidine from 27.2 ± 3.5 to 22.6 ± 2.9 pg/ml (p < 0.05) and from 139.7 ± 31.2 to 76.0 ± 15.2 U/ml (p < 0.05), respectively. However, amlodipine did not modify these variables. There were no alterations in plasma renin activity, and plasma aldosterone after moxonidine, although amlodipine significantly increased the plasma renin activity from 31.4 ± 4.6 to 47.7 ± 5.6 ng/ml/h (p = 0.03). Moxonidine and amlodipine had no significant effect on the other variables. This study shows a comparable reduction of blood pressure with both antihypertensive drugs. Moxonidine decreased sympathetic nervous activity, improved insulin resistance and reduced the plasma levels of leptin.
Physiological Reports, 2019
We aimed to investigate the effects of nitric oxide (NO) synthesis inhibition by NO synthase inhibitor N-nitro-L-arginine-methyl ester (L-NAME) treatment on the sympathetic vasomotor nerve activity (SNA) on two sympathetic vasomotor nerves, the renal and splanchnic. NO plasma level and systemic oxidative stress were assessed. Hypertension was induced by L-NAME (20 mg/ kg per day, by gavage, for seven consecutive days) in male Wistar rats. At the end of the treatment, blood pressure, heart rate, arterial baroreflex sensitivity, renal SNA (rSNA), and splanchnic SNA (sSNA) were assessed in urethane anesthetized rats. L-NAME-treated rats presented increased blood pressure (152 AE 2 mmHg, n = 17) compared to the control group (101 AE 2 mmHg, n = 15). Both rSNA (147 AE 10, n = 15 vs. 114 AE 5 Spikes/s, n = 9) and sSNA (137 AE 13, n = 14 vs. 74 AE 13 spikes/s, n = 9) were significantly increased in the L-NAME-treated compared to the control group. A differential response on baroreflex sensitivity was found, with a significant reduction for rSNA but not for sSNA arterial baroreceptor sensitivity in L-NAME-treated rats. The adjusted regression model revealed that the reduction of systemic NO levels partially explains the variation in sSNA and blood pressure, but not rSNA. Taken together, our data show that hypertension induced by NO synthase blockade is characterized by increased SNA to the rSNA and sSNA. In addition, we found that the rats that had the greatest reduction in NO levels in plasma by L-NAME were those that developed higher blood pressure levels. The reduction in the NO level partially explains the variations in sSNA but not in rSNA.
Journal of Physiology and Biochemistry, 2011
The contribution of α-adrenoceptors and nitric oxide (NO) on the alterations of sympathetically mediated cardiovascular responses after acute (AcH) and chronic (ChH) hypertension was evaluated in pithed aortic coarcted hypertensive rats. Pressor and tachycardia response produced by electrical stimulation of preganglionic sympathetic fibers or exogenous noradrenaline (NA) were recorded in the absence and presence of prazosin (α 1-antagonist), rauwolscine (α 2-antagonist), or N G-nitro-L-arginine methyl ester (L-NAME; an inhibitor of NO synthase). Compared with age-matched sham-operated rats (Nt), the pressor response produced by electrical stimulation or NA was smaller in AcH rats and larger in ChH rats. Prazosin caused a decrease of pressor response elicited by electrical stimulation or NA in all groups. However, this effect was higher in ChH. Rauwolscine produced a similar increase of sympathetically mediated pressor response in Nt and AcH rats. Nevertheless, this antagonist did not affect the sympathetically mediated pressor response in ChH rats. In addition, rauwolscine did not affect the NA-induced pressor response in all groups. The pressor response elicited by L-NAME was larger in all groups compared without L-NAME and in presence of L-arginine. Moreover, L-NAME in the presence of NA increased sympathetically mediated pressor response is in all groups, compared without it or in the presence of L-arginine. Compared with Nt, basally produced NO in aortic rings was increased in AcH but decreased in ChH. Collectively, our data suggest that decreased cardiovascular reactivity in AcH is due to an increase in basally produced NO. In ChH, enhanced cardiovascular response appears to be associated with a decrease in produced NO and an increase in released NA from sympathetic nerves.
Involvement of α2-adrenoceptors in the cardiovascular effects of moxonidine
European Journal of Pharmacology, 1995
The central sympathoinhibition caused by moxonidine has been explained by activation of a2-adrenoceptors on the one hand, and by an action at imidazoline 11 receptors on the other hand. In order to examine these possibilities, effects of moxonidine were compared with those of 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline (UK 14304), an az-adrenoceptor agonist with very low affinity for I1 receptors, in conscious rabbits. The interaction with yohimbine, an a2-adrenoceptor antagonist with very low affinity for imidazoline I a receptors, was also studied. Moxonidine 3-100 p.g kg-1 and UK 14304 1-30 /~g kg l i.v. elicited similar effects: they decreased arterial blood pressure after a transient increase, decreased renal sympathetic nerve activity (recorded with chronically implanted electrodes), decreased heart rate and decreased the plasma noradrenaline concentration. Yohimbine given i.v. antagonized the effects of moxonidine and of UK 14304 in a similar manner. Yohimbine injected into the cisterna magna (i.c.) prevented the hypotension but did not change the decrease in plasma noradrenaline and heart rate, again in the case of both moxonidine and UK 14304. The agreement of the effect patterns of moxonidine and UK 14304, and the similar antagonism of yohimbine against either drug, demonstrate involvement of a2-adrenoceptors in their central sympathoinhibitory action. The resistance of the bradycardia and the plasma noradrenaline fall against yohimbine i.c. indicates a contribution of presynaptic a2-adrenergic inhibition of transmitter release from postganglionic sympathetic neurons to the overall reduction of sympathetic tone.
Effect of acute nitric oxide synthase inhibition in the modulation of heart rate in rats
Brazilian Journal of Medical and Biological Research, 2003
Acute nitric oxide synthase inhibition with N G-nitro-L-arginine methyl ester (L-NAME) on chronotropic and pressor responses was studied in anesthetized intact rats and rats submitted to partial and complete autonomic blockade. Blood pressure and heart rate were monitored intra-arterially. Intravenous L-NAME injection (7.5 mg/kg) elicited the same hypertensive response in intact rats and in rats with partial (ganglionic and parasympathetic blockade) and complete autonomic blockade (38 ± 3, 55 ± 6, 54 ± 5, 45 ± 5 mmHg, respectively; N = 9, P = NS). L-NAME-induced bradycardia at the time when blood pressure reached the peak plateau was similar in intact rats and in rats with partial autonomic blockade (43 ± 8, 38 ± 5, 46 ± 6 bpm, respectively; N = 9, P = NS). Rats with combined autonomic blockade showed a tachycardic response to L-NAME (10 ± 3 bpm, P<0.05 vs intact animals, N = 9). Increasing doses of L-NAME (5.0, 7.5 and 10 mg/kg, N = 9) caused a similar increase in blood pressure (45 ± 5, 38 ± 3, 44 ± 9 mmHg, respectively; P = NS) and heart rate (31 ± 4, 34 ± 3, 35 ± 4 bpm, respectively; P = NS). Addition of L-NAME (500 µM) to isolated atria from rats killed by cervical dislocation and rats previously subjected to complete autonomic blockade did not affect spontaneous beating or contractile strength (N = 9). In vivo results showed that L-NAME promoted a tachycardic response in rats with complete autonomic blockade, whereas the in vitro experiments showed no effect on intrinsic heart rate, suggesting that humoral mechanisms may be involved in the L-NAME-induced cardiac response.