Central serotonergic and adrenergic/imidazoline inhibitory mechanisms on sodium and water intake

Recent studies have shown the existence of two important inhibitory mechanisms for the control of NaCl and water intake: one mechanism involves serotonin in the lateral parabrachial nucleus (LPBN) and the other depends on alpha(2)-adrenergic/imidazoline receptors probably in the forebrain areas. In the present study we investigated if alpha(2)-adrenergic/imidazoline and serotonergic inhibitory mechanisms interact to control NaCl and water intake. Male Holtzman rats with cannulas implanted simultaneously into the lateral ventricle (LV) and bilaterally into the LPBN were used. The ingestion of 0.3 M NaCl and water was induced by treatment with the diuretic furosemide (10 mg/kg of body weight)+the angiotensin converting enzyme inhibitor captopril (5 mg/kg) injected subcutaneously 1 h before the access of rats to water and 0.3 M NaCl. Intracerebroventricular (i.c.v.) injection of the alpha(1)-adrenergic/imidazoline agonist clonidine (20 nmol/l RI) almost abolished water (1.6 +/- 1.2, vs. vehicle: 7.5 +/- 2.2 ml/2 h) and 0.3 M NaCl intake (0.5 +/- 0.3, vs. vehicle: 2.2 0.8 ml/2 h). Similar effects were produced by bilateral injections of the 5HT(2a/2b) serotonergic agonist 2,5-dimetoxy-4-iodoamphetamine (DOI, 5 mug/0.2 mul each site) into the LPBN on water (3.6 +/- 0.9 ml/2 h) and 0.3 M NaCl intake (0.4 +/- 0.2 m1/2 h). Injection of the (alpha(2)-adrenergic/imidazoline antagonist idazoxan (320 nmol) i.c.v. completely blocked the effects of clonidine on water (8.4 +/- 1.5 ml/2 h) and NaCl intake (4.0 +/- 1.2 ml/2 h), but did not change the effects of LPBN injections of DOI on water (4.2 +/- 1.0 ml/2 h) and NaCl intake (0.7 +/- 0.2 ml/2 h). Bilateral injections of methysergide (4 mug/0.2 mul each site) into the LPBN increased 0.3 M NaCl intake (6.4 +/- 1.9 ml/2 h), not water intake. The inhibitory effect of i.c.v. clonidine on water and 0.3 M NaCl was still present after injections of methysergide into the LPBN (1.5 +/- 0.8 and 1.7 +/- 1.4 ml/2 h, respectively). The results show that the inhibitory effects of the activation of a,-adrenergic/imidazoline receptors in the forebrain are still present after blockade of the LPBN serotonergic mechanisms and vice versa for the activation of serotonergic mechanisms of the LPBN. Therefore, each system may act independently to inhibit NaCl and water intake. (C) 2002 Elsevier B.V. B.V. All rights reserved.

Lateral parabrachial nucleus and serotonergic mechanisms in the control of salt appetite in rats

This study investigated the effects of bilateral injections of serotonergic receptor agonist and antagonist into the lateral parabrachial nucleus (LPBN) on the ingestion of water and 0.3 M NaCl induced by intracerebroventricular angiotensin II (ANG II) or by combined subcutaneous injections of the diuretic furosemide (Furo) and the angiotensin-converting enzyme inhibitor captopril (Cap). Rats had stainless steel cannulas implanted bilaterally into the LPBN and into the left lateral ventricle. Bilateral LPBN pretreatment with the serotonergic 5-HT1/5-HT2 receptor antagonist methysergide (4 mu g/200 nl each site) increased 0.3 M NaCl and water intakes induced by intracerebroventricular ANG II (50 ng/mu l) and 0.3 M NaCl intake induced by subcutaneous Furo + Cap. Pretreatment with bilateral LPBN injections of a serotonergic 5-HT2A/2C receptor agonist DOI (5 mu g/200 nl) significantly reduced 0.3 M NaCl intake induced by subcutaneous Furo + Cap. Pretreatment with methysergide or DOI into the LPBN produced no significant changes in the water intake induced by subcutaneous Furo + Cap. These results suggest that serotonergic mechanisms associated with the LPBN may have inhibitory roles in water and sodium ingestion in rats.

Salt appetite: interaction of forebrain angiotensinergic and hindbrain serotonergic mechanisms

Methysergide injected bilaterally into the lateral parabrachial nucleus (LPBN) increases NaCl intake in several models of renin-dependent salt appetite. The present study investigated the role of angiotensin Type 1 (AT(1)) receptors in the subfornical organ (SFO) on this effect. The intake of 0.3 M NaCl and water was induced by combined administration of the diuretic, furosemide (FURO), and the angiotensin-converting enzyme inhibitor, captopril (CAP). Pretreatment of the SFO with an AT, receptor antagonist, losartan (1 mu g/200 nl), reduced water intake but not 0.3 M NaCl intake induced by subcutaneous FURO + CAP. Methysergide (4 mu g/200 nl) injected bilaterally into the LPBN increased 0.3 M NaC1 intake after FURO + CAP. Losartan injected into the SFO prevented the additional 0.3 M NaC1 intake caused by LPBN methysergide injections. These results indicate that AT, receptors located in the SFO may have a role in mediating an enhanced sodium intake produced by methysergide treatment. (C) 1998 Elsevier B.V. B.V. All rights reserved.

Effect of intracerebroventricular injection of ramipril on the drinking response caused by injection of noradrenaline into the third ventricle

We studied the effect of ramipril injected into the third ventricle (3rdV) on the control of water intake induced by injection of noradrenaline into the 3rdV of adult male Holtzman rats (250-300 g) implanted with a chronic stainless steel cannula into the 3rdV. The injection volume was always 1 mu l and was injected over a period of 30-60 sec. Control animals were injected with 0.15 M NaCl. After the injection of isotonic saline (control, 0.15 M NaCl) into the 3rdV, water ingestion was 0.3 +/- 0.1 ml/h. Ramipril (1 mu g/mu l) injected into the 3rdV prior to isotonic saline produced no changes in water ingestion (0.4 +/- 0.2 ml/h). The injection of noradrenaline (40 nmol/mu l) after isotonic saline induced an increase in water intake (3.0 +/- 1.1 ml/h). The prior injection of ramipril decreased this ingestion to 1.8 +/- 0.3 ml/h. These data show that the inhibition of converting enzyme in the brain reduces the water intake induced by catecholaminergic stimulation. We conclude that the brain is able to transform the prodrug ramipril into the active drug ramiprilat.

ESTUDO COMPARATIVO DUPLO-CEGO DA EFICACIA E SEGURANCA DO CILAZAPRIL COMPARADAS A NIFEDIPINE 'RETARD' NO TRATAMENTO DA HIPERTENSAO ARTERIAL LEVE E MODERADA

Purpose: To evaluate the antihypertensive efficacy and safety of cilazapril compared to nifedipine retard in mild to moderate hypertension. Methods: Forty randomized out-patients with mild moderate hypertension, diastolic pressure (DP) between 95 and 115 mmg/Hg, with placebo for 15 days were randomized and allocated for treatment, double-blind, once daily with cilazapril 2.5 mg (n = 20) or nifedipine retard 20 mg (20 = n) for four weeks. The non-responders (DP > 90 mmHg) had the dosage increased twice, b.i.d., while responders were maintained up to 10 weeks. Clinical visits were performed before, at baseline and every two weeks and the laboratory test was performed after placebo run-in, 4th and 10th weeks of treatment. Results: The blood pressure (BP) were similar between groups at the end of the placebo (cilazapril 151 ± 14/103 ± 5 - nifedipine 157 ± 17/108 ± 7 mmHg, p > 0.05). DP decreased already at second weeks (cilazapril 95 ± 9 - nifedipine 96 ± 11 mmHg, p < 0.05, compared to week 0) in both groups at the end of study with no differences inter groups. BP normalization was obtained in 58% of the patients with cilazapril and in 61% in the nifedipine group. Adverse biochemical effects were not observed in any group. Six (16%) patients of the cilazapril and 15 (39%) of nifedipine related collateral events, although no difference were observed between groups. Conclusion: Cilazapril 2.5 to 5 mg normalized BP in 58% of mild and moderate hypertension patients, and this efficacy was similar to sustained-release nifedipine 20 to 40 mg. Cilazapril had no adverse effects on the biochemical parameters with low incidence of collateral effects.

TRATAMENTO DA HIPERTENSAO ARTERIAL LEVE E MODERADA COM FOSINOPRIL. COMPARACAO DE EFEITOS ADVERSOS COM OUTROS ANTI-HIPERTENSIVOS

Purpose - To evaluate the adverse reactions of fosinopril with other antihypertensives used as monotherapy. Methods - Out-patients (n = 2,568) with diagnostic of mild to moderate hypertension, diastolic blood pressure (DBP) 95-115 mmHg, with no antihypertensive treatment for 15 days, were included to treatment initially with fosinopril (F) 10mg, once daily, for six weeks. After this period, patients with DBP >95mmHg had the dosage, once daily, increased to 20 mg, while the others were maintained with the same dosage for six more weeks. Adverse reactions of 822 patients treated as monotherapy were grouped as absent, musculoskeletal, cardiovascular, cough, gastrointestinal, neurological, genital-urinary dysfunctions and dermatological and compared with 1,568 with F. Monotherapy consist in α-methyldopa (100 patients); β-blocker (129); calcium blocker (106); diuretic (394); and another ACE inhibitors (93). Results - At the end of the period without treatment, the blood pressure (BP), 165 ± 16/105 ± 7 mmHg decreased significantly at 6(th) week to 144 ± 15/91 ± 9 mmHg (p < 0.05 vs week 0) with further lowering to 139 ± 13/86 ± 7 mmHg till the end of 12(th) week. BP response (DBP ≤90 mmHg) was obtained in 89% of the patients with F. Absence of adverse reactions were ≥70% in patients with F compared to other drugs. Conclusion - Fosinopril has demonstrated therapeutic efficacy and less adverse reactions compared to antihypertensives used previously as monotherapy.

EFICACIA E TOLERABILIDADE DA ASSOCIACAO CAPTOPRIL + HIDROCLOROTIAZIDA NO TRATAMENTO DA HIPERTENSAO ARTERIAL LEVE A MODERADA. ESTUDO MULTICENTRICO

Purpose. To evaluate the antihypertensive efficacy and tolerability of captopril 50 mg + hydrochlorothiazide 25 mg daily in mild to moderate primary hypertension. Methods. Out-patients (n = 471) with mild to moderate hypertension, diastolic blood pressure (DBP) 95-115 mmHg, with 15 days of washout, were included to the treatment initially with half tablet of the association of captopril 50 mg + hydrochlorothiazide 25 mg once daily, for 30 days. After this period, patients with DBP > 90 mmHg had the dosage duplicated, while the others had the same dosage for 60 days more. Evaluation was performed 15 days before and then every month during active drug. Results. Twenty six patients were withdrawn, 13 (2,7%) by adverse effects and 13 by protocol violation. At the end of the wash-out period, the blood pressure (BP), 162 ± 16/103 ± 6 mmHg decreased significantly at the 30th day to 146 ± 14/92 ± 8 mmHg (p < 0,001 vs 0th day); 139 ± 12/86 ± 7 mmHg at the 60th day, (p < 0,001 vs 30th day), and further to 136 ± 11/84 ± 5 mmHg (p < 0,001 vs day 0) till the end of the 90th day. Antihypertensive efficay (DBP ≤ 90 mmHg and decreased for the DBP ≥ 10 mmHg) was obtained in 82% of the patients. There was no difference in BP control considering race, hypertension level, previous antihypertensive treatment and obesity. Cough (4%) was the main adverse event. Conclusion. Captopril + hydrochlorothiazide was effective and safe in the treatment of mild to moderate hypertension. The favorable response was observed in 82% of the patients independently of race, hypertensive level, previous antihypertensive treatment and obesity. Low incidence of side effects was reported, with no difference from others reported in the literature.

Functional evidence that the central renin-angiotensin system plays a role in the pressor response induced by central injection of carbachol

We investigated the effects of losartan, an AT 1-receptor blocker, and ramipril, a converting enzyme inhibitor, on the pressor response induced by angiotensin II (ANG II) and carbachol (a cholinergic receptor agonist). Male Holtzman rats (250-300 g) with a stainless steel cannula implanted into the lateral ventricle (LV) were used. The injection of losartan (50 nmol/l μl) into the LV blocked the pressor response induced by ANG II (12 ng/l μl) and carbachol (2 nmol/l μl). After injection of ANG II and carbachol into the LV, mean arterial pressure (MAP) increased to 31 ± 1 and 28 ± 2 mmHg, respectively. Previous injection of losartan abolished the increase in MAP induced by ANG II and carbachol into the LV (2 ± 1 and 5 ± 2 mmHg, respectively). The injection of ramipril (12 ng/l μl) prior to carbachol blocked the pressor effect of carbachol to 7 ± 3 mmHg. These results suggest an interaction between central cholinergic pathways and the angiotensinergic system in the regulation of arterial blood pressure.

Efeito de drogas utilizadas no tratamento de hipertensão arterial sistêmica sobre a pressão intra-ocular: Estudo experimental no cão

Purpose: To study the effects of two drugs (captopril and propranolol) used in the treatment of systemic hypertension, on the intraocular pressure (IOP) of anesthetized dogs. Methods: 24 dogs, divided into 3 groups of 8 each. In the first group, 1.5 mg/kg IV of captopril (an angiotensin converting enzyme inhibitor) was administered. In the second group, 1.5 mg/kg IV of propranolol (a beta-blocker) was administered. The third group was the control. IOP and blood pressure (BP) were measured by manometry. The perfusion pressure was calculated by the difference between BP and IOP (BP-IOP). The parameters were studied at 6 moments (0, 10, 30, 60, 90 and 120 minutes). Results: There was significant reduction of IOP (p<0.05) with captopril and propranolol, without difference between the drugs. With captopril the BP and PP decreased markedly at 10 and 30 minutes. With propranolol there was no reduction of BP or PP. Conclusions: Captopril and propranolol reduced IOP. However, the marked reduction of BP, and consequently of PP caused by captopril may be undesirable for irrigation of the optic nerve.

Gastrointestinal changes associated to heart failure

Over the last decade, several studies were conducted on the gastrointestinal changes associated to chronic heart failure. This article presents a literature review on the physiopathology and clinical consequences of pathological digestive changes of heart failure patients. Structural and functional abnormalities of the gastrointestinal tract, such as edema of absorptive mucosa and intestinal bacterial overgrowth, have been leading to serious clinical consequences. Some of these consequences are cardiac cachexia, systemic inflammatory activation and anemia. These conditions, alone or in combination, may lead to worsening of the pre-existing ventricular dysfunction. Although currently there is no therapy specifically earmarked for gastrointestinal changes associated to heart failure, the understanding of digestive abnormalities is germane for the prevention and management of systemic consequences.

Facilitation of sodium intake by combining noradrenaline into the lateral parabrachial nucleus with prazosin peripherally

Injections of noradrenaline into the lateral parabrachial nucleus (LPBN) increase arterial pressure and 1.8% NaCl intake and decrease water intake in rats treated with the diuretic furosemide (FURO) combined with a low dose of the angiotensin converting enzyme inhibitor captopril (CAP). In the present study, we investigated the influence of the pressor response elicited by noradrenaline injected into the LPBN on FURO + CAP-induced water and 1.8% NaCl intake. Male Holtzman rats with bilateral stainless steel guide-cannulas implanted into LPBN were used. Bilateral injections of noradrenaline (40 nmol/0.2 μl) into the LPBN increased FURO + CAP-induced 1.8% NaCl intake (12.2 ± 3.5, vs., saline: 4.2 ± 0.8 ml/180 min), reduced water intake and strongly increased arterial pressure (50 ± 7, vs. saline: 1 ± 1 mm Hg). The blockade of the α1 adrenoceptors with the prazosin injected intraperitoneally abolished the pressor response and increased 1.8% NaCl and water intake in rats treated with FURO + CAP combined with noradrenaline injected into the LPBN. The deactivation of baro and perhaps volume receptors due to the cardiovascular effects of prazosin is a mechanism that may facilitate water and NaCl intake in rats treated with FURO + CAP combined with noradrenaline injected into the LPBN. Therefore, the activation of α2 adrenoceptors with noradrenaline injected into the LPBN, at least in dose tested, may not completely remove the inhibitory signals produced by the activation of the cardiovascular receptors, particularly the signals that result from the extra activation of these receptors with the increase of arterial pressure. © 2013 Elsevier Inc.

Respostas cardiovasculares e na ingestão de água e NaCl hipertônico em ratos com doença periodontal tratados com agonista GABAA no núcleo parabraquial lateral

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Mecanismos prosencefálicos envolvidos na ingestão de sódio e água induzida pela ativação gabaérgica do núcleo parabraquial lateral

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Efeitos cardiovasculares e na ingestão de NaCl e água induzida pela injeção de trans-4-aminocrotonic acid (TACA) no núcleo parabraquial lateral (NPBL) de ratos

Pós-graduação em Ciências Fisiológicas - FOA

Influência do interior do inibidor da enzina conversora da angiotensina na remodelação cardíaca induzida pela exposição á fumaça do cigarro

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)