Sedation and need-free salt intake in rats treated with clonidine

The effect of intraperitoneal injection of clonidine (9-72 mu g/kg) on need-free 1.5% NaCl intake and on performance (defined as percent of a complete trial) in the rotarod test, was studied in normovolemic adult male rats. Clonidine (18 and 36 mu g/kg) inhibited the 1.5% NaCl intake in a 2-h test at doses that did not alter the performance in the rotarod test. The dose of 36 mu g/kg did not inhibit 10% sucrose intake. Only the highest dose (72 mu g/kg) of clonidine inhibited the 1.5% NaCl intake and the performance in the rotarod test, and produced signs of sedation. Sedation was determined either by change in posture (immobility or lack of postural tonus) of the animals during the ingestive test or by their performance in the rotarod test. The results suggest that sedation is not a determinant effect on the inhibition of 1.5% NaCl intake induced by clonidine. (C) 1999 Elsevier B.V.

PROGESTERONE ADMINISTRATION TO OVARIECTOMIZED RATS REDUCES WATER AND SALT INTAKE INDUCED BY CENTRAL ADMINISTRATION OF ANGIOTENSIN-II

We tested the effects of estradiol, progesterone and testosterone on water and salt intake induced by angiotensin II (ANG II) injected into the third ventricle of female Holtzman rats weighing 250-300 g. The water and salt ingestion observed after 120 min in the control experiments (injection of 0.5 mu l of 0.15 M NaCl into the third ventricle) was 1.6 +/- 0.3 ml (N = 10) and 0.3 +/- 0.1 ml (N = 8) in intact rats, respectively, and 1.4 +/- 0.3 ml (N = 10) and 0.2 +/- 0.1 (N = 8) in ovariectomized rats, respectively. ANG II injected in intact rats (4, 6, 12, 25, and 50 ng, icv, in 0.5 mu l saline) induced an increase in water intake (4.3 +/- 0.6, 5.4 +/- 0.7. 7.8 +/- 0.8, 10.4 +/- 1.2, 11.2 +/- 1.4 ml/120 min, respectively) (N = 43). The same doses of icv ANG II in intact rats increased the 3% NaCl intake (0.9 +/- 0.2; 1.4 +/- 0.3, 2.3 +/- 0.4, 2.2 +/- 0.3. and 2.5 +/- 0.4 ml/120 min, respectively) (N = 42). When administered to ovariectomized rats ANG II induced comparable amounts of water intake (4.0 +/- 0.5, 4.8 +/- 0.6, 6.9 +/- 0.7. 9.6 +/- 0.8, and 10.9 +/- 1.2 ml/120 min, respectively) (N = 43) but there was a significant decrease of 3% NaCl solution ingestion (0.3 +/- 0.1, 0.4 +/- 0.1, 0.8 +/- 0.2, 0.7 +/- 0.2, and 0.6 +/- 0.2 ml/120 min, respectively) (N = 44). Estrogen (50 mu g), progesterone (25 ng), and testosterone (300 mu g) were injected daily into ovariectomized rats for 21 days. Treatment with estrogen decreased the water intake and abolished the saline ingestion induced by icy injection of ANG II (12 ng (2.8 +/- 1.2 and 0.3 +/- 0.1 ml/120 min, respectively) (N = 8). Treatment with progesterone also reduced the water intake (3.3 +/- 0.6 ml/120 min) (N = 8) and abolished the ANG II-induced saline ingestion (0.4 +/- 0.1 ml/120 min) (N = 8), but these effects were not observed with testosterone (6.4 +/- 0.8 and 2.2 +/- 0.3 ml/120 min, respectively) (N = 8). These results indicate that ANG II induces a greater increase in sodium intake in intact female rats than in ovariectomized rats and that estrogen and progesterone impair water and sodium intake in ovariectomized rats.

Ibotenate lesion of the medial hypothalamus alters the salt intake and pressor responses to activation of the median preoptic nucleus in rats

We investigated the influence of ibotenic acid lesions of the medial hypothalamus (MH) on salt appetite and arterial blood pressure responses induced by angiotensinergic and adrenergic stimulation of the median preoptic nucleus (MnPO) of rats. Previous injection of the adrenergic agonists norepinephrine, clonidine, phenylephrine, and isoproterenol into the MnPO of sham MH-lesioned rats caused no change in the sodium intake induced by ANG II. ANG II injected into the MnPO of MH-lesioned rats increased sodium intake compared with sham-lesioned rats. Previous injection of clonidine and isoproterenol increased, whereas phenylephrine abolished the salt intake induced by ANG II into the MnPO of MH-lesioned rats. Previous injection of norepinephrine and clonidine into the MnPO of sham MH-lesioned rats caused no change in the mean arterial pressure (MAP) induced by ANG II. Under the same conditions, previous injection of phenylephrine increased, whereas isoproterenol reversed the increase in MAP induced by angiotensin II (ANG II). ANG II injected into the MnPO of MH-lesioned rats induce a decrease in MAP compared with sham-lesioned rats. Previous injection of phenylephrine or norepinephrine into the MnPO of MH-lesioned rats induced a negative MAP, whereas pretreatment with clonidine or isoproterenol increased the MAP produced by ANG II injected into the MnPO of sham- or MH-lesioned rats. These data show that ibotenic acid lesion of the MH increases the sodium intake and presser responses induced by the concomitant angiotensinergic, alpha(2) and beta adrenergic activation of the MnPO, whereas alpha(1) activation may have opposite effects. MH involvement in excitatory and inhibitory mechanisms related to sodium intake and MAP control is suggested.

Effect of ibotenate lesions of the ventromedial hypothalamus on the water and salt intake induced by activation of the median preoptic nucleus in sodium-depleted rats

In this study we investigated the influence of a ventromedial hypothalamus (VMH) lesion with ibotenic acid on water and sodium intake and presser responses induced by combined treatment of the median preoptic nucleus (MnPO) with angiotensin Il (ANG II) and adrenergic agonists (phenylephrine, norepinephrine, isoproterenol and clonidine). Male Holtzman rats with a stainless steel cannula implanted into the MnPO and bilateral sham (vehicle) or VMH lesions with ibotenic acid were used. The ingestion of water and sodium and mean arterial pressure (MAP) were determined in separate groups submitted to sodium depletion with the diuretic furosemide (20 mg/rat). ANG II (10 pmol) injection into the MnPO of sham-lesioned rats induced water and sodium intake and presser responses. VMH-lesion reduced ANG II-induced water intake and increased saline intake, In sham rats phenylephrine (80 nmol) into MnPO increased, whereas norepinephrine (80 nmol) and clonidine (40 nmol) reduced ANG II-induced water intake while sodium intake was reduced only by clonidine into MnPO. In VMH-lesioned rats, phenylephrine reduced, noradrenaline increased and clonidine produced no effect on ANG II-induced water intake. In lesioned rats ANG II-induced sodium intake was reduced by phenylephrine and noradrenaline, whereas clonidine produced no change. ANG II-induced presser response was reduced in VMH-lesioned rats, but the presser response combining ANG II and phenylephrine or noradrenaline in VMH-lesioned rats was bigger than sham rats. These results show that the VMH is important for the changes in water and sodium intake and cardiovascular responses induced by angiotensinergic and adrenergic activation of the MnPO. (C) 1997 Elsevier B.V. B.V.

Protective effect of prior physical conditioning on relaxing response of corpus cavernosum from rats made hypertensive by nitric oxide inhibition

The aim of this work was to evaluate the influence of run training on the responsiveness of corpus cavernosum (CC) from rats made hypertensive by treatment with nitric oxide (NO) synthesis inhibitor. Wistar rats were divided into sedentary control (C-SD), exercise training (C-TR), N(omega)-nitro-L-arginine methyl ester (L-NAME) sedentary (LN-SD) and L-NAME trained (LN-TR) groups. The run training program consisted in 8 weeks in a treadmill, 5 days/week, each session lasted 60 min. L-NAME treatment (2 and 10mg/rat/day) started after 4 weeks of prior physical conditioning and lasted 4 weeks. Concentration-response curves were obtained for acetylcholine (ACh), sodium nitroprusside (SNP), sildenafil and BAY 41-2272. The effect of electrical field stimulation (EFS) on the relaxations responses of CC was evaluated. Run training prevented the arterial hypertension induced by L-NAME treatment (LN-SD: 135+/-2 and 141+/-2 mm Hg for both doses of L-NAME) compared to LN-SD groups (154+/-1 and 175+/-2 mm Hg, for 2 and 10 mg of L-NAME, respectively). Run training produced an increase in the maximal responses (E(max)) of CC for ACh (C-SD: 47+/-3; C-TR: 5271; and LN-TR: 53+/-3%) and SNP (C-SD: 8971; C-TR: 9871; and LN-TR: 95+/-1%). Both potency and E(max) for ACh were reduced in a dose of 10 mg of L-NAME, and run training restored the reduction of E(max) for ACh. No changes were found for BAY 41-2271 and sildenafil. Relaxing responses to EFS was reduced by L-NAME treatment that was restored by prior physical conditioning. In conclusion, our study shows a beneficial effect of prior physical conditioning on the impaired CC relaxing responses in rats made hypertensive by chronic NO blockade.

EFFECT OF LATERAL HYPOTHALAMUS LESIONS ON THE WATER AND SALT INTAKE, AND SODIUM AND URINE EXCRETION INDUCED BY ACTIVATION OF THE MEDIAN PREOPTIC NUCLEUS IN CONSCIOUS RATS

In this-study we investigated the influence of electrolytic lesion of the lateral hypothalamus (LH) on the water and salt appetite, and the natriuretic, diuretic and cardiovascular effects induced by angiotensinergic, cholinergic and noradrenergic stimulation of the median preoptic nucleus (MnPO) in rats. Male Holtzman rats were implanted with a cannula into the MnPO. Other groups of sham- and LH-lesioned rats received a stainless steel cannula implanted into the MnPO. ANGII injection into the MnPO induced water and sodium intake, and natriuretic, diuretic, presser and tachycardic responses. Carbachol induced water intake, and natriuretic, presser and bradycardic responses, whereas noradrenaline increased urine, sodium excretion and blood pressure, and induced bradycardia. In rats submitted to LH-lesion only, water and sodium intake was reduced compared with sham rats. LH lesion also reduced the sodium ingestion induced by ANGII (12 ng) into the MnPO. In LH-lesioned rats, the dipsogenic, diuretic and presser responses induced by ANGII (12 ng), carbachol (2 nmol) and noradrenaline (20 nmol) injection into the MnPO were reduced. The same occurred with sodium excretion when carbachol (2 nmol) and noradrenaline (20 nmol) were injected into the MnPO of LH-lesioned rats, whereas ANGII(12 ng) induced an increase in sodium excretion. These data show that electrolytic lesion of the LH reduces fluid and sodium intake, and presser responses to angiotensinergic, cholinergic and noradrenergic activation of the MnPO. LH involvement with MnPO excitatory and inhibitory mechanisms related to water and sodium intake, sodium excretion and cardiovascular control is suggested.

Differential vascular adaptive response in spontaneously hypertensive and Wistar rats: Role of nitric oxide, and prehypertensive and hypertensive states

Stress-induced vascular adaptive response in SHR was investigated, focusing on the endothelium. Noradrenaline responses were studied in intact and denuded aortas from 6-week-old (prehypertensive) and 14-week-old (hypertensive) SHR and age-matched Wistar rats submitted or not to acute stress (20-min swimming and I-h immobilization 25 min apart), preceded or not by chronic stress (2 sessions 2 days apart of 1-h day immobilization for 5-consecutive days). Stress did not alter the reactivity of denuded aorta. Moreover, no alteration in the EC50 values was observed after stress exposure. In intact aortas, acute stress-induced hyporeactivity to noradrenaline similar between strains at both age. Chronic stress potentiated this adaptive response in 6- and 14-week-old Wistar but not in 6-week-old SHR, and did not alter the reactivity of 14-week-old SHR. Maximum response (g) in intact aortas [6-week-old: Wistar 3.25 +/- 0.12, Wistar/acute 1.95 +/- 0.12*, Wistar/chronic 1.36 +/- 0.21*(+), SHR 1.75 +/- 0.11, SHR/acute 0.88 +/- 0.08*, SHR/chronic 0.85 +/- 0.05*; 14-week-old: Wistar 3.83 +/- 0.13, Wistar/acute 2.72 +/- 0.13*, Wistar/chronic 1.91 +/- 0.19*', SHR 4.03 +/- 0.17, SHR/acute 2.26 +/- 0.12*, SHR/chronic 4.10 +/- 0.23; inside the same strain: *P < 0.05 relate to non-stressed rat, (+)P < 0.05 related to acute stressed rat; n = 6-18]. Independent of age and strain, L-NAME and endothelium removal abolished the stress-induced aorta hyporeactivity. Conclusion: the vascular adaptive response to stress is impaired in SHR, independently of the hypertensive state. Moreover, this vascular adaptive response is characterized by endothelial nitric oxide-system hyperactivity in both strains. (c) 2006 Elsevier B.V. All rights reserved.

A1 Noradrenergic Neurons Lesions Reduce Natriuresis and Hypertensive Responses to Hypernatremia in Rats

Noradrenergic neurons in the caudal ventrolateral medulla (CVLM; A1 group) contribute to cardiovascular regulation. The present study assessed whether specific lesions in the A1 group altered the cardiovascular responses that were evoked by hypertonic saline (HS) infusion in non-anesthetized rats. Male Wistar rats (280-340 g) received nanoinjections of antidopamine-β-hydroxylase-saporin (A1 lesion, 0.105 ng.nL-1) or free saporin (sham, 0.021 ng.nL-1) into their CVLMs. Two weeks later, the rats were anesthetized (2% halothane in O2) and their femoral artery and vein were catheterized and led to exit subcutaneously between the scapulae. On the following day, the animals were submitted to HS infusion (3 M NaCl, 1.8 ml • kg-1, b.wt., for longer than 1 min). In the sham-group (n = 8), HS induced a sustained pressor response (ΔMAP: 35±3.6 and 11±1.8 mmHg, for 10 and 90 min after HS infusion, respectively; P<0.05 vs. baseline). Ten min after HS infusion, the pressor responses of the anti-DβH-saporin-treated rats (n = 11)were significantly smaller(ΔMAP: 18±1.4 mmHg; P<0.05 vs. baseline and vs. sham group), and at 90 min, their blood pressures reached baseline values (2±1.6 mmHg). Compared to the sham group, the natriuresis that was induced by HS was reduced in the lesioned group 60 min after the challenge (196±5.5 mM vs. 262±7.6 mM, respectively; P<0.05). In addition, A1-lesioned rats excreted only 47% of their sodium 90 min after HS infusion, while sham animals excreted 80% of their sodium. Immunohistochemical analysis confirmed a substantial destruction of the A1 cell group in the CVLM of rats that had been nanoinjected withanti-DβH-saporin. These results suggest that medullary noradrenergic A1 neurons are involved in the excitatory neural pathway that regulates hypertensive and natriuretic responses to acute changes in the composition of body fluid. © 2013 da Silva et al.

Antidepressant treatment decreases daily salt intake and prevents heart dysfunction following subchronic aortic regurgitation in rats

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Gene by environment QTL mapping through multiple trait analyses in blood pressure salt-sensitivity: identification of a novel QTL in rat chromosome 5

Background The genetic mechanisms underlying interindividual blood pressure variation reflect the complex interplay of both genetic and environmental variables. The current standard statistical methods for detecting genes involved in the regulation mechanisms of complex traits are based on univariate analysis. Few studies have focused on the search for and understanding of quantitative trait loci responsible for gene × environmental interactions or multiple trait analysis. Composite interval mapping has been extended to multiple traits and may be an interesting approach to such a problem. Methods We used multiple-trait analysis for quantitative trait locus mapping of loci having different effects on systolic blood pressure with NaCl exposure. Animals studied were 188 rats, the progenies of an F2 rat intercross between the hypertensive and normotensive strain, genotyped in 179 polymorphic markers across the rat genome. To accommodate the correlational structure from measurements taken in the same animals, we applied univariate and multivariate strategies for analyzing the data. Results We detected a new quantitative train locus on a region close to marker R589 in chromosome 5 of the rat genome, not previously identified through serial analysis of individual traits. In addition, we were able to justify analytically the parametric restrictions in terms of regression coefficients responsible for the gain in precision with the adopted analytical approach. Conclusion Future work should focus on fine mapping and the identification of the causative variant responsible for this quantitative trait locus signal. The multivariable strategy might be valuable in the study of genetic determinants of interindividual variation of antihypertensive drug effectiveness.

Potassium restores vasorelaxation of resistance arterioles in non-hypertensive DOCA/salt fed mice

Potassium-enriched diets exert renal and cardiovascular protective effects, but the underlying mechanisms are largely unknown.