Angiotensin II interacts with nitric oxide-cyclic GMP pathway in the central control of drinking behaviour: mapping with c-fos and NADPH-diaphorase

doi:10.1016/S0306-4522(96)00686-0

Neuroscience

Volume 79, Issue 2, 12 May 1997, Pages 543-553

https://doi.org/10.1016/S0306-4522(96)00686-0 Get rights and content

Abstract

Recognition of the role of nitric oxide in cell-to-cell communication has changed the concept of traditional neurotransmission. We have shown previously that N-methyl-d-aspartate receptors mediate dipsogenic responses and c-Fos expression induced by intracerebroventricular infusion of angiotensin II. Since these receptors are known to be linked to the nitric oxide-cyclic GMP pathway, the present study explores the contribution of this path to the behavioural and cellular effects of intracerebroventricular angiotensin II by using behavioural testing, NADPH-diaphorase histochemistry and immunocytochemical staining for the immediate-early gene, c-fos. N^G-nitro-l-arginine methyl ester (125 and 250 μg, intracerebroventricular), an inhibitor of nitric oxide synthase, and Methylene Blue (100 μg), an inhibitor of guanylate cyclase activation, antagonized water intake induced by intracerebroventricular injection of 25 pmol angiotensin II. The effects of N^G-nitro-l-arginine methyl ester were reversed by co-injection of l-arginine, the substrate for nitric oxide synthase. However, N^G-nitro-l-arginine methyl ester did not alter the pattern of angiotensin II-induced c-fos expression in the organum vasculosum of the lamina terminalis, median preoptic nucleus, hypothalamic paraventricular nucleus and supraoptic nucleus. Double staining with NADPH-diaphorase histochemistry and c-Fos immunocytochemistry showed that neurons staining for both were localized to the anterior third ventricle. However, only 19–25% of the c-Fos-positive neurons expressed NADPH. There were also substantial numbers of neurons in which angiotensin II induced c-Fos that were NADPH-negative.

Extensive co-distribution of NADPH-diaphorase-stained cells and those expressing c-fos in response to intracerebroventricular injection of angiotensin II, especially in the median preoptic nucleus, imply that nitric oxide might participate in the mechanism of angiotensin II-induced drinking behaviour. However, a low rate of co-localization of the two markers to individual cells suggests that angiotensin II stimulated the production of nitric oxide and c-Fos in different populations of neurons. Since our previous results showed that glutamate blockade, but not nitric oxide synthase inhibition, suppressed angiotensin II-induced c-Fos, the experiments reported here further suggest that nitric oxide release is not an essential requirement for the expression of c-fos elicited by angiotensin II. They also provide evidence that the dipsogenic and c-Fos responses to angiotensin II are dissociated at a cellular level.

Section snippets

Animals

Male rats (Lister hooded, Olac, Bicester, U.K.), average body weight 250–280 g, were housed singly (cages 38×25×18 cm) under reversed light-dark cycles (lights off 09.00, 12 h each phase) in a temperature-controlled room. Food (SDS commercial pellets) and water were available ad libitum.

Cannulation

Lateral ventricular cannulation: All rats were anaesthetized with avertin (tribromoethanol: tertiary amyl alcohol, 1 ml/100 g body weight; Fluka AG, Germany). The rat's head was fixed in a stereotaxic frame and a

Experiment 1: The inhibitory effects of L-NAME on water ingestion and the counter effects of l-arginine

The amounts of water intake in the first 15 min after the injections were significantly different among four groups (one-way ANOVA; F=31.85, P<0.001, Fig. 1). Rats (n=8) infused with i.c.v. saline followed by 25 pmol angiotensin II drank 8.0±1.84 ml in the first 15 min, but those infused with either 250 μg (n=11) or 125 μg L-NAME (n=7) and then angiotensin II drank only 2.8±1.08 or 4.4±1.19 ml. The effects of L-NAME were blocked by co-injection of 500 μg l-arginine rats. Rats (n=8) infused with i.c.v. l

Nitric oxide-cGMP pathway involvement in angiotensin II-induced drinking behaviour

Central actions of angiotensin II have been extensively studied in the past two decades since Epstein et al. discovered the angiotensin II elicited drinking when centrally administrated.[10]A brain renin-angiotensin system is now known to exist.27, 41, 42, 55Angiotensin II has many of the properties of a neurotransmitter. Neuropharmacological studies have demonstrated that angiotensin II interacts with catecholaminergic, cholinergic, and other peptidergic brain pathways in the central control

Conclusion

The results described in this paper provide behavioural and morphological evidence for angiotensin II interactions with nitric oxide in the central control of drinking behaviour, but not in the induction of c-Fos. Together with our previous finding that dizocilpine (maleate) suppressed the dipsogenic action and c-fos expression induced by angiotensin II, we postulate that the nitric oxide-cGMP pathway is involved in angiotensin II-induced behavioural responses, presumably through activation of

Acknowledgements

We thank Julie Lane, Margaret Allen, Peter Phillips, Eduado Torres and Helen Shiers for technical help, and the Medical Research Council and Cambridge Overseas Trust for support. B.Z. was in receipt of an Overseas Research Studentship.

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Despite this, our results showed that previous inhibition of glial cell activity with FCt reduced water and sodium intake induced by L-NAME, suggesting a central interaction between NO and glial cells to modulate drinking behavior. In addition, the nitrergic system is known to participate in neuroendocrine, fluid intake, and pressor responses induced by central ANG-II (Calapai and Caputi, 1996; Zhu and Herbert, 1997; Saad et al., 1999; Reis et al., 2010). Recently, we showed that glial cells are also involved in this integrative response induced by central ANG-II (Flôr et al., 2018).
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Subfornical organ mediates pressor effect of angiotensin: Influence of nitric oxide synthase inhibitors, AT<inf>1</inf> and AT<inf>2</inf> angiotensin antagonist's receptors
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Thus, a Nox2-contained b-nicotinamide adenine dinucleotide diphosphate (NADPH) oxidase is the critical link between ANG II and the enhancement of Ca2+ currents that explained the actions of ANG II on autonomic regulation by the CNS.28 ANG II interaction with NO cyclic guanosine monophosphate (cGMP) pathway is also demonstrated in the central control of drinking behavior: mapping with c-fos and NADPH-diaphorase.29 NO is presented into SFO in large quantities.30
We investigated the influence of voltage-dependent calcium channels and nitric oxide (NO) on angiotensin II (ANG II)-pressor effect injected into subfornical organ (SFO). The influence of NO on nifedipine antipressor action has also been studied by utilizing N^W-nitro-L-arginine methyl ester (L-NAME) (20 μg × 0.2 μl⁻¹) a nitric oxide synthase inhibitor (NOSI) and 7-nitroindazole (7-NIT) (20 μg × 0.2 μl⁻¹), a specific neuronal nitric oxide synthase inhibitor (nNOSI). We have also investigated the role of losartan and PD123319, selective ANG II AT₁ and AT₂ receptor nonpeptide antagonists, in the pressor effect of ANG II and in the effect of L-NAME and 7-NIT, injected into the SFO. Adult male Holtzman rats (220 to 280 g) were anesthetized with ketamine (80 mg/kg⁻¹ of body weight) plus xylazine (7 mg/kg⁻¹ of body weight), placed in a stereotaxic apparatus (David Kopf model for rats), and implanted with cannula into the SFO. Direct mean arterial blood pressure (MAP) was recorded in conscious rats in a test cage, without access to food or water. The previously implanted catheter into femoral artery was connected to a Statham (P23 Db) pressure transducer (Statham-Gould, Valley View, OH) coupled to a multichannel recorder (PowerLab Multirecord). MAP increased after ANG II injection. Pre-treatment with nifidipine (50 μg × 0.2 μl⁻¹ or 100 μg × 0.2 μl⁻¹) followed by 25 pmol × 0.2 μl⁻¹ of ANG II, decreased ANG II-pressor effect. L-NAME and 7-NIT increased the elevation in MAP induced by ANG II, which was blocked by the prior injection of nifedipine. The AT₁ angiotensin antagonist losartan injected into the SFO blocked the effect of ANG II and the effects of L-NAME and 7-NIT while PD123319 did not. These results provide evidence that ANG II-pressor effect is influenced by nitrergic pathways that utilize L-type calcium channels in the SFO.
l-Type calcium channels mediate water intake induced by angiotensin injection into median preoptic nucleus
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Calcium ions are widely accepted as critically important in responses of neurons to a stimulus. We have show previously the central involvement of angiotensin II (ANGII) in water intake. This study determined whether voltage-dependent calcium channels are involved in ANGII-induced behavioral drinking implicating nitrergic mechanism. The antidipsogenic actions of l-type calcium channel antagonists nifedipine, on ANGII-induced drinking behavior were studied when it is injected into the median preoptic nucleus (MnPO). The influence of nitric oxide (NO) on nifedipine antidipsogenic action was also studied by utilizing the N^W-nitro-l-arginine methyl ester (l-NAME) a constitutive nitric oxide synthase inhibitor constitutive (cNOSI) and 7-nitroindazol (7-NIT) a specific neuronal nitric oxide synthase inhibitor (nNOSI) and l-arginine a NO donor. Rats 200–250 g, with cannulae implanted into MnPO, pre-treated into MnPO with either nifedipine, followed by ANGII, drank significantly less water than controls during the first 15 min after injection. However, l-NAME potentiated the dipsogenic effect of ANGII that is blocked by prior injection of nifedipine and l-arginine. 7-NIT injected prior to ANGII into MnPO also potentiated the dipsogenic effect of ANGII but with a less intensity than l-NAME that it is also blocked by prior injection of nifedipine. The results described in this paper provide evidence that calcium channels play important roles in the ANGII-induced behavioral water intake. The structures containing NO in the brain such as MnPO include both endothelial cells and neurons might be responsible for the influence of nifedipine on dipsogenic effect of ANGII. These data shows the correlation between l-type calcium channel and a free radical gas NO produced endogenously from amino acids l-arginine by endothelial and neuronal NO synthase in the control of ANGII-dipsogenic effect. This suggests that an l-type calcium channel participates in both short- and longer-term neuronal actions of ANGII by nitrergic way.
Interaction of central Ang II and NO on the cardiac sympathetic afferent reflex in dogs
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The aim of this study was to test the hypothesis that the central angiotensin II (Ang II) and nitric oxide (NO) systems interact to modulate the cardiac sympathetic afferent reflex (CSAR). All dogs were anesthetized with α-chloralose (100 mg/kg, iv). They were sino-aortic baroreceptor denervated and vagotomized throughout the experiment renal sympathetic nerve activity responses to cardiac sympathetic afferent stimulation and the central gain of the CSAR were measured. Three protocols were performed: (1) intracerebroventricular injection (icv, 3 μg/h or 6 μg/h) of Ang II with and without N^ω-nitro-l-arginine methyl ester (l-NAME) (icv, 1 mg/kg), (2) l-NAME (icv) with and without Ang II (icv, 6 μg/h), and (3) administration of the specific neural NO synthase (nNOS) inhibitor, S-Methyl-l-thiocitrulline (MeTC) (icv, 0.1 or 1 mM, 0.5 ml in 5 min) with and without pretreatment with the angiotensin type 1 receptor antagonist, losartan (icv, 0.125 mg/kg). The primary findings were (1) Ang II alone did not significantly affect the central sensitivity of the CSAR. However, Ang II with l-NAME enhanced this reflex, (2) even though l-NAME alone augmented the CSAR, this excitatory effect was further potentiated in the presence of Ang II and (3) MeTC significantly enhanced the central sensitivity of the CSAR. However, this enhancement did not occur after pretreatment with losartan. These data suggest that Ang II interacts with NO in the brain to modulate the CSAR and that inhibition of NO is required for facilitation of the CSAR by Ang II.
Lateral hypothalamus lesions influences water and salt intake, and sodium and urine excretion, and arterial blood pressure induced by L-NAME and FK 409 injections into median preoptic nucleus in conscious rats
2004, Life Sciences
Male Holtzman rats weighting 200–250 g were anesthetized with zoletil 50 mg/Kg (tiletamine chloridrate 125,0 mg and zolazepan chloridrate 125,0 mg) into quadriceps muscle and submitted an electrolytic lesion of the lateral hypothalamus (LH) and a stainless steel cannula was implanted into their median preoptic nucleus (MnPO). We investigated the effects of the injection into the (MnPO) of FK 409 (20 μg/0.5 μl), a nitric oxide (NO) donor, and N^W-nitro-L-arginine methyl ester (L-NAME) 40 μg/0.5 μl, a nitric oxide synthase inhibitor (NOSI), on the water and sodium appetite and the natriuretic, diuretic and cardiovascular effects induced by injection of L-NAME and FK 409 injected into MnPO in rats with LH lesions. Controls were injected with a similar volume of 0.15 M NaCl. L-NAME injected into MnPO produced an increase in water and sodium intake and in sodium and urine excretion and increase de mean arterial pressure (MAP). FK 409 injected into MnPO did not produce any change in the hydro electrolytic and cardiovascular parameters in LH-sham and lesioned rats. FK 409 injected before L-NAME attenuated its effects. These data show that electrolytic lesion of the LH reduces fluid and sodium intake as well as sodium and urine excretion, and the pressor effect induced by L-NAME. LH involvement with NO of the MnPO excitatory and inhibitory mechanisms related to water and sodium intake, sodium excretion and cardiovascular control is suggested.
Nitric oxide and angiotensin II: Neuromodulation of thermoregulation during combined heat and hypohydration stress
2004, Brain Research
Citation Excerpt :
Two neuromodulator candidates are nitric oxide (NO) and angiotensin II (AngII). Nitric oxide acts as a stimulatory agent to dehydration-induced drinking, hypovolemia, salt intake, and AngII activity [18,27,49]. Evidence that the neurons involved in the central control of body fluid homeostasis can use NO as a major neuromodulator has been reported [7].
We investigated the central role of nitric oxide and AngII on thermoregulation in rats (Rattus norvegicus, Sabra strain,) undergoing heat-stress in euhydration or hypohydration (water deprivation, −10% b.wgt). Experimental rats received AngII (100 pm), 7-nitroindazole—an antagonist of neuronal nitric oxide synthase (7NI—100 nm), or AngII+7NI in a 5-μl bolus intracerebroventricularly (i.c.v.) under light chloroform anesthesia; untreated control rats received saline or DMSO (5%). We used three experimental paradigms: (1) heat defense responses [salivation (STsh), vasodilatation (VTsh) temperature thresholds and heat-endurance] in conscious, heat-stressed (39 °C) rats; (2) Western immunoblotting to detect AngII AT₁ and AT₂ receptors and nNOS protein expression; (3) real-time PCR to measure gene transcripts. In the in vivo experiment, 7NI decreased thermoregulatory thresholds, namely, NO had a reciprocal effect that was more pronounced during hypohydration (e.g. euhydration: STsh: −0.7±0.01 °C, hypohydration: −0.9±0.18 °C, p<0.05). AngII decreased STsh by 0.9±0.18 °C (p<0.05) upon euhydration but increased it in hypohydration (+1.7±0.28 °C, p<0.05). A novel finding was the involvement of AT₂ receptors in thermoregulation, which was more pronounced upon hypohydration. The response to NO was mediated via AT₁ and AT₂ receptors signaling, as well as independently. A synthesis of the results from all experimental paradigms suggests (1) a dominant influence (decrease) of NO on AT₁ receptors, thereby changing AT₁/AT₂ receptor ratio and their signaling pathway; primarily upon hypohydration; (2) an influence of AngII (increase) on receptor density, more pronounced during hypohydration, at both gene transcription and translation levels; and (3) an effect of AngII on nNOS protein levels, implying a mutual effect of AngII and NO.

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Angiotensin II interacts with nitric oxide-cyclic GMP pathway in the central control of drinking behaviour: mapping with c-fos and NADPH-diaphorase

Abstract

Section snippets

Animals

Cannulation

Experiment 1: The inhibitory effects of L-NAME on water ingestion and the counter effects of l-arginine

Nitric oxide-cGMP pathway involvement in angiotensin II-induced drinking behaviour

Conclusion

Acknowledgements

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