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Nitric oxide and L-type calcium channel influences the changes in arterial blood pressure and heart rate induced by central angiotesin II

Nitric oxide and L-type calcium channel influences the changes in arterial blood pressure and... We study the voltage dependent calcium channels and nitric oxide involvement in angiotensin II- induced pressor effect. The antipressor action of L-Type calcium channel antagonist, nifedipine, has been studied when it was injected into the third ventricle prior to angiotensin II. The influence of nitric oxide on nifedipine antipressor action has also been studied by utilizing N -nitro-L-arginine methyl ester (LNAME) (40 µg/0.2 µl) a nitric oxide synthase inhibitor and L-arginine (20 µg/0.2 µl), a nitric oxide donor agent. Adult male Holtzman rats weighting 200–250 g, with cannulae implanted into the third ventricle were injected with angiotensin II. Angiotensin II produced an elevation in mean arterial pressure and a decreased in heart rate. Such effects were potentiated by the prior injection of LNAME. L-arginine and nifedipine blocked the effects of angiotensin II. These data showed the involvement of L-Type calcium channel and a free radical gas nitric oxide in the central control of angiotensin II-induced pressor effect. This suggested that L-Type calcium channel of the circunventricular structures of central nervous system participated in both short and long term neuronal actions of ANG II with the influence of nitrergic system. nel blocked agent) and nitrergic system of the circumven- Background Nitric oxide plays an important role in the hydromineral tricular third ventricle structures of the central nervous and cardiovascular regulation and influence several cen- system on the angiotensin II cardiovascular regulation has tral angiotensin physiological parameters [1,2]. LNAME not been demonstrated. increases blood pressure which is at least in part salt sen- sitive [3]. A major factor that detemined a neuronal cal- The subfornical organ is an important circumventricular cium-dependent signal is the opening of permeability structure of the central nervous system that participated in pathways for calcium in the cell membrane [4]. However, the regulation of body fluid homeostasis [5-7]. LNAME the interaction between nifedipine (L-Type calcium chan- significantly increased the discharge of neurons of the Page 1 of 6 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:22 http://www.behavioralandbrainfunctions.com/content/4/1/22 subfornical organ showing the importance of nitric oxide The results are reported as mean ± S.E.M. The Analysis of in the electrical activity of this structure [8]. FK 409 (a variance and Newman-Keuls post-hoc test were used to nitric oxide donor agent) injected into median preoptic determine the significance. The values were considered nucleus of conscious rats decreased mean arterial pressure statistically significant with 5% level (p < 0.05). [9]. Results Treatment of neonatal rats with monosodium glutamate At the end of the experiments, the rats were anesthetized induced a substantial reduction in the volume of the sub- with ether and perfused with saline and buffered forma- fornical organ and in the number of its nitrergic cells with lin. The brains were removed, fixed in 10% formalin, fro- regards to control animals [10]. These findings suggested zen to -25°C and cut into 20–30 µm coronal sections. that the subfornical organ could be implicated in some Only animals in which the injection was placed into the physiological functions such as salivary secretion and car- third ventricle were used in this study (figure 1). diovascular alterations observed in monosodium gluta- mate-treated rats. Effects of nifedipine and L-arginine on the mean arterial pressure and heart rate induced by the injection of The objective of this study was to determined the role of angiotensin II into the third ventricle Figure 2, 3 voltage-sensitive calcium channels in angiotensin II- Microinjections of angiotensin II into the third ventricle induced pressor response when it was injected into the induced increase in means arterial pressure compared to third ventricle of conscious rats. We also studied the influ- control (∆18 ± 2 vs. control ∆4 ± 1 mmHg p < 0.05) and ence of a nitric oxide on the nifedipine effect. decreased heart rate compared to control ∆-70 ± 16 vs. 21 ± 9 bpm p < 0.05). The microinjection of saline+nifed- Methods ipine into the third ventricle caused no change in the The Medical Ethics Committee of the Universidade Estad- mean arterial pressure (∆3.5 ± 1 mmHg) and heart rate ual Paulista UNESP approved all protocols in this study. (∆20 ± 9 bpm). Nifedipine 50 µg injected into the third ventricle followed by angiotensin II decreased the pressor Male Holtzman rats weighing 250–300 g were anesthe- effect (∆11 ± 1 mmHg p < 0.01) with a decreased in heart tized with ketamine (80 mg/Kg of body weight) plus xyla- rate ∆-10 ± 2 bpm p < 0.01). Nifedipine 100 µg injected zine (7 mg/Kg of body weight). A stainless steel cannula into the third ventricle followed by angiotensin II blocked with 10 and 12-mm long and 0.7-mm OD was implanted angiotensin II-pressor effect (5 ± 1 mmHg p < 0.01) and rd into the 3 V according to the coordinates of Paxinos and no changes in heart rate was observed (∆23 ± 9 bpm). The Watson atlas rat brain [11]. injection of L-arginine also blocked the pressor effect of angiotensin II (∆4 ± 1 mmHg p < 0.01) no alterations in After the animals recovery from brain surgery (5 days) PE- heart rate was observed (∆19 ± 8 bpm). No alterations in 10 polyethylene tubing connected to PE-50 tubing was mean arterial pressure and in heart rat was observed when inserted into the abdominal aorta through the femoral L-arginine was injected alone into the third ventricle (F artery. Direct mean arterial pressure and heart rate was (6,64) = 63.4, p < 0.01) and (F (6,64) = 63.4, p < 0.01) record in unaesthetized and unrestrained rats. The ani- respectively. mals were removed from their home cages and placed in Effects of nifedipine and LNAME on the mean arterial test cages, without access to food or water. The previously implanted catheter was connected to a Statham (P23 Db) pressure and heart rate induced by the injection of pressure transducer (Statham-Gould, Valley View, OH) angiotensin II into the third ventricle Figure 4, 5 coupled to a multi channel recorded (PowerLab Multi- Angiotensin II injected into the third ventricle increased record). This program permits the acquisition of cardio- mean arterial pressure and decreased heart rate. Nifed- vascular data by computer. In these experiments the rats ipine injected prior to angiotensin II decreased mean arte- were chosen at random. Each animal was used no more rial pressure without changes in heart rate (F (4,38) = 81.3 than tree times. P < 0.01) and F (4,38) = 78.3 P < 0.01 respectively. The increased of mean arterial pressure induced by angi- The drugs were injected into the third ventricle by using a otensin II (∆17 ± 1 mmHg) was potentiated by L-NAME Hamilton micro syringe (5 µl) connected by a PE-10 pol- (25 ± 2 mmHg p < 0.01) with decreased in heart rate (∆- yethylene tubing (25 cm) to a needle (0.3 mm o. d.), 60 ± 6 vs. -80 ± 10 bpm p < 0.05). Rats injected with nifed- which was introduced into the brain through the cannula ipine 100 µg prior to L-NAME followed by angiotensin II previously fixed to the animals' head. decreased the mean arterial presure (7 ± 2 mmHg p < 0.01) no alterations in heart rate was ovserved (20 ± 1 Mean arterial pressure and heart rate were record in con- bpm) (F (4,38) = 81.3 P < 0.01) and F (4,38) = 78.3 P < scious rats in a test cage, without access to food or water. 0.01 respectively. Page 2 of 6 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:22 http://www.behavioralandbrainfunctions.com/content/4/1/22 opvserved. The injection of nifedipine combined with L- NAME, which were injected prior to angiotensin II into the third ventricle, blocked the potentiation effect of L- NAME. It has been demonstrated that injection of L- NAME into the median proptic area increased the mean arterial pressure [12]. The treatment with L-NAME increased arterial blood pres- sure, which is at least in part salt sensitive. The action of L- NAME also may be due to a local vasoconstriction. Fur- thermore, the salt-sensitive component appears to be angiotensin II-dependent, as it was associated with increase of plasma angiotensin II levels and could be reversed by the treatment with angiotensin II receptor antagonist [3]. rd Figure 1 Photom the cannula into th icrograph of th e 3 e b V ( ra ain showing rrow) the place reached by These data, suggest that structures surrounding cerebral Photomicrograph of the brain showing the place reached by ventricles may release angiotensin II which acts as a neu- rd the cannula into the 3 V (arrow). rotransmitter resulted in postsynaptic effects, which in turn influenced blood pressure and heart rate control. Angiotensinergic neural pathways and calcium channels Discussion are important in neural function and may have important In these experiments microinjections of angiotensin II homeostatic roles, particularly related to cardiovascular into the third ventricle increased mean arterial pressure function by involved nitric oxide. It has been demon- and decreased heart rate. which were blocked by nifed- strated that niric oxide antagonized the vasoconstrictive ipine and potentiated by L-NAME. The microinjection of and pro-atherosclerotic effects of angiotensin II whereas L-arginine into third ventricle decreased the pressor effect angiotensin II decreased nitric oxide bioavailability by of angiotensin II no alterations in heart rate was promoting oxidative stress. E Figure 2 ffect of nifedipine and L-arginine on mean arterial pressure induced by the injection of angiotensin II into the third ventricle Effect of nifedipine and L-arginine on mean arterial pressure induced by the injection of angiotensin II into the third ventricle. Number of animals at the top of each column. Data are means ± S.E.M. *p < 0.05 vs.saline+saline, P < 0.05 vs. saline+angi- otensin II (Neuman-Keuls post-hoc test). Page 3 of 6 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:22 http://www.behavioralandbrainfunctions.com/content/4/1/22 E Figure 3 ffect of nifedipine and L-arginine on heart rate induced by the injection of angiotensin II into the third ventricle Effect of nifedipine and L-arginine on heart rate induced by the injection of angiotensin II into the third ventricle. Number of animals at the top of each column. Data are means ± S.E.M. *p < 0.05 vs.saline+saline, P < 0.05 vs. saline+angiotensin II (Neu- man-Keuls post-hoc test). Figure 4 Effects of nifedipine and LNAME on the mean arterial pressure induced by the injection of angiotensin II into the third ventricle Effects of nifedipine and LNAME on the mean arterial pressure induced by the injection of angiotensin II into the third ventricle. Number of animals at the top of each column. Data are means ± S.E.M. *P < 0.05 vs. saline+saline, P < 0.05 vs. saline+angi- otensin II and P < 0.05 vs. LNAME+angiotensin II (Neuman-Keuls post-hoc test). Page 4 of 6 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:22 http://www.behavioralandbrainfunctions.com/content/4/1/22 Figure 5 Effects of nifedipine and LNAME on heart rate induced by the injection of angiotensin II into the third ventricle Effects of nifedipine and LNAME on heart rate induced by the injection of angiotensin II into the third ventricle. Number of ani- + O mals at the top of each column. Data are means ± S.E.M. *P < 0.05 vs. saline+saline, P < 0.05 vs. saline+angiotensin II and P < 0.05 vs. LNAME+angiotensin II (Neuman-Keuls post-hoc test). By the results of the present study we can suggested that explained these results. Finally we demonstrated that nifedipine may have interfered with calcium influx in the angiotensin II utilized the calcium channel and nitric presynaptic terminals, where L-type calcium channels oxide to exerced the central regulation of arterial blood play important roles in modulated presynaptic neuro- and heart rate. These results provide support to future 2+ transmitter release. It may also have altered Ca -depend- studies that involved specific circumventricular structures. ent signal events in postsynaptic neurons since previous studies demonstrated the permissive effects of voltage sen- List of abreviations sitive calcium channels on monosodium glutamate- SAL: saline; ANGII: angiotensin II; LAR: L-arginine; NIF: treated rats receptor-mediated calcium influx. In most nifedipine; L-NAME: L-NAME neurons of the central nervous system, there are at least two major classes of calcium channel: voltage sensitive Competing interests and receptor-operated calcium channels. Ours results are The authors declare that they have no competing interests. strongly supported by the results of others that demon- strated the hypertensive effect of angiotensin II signifi- Authors' contributions cantly enhanced by prior microinjection of LNAME into WAS made substantial contributions to conception and paraventricular nucleus this showed that the effect of angi- design, or acquisition of data otensin II in arterial blood pressure interact with nitric oxide [13-16]. IFMSG analyzed the data and have been involved in draft- ing the manuscript Conclusion The main find of these experiments is that nifedipine with LAAC revised and made critically for important intellec- or without L-NAME blocked the effect of angiotensin II on tual content arterial blood pressure and heart rate. We can explained that the pressor effect of angiotensin II injected into third TAFBS made the figures and performed the statistical anal- ventricle acted into the circumventricular structures and ysis utilized L-Type calcium channel to exerted it effects. The nitric oxide also participated in angiotensin II effect. The Acknowledgements The authors greatly appreciate the assistance of Luciana Rizuti Saad for influence of L-Type calcium channel and nitric oxide uti- preparation of the manuscript, and Ana V. Oliveira and Fernando L. Capelli lizing cGMP pathways on angiotensin II pressor effect for animal care. Research supported by CNPq (520408/96.9), FAPESP (99/ Page 5 of 6 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:22 http://www.behavioralandbrainfunctions.com/content/4/1/22 06582-2 and 02/03806-1), FUNDUNESP (01/06756-3), PRONEX and FUNADESP-UNIARA. References 1. Saad WA, Guarda IFMS, Guarda RS, Camargo LAA, Santos TAFB, Saad WA, Simões S: Role of nitric oxide and beta receptors of the central nervous system on the salivary flow induced by pilocarpine injection into the lateral ventricle. Pharmacol Bio- chem Behav 2002, 72(1-2):229-235. 2. WA Saad WA, LAA Camargo LAA, IFSM Guarda IFMS, TAFB Santos TAFB, Guarda RS, Saad WA, Simões S, Antunes Rodrigues J: Role of nitric oxide of the median preoptic nucleus (MnPO) in the alterations of salivary flow, arterial pressure and heart rate induced by injection of pilocarpine into the MnPO and intrperitoneally. Braz J Med Biol Res 2003, 36:897-905. 3. Hodge G, Ye VZ, Duggan KA: Salt-sensitive hypertension result- ing from nitric oxide synthase inhibition is associated with loss of regulation of angiotensin II in the rat. Exp Physiol 2002, 87:1-8. 4. Tsien RW, Lipscombe V, Madison DV, Bley KR, Fox AP: Multiple types of neuronal calcium channels and their selective mod- ulation. Trends Neurosci 1988, 11:431-438. 5. Mangiapane ML, Simpson JB: Subfornical organ: forebrain site of pressor and dipsogenic action of angiotensin II. Am J Physiol 1980, 239:R382-R389. 6. Thunhorst RL, Erlich KJ, Simpson JB: Subfornical organ partici- pates in salt appetite. Behav Neurosci 1990, 104:637-642. 7. Yang H, Lu D, Raizafa MK: Lack of cross talk between α - adren- ergic and angiotensin type 1 receptors in neurons of sponta- neous hypertensive rats. Hypertension 1996, 27:1277-1283. 8. Li M, Wang QS, Chen Y, Wang ZM, Lui Z, Guo SM: Resveratrol inhibits the electrical activity of subfornical organ neurons in rat. Sheng Li Xue Bao 2005, 57(4):523-528. 9. Saad WA, Gutierrez LI, Guarda IFSM, Camargo LAA, Santos TAFB, Saad WA, Simões Silvio, Guarda RS: Lateral hypothalamus lesions influences water and salt intake, and sodium and urine excretion, arterial blood pressure induced by L-NAME and FK 409 injections into median preoptic nucleus in con- scious rats. Life Sci 2004, 75:685-697. 10. Pesini P, Rois JL, Menendez L, Vidal S: The neonatal treatment of rats with monosodium glutamate induces morphological changes in the subfornical organ. Anat Histol Embryol 2004, 33:273-277. 11. Paxinos G, Watson C: The rat brain in stereotaxic coordinates. New York: Academic Press; 1986. 12. Saad WA, Gutierrez LI, Guarda IFMS, Camargo LAA, Santos TAFB, Saad WA, Simões S, Guarda RS: Lateral hypothalamus lesions influences water and salt intake, and sodium and urine excretion, arterial blood pressure induced by L-NAME and FK 409 injections into median preoptic nucleus in conscious rats. Life Sci 2004, 75:685-697. 13. Saad WA, Camargo LAA, Rodrigues JA, Saad WA, Guarda IFMS, Guarda RS: Interaction between arginine vasopressin and angiotensin II receptors in the central Nervous system in the regulation of sodium balance. Regul Pept 2005, 132(1-3):53-58. 14. Saad WA, Camargo LAA, Guarda IFMS, Saad WA: l-type calcium channel mediate water intake induced by angiotensin injec- tion into median preoptic nucleus. Pharmacol Biochem Behav 2006, 83(4):598-602. 15. Saad WA, Camargo LAA, Guarda IFMS, Saad WA: Functional rela- Publish with Bio Med Central and every tionship between subfornical organ cholinergic stimulation scientist can read your work free of charge and nitrergic activation influencing cardiovascular and body fluid homeostasis. Regul Pept 2007, 143(1-3):28-33. "BioMed Central will be the most significant development for 16. Li YF, Wang W, Mayhan WG, Patel KP: Angiotensin-mediated disseminating the results of biomedical researc h in our lifetime." increase in renal sympathetic nerve discharge within the Sir Paul Nurse, Cancer Research UK PVN: role of nitric oxide. Am J Physiol Regul Integr Comp Physiol 2006, 290(4):R1035-R1043. Your research papers will be: available free of charge to the entire biomedical community peer reviewed and published immediately upon acceptance cited in PubMed and archived on PubMed Central yours — you keep the copyright BioMedcentral Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 6 of 6 (page number not for citation purposes) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Behavioral and Brain Functions Springer Journals

Nitric oxide and L-type calcium channel influences the changes in arterial blood pressure and heart rate induced by central angiotesin II

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Springer Journals
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Copyright © 2008 by Saad et al; licensee BioMed Central Ltd.
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Biomedicine; Neurosciences; Neurology; Behavioral Therapy; Psychiatry
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Abstract

We study the voltage dependent calcium channels and nitric oxide involvement in angiotensin II- induced pressor effect. The antipressor action of L-Type calcium channel antagonist, nifedipine, has been studied when it was injected into the third ventricle prior to angiotensin II. The influence of nitric oxide on nifedipine antipressor action has also been studied by utilizing N -nitro-L-arginine methyl ester (LNAME) (40 µg/0.2 µl) a nitric oxide synthase inhibitor and L-arginine (20 µg/0.2 µl), a nitric oxide donor agent. Adult male Holtzman rats weighting 200–250 g, with cannulae implanted into the third ventricle were injected with angiotensin II. Angiotensin II produced an elevation in mean arterial pressure and a decreased in heart rate. Such effects were potentiated by the prior injection of LNAME. L-arginine and nifedipine blocked the effects of angiotensin II. These data showed the involvement of L-Type calcium channel and a free radical gas nitric oxide in the central control of angiotensin II-induced pressor effect. This suggested that L-Type calcium channel of the circunventricular structures of central nervous system participated in both short and long term neuronal actions of ANG II with the influence of nitrergic system. nel blocked agent) and nitrergic system of the circumven- Background Nitric oxide plays an important role in the hydromineral tricular third ventricle structures of the central nervous and cardiovascular regulation and influence several cen- system on the angiotensin II cardiovascular regulation has tral angiotensin physiological parameters [1,2]. LNAME not been demonstrated. increases blood pressure which is at least in part salt sen- sitive [3]. A major factor that detemined a neuronal cal- The subfornical organ is an important circumventricular cium-dependent signal is the opening of permeability structure of the central nervous system that participated in pathways for calcium in the cell membrane [4]. However, the regulation of body fluid homeostasis [5-7]. LNAME the interaction between nifedipine (L-Type calcium chan- significantly increased the discharge of neurons of the Page 1 of 6 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:22 http://www.behavioralandbrainfunctions.com/content/4/1/22 subfornical organ showing the importance of nitric oxide The results are reported as mean ± S.E.M. The Analysis of in the electrical activity of this structure [8]. FK 409 (a variance and Newman-Keuls post-hoc test were used to nitric oxide donor agent) injected into median preoptic determine the significance. The values were considered nucleus of conscious rats decreased mean arterial pressure statistically significant with 5% level (p < 0.05). [9]. Results Treatment of neonatal rats with monosodium glutamate At the end of the experiments, the rats were anesthetized induced a substantial reduction in the volume of the sub- with ether and perfused with saline and buffered forma- fornical organ and in the number of its nitrergic cells with lin. The brains were removed, fixed in 10% formalin, fro- regards to control animals [10]. These findings suggested zen to -25°C and cut into 20–30 µm coronal sections. that the subfornical organ could be implicated in some Only animals in which the injection was placed into the physiological functions such as salivary secretion and car- third ventricle were used in this study (figure 1). diovascular alterations observed in monosodium gluta- mate-treated rats. Effects of nifedipine and L-arginine on the mean arterial pressure and heart rate induced by the injection of The objective of this study was to determined the role of angiotensin II into the third ventricle Figure 2, 3 voltage-sensitive calcium channels in angiotensin II- Microinjections of angiotensin II into the third ventricle induced pressor response when it was injected into the induced increase in means arterial pressure compared to third ventricle of conscious rats. We also studied the influ- control (∆18 ± 2 vs. control ∆4 ± 1 mmHg p < 0.05) and ence of a nitric oxide on the nifedipine effect. decreased heart rate compared to control ∆-70 ± 16 vs. 21 ± 9 bpm p < 0.05). The microinjection of saline+nifed- Methods ipine into the third ventricle caused no change in the The Medical Ethics Committee of the Universidade Estad- mean arterial pressure (∆3.5 ± 1 mmHg) and heart rate ual Paulista UNESP approved all protocols in this study. (∆20 ± 9 bpm). Nifedipine 50 µg injected into the third ventricle followed by angiotensin II decreased the pressor Male Holtzman rats weighing 250–300 g were anesthe- effect (∆11 ± 1 mmHg p < 0.01) with a decreased in heart tized with ketamine (80 mg/Kg of body weight) plus xyla- rate ∆-10 ± 2 bpm p < 0.01). Nifedipine 100 µg injected zine (7 mg/Kg of body weight). A stainless steel cannula into the third ventricle followed by angiotensin II blocked with 10 and 12-mm long and 0.7-mm OD was implanted angiotensin II-pressor effect (5 ± 1 mmHg p < 0.01) and rd into the 3 V according to the coordinates of Paxinos and no changes in heart rate was observed (∆23 ± 9 bpm). The Watson atlas rat brain [11]. injection of L-arginine also blocked the pressor effect of angiotensin II (∆4 ± 1 mmHg p < 0.01) no alterations in After the animals recovery from brain surgery (5 days) PE- heart rate was observed (∆19 ± 8 bpm). No alterations in 10 polyethylene tubing connected to PE-50 tubing was mean arterial pressure and in heart rat was observed when inserted into the abdominal aorta through the femoral L-arginine was injected alone into the third ventricle (F artery. Direct mean arterial pressure and heart rate was (6,64) = 63.4, p < 0.01) and (F (6,64) = 63.4, p < 0.01) record in unaesthetized and unrestrained rats. The ani- respectively. mals were removed from their home cages and placed in Effects of nifedipine and LNAME on the mean arterial test cages, without access to food or water. The previously implanted catheter was connected to a Statham (P23 Db) pressure and heart rate induced by the injection of pressure transducer (Statham-Gould, Valley View, OH) angiotensin II into the third ventricle Figure 4, 5 coupled to a multi channel recorded (PowerLab Multi- Angiotensin II injected into the third ventricle increased record). This program permits the acquisition of cardio- mean arterial pressure and decreased heart rate. Nifed- vascular data by computer. In these experiments the rats ipine injected prior to angiotensin II decreased mean arte- were chosen at random. Each animal was used no more rial pressure without changes in heart rate (F (4,38) = 81.3 than tree times. P < 0.01) and F (4,38) = 78.3 P < 0.01 respectively. The increased of mean arterial pressure induced by angi- The drugs were injected into the third ventricle by using a otensin II (∆17 ± 1 mmHg) was potentiated by L-NAME Hamilton micro syringe (5 µl) connected by a PE-10 pol- (25 ± 2 mmHg p < 0.01) with decreased in heart rate (∆- yethylene tubing (25 cm) to a needle (0.3 mm o. d.), 60 ± 6 vs. -80 ± 10 bpm p < 0.05). Rats injected with nifed- which was introduced into the brain through the cannula ipine 100 µg prior to L-NAME followed by angiotensin II previously fixed to the animals' head. decreased the mean arterial presure (7 ± 2 mmHg p < 0.01) no alterations in heart rate was ovserved (20 ± 1 Mean arterial pressure and heart rate were record in con- bpm) (F (4,38) = 81.3 P < 0.01) and F (4,38) = 78.3 P < scious rats in a test cage, without access to food or water. 0.01 respectively. Page 2 of 6 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:22 http://www.behavioralandbrainfunctions.com/content/4/1/22 opvserved. The injection of nifedipine combined with L- NAME, which were injected prior to angiotensin II into the third ventricle, blocked the potentiation effect of L- NAME. It has been demonstrated that injection of L- NAME into the median proptic area increased the mean arterial pressure [12]. The treatment with L-NAME increased arterial blood pres- sure, which is at least in part salt sensitive. The action of L- NAME also may be due to a local vasoconstriction. Fur- thermore, the salt-sensitive component appears to be angiotensin II-dependent, as it was associated with increase of plasma angiotensin II levels and could be reversed by the treatment with angiotensin II receptor antagonist [3]. rd Figure 1 Photom the cannula into th icrograph of th e 3 e b V ( ra ain showing rrow) the place reached by These data, suggest that structures surrounding cerebral Photomicrograph of the brain showing the place reached by ventricles may release angiotensin II which acts as a neu- rd the cannula into the 3 V (arrow). rotransmitter resulted in postsynaptic effects, which in turn influenced blood pressure and heart rate control. Angiotensinergic neural pathways and calcium channels Discussion are important in neural function and may have important In these experiments microinjections of angiotensin II homeostatic roles, particularly related to cardiovascular into the third ventricle increased mean arterial pressure function by involved nitric oxide. It has been demon- and decreased heart rate. which were blocked by nifed- strated that niric oxide antagonized the vasoconstrictive ipine and potentiated by L-NAME. The microinjection of and pro-atherosclerotic effects of angiotensin II whereas L-arginine into third ventricle decreased the pressor effect angiotensin II decreased nitric oxide bioavailability by of angiotensin II no alterations in heart rate was promoting oxidative stress. E Figure 2 ffect of nifedipine and L-arginine on mean arterial pressure induced by the injection of angiotensin II into the third ventricle Effect of nifedipine and L-arginine on mean arterial pressure induced by the injection of angiotensin II into the third ventricle. Number of animals at the top of each column. Data are means ± S.E.M. *p < 0.05 vs.saline+saline, P < 0.05 vs. saline+angi- otensin II (Neuman-Keuls post-hoc test). Page 3 of 6 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:22 http://www.behavioralandbrainfunctions.com/content/4/1/22 E Figure 3 ffect of nifedipine and L-arginine on heart rate induced by the injection of angiotensin II into the third ventricle Effect of nifedipine and L-arginine on heart rate induced by the injection of angiotensin II into the third ventricle. Number of animals at the top of each column. Data are means ± S.E.M. *p < 0.05 vs.saline+saline, P < 0.05 vs. saline+angiotensin II (Neu- man-Keuls post-hoc test). Figure 4 Effects of nifedipine and LNAME on the mean arterial pressure induced by the injection of angiotensin II into the third ventricle Effects of nifedipine and LNAME on the mean arterial pressure induced by the injection of angiotensin II into the third ventricle. Number of animals at the top of each column. Data are means ± S.E.M. *P < 0.05 vs. saline+saline, P < 0.05 vs. saline+angi- otensin II and P < 0.05 vs. LNAME+angiotensin II (Neuman-Keuls post-hoc test). Page 4 of 6 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:22 http://www.behavioralandbrainfunctions.com/content/4/1/22 Figure 5 Effects of nifedipine and LNAME on heart rate induced by the injection of angiotensin II into the third ventricle Effects of nifedipine and LNAME on heart rate induced by the injection of angiotensin II into the third ventricle. Number of ani- + O mals at the top of each column. Data are means ± S.E.M. *P < 0.05 vs. saline+saline, P < 0.05 vs. saline+angiotensin II and P < 0.05 vs. LNAME+angiotensin II (Neuman-Keuls post-hoc test). By the results of the present study we can suggested that explained these results. Finally we demonstrated that nifedipine may have interfered with calcium influx in the angiotensin II utilized the calcium channel and nitric presynaptic terminals, where L-type calcium channels oxide to exerced the central regulation of arterial blood play important roles in modulated presynaptic neuro- and heart rate. These results provide support to future 2+ transmitter release. It may also have altered Ca -depend- studies that involved specific circumventricular structures. ent signal events in postsynaptic neurons since previous studies demonstrated the permissive effects of voltage sen- List of abreviations sitive calcium channels on monosodium glutamate- SAL: saline; ANGII: angiotensin II; LAR: L-arginine; NIF: treated rats receptor-mediated calcium influx. In most nifedipine; L-NAME: L-NAME neurons of the central nervous system, there are at least two major classes of calcium channel: voltage sensitive Competing interests and receptor-operated calcium channels. Ours results are The authors declare that they have no competing interests. strongly supported by the results of others that demon- strated the hypertensive effect of angiotensin II signifi- Authors' contributions cantly enhanced by prior microinjection of LNAME into WAS made substantial contributions to conception and paraventricular nucleus this showed that the effect of angi- design, or acquisition of data otensin II in arterial blood pressure interact with nitric oxide [13-16]. IFMSG analyzed the data and have been involved in draft- ing the manuscript Conclusion The main find of these experiments is that nifedipine with LAAC revised and made critically for important intellec- or without L-NAME blocked the effect of angiotensin II on tual content arterial blood pressure and heart rate. We can explained that the pressor effect of angiotensin II injected into third TAFBS made the figures and performed the statistical anal- ventricle acted into the circumventricular structures and ysis utilized L-Type calcium channel to exerted it effects. The nitric oxide also participated in angiotensin II effect. The Acknowledgements The authors greatly appreciate the assistance of Luciana Rizuti Saad for influence of L-Type calcium channel and nitric oxide uti- preparation of the manuscript, and Ana V. Oliveira and Fernando L. Capelli lizing cGMP pathways on angiotensin II pressor effect for animal care. Research supported by CNPq (520408/96.9), FAPESP (99/ Page 5 of 6 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:22 http://www.behavioralandbrainfunctions.com/content/4/1/22 06582-2 and 02/03806-1), FUNDUNESP (01/06756-3), PRONEX and FUNADESP-UNIARA. References 1. 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Trends Neurosci 1988, 11:431-438. 5. Mangiapane ML, Simpson JB: Subfornical organ: forebrain site of pressor and dipsogenic action of angiotensin II. Am J Physiol 1980, 239:R382-R389. 6. Thunhorst RL, Erlich KJ, Simpson JB: Subfornical organ partici- pates in salt appetite. Behav Neurosci 1990, 104:637-642. 7. Yang H, Lu D, Raizafa MK: Lack of cross talk between α - adren- ergic and angiotensin type 1 receptors in neurons of sponta- neous hypertensive rats. Hypertension 1996, 27:1277-1283. 8. Li M, Wang QS, Chen Y, Wang ZM, Lui Z, Guo SM: Resveratrol inhibits the electrical activity of subfornical organ neurons in rat. Sheng Li Xue Bao 2005, 57(4):523-528. 9. Saad WA, Gutierrez LI, Guarda IFSM, Camargo LAA, Santos TAFB, Saad WA, Simões Silvio, Guarda RS: Lateral hypothalamus lesions influences water and salt intake, and sodium and urine excretion, arterial blood pressure induced by L-NAME and FK 409 injections into median preoptic nucleus in con- scious rats. 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Saad WA, Camargo LAA, Guarda IFMS, Saad WA: l-type calcium channel mediate water intake induced by angiotensin injec- tion into median preoptic nucleus. Pharmacol Biochem Behav 2006, 83(4):598-602. 15. Saad WA, Camargo LAA, Guarda IFMS, Saad WA: Functional rela- Publish with Bio Med Central and every tionship between subfornical organ cholinergic stimulation scientist can read your work free of charge and nitrergic activation influencing cardiovascular and body fluid homeostasis. Regul Pept 2007, 143(1-3):28-33. "BioMed Central will be the most significant development for 16. Li YF, Wang W, Mayhan WG, Patel KP: Angiotensin-mediated disseminating the results of biomedical researc h in our lifetime." increase in renal sympathetic nerve discharge within the Sir Paul Nurse, Cancer Research UK PVN: role of nitric oxide. Am J Physiol Regul Integr Comp Physiol 2006, 290(4):R1035-R1043. 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