Effect of the cholinergic system of the lateral periaqueductal gray (lPAG) on blood pressure and heart rate in normal and hydralazine hypotensive rats.

Objectives: Due to the presence of the cholinergic system in the lateral periaqueductal gray (lPAG) column, the cardiovascular effects of acetylcholine (ACH) and its receptors in normotensive and hydralazine (HYD) hypotensive rats in this area were evaluated. Materials and Methods: After anesthesia, the femoral artery was cannulated and systolic blood pressure (SBP), mean arterial pressure (MAP), heart rate (HR), and also electrocardiogram for evaluation of low frequency (LF) and high frequency (HF) bands, important components of heart rate variability (HRV), were recorded. ACH, atropine (Atr, a muscarinic antagonist), and hexamethonium (Hex, an antagonist nicotinic) alone and together microinjected into lPAG, changes (Δ) of cardiovascular responses and normalized (n) LF, HF, and LF/HF ratio were analyzed. Results: In normotensive rats, ACH decreased SBP and MAP, and enhanced HR while Atr and Hex did had no effects. In co-injection of Atr and Hex with ACH, only ACH+Atr significantly attenuated parameters. In HYD hypotension, ACH had no affect but Atr and Hex significantly improved the hypotensive effect. Co-injection of Atr and Hex with ACH decreased the hypotensive effect but the effect of Atr+ACH was higher. In normotensive rats, ACH decreased nLF, nHF, and nLF/nHF ratio. These parameters in the Atr +ACH group were significantly higher than in ACH group. In HYD hypotension nLF and nLF/nHF ratio increased which was attenuated by ACH. Also, Atr+ACH decreased nLF and nLF/nHF ratio and increased nHF. Conclusion: The cholinergic system of lPAG mainly via muscarinic receptors has an inhibitory effect on the cardiovascular system. Based on HRV assessment, peripheral cardiovascular effects are mostly mediated by the parasympathetic system.

The role of nitric oxide in the dorsomedial periaqueductal gray (dmPAG) column in cardiovascular responses in urethane-anesthetized male rats.

BACKGROUND: The dorsomedial periaqueductal gray (dmPAG) is a mesencephalic area and has numerous functions including cardiovascular regulation. Because nitric oxide (NO) is present in the dmPAG, here we investigate, the probable cardiovascular effect of NO in the dmPAG. METHODS: Five groups (n = 6 for each group) were used as follows: (1) control; (2) L-NAME (NG -nitro-L-arginine methyl ester, a NO synthase inhibitor, 90 nmol); (3) L-arginine (L-Arg, a precursor for NO, 60 nmol); (4) Sodium nitroprusside (SNP, a NO donor, 27 nmol); and (5) L-Arg + L-NAME. The cardiovascular parameters were recorded by a Power Lab device after cannulation of the femoral artery. Drugs were injected using a stereotaxic instrument. The changes (∆) in systolic blood pressure (SBP), mean arterial pressure (MAP), and heart rate (HR) were calculated at different times and compared to the control group. RESULTS: Microinjection of L-NAME significantly increased ∆SBP, ∆MAP, and ∆HR more than saline (from p < 0.05 to p < 0.001). L-Arg only significantly increased ∆HR (p < 0.05). In the L-Arg + L-NAME group, the above parameters also significantly increased (from p < 0.01 to p < 0.05) but not as significantly as with L-NAME alone. Microinjection of SNP significantly decreased ∆SBP and ∆MAP more than in the control and L-NAME groups (from p < 0.01 to p < 0.001), but ∆HR did not change significantly. CONCLUSION: The results indicated that NO in dmPAG has an inhibitory effect on cardiovascular responses in anesthetized rats.

Cardiovascular Effect of Dorsal Periaqueductal Gray During Lipopolysaccharide-induced Hypotension.

Introduction: The central mechanism related to the cardiovascular response to lipopolysaccharide (LPS)-induced hypotension is not entirely known, but it is suggested that numerous brain areas such as dorsal periaqueductal gray (dPAG) are involved in this process. In the current work, the cardiovascular effect of the dPAG during LPS-induced hypotension is investigated. Methods: The study animals (rats) were divided into four groups: control (saline microinjected into dPAG), lidocaine 2%, LPS (intravenously injected), and lidocaine + LPS. Catheterization of the femoral artery and vein was performed to record blood pressure and LPS injection, respectively. Saline and lidocaine were microinjected into the dPAG nucleus then the LPS injection was performed. The changes (Δ) in systolic blood pressure (SBP), mean arterial pressure (MAP), and heart rate (HR) were measured and compared with those of the control and LPS groups. Results: LPS significantly declined ΔMAP and ΔSBP (P<0.05) but did not change the ΔHR compared to the control. Lidocaine did not significantly affect basic ΔSBP, ΔMAP, and ΔHR compared to the control. Injection of lidocaine before LPS significantly attenuated the reduction of ΔSBP and ΔMAP evoked by LPS (P<0.05). Conclusion: Our data showed that blockade of the dPAG by lidocaine significantly ameliorates the hypotension induced by LPS. this finding confirms the involvement of the dPAG in cardiovascular regulation during LPS-induced hypotension. Highlights: Inactivation of the dPAG by lidocaine significantly ameliorates cardiovascular responses in hypotensive rats.LPS significantly lowers blood pressure and does not affect the heart rate. Plain Language Summary: The mechanism of hypotension induced by endotoxin is not yet clear. However, it is often attributed to the direct effect of lipopolysaccharide (LPS) as a component of the outer wall of Gram-negative bacteria and other vascular mediators, including tumor necrosis factor (TNF) and nitric oxide (NO). One possibility is that the initial drop in LPS-induced arterial hypertension is mediated by a central mechanism. The ventral region of the transcranial gray matter is involved in lowering blood pressure, and the dorsal region is involved in increasing blood pressure. The dorsolateral region of the transcranial gray matter (dlPAG) also causes tachycardia, vasodilation in muscles, and tachypnea. dlPAG contains cells that produce NO and serotonin (5HT) and 5HT1 and 5HT2 receptors, which may play a role in hypotension due to stimulation of this region. LPS (1 mg/kg or higher IV) typically elicits a biphasic hypotensive response in rats. The first stage of this response begins immediately after LPS injection. The second phase begins about 1 hour after LPS injection. Thus, endotoxic hypertension begins through a central mechanism and further suggests that hypotension may play a critical role in developing fatal hypotension, representing the second stage of septic shock. Although dlPAG is an important site for regulating cardiovascular responses, its role in hypotension induced by LPS has not been investigated. We investigated the role of this nucleus in cardiovascular changes after LPS injection.

Effect of the Non-N-Methyl-D-aspartate Receptor of the Glutamatergic System of the Pedunculopontine Tegmental Nucleus on Cardiovascular Responses in Normotensive and Hydralazine-Induced Hypotensive Rats.

Background: Glutamate is an important excitatory neurotransmitter in the pedunculopontine tegmental (PPT) nucleus. The cardiovascular effect of glutamate and its non-N-methyl-D-aspartate (NMDA) receptor in the PPT is unknown; therefore, we evaluated glutamate and its non-NMDA receptor on cardiovascular parameters in normotensive and hypotensive induced by hydralazine (HLZ) in rat. Materials and Methods: After anesthesia, the femoral artery was cannulated for recording of cardiovascular parameters. Microinjection of drugs was done stereotaxically. L-Glutamate (L-Glu) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (an antagonist of nonNMDA receptor) were microinjected into the PPT in normotensive and HLZ hypotensive rats. Changes (Δ) of mean arterial pressure (MAP), systolic blood pressure (SBP), and heart rate (HR) were obtained and compared with the control group. Results: In normotensive rats, L-Glu significantly increased SBP and MAP (P < 0.001) and decreased HR (P < 0.01), whereas CNQX alone did not significantly effect. Coinjection L-Glu + CNQX significantly attenuates the cardiovascular effect of L-Glu (P < 0.05 to P < 0.01). In hypotension induced by HLZ, SBP and MAP significantly decrease but HR did not change. In HLZ groups, L-Glu significantly improves (P < 0.05) and CNQX deteriorated hypotension induced by HLZ (P < 0.05). Coinjection of L-Glu + CNQX also attenuates the effect of L-Glu on Δ MAP and Δ SBP. In hypotension, ΔHR induced by L-Glu was significantly higher than CNQX (P < 0.01). In L-Glu + CNQX group, ΔHR also was lower than L-Glu (P < 0.05). Conclusion: Our findings revealed that glutamatergic system of the PPT in both normotensive and hypotension induced by HLZ plays a pressor with bradycardic responses that partly mediated by non-NMDA receptor.

The effects of curcumin in learning and memory impairment associated with hypothyroidism in juvenile rats: the role of nitric oxide, oxidative stress, and brain-derived neurotrophic factor.

The effect of curcumin (Cur) on cognitive impairment and the possible role of brain tissue oxidative stress, nitric oxide (NO) levels, and brain-derived neurotrophic factor (BDNF) were investigated in juvenile hypothyroid rats. The juvenile rats (21 days old) were allocated into the following groups: (1) control; (2) hypothyroid (0.05% propylthiouracil (PTU) in drinking water); (3-5) hypothyroid-Cur 50, 100, and 150, which in these groups 50, 100, or 150 mg/kg, Cur was orally administered by gavage during 6 weeks. In the hypothyroid rats, the time elapsed and the traveled distance to locate the hidden platform in the learning trials of Morris water maze (MWM) increased, and on the probe day, the amount of time spent in the target quadrant and the distance traveled in there was decreased. Hypothyroidism also decreased the latency and increased the time spent in the darkroom of the passive avoidance (PA) test. Compared with the hypothyroid group, Cur enhanced the performance of the rats in both MWM and PA tests. In addition, Cur reduced malondialdehyde concentration and NO metabolites; however, it increased thiol content as well as the activity of catalase (CAT) and superoxide dismutase enzymes in both the cortex and hippocampus. Cur also increased hippocampal synthesis of BDNF in hypothyroid rats. The beneficial effects of Cur cognitive function in juvenile hypothyroid rats might be attributed to its protective effect against oxidative stress and potentiation of BDNF production.

Effect of MK-801, an antagonist of NMDA receptor in the pedunculopontine tegmental nucleus, on cardiovascular parameters in normotensive and hydralazine hypotensive rats.

Objectives: In the present study, the cardiovascular effects of glutamate NMDA receptor of the pedunculopontine tegmental nucleus (PPT) in normotensive and hydralazine (HLZ) hypotensive rats were evaluated. Materials and Methods: In the normotensive condition, MK-801(1 nmol; an NMDA receptor antagonist) and L-glutamate (L-Glu, 50 nmol an agonist) alone and together were microinjected into the nucleus using a stereotaxic device. In hypotensive condition, 2 min after induction of hypotension by HLZ (10 mg/kg, intravenous), drugs, same as in normotensive condition, were microinjected into the PPT. Recorded mean arterial pressure (MAP), systolic blood pressure (SBP), and heart rate (HR) were recorded throughout the experiment by a Power lab apparatus that was connected to a catheter inserted into the femoral arty. The cardiovascular changes (Δ) induced by microinjection drugs were computed and statistically analyzed. Results: In the normotensive condition, L-Glu significantly increased ΔMAP and ΔSBP (P<0.001) and decreased ΔHR (P<0.01) compared with the control. MK-801 alone significantly increased HR (P<0.05) while co-injected with L-Glu + MK-801 it significantly attenuated the L-Glu effect on ΔMAP and ΔSBP but augmented ΔHR (P<0.01). In the hydralazine hypotension condition, L-Glu significantly improved hypotension (P<0.01) and deteriorated bradycardia induced by HLZ (P<0.05). MK-801 alone did not significantly affect ΔMAP, ΔSBP, and ΔHR but when co-injected with L-Glu (L-Glu + MK-801) it could significantly attenuate the cardiovascular effect of L-Glu in the PPT. Conclusion: We found that activation of NMDA receptors of the glutamatergic system in the PPT evoked blood pressure and inhibited HR in both normotensive and hypotensive conditions in rats.

Cardiovascular responses induced by the activation of muscarinic receptors of the pedunculopontine tegmental nucleus in anesthetized rats.

BACKGROUND: The cardiovascular effects of nicotinic receptors of cholinergic system in the pedunculopontine tegmental nucleus (PPT) were shown. OBJECTIVE: In the following, the cardiovascular effects of the muscarinic receptor, another receptor in this system, were examined. METHODS: Rats were divided into eight groups: 1) control; 2 and 3) Ach (acetylcholine, an agonist) 90 and 150 nmol; 4 and 5) Atr (atropine; a muscarinic antagonist) 3 and 9 nmol; 6) Atr 3 + Ach 150; 7) Atr 9 + Ach 150; and 8) Atr 3 + hexamethonium (Hexa; 300 nmol) + Ach 150. After anesthesia, cannulation of the femoral artery was performed, and then the mean arterial pressure (MAP), systolic blood pressure (SBP), and heart rate (HR) were recorded using a power lab apparatus. RESULTS: Following drug microinjection, the maximum change (Δ) in MAP, SBP, and HR was calculated and analyzed. Both doses of Ach (90 and 150) significantly decreased ΔMAP and ΔSBP but could not change ΔHR. Neither of the doses of Atr significantly affected ΔMAP, ΔSBP, and ΔHR. Co-injection of Atr 3 + Ach 150 only increased ΔHR, but Atr 9 + Ach 150 decreased ΔMAP and ΔSBP than Ach 150 alone. The effect of the co-injection of Atr 9 + Hexa 300 + Ach 150 was also the same as the Atr 9 + Ach 150 group. CONCLUSION: The present results revealed that cholinergic muscarinic receptors in the PPT have an inhibitory effect on MAP and SBP with no important effect on HR.

The possible role of pedunculopontine tegmental nucleus (PPT) opioid receptors in the cardiovascular responses in normotensive and hemorrhagic hypotensive rats.

BACKGROUND: The pedunculopontine tegmental nucleus (PPT) is involved in cardiovascular regulation. The presence of mu (µ) opioid receptors in the PPT nucleus has been determined. In the present study, the role of this nucleus in normotensive conditions and then the role of these receptors on cardiovascular function in hypotension induced by hemorrhage (HEM) were investigated. METHOD: Animals were divided into the following groups: Group 1: control, Group 2: HEM, Group 3: morphine at dose 100 nmol (a general opioid receptor agonist), Group 4: naloxone at dose 100 nmol (a general opioid receptor antagonist), Group 5: morphine + HEM, and Group 6: naloxone + HEM. After anesthesia, two femoral arteries were cannulated to record the cardiovascular parameters and blood withdrawal. Two minutes after induction of HEM, drugs were injected into the nucleus, and cardiovascular parameters were measured. Changes (Δ) in cardiovascular responses due to drug injection and HEM were calculated and compared to control and HEM groups. RESULTS: HEM significantly reduced changes in systolic and mean arterial pressures and increased heart rate changes compared to control. Morphine microinjection in normotensive and HEM rats significantly decreased systolic blood pressure, mean arterial pressure, and heart rate, and naloxone significantly increased all these parameters. CONCLUSION: This study showed that the PPT nucleus plays a role in modulating the cardiovascular responses induced by HEM. The µ opioid receptor of the PPT nucleus in the normotensive and HEM rats have inhibitory effects on blood pressure and heart rate mainly, and these effects are eliminated by naloxone microinjection.

The alteration of neuronal activities of the cuneiform nucleus in non-hypovolemic and hypovolemic hypotensive conditions.

BACKGROUND: The cuneiform nucleus is located in the center of the circuit that mediates autonomic responses to stress. Hemorrhagic hypotension leads to chemoreceptor anoxia, which consequently results in the reduction of baroreceptor discharge and stimulation of the chemoreceptor. OBJECTIVE: Using the single-unit recording technique, the neuronal activities of the cuneiform nucleus were investigated in hypotensive states induced by hemorrhage and administration of an anti-hypertensive drug (hydralazine). METHODS: Thirty male rats were divided into the control, hemorrhage, and hydralazine groups. The femoral artery was cannulated for the recording of cardiovascular responses, including systolic blood pressure, mean arterial pressure, and heart rate. Hydralazine was administered via tail vein. The single-unit recording was performed from the cuneiform nucleus. RESULTS: The maximal systolic blood pressure and the mean arterial pressure significantly decreased and heart rate significantly increased after the application of hydralazine as well as the following hemorrhage compared to the control group. Hypotension significantly increased the firing rate of the cuneiform nucleus in both the hemorrhage and hydralazine groups compared to the control group. CONCLUSIONS: The present data indicate that the cuneiform nucleus activities following hypotension may play a crucial role in blood vessels and vasomotor tone.

The alteration of neuronal activities of the cuneiform nucleus in non-hypovolemic and hypovolemic hypotensive conditions / Alterações da atividade neuronal no núcleo cuneiforme em condições hipovolêmicas e não hipovolêmicas

Abstract Background: The cuneiform nucleus is located in the center of the circuit that mediates autonomic responses to stress. Hemorrhagic hypotension leads to chemoreceptor anoxia, which consequently results in the reduction of baroreceptor discharge and stimulation of the chemoreceptor. Objective: Using the single-unit recording technique, the neuronal activities of the cuneiform nucleus were investigated in hypotensive states induced by hemorrhage and administration of an anti-hypertensive drug (hydralazine). Methods: Thirty male rats were divided into the control, hemorrhage, and hydralazine groups. The femoral artery was cannulated for the recording of cardiovascular responses, including systolic blood pressure, mean arterial pressure, and heart rate. Hydralazine was administered via tail vein. The single-unit recording was performed from the cuneiform nucleus. Results: The maximal systolic blood pressure and the mean arterial pressure significantly decreased and heart rate significantly increased after the application of hydralazine as well as the following hemorrhage compared to the control group. Hypotension significantly increased the firing rate of the cuneiform nucleus in both the hemorrhage and hydralazine groups compared to the control group. Conclusions: The present data indicate that the cuneiform nucleus activities following hypotension may play a crucial role in blood vessels and vasomotor tone.

RESUMO Antecedentes: O núcleo cuneiforme está localizado no centro do circuito que media as respostas autonômicas ao estresse. A hipotensão hemorrágica leva à anóxia dos quimiorreceptores, que, consequentemente, resulta na redução da descarga dos barorreceptores e estimulação do quimiorreceptor. Objetivo: Utilizando a técnica de registro em unidade única, as atividades neuronais do núcleo cuneiforme foram investigadas em estados de hipotensão induzida por hemorragia e administração de um anti-hipertensivo (hidralazina). Métodos: Trinta ratos machos foram divididos nos grupos controle, hemorragia e hidralazina. A artéria femoral foi canulada, para o registro de respostas cardiovasculares, incluindo pressão arterial sistólica, pressão arterial média e frequência cardíaca. A hidralazina foi administrada na veia da cauda. O registro de unidade única foi realizado a partir do núcleo cuneiforme. Resultados: A pressão arterial sistólica máxima e a pressão arterial média diminuíram significativamente, e a frequência cardíaca aumentou significativamente após a aplicação de hidralazina, bem como a hemorragia seguinte, em comparação com o grupo controle. A hipotensão aumentou significativamente a taxa de disparo da população do núcleo cuneiforme em ambos os grupos de hemorragia e hidralazina, em comparação com o grupo de controle. Conclusões: Os presentes dados indicam que as atividades do núcleo cuneiforme após hipotensão podem desempenhar um papel crucial nos vasos sanguíneos e no tônus vasomotor.

Effects of hydroalcoholic extract of saffron petal on blood pressure and heart rate in hypertension induced by angiotensin II and L-NAME in anesthetized rats.

The saffron petals are a by-product part of the saffron flower with a cardiovascular effect. This study evaluated the effect of the saffron petal on hypertension induced by angiotensin II (AII) and NG-nitro-L-arginine methyl ester (L-NAME, a NOS inhibitor). Rats were divided into 11 groups: 1) Control, 2) AII (50.00 ng kg-1), 3) Losartan+ AII, 4) L-NAME (10.00 mg kg-1), 5) sodium nitroprusside (SNP) + L-NAME, 6, 7) Saffron petals extract; 8, 9) saffron petals (100 and 200 mg kg-1) + AII and 10,11) saffron petals (100 and 200 mg kg-1) + L-NAME. Hypertension induced by intravenous injection of AII and L-NAME in separate groups. In treated groups, 30 min before injection of AII or L-NAME rats received two doses of extract via intraperitoneal administration. The femoral artery was cannulated and cardiovascular parameters recorded by a transducer connected to power lab apparatus. Maximal changes (∆) of mean arterial pressure (MAP), systolic blood pressure (SBP) and heart rate (HR) from baseline were calculated and compared to with those in hypertensive and control groups. Results showed that both AII and L-NAME significantly increased SBP and MAP than control, however, HR in AII was decreased and in the L-NAME group increased. Pre-treatment with saffron petals could significantly attenuate the cardiovascular responses induced by both AII and L-NAME. However, the effect of the extract in AII hypertensive rats was more effective than L-NAME groups. The findings showed that the hydroalcoholic extract of the saffron petals had an antihypertensive effect that mainly was mediated by inhibition of AII activity.

Role of the glutamatergic system of ventrolateral periaqueductal gray (vlPAG) in the cardiovascular responses in normal and hemorrhagic conditions in rats.

OBJECTIVES: Periaqueductal gray (PAG) is a mesencephalic area divided into four columns including ventrolateral periaqueductal gray (vlPAG). vlPAG plays a role in cardiovascular regulation during normal and hemorrhagic (Hem) conditions. Due to presence of glutamate in this area, we evaluated the effect of glutamatergic receptors of this area on cardiovascular activity in normotensive and hypovolemic Hem rats. MATERIALS AND METHODS: Animals were divided into twelve groups: saline (vehicle), Glutamate, GYK52466 (non-NMDA receptor antagonist), and MK801 (NMDA receptor antagonist) with and without Glu microinjected into vlPAG in normal and Hem conditions. Following the femoral artery cannulating and microinjecting, changes (Δ) of heart rate (HR), systolic blood pressure (SBP), and mean arterial pressure (MAP) were recorded via a PowerLab unit. RESULTS: In normotensive conditions, microinjection of Glu increased ΔMAP, ΔSBP, and ΔHR (P<0.001). MK-801 and GYKI-52466 nonsignificant reduced cardiovascular responses than vehicle while their changes were significant compared with glutamate (P<0.001). Co-injection of GYKI- 52466 with Glu did not significantly reduce ΔSBP and ΔMAP induced by Glu (P>0.05) but co-injection of MK-801 with Glu significantly attenuate these effects(P<0.01). In Hem, Glu increased ΔSBP, ΔMAP, and ΔHR (P<0.05). GYKI-52466 alone did not change cardiovascular responses but MK-801 decreased ΔSBP than Hem (P<0.01). Co-injection of GYKI-52466 with Glu had significant(P<0.05) but MK-801 with Glu had no significant effect compared with Hem (P>0.05). CONCLUSION: The glutamatergic system of vlPAG increases cardiovascular values that are mostly mediated through the NMDA receptor. Since vlPAG is well known as an inhibitory region, it seems that glutamate does not have a noteworthy cardiovascular role in vlPAG during Hem and normal conditions.

A standardized extract of Ziziphus jujuba Mill protects against adriamycin-induced liver, heart, and brain toxicity: An oxidative stress and biochemical approach.

Due to the antioxidant effects of the Ziziphus jujuba Mill (Z. jujuba), we investigated the liver, heart, and brain-protective effects of this herb against toxicity induced by adriamycin (ADR). In this study, Wistar rats were divided into 1) control, 2) ADR and 3, 4, and 5) treated groups orally administrated three doses of Z. jujuba hydroalcoholic extract for 1 month. The liver, heart, and brain were removed for evaluation of the oxidative markers. Blood samples were evaluated to determine the levels of Lactate dehydrogenase, total and direct bilirubin, alkaline phosphatase, Aspartate transaminase, and Alanine aminotransferase. Administration of Z. jujuba significantly decreased the biochemical enzymes compared to the ADR. Oxidative condition in treated rats with different doses of Z. jujuba was improved compared to the ADR group. Z. jujuba could decrease the oxidative injury through invigoration of the tissues antioxidant system. The mentioned hepatic and cardiac parameters levels improved during extract administration. PRACTICAL APPLICATIONS: In the first stage, our findings and other supplementary works have shown that administration of jujube extract has prevented the effects of histotoxicity caused by adriamycin, so it seems that in the next stage, the effects of this herbal plant on patients with tissue toxicity caused by adriamycin should be evaluated and if the results are positive in pharmacological studies, it should be used as a complementary drug in the treatment of these patients.

trans-Anethole attenuated renal injury and reduced expressions of angiotensin II receptor (AT1R) and TGF-ß in streptozotocin-induced diabetic rats.

Fibrosis is a pathological process in diabetic nephropathy that causes renal failure and dysfunction. Given the known anti-diabetic effects of trans-Anethole (TA), we aimed to investigate its renoprotective and anti-fibrotic effect alone and in combination with losartan in diabetic nephropathy. Male Wistar rats received a single intraperitoneal injection of 65 mg/kg streptozotocin (STZ) for diabetes induction. Diabetic rats were treated orally with saline, TA (80 mg/kg), losartan (Los; 10 mg/kg), or the combination of TA and losartan (TA-Los) daily for five weeks. Renal function was monitored during the study, and renal fibrosis, oxidative stress markers, apoptotic cells, and the expression and localization of AT1R, TGF-ß1, and Col-IV were detected in the kidney. Results showed that TA alone and in combination with losartan was able to decrease blood glucose, urea, and creatinine levels and improve kidney function parameters. TA, Los, and TA-Los significantly reduced tubule vascular degeneration, glomerular and tubulointerstitial sclerosis, oxidative stress, and apoptotic cells. Immunohistochemistry analyses showed that TA, losartan, and TA-losartan combination downregulated the AT1R, Col IV, and TGF-ß1 expression and distribution in diabetic rat kidneys. Results suggest that TA is able to suppress diabetic nephropathy in rats effectively, probably by decreasing blood glucose levels and downregulating AT1R and TGF-ß1 expression.

Effect of Standardized Hydroalcoholic Extract of Saffron Stamen on High Blood Pressure and Baroreflex Sensitivity in Anesthetized Rats.

OBJECTIVE: The stamen is a byproduct of saffron (Crocus sativus) flowers. Herein, its cardiovascular effects were evaluated on hypertension induced by angiotensin II (AngII) and NG-nitro-Larginine methyl ester (L-NAME), as well as baroreflex sensitivity (BRS). METHODS: Rats were randomly divided into 10 groups: 1) control, 2) AngII (50 ng/kg, i.v.), 3) losartan (10 mg/kg, i.p.) + AngII, 4) L-NAME (10 mg/kg, i.v.), 5) sodium nitroprusside (SNP) (50 mg/kg, i.p.) + L-NAME, 6, 7) saffron stamen extract (SS) (100 and 200 mg/kg, i.p.) + AngII and 8, 9) SS (100 and 200 mg/kg) + L-NAME, and 10) SS (200 mg/kg) + phenylephrine (Phen, i.v.). The treated rats first received two doses of SS, 30 min after the injection of L-NAME, AngII, and Phen in separate groups. The cardiovascular parameters were recorded by the PowerLab apparatus via an angiocatheter inserted into the femoral artery. The maximal changes (Δ) of mean arterial pressure (MAP), systolic blood pressure (SBP), and heart rate (HR) in the treated groups were compared with those of the hypertensive and control groups. The changes in MAP and HR induced by Phen were used for BRS evaluation. RESULTS: The SS extract did not significantly affect the basal cardiovascular parameters. The injection of AngII significantly increased the MAP and SBP (P<0.01-P<0.001) with no significant effect on the HR. The SS extract significantly attenuated the pressor effect induced by AngII (P<0.001). Increased MAP and SBP induced by L-NAME (P<0.001) were also significantly attenuated by the SS extract (P<0.01). The effect of SS extract on L-NAME was significantly higher than that of AngII (P<0.05). Moreover, BRS was significantly improved by the SS extract. CONCLUSION: Our findings provide evidence that the SS extract has anti-hypertensive effects that are probably mediated by an inhibitory effect on AngII, increasing nitric oxide production, or improving baroreflex sensitivity.

Effect of opioid receptors of the cuneiform nucleus on cardiovascular responses in normotensive and hypotensive hemorrhagic rats.

The presence of opioid receptors in the cuneiform nucleus (CnF), which is a mesencephalic area, and their involvement in the central cardiovascular responses have been shown. Therefore, this study is designed to examine the possible role of mu- (µ) and delta- (δ) opioid receptors in the CnF in the cardiovascular responses in normotensive and hemorrhagic hypotensive rats. Following anesthesia and the recording of the blood pressure, the agonist and antagonist of µ- (morphine and naloxone) and δ- (D-Pen 2, 5]-Enkephalin hydrate (DPDPE) and naltridole) receptors were microinjected into the CnF. In the hemorrhagic groups, the drugs were microinjected into the nucleus 2 min after withdrawing 15 % of the total blood volume (TBV). Time-course changes (Δ) in the mean arterial pressure (MAP), systolic blood pressure (SBP), and heart rate (HR) were obtained and compared with the control and hemorrhage groups. Microinjecting morphine in both normotensive and hemorrhagic rats significantly decreased ΔSBP, ΔMAP, and ΔHR; also, naloxone significantly increased all these parameters. The cardiovascular effects of DPDPE and naltridole were not significant in the normotensive rats; however, DPDPE attenuated only the tachycardia induced by the hypotensive hemorrhage. The findings of this study revealed that the opioid receptors in the CnF had an inhibitory effect on the cardiovascular parameters in both normotensive and hypotensive hemorrhagic conditions and these effects were mostly mediated by µ-opioid receptors.

Determining the cardiovascular effects of nitric oxide in the dorsolateral Periaqueductal Gray (dlPAG) in anaesthetised rats.

OBJECTIVE: The dorsolateral periaqueductal gray (dlPAG) is an area located in the brain stem that performs a host of functions including cardiovascular regulation. Owing to the presence of nitric oxide (NO) in this area, we investigated its effect on the cardiovascular system. METHODS: We divided rats into four groups: 1) control; 2) l-arginine (L-Arg, a precursor for nitric oxide, 60 nmol); 3) l-NAME (N omega-nitro-l-arginine methyl ester, a nitric oxide synthase inhibitor, 90 nmol); and 4) sodium nitroprusside (SNP, a nitric oxide donor, 27 nmol). After anaesthesia, the rats were mounted on a stereotaxic apparatus and the drugs were microinjected into the dlPAG. Cardiovascular parameters were continuously recorded by a PowerLab system connected to the cannulated femoral artery via a pressure transducer. The changes (Δ) of systolic blood pressure (SBP), mean arterial pressure (MAP), and heart rate (HR) were calculated at different times as compared to the control group. RESULTS: In the l-NAME group, the ΔSBP, ΔMAP, and ΔHR were not significantly affected compared to the control group. In the L-Arg group, ΔSBP and ΔMAP increased; however, only SBP showed a significant increase compared to the control group. In the SNP group, SBP and MAP were significantly affected in comparison to the controls. Additionally, ΔHR decreased in both L-Arg and SNP, but was only significant in L-Arg. CONCLUSION: Our study showed that NO of dlPAG has a pressor effect and attenuates baroreflex bradycardia. However, its pressor effect is more significant.

Cardiovascular Effect of Cuneiform Nucleus During Hemorrhagic Hypotension.

INTRODUCTION: The underlying mechanism responsible for the cardiovascular response to Hemorrhage (HEM) is still unknown; however, several brain areas, such as the Cuneiform nucleus (CnF) have shown to be involved. In this study, the cardiovascular effect of the CnF during HEM was evaluated. METHODS: The animals were divided into the following groups: 1. Vehicle; 2. HEM; 3. Cobalt chloride (CoCl2); 4. CoCl2+saline; and 5. CoCl2+HEM. Catheterization of the left and right femoral artery was performed to record blood pressure and blood withdrawal, respectively. Saline and CoCl2 were microinjected into the CnF nucleus, and then blood withdrawal was done for HEM induction. Cardiovascular regulation throughout the experiments was recorded and changes (Δ) in the Systolic Blood Pressure (SBP), Mean Arterial Pressure (MAP) and Heart Rate (HR) were calculated over time and compared with those treated with saline and HEM, using repeated-measures ANOVA. RESULTS: HEM significantly reduced ΔSBP and ΔMAP and augmented ΔHR than the vehicle group. CoCl2 did not significantly affect basic ΔSBP, ΔMAP, and ΔHR compared with the vehicle group. However, injection of CoCl2 into the CnF before HEM (CoCl2+HEM group) significantly decreased ΔSBP, ΔMAP, and tachycardia, induced by HEM. CONCLUSION: Our results indicated that blockade of the CnF by CoCl2 significantly reduced the hypotension and tachycardia, induced by HEM indicating the involvement of CnF in cardiovascular regulation during HEM.

Involvement of the 5-HT1A receptor of the cuneiform nucleus in the regulation of cardiovascular responses during normal and hemorrhagic conditions.

OBJECTIVES: The 5-hydroxytryptamine1A (5-HT1A) receptor is one of the serotonin receptors in the brain, which regulates cardiovascular responses, especially in hemorrhage. Presence of this receptor in the cuneiform nucleus (CnF) has been shown. The present study evaluates the cardiovascular effect of this receptor of the CnF in normal and hypotensive hemorrhagic rats. MATERIALS AND METHODS: Agonist (8-OH-DPAT) and antagonist (WAY-100635) of 5-HT1A microinjected into the CnF in basal and hemorrhagic conditions and cardiovascular responses were evaluated. Hemorrhage induced by blood withdrawal from the femoral artery and 2 min after that drugs microinjected. Time course and peak changes (∆) of the mean arterial pressure (MAP), systolic blood pressure (SBP) and heart rate (∆HR) were obtained and compared to the control and hemorrhage groups. RESULTS: In basal condition, 8-OH-DPAT significantly decreased ∆SBP, ∆MAP and ∆HR compared to the control (P<0.05-P<0.01), while way-100635 did not have a significant effect. Hypotension and tachycardia induced by hemorrhage ameliorated by agonist (P<0.05-P<0.01), while antagonist deteriorated hypotension (P<0.05) but attenuated tachycardia (P<0.01). CONCLUSION: This study shows that 5-HT1A receptor of the CnF involves in regulation of the cardiovascular responses. However, this effect in basal and hemorrhage conditions is different.

Effect of Aqueous and Ethyl Acetate Fractions of Ziziphus jujuba Mill Extract on Cardiovascular Responses in Hypertensive Rats.

BACKGROUND: Ziziphus jujuba Mill (ZJ) is a plant with anti-hypertensive property. In this regard, the present study investigated the effect of aqueous and ethyl acetate fractions of ZJ extract on acute hypertension (HTN) induced by nitro-L-arginine methyl ester (L-NAME). METHODS: The current study was carried on 49 hypertensive rats divided into seven groups, including i) control; ii) L-NAME (10 mg/kg); iii) sodium nitroprusside (SNP) (50 µg/kg) plus L-NAME; iv and v) aqueous fraction of ZJ (150 mg/kg and 300 mg/kg) plus L-NAME; vi) and vii) ethyl acetate fractions of ZJ (150 mg/kg and 300 mg/kg) plus L-NAME. The rats were orally treated with both fractions for four weeks and received intravenous L-NAME on the 28th day. The mean arterial pressure (MAP), systolic blood pressure (SBP) and heart rate (HR) of the rats were recorded then maximal changes (Δ) of MAP, SBP and HR were calculated and compared with changes of control and L-NAME. RESULTS: According to the obtained results of the present study, it was shown that the administration of L-NAME significantly increased ΔMAP, ΔSBP and ΔHR, and these effects were significantly attenuated by administration of SNP. The pre-treatment with both doses (150 mg/kg and 300 mg/kg) of aqueous and ethyl acetate fractions could significantly reduce cardiovascular responses induced by L-NAME that comparable with SNP. However, a lower dose of aqueous fractions and higher dose of ethyl acetate fractions were reported with stronger effects. CONCLUSION: The results of the current study showed that both the aqueous and ethyl acetate fractions of ZJ through the effect on nitric oxide system can prevent the development of HTN induced by L-NAME.