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1.
Eur Rev Med Pharmacol Sci ; 27(20): 10112-10125, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37916381

ABSTRACT

OBJECTIVE: There is a need to treat cancer cells with safe and natural nanoparticles to avoid the side effects of chemotherapeutic agents. Chamomile is considered a safe, natural plant with anticancer activity. We synthesize simple, inexpensive, and eco-friendly silver nanoparticles (SNs) using Chamomile (CHM) to tune their anticancer properties. MATERIALS AND METHODS: SN-CHM was synthesized by reducing 1 mM silver nitrate aqueous solution in 100 mL with the aqueous ethanolic flower extract of CHM (18 mg/mL, w/v). The reaction proceeded overnight at 600 rpm and 28°C. SN-CHM was characterized for their % yield, average diameter, charge, morphology, and silver release. Moreover, SN-CHM was investigated for its antioxidant and anticancer activities at 200 µg/mL and 5 mg/ mL, respectively. RESULTS: A 59.12% yield and a uniform SN-CHM size of 115 ± 3.1 nm with a ζ-potential of -27.67 ± (-3.92) mv were observed. The UV-visible absorption showed shifts from 379.5 to 383.5 nm for CHM and SN-CHM, respectively. Moreover, Ag+ was ultimately released from SN-CHM after 5 h. Fourier Transform Infrared Spectroscopy (FT-IR) showed characteristic absorption peaks of CHM and produced SN-CHM. Furthermore, SN-CHM showed moderate antioxidant activity. SN-CHM inhibited the % viability of SW620 and HT-29 cell lines at 20 µM. SN-CHM may also greatly upregulate the apoptotic gene BAX while considerably downregulating the anti-apoptotic genes BCL2 and BCL-Xl. CONCLUSIONS: CHM can be a safe soft drink, especially when conjugated with Ag ions as anticancer NPs. SN-CHM is considered potent anticancer activity against SW620, and HT-29 cell lines.


Subject(s)
Colorectal Neoplasms , Matricaria , Metal Nanoparticles , Humans , Reducing Agents/pharmacology , Metal Nanoparticles/chemistry , Spectroscopy, Fourier Transform Infrared , Silver/pharmacology , Cell Death , Antioxidants/pharmacology , Plant Extracts/pharmacology , Plant Extracts/chemistry , Colorectal Neoplasms/drug therapy , Anti-Bacterial Agents/pharmacology
2.
Physiol Res ; 70(1): 13-26, 2021 03 17.
Article in English | MEDLINE | ID: mdl-33728924

ABSTRACT

Reactive oxygen species (ROS) such as superoxide (O2-) generated by NAD(P)H oxidases have emerged as important molecules in blood pressure regulation. This study investigated the effect of apocynin and catalase on blood pressure and renal haemodynamic and excretory function in an L-NAME induced hypertension model. Forty Male Wistar-Kyoto (WKY) rats (n=8 per group) were treated with either: vehicle (WKY-C); L-NAME (WKY-L, 15 mg/kg/day in drinking fluid); WKY-L given apocynin to block NAD(P)H oxidase (WKY-LApo, 73 mg/kg/day in drinking water.); WKY-L given catalase to enhance ROS scavenging (WKY-LCat, 10000 U/kg/day i.p.); and WKY-L receiving apocynin plus catalase (WKY-LApoCat) daily for 14 days. L-NAME elevated systolic blood pressure (SBP), 116+/-1 to 181±4 mmHg, reduced creatinine clearance, 1.69+/-0.26 to 0.97+/-0.05 ml/min/kg and fractional sodium excretion, 0.84+/-0.09 to 0.55+/-0.09 % at day 14. Concomitantly, plasma malondialdehyde (MDA) increased six fold, while plasma total superoxide dismutase (T-SOD), plasma nitric oxide (NO) and plasma total antioxidant capacity (T-AOC) were decreased by 60-70 % and Nox 4 mRNA expression was increased 2-fold. Treatment with apocynin and catalase attenuated the increase in SBP and improved renal function, enhanced antioxidative stress capacity and reduced the magnitude of Nox4 mRNAs expression in the L-NAME treated rats. This study demonstrated that apocynin and catalase offset the development of L-NAME induced hypertension, renal dysfunction and reduced oxidative stress status, possibly contributed by a reduction in Nox4 expression during NOS inhibition. These findings would suggest that antioxidant compounds such as apocynin and catalase have potential in treating cardiovascular diseases.


Subject(s)
Acetophenones/pharmacology , Catalase/pharmacology , Hypertension/drug therapy , NADPH Oxidase 4/metabolism , NG-Nitroarginine Methyl Ester/toxicity , Reactive Oxygen Species/metabolism , Animals , Antioxidants/pharmacology , Disease Models, Animal , Drug Therapy, Combination , Enzyme Inhibitors/toxicity , Hemodynamics , Hypertension/chemically induced , Hypertension/physiopathology , Male , Rats , Rats, Inbred WKY
3.
Physiol Res ; 69(6): 1051-1066, 2020 12 22.
Article in English | MEDLINE | ID: mdl-33210935

ABSTRACT

L-arginine is a substrate for nitric oxide synthase (NOS) responsible for the production of NO. This investigation studied the effect of apocynin, an NADPH oxidase inhibitor and catalase, an H2O2 scavenger on L-arginine induced oxidative stress and hypotension. Forty Wistar-Kyoto rats were treated for 14 days with vehicle, L-arginine (12.5mg/ml p.o.), L-arginine+apocynin (2.5mmol/L p.o.), L-arginine+catalase (10000U/kg/day i.p.) and L-arginine plus apocynin+catalase respectively. Weekly renal functional and hemodynamic parameters were measured and kidneys harvested at the end of the study for histopathological and renal NADPH oxidase 4 (Nox4) assessments. L-arginine administration in normotensive rats decreased systolic blood pressure (120±2 vs 91±2mmHg) and heart rate (298±21 vs 254±15b/min), enhanced urinary output (21.5±4.2 vs 32±1.9ml/24h , increased creatinine clearance (1.72±0.56 vs 2.62±0.40ml/min/kg), and fractional sodium excretion (0.88±0.16 vs 1.18±0.16 %), caused proteinuria (28.10±1.93 vs 35.26±1.69mg/kg/day) and a significant decrease in renal cortical blood perfusion (292±3 vs 258±5bpu) and pulse wave velocity (3.72±0.20 vs 2.84±0.13m/s) (all P<0.05). L-arginine increased plasma malondialdehyde (by ~206 % P<0.05) and NO (by~51 %, P<0.05) but decreased superoxide dismutase (by~31 %, P<0.05) and total antioxidant capacity (by~35 %, P<0.05) compared to control. Renal Nox4 mRNA activity was approximately 2.1 fold higher (P<0.05) in the L-arginine treated rats but was normalized by apocynin and apocynin plus catalase treatment. Administration of apocynin and catalase, but not catalase alone to rats fed L-arginine, restored the deranged renal function and structure, prevented hypotension and enhanced the antioxidant capacity and suppressed Nox4 expression. These findings suggest that apocynin and catalase might be used prophylactically in states of oxidative stress.


Subject(s)
Acetophenones/pharmacology , Arginine/pharmacology , Catalase/pharmacology , Hypotension/drug therapy , Kidney/drug effects , Oxidative Stress/drug effects , Animals , Antioxidants/pharmacology , Blood Pressure/drug effects , Disease Models, Animal , Hypotension/chemically induced , Hypotension/metabolism , Hypotension/pathology , Kidney/metabolism , Kidney/pathology , Male , NADPH Oxidase 4/metabolism , Pulse Wave Analysis/methods , Rats , Rats, Inbred WKY
4.
Acta Physiol (Oxf) ; 221(4): 250-265, 2017 Dec.
Article in English | MEDLINE | ID: mdl-28456134

ABSTRACT

AIM: This investigation explored the hypothesis that in obesity an inflammatory response in the kidney contributed to a renal nerve-dependent blunting of the baroreflex regulation of renal sympathetic nerve activity. METHODS: Rats received a normal (12% kcal) or high-fat (45% kcal) diet for 8 weeks plus daily injections of vehicle (0.9% NaCl i.p) or tacrolimus (0.25 mg kg-1 day-1 i.p) from weeks 3-8. Following anaesthesia, left renal sympathetic nerve activity was recorded, baroreflex gain curves were generated, by infusing phenylephrine and sodium nitroprusside, and cardiopulmonary baroreceptors challenged by infusing a saline load. RESULTS: The high-fat diet elevated weight gain and adiposity index by 89 and 129% (both, P < 0.001). Mean blood pressure (132 ± 4 vs 103 ± 5 mmHg), fractional noradrenaline excretion and creatinine clearance (5.64 ± 0.55 vs 3.32 ± 0.35 mL min-1 kg-1 ) were 28, 77 and 69% higher (all P < 0.05), but urine flow and fractional sodium excretions were 42 and 72% (both P < 0.001) lower compared to normal rats. Plasma and renal TNF-α and IL-6 concentrations were fourfold to fivefold (P < 0.001) and 22 and 20% higher (both, P < 0.05), in obese rats but normalized following tacrolimus. In obese rats, baroreflex sensitivity was reduced by 80% (P < 0.05) but restored by renal denervation or tacrolimus. Volume expansion reduced renal sympathetic nerve activity by 54% (P < 0.001) in normal and obese rats subjected to renal denervation and tacrolimus, but not in obese rats with an intact renal innervation. CONCLUSION: Obesity induced a renal inflammation and pointed to this being both the origin of autonomic dysregulation and a potential focus for targeted therapy.


Subject(s)
Baroreflex , Kidney Diseases/etiology , Obesity/complications , Sympathetic Nervous System/physiopathology , Adiposity , Animals , Cytokines/blood , Immunosuppressive Agents , Kidney/immunology , Kidney/innervation , Kidney/metabolism , Kidney Diseases/metabolism , Kidney Diseases/physiopathology , Male , Norepinephrine/metabolism , Obesity/metabolism , Obesity/physiopathology , Rats, Sprague-Dawley , Tacrolimus
5.
Acta Physiol (Oxf) ; 220(4): 404-416, 2017 08.
Article in English | MEDLINE | ID: mdl-28181735

ABSTRACT

Extensive investigations have revealed that renal sympathetic nerves regulate renin secretion, tubular fluid reabsorption and renal haemodynamics which can impact on cardiovascular homoeostasis normally and in pathophysiological states. The significance of the renal afferent innervation and its role in determining the autonomic control of the cardiovascular system is uncertain. The transduction pathways at the renal afferent nerves have been shown to require pro-inflammatory mediators and TRPV1 channels. Reno-renal reflexes have been described, both inhibitory and excitatory, demonstrating that a neural link exists between kidneys and may determine the distribution of excretory and haemodynamic function between the two kidneys. The impact of renal afferent nerve activity on basal and reflex regulation of global sympathetic drive remains opaque. There is clinical and experimental evidence that in states of chronic kidney disease and renal injury, there is infiltration of T-helper cells with a sympatho-excitation and blunting of the high- and low-pressure baroreceptor reflexes regulating renal sympathetic nerve activity. The baroreceptor deficits are renal nerve-dependent as the dysregulation can be relieved by renal denervation. There is also experimental evidence that in obese states, there is a sympatho-excitation and disrupted baroreflex regulation of renal sympathetic nerve activity which is mediated by the renal innervation. This body of information provides an important basis for directing greater attention to the role of renal injury/inflammation causing an inappropriate activation of the renal afferent nerves as an important initiator of aberrant autonomic cardiovascular control.


Subject(s)
Acute Kidney Injury/physiopathology , Hemodynamics/physiology , Inflammation/physiopathology , Kidney/innervation , Sympathetic Nervous System/physiology , Animals , Cardiovascular System/physiopathology , Humans
6.
Acta Physiol (Oxf) ; 218(3): 212-224, 2016 11.
Article in English | MEDLINE | ID: mdl-27614105

ABSTRACT

AIM: This study investigated the effect of renal bradykinin B1 and B2 receptor blockade on the high- and low-pressure baroreceptor reflex regulation of renal sympathetic nerve activity (RSNA) in rats with cisplatin-induced renal failure. METHODS: Cisplatin (5 mg/kg) or saline was given intraperitoneally 4 days prior to study. Following chloralose/urethane anaesthesia, rats were prepared for measurement of mean arterial pressure (MAP), heart rate and RSNA and received intrarenal infusions of either Lys-[des-Arg9 , Leu8 ]-bradykinin (LBK), a bradykinin B1 receptor blocker, or bradyzide (BZ), a bradykinin B2 receptor blocker. RSNA baroreflex gain curves and renal sympatho-inhibitory responses to volume expansion (VE) were obtained. RESULTS: In the control and renal failure groups, basal MAP (89 ± 3 vs. 80 ± 8 mmHg) and RSNA (2.0 ± 0.3 vs. 1.7 ± 0.6 µV.s) were similar but HR was lower in the latter group (331 ± 8 vs. 396 ± 9 beats/min). The baroreflex gain for RSNA in the renal failure rats was 39% (P < 0.05) lower than the control but was restored to normal values following intrarenal infusion of BZ, but not LBK. VE had no effect on MAP or HR but reduced RSNA by some 40% (P < 0.05) in control but not renal failure rats. Intrarenal LBK infusion in the renal failure rats normalized the VE induced renal sympatho-inhibition whereas BZ only partially restored the response. CONCLUSION: These findings suggest that pro-inflammatory bradykinin acting at different receptors within the kidney generates afferent neural signals which impact differentially within the central nervous system on high- and low-pressure regulation of RSNA.


Subject(s)
Baroreflex/drug effects , Blood Pressure/drug effects , Bradykinin Receptor Antagonists/pharmacology , Heart Rate/drug effects , Kidney/innervation , Renal Insufficiency/physiopathology , Sympathetic Nervous System/drug effects , Animals , Cisplatin , Male , Pyrrolidines/pharmacology , Rats , Rats, Wistar , Renal Insufficiency/chemically induced , Thiosemicarbazones/pharmacology
7.
J Physiol Pharmacol ; 67(1): 31-44, 2016 Feb.
Article in English | MEDLINE | ID: mdl-27010893

ABSTRACT

The present study investigated the role of endothelial nitric oxide synthase (eNOS) enzyme in the development of left ventricular hypertrophy (LVH) in Wistar-Kyoto rats. The effect of L-arginine administration on cardiac structure, arterial stiffness, renal and systemic hemodynamic parameters was studied and the change in expression of eNOS and cystathione γ lyase (CSE) in the myocardium of LVH rats was evaluated. LVH was induced using isoprenaline (5 mg/kg, S.C.) and caffeine (62 mg/L in drinking water) for 14 days. Following to that, L-arginine (1.25 g/L in drinking water) was given for 5 weeks as a donor of NO. eNOS and CSE gene expressions were down regulated in the LVH group by about 35% and 67% respectively when compared to control. However, in the LVH group treated with L-arginine there was up regulation of eNOS by almost 27% and down regulation in CSE by 24% when compared to control (all P < 0.05). Heart index and H2S plasma levels were reduced by almost 53% in the L-arginine treated LVH group compared to the control (all P < 0.05). Mean arterial pressure, heart rate and pulse wave velocity were reduced while renal blood perfusion increased in L-arginine treated LVH rats compared to their untreated counterparts (all P < 0.05). The enhanced expression of eNOS in L-arginine treated LVH rats resulted in the amelioration of oxidative and haemodynamic parameters suggesting that NO system is an important therapeutic target in cardiac and LV hypertrophies.


Subject(s)
Arginine/pharmacology , Gene Expression/drug effects , Heart/drug effects , Hypertrophy, Left Ventricular/drug therapy , Myocardium/metabolism , Nitric Oxide Synthase Type III/metabolism , Animals , Arterial Pressure/drug effects , Blood Flow Velocity/drug effects , Down-Regulation/drug effects , Heart Rate/drug effects , Hemodynamics/drug effects , Hypertrophy, Left Ventricular/metabolism , Nitric Oxide/metabolism , Pulse Wave Analysis/methods , Rats , Rats, Inbred WKY , Up-Regulation/drug effects
8.
Acta Physiol (Oxf) ; 214(3): 390-401, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25846561

ABSTRACT

AIM: This study investigated the role of the renal innervation in arterial and cardiopulmonary baroreflex regulation of renal sympathetic nerve activity (RSNA) and heart rate (HR) in rats fed a high-fat diet to induce obesity. METHODS: Rats received either a normal (12% kcal) or high (45% kcal) fat diet for 60 days. On day 61, rats were anesthetized and prepared for recording left RSNA. In one group, the renal nerves remained intact, while in the other, both kidneys were denervated. Baroreflex gain curves for RSNA and HR were generated by increasing and decreasing blood pressure. Low-pressure baroreceptors were challenged by infusing a saline load. RESULTS: Mean blood pressure was 135 mmHg in the fat-fed and 105 mmHg (P < 0.05) in normal rats. Weight gain, adiposity index and creatinine clearance were 37, 82 and 55% higher (P < 0.05-0.001), but urine flow rate and fractional sodium excretions were 53 and 65% (both P < 0.001) lower, respectively, in the fat-fed compared to normal rats. In fat-fed rats with innervated kidneys, RSNA and HR arterial baroreflex sensitivities were reduced by 73 and 72% (both P < 0.05) but were normal in renally denervated rats. Volume expansion decreased RSNA by 66% (P < 0.001) in normal rats, but not in the intact fat-fed rats and by 51% (P < 0.01) in renally denervated fat-fed rats. CONCLUSION: Feeding a high-fat diet caused hypertension associated with dysregulation of the arterial and cardiopulmonary baroreflexes which was dependent on an intact renal innervation. This suggests that in obese states neural signals arising from the kidney contribute to a deranged autonomic control.


Subject(s)
Baroreflex , Blood Pressure , Heart Rate , Kidney/physiopathology , Obesity/physiopathology , Sympathetic Nervous System/physiopathology , Animals , Kidney/innervation , Male , Rats , Rats, Sprague-Dawley
9.
Cell Death Dis ; 6: e1614, 2015 Jan 22.
Article in English | MEDLINE | ID: mdl-25611389

ABSTRACT

Despite recent advances in cancer management, colorectal cancer (CRC) remains the third most common cancer and a major health-care problem worldwide. MicroRNAs have recently emerged as key regulators of cancer development and progression by targeting multiple cancer-related genes; however, such regulatory networks are not well characterized in CRC. Thus, the aim of this study was to perform global messenger RNA (mRNA) and microRNA expression profiling in the same CRC samples and adjacent normal tissues and to identify potential miRNA-mRNA regulatory networks. Our data revealed 1273 significantly upregulated and 1902 downregulated genes in CRC. Pathway analysis revealed significant enrichment in cell cycle, integrated cancer, Wnt (wingless-type MMTV integration site family member), matrix metalloproteinase, and TGF-ß pathways in CRC. Pharmacological inhibition of Wnt (using XAV939 or IWP-2) or TGF-ß (using SB-431542) pathways led to dose- and time-dependent inhibition of CRC cell growth. Similarly, our data revealed up- (42) and downregulated (61) microRNAs in the same matched samples. Using target prediction and bioinformatics, ~77% of the upregulated genes were predicted to be targeted by microRNAs found to be downregulated in CRC. We subsequently focused on EZH2 (enhancer of zeste homolog 2 ), which was found to be regulated by hsa-miR-26a-5p and several members of the let-7 (lethal-7) family in CRC. Significant inverse correlation between EZH2 and hsa-miR-26a-5p (R(2)=0.56, P=0.0001) and hsa-let-7b-5p (R(2)=0.19, P=0.02) expression was observed in the same samples, corroborating the belief of EZH2 being a bona fide target for these two miRNAs in CRC. Pharmacological inhibition of EZH2 led to significant reduction in trimethylated histone H3 on lysine 27 (H3K27) methylation, marked reduction in cell proliferation, and migration in vitro. Concordantly, small interfering RNA-mediated knockdown of EZH2 led to similar effects on CRC cell growth in vitro. Therefore, our data have revealed several hundred potential miRNA-mRNA regulatory networks in CRC and suggest targeting relevant networks as potential therapeutic strategy for CRC.


Subject(s)
Colorectal Neoplasms/genetics , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Gene Regulatory Networks , MicroRNAs/genetics , Adenosine/analogs & derivatives , Adenosine/pharmacology , Adult , Aged , Base Sequence , Cell Movement/drug effects , Cell Movement/genetics , Cell Proliferation/drug effects , Cell Survival/drug effects , Colorectal Neoplasms/pathology , Enhancer of Zeste Homolog 2 Protein , Female , Gene Expression Regulation, Neoplastic/drug effects , Gene Regulatory Networks/drug effects , Genome, Human , Humans , Male , MicroRNAs/metabolism , Middle Aged , Molecular Sequence Data , Polycomb Repressive Complex 2/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism
10.
Acta Physiol (Oxf) ; 210(3): 690-700, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24438102

ABSTRACT

AIM: There is evidence that in chronic renal failure, the sympathetic nervous system is activated. This study investigated the role of the renal innervation in suppressing high- and low-pressure baroreflex control of renal sympathetic nerve activity and heart rate in cisplatin-induced renal failure. METHODS: Renal failure was induced using cisplatin (5 mg kg(-1) , i.p.) and the rats used 7 days later. Groups of rats were anaesthetized and prepared for measurement of renal sympathetic nerve activity and heart rate. Acute unilateral or bilateral renal denervation was performed, and renal sympathetic nerve activity and heart rate baroreflex gain curves were generated while the cardiopulmonary receptors were stimulated using an acute saline volume load. RESULTS: Cisplatin administration reduced (P < 0.05) glomerular filtration rate by 27%, increased sodium fractional excretions fourfold, plasma creatinine and kidney index by 39 and 30% respectively, (all P < 0.05) compared with control rats. In the renal failure rats, baroreflex sensitivity for renal sympathetic nerve activity and heart rate was reduced (P < 0.05) by 29% and 27% (both P < 0.05) compared with control animals. Bilateral, but not unilateral, renal denervation restored baroreflex sensitivity to normal values. Volume expansion reduced (P < 0.05) renal sympathetic nerve activity by 34% in control rats, but remained unchanged in the renal failure rats. Unilateral and bilateral renal denervation progressively restored the volume expansion induced renal sympathoinhibition to control values. CONCLUSION: These findings reveal a significant role of the renal sensory innervation in cisplatin-damaged kidneys which blunt the normal baroreflex control of renal sympathetic nerve activity.


Subject(s)
Baroreflex/physiology , Heart Rate/physiology , Kidney/innervation , Kidney/physiology , Renal Insufficiency/physiopathology , Animals , Cisplatin/toxicity , Cross-Linking Reagents/toxicity , Disease Models, Animal , Male , Rats , Rats, Inbred WKY , Renal Insufficiency/chemically induced , Sympathectomy
11.
Acta Physiol (Oxf) ; 210(4): 832-44, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24279649

ABSTRACT

AIM: Nitric oxide (NO) interacts with the local brain renin-angiotensin system to modulate sympathetic outflow and cardiovascular homoeostasis. This study investigated whether NO influenced the ability of angiotensin AT2 receptor activation to modify the high-pressure baroreceptor regulation of renal sympathetic nerve activity (RSNA) and heart rate (HR). METHODS: Anaesthetized (chloralose/urethane) rats were prepared to allow generation of baroreflex gain curves for RSNA or HR following intracerebroventricular (I.C.V.) CGP42112 (AT2 receptor agonist), PD123319 (AT2 receptor antagonist) or losartan (AT1 receptor antagonist), and then in combination with L-NAME (NO synthase inhibitor). RESULTS: I.C.V. PD123319, CGP42112, and Losartan did not change baseline mean arterial pressure, HR or RSNA. Baroreflex sensitivities for RSNA and HR were increased following AT2 receptor activation with CGP42112 by 112 and 157%, respectively, but were reduced following PD123319 by 20% (all P < 0.05). L-NAME alone increased baroreflex sensitivity for both RSNA and HR, by 62 and 158%, respectively, but when co-infused with either CGP42112 or PD123319, the baroreflex sensitivity fell to values comparable to those obtained during I.C.V. saline infusion. The baroreflex sensitivities for RSNA and HR were increased by losartan by 92% and 192%, respectively, but in the presence of L-NAME were no different from those obtained during I.C.V. saline infusion. CONCLUSION: There is an important facilitatory role for AT2 receptors in the high-pressure baroreflex regulation of RSNA and HR which is dependent on a functional NO/NOS system. Conversely, AT1 receptors have an inhibitory effect on the baroreflex, an action that relies on a tonic inhibition of NO.


Subject(s)
Blood Pressure/physiology , Kidney/innervation , Nitric Oxide/metabolism , Receptor, Angiotensin, Type 2/metabolism , Sympathetic Nervous System/physiology , Angiotensin II Type 2 Receptor Blockers/pharmacology , Animals , Baroreflex , Male , Rats , Rats, Wistar , Receptor, Angiotensin, Type 2/agonists , Receptor, Angiotensin, Type 2/genetics
12.
Auton Autacoid Pharmacol ; 31(1-2): 13-20, 2011.
Article in English | MEDLINE | ID: mdl-21166975

ABSTRACT

1 Interaction between renin-angiotensin (RAS) and sympathetic nervous systems (SNS) was investigated by examining the effect of cumulative blockade of angiotensin II (Ang II) and adrenergic receptors in normal Sprague Dawley rats. 2 Rats were treated with losartan (10 mg/kg), carvedilol (5 mg/kg), or losartan plus carvedilol (10+5 mg/kg) orally for 7 days. On day 8, the animals were anaesthetized with pentobarbitone and prepared for systemic haemodynamic study. Dose-response relationships for the elevation of mean arterial pressure or change in heart rate (HR) in response to intravenous injections of noradrenaline (NA), phenylephrine (PE), methoxamine (ME) and Ang II were determined. 3 Losartan or the combination of losartan with carvedilol blunted vasopressor responses to ME and Ang II. Dose-response relationships for agonist action on HR were significantly inhibited by all treatments except for the combination of losartan and carvedilol on the decrease in HR induced by PE. Carvedilol decreased vasopressor responses to NA, PE and Ang II, and HR responses to NA, ME and Ang II. Combination treatment produced similar effects to losartan on the vasopressor and HR responses but had a greater effect on vasopressor responses to ME and Ang II, and on HR responses to NA and Ang II than carvedilol alone. 4 It is concluded that peripheral vasoconstriction induced by Ang II is partly mediated by adrenergic action and that the vasopressor responses to adrenergic agonists depend on an intact RAS. These observations suggest an interactive relationship between RAS and SNS in determining systemic haemodynamic responses in 'normal' rats.


Subject(s)
Adrenergic Agonists/pharmacology , Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin II/physiology , Blood Pressure/drug effects , Carbazoles/pharmacology , Losartan/pharmacology , Propanolamines/pharmacology , Vasoconstrictor Agents/pharmacology , Adrenergic Antagonists/pharmacology , Angiotensin II/antagonists & inhibitors , Angiotensin II/pharmacology , Animals , Blood Pressure/physiology , Carvedilol , Dose-Response Relationship, Drug , Heart Rate/drug effects , Male , Methoxamine/antagonists & inhibitors , Methoxamine/pharmacology , Norepinephrine/antagonists & inhibitors , Norepinephrine/pharmacology , Phenylephrine/antagonists & inhibitors , Phenylephrine/pharmacology , Rats , Rats, Sprague-Dawley , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/physiology , Sympathetic Nervous System/drug effects , Sympathetic Nervous System/physiology , Vasoconstrictor Agents/antagonists & inhibitors
13.
Acta Physiol (Oxf) ; 195(3): 397-404, 2009 Mar.
Article in English | MEDLINE | ID: mdl-19183357

ABSTRACT

AIM: This study investigated the influence of angiotensin II (Ang II) receptor and adrenergic blockade on the renal vasoconstrictions caused by Ang II and adrenergic agonists in spontaneously hypertensive rats (SHR). METHODS: Forty-eight SHR were subjected to 7 days of losartan (10 mg kg(-1) day(-1) p.o.), carvedilol (5 mg kg(-1) day(-1) p.o.) or losartan + carvedilol (10 mg kg(-1) day(-1) + 5 mg kg(-1) day(-1) p.o.). On day 8, the rats were anaesthetized and renal vasoconstrictor experiments performed. One group of rats underwent acute unilateral renal denervation. RESULTS: There were significant (P < 0.05) reductions in the renal vasoconstrictor responses to noradrenaline, phenylephrine, methoxamine and Ang II after losartan and carvedilol treatments compared with that in untreated rats (all P < 0.05). However, in renally denervated SHR treated with carvedilol, the vasoconstrictor responses to all the vasoactive agents were enhanced compared with those in SHR with intact renal nerves treated with carvedilol. Intact SHR given both losartan and carvedilol showed greater renal vasoconstrictor responses to the vasoactive agents than when given either losartan or carvedilol alone (all P < 0.05). CONCLUSION: Carvedilol reduced the vasoconstrictor response to Ang II and all the adrenergic agonists in the presence of the renal nerves, but, following the removal of renal sympathetic activity, carvedilol enhanced the sensitivity of both renal alpha(1)-adrenoceptors and AT(1) receptors to the vasoactive agents. Co-treatment with losartan and carvedilol reduced the renal vasoconstrictor responses to exogenously administered vasoactive agents but to a lesser extent than losartan or carvedilol alone. The results obtained demonstrate an interaction between Ang II receptors and adrenergic neurotransmission in the SHR.


Subject(s)
Hypertension/physiopathology , Renal Circulation/drug effects , Vasoconstriction/drug effects , Vasoconstrictor Agents/pharmacology , Adrenergic Agonists/pharmacology , Adrenergic alpha-Antagonists/pharmacology , Angiotensin II/antagonists & inhibitors , Angiotensin II/pharmacology , Angiotensin II Type 1 Receptor Blockers/pharmacology , Animals , Carbazoles/pharmacology , Carvedilol , Drug Interactions , Kidney/innervation , Losartan/pharmacology , Male , Propanolamines/pharmacology , Rats , Rats, Inbred SHR , Renal Circulation/physiology , Sympathetic Nervous System/physiopathology , Vasoconstriction/physiology , Vasoconstrictor Agents/antagonists & inhibitors
14.
Auton Autacoid Pharmacol ; 28(4): 95-101, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18778332

ABSTRACT

1. This study was undertaken to elucidate the effects of inhibiting the renin-angiotensin system (RAS) with losartan, and acute unilateral renal denervation on renal haemodynamic responses to intrarenal administration of vasoconstrictor doses of dopamine and vasodilator doses of isoprenaline in Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). 2. Acute unilateral renal denervation of the left kidney in rats was confirmed by a drop in the renal vasoconstrictor response to renal nerve stimulation (P < 0.05) along with diuresis and natriuresis. Rats were pretreated with losartan for 7 days and thereafter animals fasted overnight were anaesthetized (sodium pentobarbitone, 60 mg/kg i.p.) and acute renal haemodynamic responses studied. 3. Dose-response curves were constructed for dopamine and isoprenaline that induced falls or increases in renal blood flow, respectively. It was observed that renal vascular responses were greater in the denervated as compared with rats with intact renal nerves (all P < 0.05). Dopamine-induced renal vasoconstrictor responses were markedly lower in losartan-treated denervated WKY and SHR compared with their untreated counterparts (all P < 0.05). It was also observed that in losartan-treated and denervated WKY rats the vasodilatory responses to isoprenaline were markedly lower compared with untreated rats (all P < 0.05). However, in SHR, under the same conditions, there was no difference in the renal response to isoprenaline whether or not rats were treated with losartan (P > 0.05). 4. The data obtained showed that the renal vasoconstrictor effect of dopamine depends on intact renal nerves and RAS in WKY and SHR. Isoprenaline responses were likewise sensitive to renal denervation and RAS inhibition in WKY rats but not SHRs. Our observations reveal a possible relationship between renal AT(1) receptors and alpha(1)-adrenoceptors in WKY and SHR. There is also evidence to suggest an interaction between renal beta-adrenoceptors and AT(1) receptors in WKY rats.


Subject(s)
Angiotensin II/antagonists & inhibitors , Dopamine/pharmacology , Isoproterenol/pharmacology , Renin-Angiotensin System/physiology , Sympathetic Nervous System/physiology , Angiotensin II Type 1 Receptor Blockers/pharmacology , Animals , Blood Pressure/drug effects , Blood Pressure/physiology , Hemodynamics/drug effects , Hemodynamics/physiology , Hypertension/physiopathology , Kidney/blood supply , Kidney/innervation , Losartan/pharmacology , Male , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Renal Circulation/drug effects , Renal Circulation/physiology , Renin-Angiotensin System/drug effects , Sodium/urine , Species Specificity , Sympathectomy , Sympathetic Nervous System/drug effects , Sympathetic Nervous System/surgery , Sympathomimetics/pharmacology
15.
Auton Autacoid Pharmacol ; 28(2-3): 87-94, 2008.
Article in English | MEDLINE | ID: mdl-18598290

ABSTRACT

1 This study was undertaken to characterize the renal responses to acute unilateral renal denervation in anaesthetized spontaneously hypertensive rats (SHR) by examining the effect of acute unilateral renal denervation on the renal hemodynamic responses to a set of vasoactive agents and renal nerve stimulation. 2 Twenty-four male SHR rats underwent acute unilateral renal denervation and the denervation was confirmed by significant drop (P < 0.05) in renal vasoconstrictor response to renal nerve stimulation along with marked diuresis and natriuresis following denervation. After 7 days treatment with losartan, the overnight fasted rats were anaesthetized (sodium pentobarbitone, 60 mg kg(-1) i.p.) and renal vasoconstrictor experiments were performed. The changes in the renal vasoconstrictor responses were determined in terms of reductions in renal blood flow caused by renal nerve stimulation or intrarenal administration of noradrenaline, phenylephrine, methoxamine and angiotensin II. 3 The data showed that there was significantly (all P < 0.05) increased renal vascular responsiveness to the vasoactive agents in denervated rats compared to those with intact renal nerves. In losartan-treated denervated SHR rats, there were significant (all P < 0.05) reductions in the renal vasoconstrictor responses to neural stimuli and vasoactive agents as compared with that of untreated denervated SHR rats. 4 The data obtained in denervated rats suggested an enhanced sensitivity of the alpha(1)-adrenoceptors to adrenergic agonists and possible increase of AT(1) receptors functionality in the renal vasculature of these rats. These data also suggested a possible interaction between sympathetic nervous system and renin-angiotensin system in terms of a crosstalk relationship between renal AT(1) and alpha(1)-adrenoceptor subtypes.


Subject(s)
Hemodynamics/physiology , Kidney/physiology , Sympathectomy , Adrenergic alpha-Agonists/pharmacology , Angiotensin II/pharmacology , Animals , Blood Pressure/drug effects , Blood Pressure/physiology , Denervation , Electric Stimulation , Hemodynamics/drug effects , Kidney/blood supply , Kidney/innervation , Losartan/pharmacology , Male , Methoxamine/pharmacology , Norepinephrine/pharmacology , Phenylephrine/pharmacology , Rats , Rats, Inbred SHR , Renal Circulation/drug effects , Renal Circulation/physiology , Sodium/urine , Urodynamics/drug effects , Vasoconstriction/drug effects , Vasoconstriction/physiology
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