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Adverse effects of melatonin on rat pups of Wistar-Kyoto dams receiving melatonin supplementation during pregnancy

Singh HJ, Keah LS, Kumar A, Sirajudeen KN

Exp. Toxicol. Pathol., 2012 Nov;64(7-8):751-2.
PMID: 21354772 DOI: 10.1016/j.etp.2011.01.011

This report documents an incidental finding during a study investigating the effects of melatonin supplementation on the development of blood pressure in SHR. Administration of 10 mg/kg/day of melatonin in drinking water during pregnancy to Wistar-Kyoto (WKY) dams caused a loss of more than 50% of the pups by the age of three weeks and 95% by the age of 6 weeks. There was no maternal morbidity or mortality in the two strains or death of any of the SHR pups. No obvious physical defects were present but mean body weight was lower in the surviving WKY rats when compared to that of melatonin supplemented SHR or non-supplemented WKY pups. The reason for the high mortality in WKY pups is uncertain and appears to be strain if not batch specific. There is a need for caution in its use, particularly during pregnancy, and clearly necessitates more detailed studies.

Matched MeSH terms: Rats, Inbred SHR
Fulltext Alpha1B-adrenoceptors mediate adrenergically-induced renal vasoconstrictions in rats with renal impairment

Khan MA, Sattar MA, Abdullah NA, Johns EJ

Acta Pharmacol Sin, 2008 Feb;29(2):193-203.
PMID: 18215348 DOI: 10.1111/j.1745-7254.2008.00727.x

This study examined whether alpha1B-adrenoceptors are involved in mediating adrenergically-induced renal vasoconstrictor responses in rats with pathophysiological and normal physiological states.

Matched MeSH terms: Rats, Inbred SHR
Altered cardiac tissue and plasma kininogen levels in hypertensive and diabetic rats

Sharma JN, Kesavarao U, Yusof AP

Immunopharmacology, 1999 Sep;43(2-3):129-32.
PMID: 10596843 DOI: 10.1016/s0162-3109(99)00070-3

The present investigation was aimed at evaluating the cardiac and total plasma kininogen levels, as well as LVWT in hypertensive and diabetic rats. STZ-induced diabetes produced a significant (P < 0.001) rise in mean arterial blood pressure (BP). The LVWT increased (P < 0.001) in SHR with and without diabetes) and diabetic WKYR. The cardiac tissue, as well as total plasma kininogen levels fell significantly (P < 0.001) in diabetic WKYR and SHR with and without diabetes compared to the control WKYR. These findings suggest that reduced kininogen levels may indicate a deficiency in kinin generation in the heart and in the peripheral circulation in diabetic and hypertensive rats. This effect may contribute to the development of LVH.

Matched MeSH terms: Rats, Inbred SHR
Angiotensin-I Converting Enzyme (ACE) Inhibitory and Anti-Hypertensive Effect of Protein Hydrolysate from Actinopyga lecanora (Sea Cucumber) in Rats

Sadegh Vishkaei M, Ebrahimpour A, Abdul-Hamid A, Ismail A, Saari N

Mar Drugs, 2016 Sep 30;14(10).
PMID: 27706040

Food protein hydrolysates are known to exhibit angiotensin converting enzyme (ACE) inhibitory properties and can be used as a novel functional food for prevention of hypertension. This study evaluated the ACE inhibitory potentials of Actinopyga lecanora proteolysate (ALP) in vivo. The pre-fed rats with ALP at various doses (200, 400, 800 mg/kg body weight) exhibited a significant (p ≤ 0.05) suppression effect after inducing hypertension. To determine the optimum effective dose that will produce maximal reduction in blood pressure, ALP at three doses was fed to the rats after inducing hypertension. The results showed that the 800 mg/kg body weight dose significantly reduced blood pressure without noticeable negative physiological effect. In addition, there were no observable changes in the rats' heart rate after oral administration of the ALP. It was concluded that Actinopyga lecanora proteolysate could potentially be used for the development of functional foods and nutraceuticals for prevention and treatment of hypertension.

Matched MeSH terms: Rats, Inbred SHR
Fulltext Anti-hypertensive effect of pink guava (Psidium guajava) puree on spontaneous hypertensive rats

Ayub, M.Y., Norazmir, M.N., Mamot, S., Jeeven, K., Hadijah, H.

International Food Research Journal, 2010;17(1):89-96.
MyJurnal

The objective of this study was to determine the physicochemical properties of pink guava (Psidium guajava) puree and its anti-hypertensive effect on Spontaneous Hypertensive Rats (SHR). Antioxidant activities of pink guava puree in water and ethanol extracts, based on 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, were 1.43±0.04 mg/gfm and 0.28±0.01 mg/gfm, respectively. A total of 24 male SHRs were divided into a control group, CG, and 3 treatment dosage groups [low dose group, LDG (0.5 g/kg body weight/day), medium dose group, MDG (1.0 g/kg body weight/day), and high dose group, HDG (2.0 g/kg body weight/day)]. Final body weights for treatment dosage groups were lower [MDG (313.01±31.25 g), HDG (318.56±17.96 g), LDG (320.01±22.70 g)] compared to CG (331.08±41.29 g). Final systolic blood pressure values from the beginning and the end of the experiment in MDG and HDG were 231-179 mmHg and 246-169mm Hg, respectively. These results were significantly lower when compared with CG (241-223 mmHg) from the beginning until the end of the experiment. As a conclusion, these results showed that pink guava puree has anti-hypertensive properties.

Matched MeSH terms: Rats, Inbred SHR
Antihypertensive activity and vascular reactivity mechanisms of Vitex pubescens leaf extracts in spontaneously hypertensive rats

Al-Akwaa AA, Asmawi MZ, Dewa A, Mahmud R

Heliyon, 2020 Jul;6(7):e04588.
PMID: 32775735 DOI: 10.1016/j.heliyon.2020.e04588

Background: Vitex pubescens has been used traditionally in hypertension treatment but not yet scientifically assessed. The objective of the study is to investigate the antihypertensive and vasorelaxant activities of V. pubescens, study its underlying pharmacological mechanisms, and identify the relevant vasoactive compounds.
Methods: Successive extractions of V. pubescens leaf were carried out to produce petroleum ether (VPPE), chloroform (VPCE), methanol (VPME), and water (VPWE) extracts. Spontaneously hypertensive rats (SHRs) received a daily oral administration of the extracts (500 mg/kg/day; n = 6) or verapamil (15 mg/kg/day; n = 6) for 2 weeks, while the systolic and diastolic blood pressures were measured using non-invasive tail-cuff method. Vasorelaxation assays of the extracts were later conducted using phenylephrine (PE, 1 μM) pre-contracted aortic ring preparation. Mechanisms of vasorelaxation by the most potent fraction were studied using vasorelaxation assays with selected blockers/inhibitors. GC-MS was conducted to determine the active compounds.
Results: VPPE elicited the most significant diminution in systolic and diastolic blood pressure of treated SHRs and produced the most significant vasorelaxation in the aortic rings. Vasorelaxant effects of F2-VPPE were significantly reduced in endothelium-denuded aortic rings by glibenclamide (1 μM), whereas calcium chloride and PE-induced contractions were significantly suppressed. Endothelium removal of the aortic rings or incubation with indomethacin (10 μM), atropine (1 μM), methylene blue (10 μM), propranolol (1μM) and L-NAME (10 μM) did not significantly alter F2-VPPE-induced vasorelaxation. Seven compounds were identified using GC-MS, including spathulenol.
Conclusion: F2-VPPE exerted its endothelium-independent vasorelaxation by inhibition of vascular smooth muscle contraction induced by extracellular Ca+2 influx through trans-membrane Ca+2 channels and/or Ca+2 release from intracellular stores, and by activation of KATP channels. The vasorelaxation effects of V. pubescens could be mediated by the compound, spathulenol.

Matched MeSH terms: Rats, Inbred SHR
Fulltext Autonomic Nervous System Mediates the Hypotensive Effects of Aqueous and Residual Methanolic Extracts of Syzygium polyanthum (Wight) Walp. var. polyanthum Leaves in Anaesthetized Rats

Ismail A, Mohamed M, Sulaiman SA, Wan Ahmad WA

Evid Based Complement Alternat Med, 2013;2013:716532.
PMID: 24454508 DOI: 10.1155/2013/716532

Syzygium polyanthum (Wight) Walp. var. polyanthum leaves are consumed as a traditional Malay treatment of hypertension. This study investigates hypotensive potential of aqueous (AESP) and residual methanolic (met-AESP) extracts of S. polyanthum leaves and possible involvement of autonomic receptors. AESP and met-AESP (20 to 100 mg/kg) were intravenously administered into anaesthetized Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Blood pressure and heart were monitored for 20 min. AESP and met-AESP induced significant dose-dependent hypotension, but only 100 mg/kg AESP caused mild bradycardia (n = 5). AESP-induced hypotension was more potent than that of met-AESP in WKY. AESP has a faster onset time than that of met-AESP in both WKY and SHR. However, met-AESP-induced hypotension was more sustained than that of AESP in SHR. Blockages of autonomic ganglion and α -adrenergic receptors using hexamethonium and phentolamine (n = 5 for each group) partially attenuated AESP-induced hypotension, suggesting involvement of α -adrenergic receptors. Blockages of autonomic ganglion, β -adrenergic, cholinergic receptors, and nitric oxide production using hexamethonium, propranolol, atropine, and N- ω -nitro-l arginine methyl ester (L-NAME) (n = 5 for each group) partially attenuated met-AESP-induced hypotension, suggesting involvement of β -adrenergic and cholinergic receptors via nitric oxide production.

Matched MeSH terms: Rats, Inbred SHR
Blood pressure and urine metabolite changes in spontaneously hypertensive rats treated with leaf extract of Ficus deltoidea var angustifolia

Kamal MSA, Mediani A, Kasim N, Ismail NH, Satar NA, Azis NA, et al.

J Pharm Biomed Anal, 2022 Feb 20;210:114579.
PMID: 35016031 DOI: 10.1016/j.jpba.2021.114579

Ficus deltoidea var angustifolia (FD-A) reduces blood pressure in spontaneously hypertensive rats (SHR) but the mechanism remains unknown. Changes in urine metabolites following FD-A treatment in SHR were, therefore, examined to identify the mechanism of its antihypertensive action. Male SHR were given either FD-A (1000 mg kg-1 day-1) or losartan (10 mg kg-1 day-1) or 0.5 mL of ethanolic-water (control) daily for 4 weeks. Systolic blood pressure (SBP) was measured every week and urine spectra data acquisition, on urine collected after four weeks of treatment, were compared using multivariate data analysis. SBP in FD-A and losartan treated rats was significantly lower than that in the controls after four weeks of treatment. Urine spectra analysis revealed 24 potential biomarkers with variable importance projections (VIP) above 0.5. These included creatine, hippurate, benzoate, trimethylamine N-oxide, taurine, dimethylamine, homocysteine, allantoin, methylamine, n-phenylacetylglycine, guanidinoacetate, creatinine, lactate, glucarate, kynurenine, ethanolamine, betaine, 3-hydroxybutyrate, glycine, lysine, glutamine, 2-hydroxyphenylacetate, 3-indoxylsulfate and sarcosine. From the profile of these metabolites, it seems that FD-A affects urinary levels of metabolites like taurine, hypotaurine, glycine, serine, threonine, alanine, aspartate and glutamine. Alterations in these and the pathways involved in their metabolism might underlie the molecular mechanism of its antihypertensive action.

Matched MeSH terms: Rats, Inbred SHR
Blood pressure lowering effect and vascular activity of Phyllanthus niruri extract: The role of NO/cGMP signaling pathway and β-adrenoceptor mediated relaxation of isolated aortic rings

Bello I, Usman NS, Dewa A, Abubakar K, Aminu N, Asmawi MZ, et al.

J Ethnopharmacol, 2020 Mar 25;250:112461.
PMID: 31830549 DOI: 10.1016/j.jep.2019.112461

ETHNOPHARMACOLOGICAL RELEVANCE: Phyllanthus niruri have a long history of use in the traditional treatment of various ailments including hypertension. Literature reports have indicated that it is a potent antihypertensive herbal medication used traditionally.
AIM OF THE STUDY: This study was carried out to investigate the antihypertensive and vasodilatory activity of four solvents extracts of P. niruri namely; petroleum ether (PEPN), chloroform (CLPN), methanol (MEPN) and water (WEPN), with the aim of elucidating the mechanism of action and identifying the phytochemical constituents.
MATERIALS AND METHODS: Male Spontaneous Hypertensive Rats (SHRs) were given oral gavage of P. niruri extract daily for two weeks and the blood pressure was recorded in vivo. We also determine the vasodilation effect of the extracts on rings of isolated thoracic aorta pre-contracted with phenylephrine (PE, 1 μM). Endothelium-intact or endothelium-denuded aorta rings were pre-incubated with various antagonists like 1H-[1,2,4] oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ, 10 μM) and Methylene blue (MB 10 μM), sGC inhibitors; Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME, 10 μM) a nitric oxide synthase (NOS) inhibitor; atropine (10 μM), a cholinergic receptor blocker; indomethacin (10 μM), a cyclooxygenase inhibitor and various K+ channel blockers such as glibenclamide (10 μM) and tetraethyl ammonium (TEA 10 μM) for mechanism study.
RESULTS: SHRs receiving P. niruri extracts showed a significant decrease in their blood pressure (BP) when compared to the baseline value, with PEPN being more potent. The extracts (0.125-4 mg/mL) also induced vasorelaxation on endothelium-intact aorta rings. PEPN elicited the most potent maximum relaxation effect (Rmax). Mechanism assessment of PEPN showed that its relaxation effect is significantly suppressed in endothelium-denuded aorta rings. Pre-incubation of aorta rings with atropine, L-NAME, ODQ, indomethacin, and propranolol also significantly attenuated its relaxation effect. Conversely, incubation with TEA and glibenclamide did not show a significant effect on PEPN-induced relaxation.
CONCLUSION: This study indicates that the antihypertensive activity of P. niruri extract is mediated by vasoactive phytoconstituents that dilate the arterial wall via endothelium-dependent pathways and β-adrenoceptor activity which, in turn, cause vasorelaxation and reduce blood pressure.

Matched MeSH terms: Rats, Inbred SHR
Blood pressure lowering effect of Ficus deltoidea var kunstleri in spontaneously hypertensive rats: possible involvement of renin-angiotensin-aldosterone system, endothelial function and anti-oxidant system

Azis NA, Agarwal R, Ismail NM, Ismail NH, Kamal MSA, Radjeni Z, et al.

Mol Biol Rep, 2019 Jun;46(3):2841-2849.
PMID: 30977084 DOI: 10.1007/s11033-019-04730-w

This study investigated the effects of a standardised ethanol and water extract of Ficus deltoidea var. Kunstleri (FDK) on blood pressure, renin-angiotensin-aldosterone system (RAAS), endothelial function and antioxidant system in spontaneously hypertensive rats (SHR). Seven groups of male SHR were administered orally in volumes of 0.5 mL of either FDK at doses of 500, 800, 1000 and 1300 mg kg- 1, or captopril at 50 mg kg- 1 or losartan at 10 mg kg- 1 body weight once daily for 4 weeks or 0.5 mL distilled water. Body weight, systolic blood pressures (SBP) and heart rate (HR) were measured every week. 24-hour urine samples were collected at weeks 0 and 4 for electrolyte analysis. At week 4, sera from rats in the control and 1000 mg kg- 1 of FDK treated groups were analyzed for electrolytes and components of RAAS, endothelial function and anti-oxidant capacity. SBP at week 4 was significantly lower in all treatment groups, including captopril and losartan, when compared to that of the controls. Compared to the controls, ACE activity and concentrations of angiotensin I, angiotensin II and aldosterone were lower whereas concentrations of angiotensinogen and angiotensin converting enzyme 2 were higher in FDK treated rats. Concentration of eNOS and total anti-oxidant capacity were higher in FDK treated rats. Urine calcium excretion was higher in FDK treated rats. In conclusion, it appears that ethanol and water extract of FDK decreases blood pressure in SHR, which might involve mechanisms that include RAAS, anti-oxidant and endothelial system.

Matched MeSH terms: Rats, Inbred SHR
Blood-pressure lowering efficacy of winged bean seed hydrolysate in spontaneously hypertensive rats, peptide characterization and a toxicity study in Sprague-Dawley rats

Chay SY, Salleh A, Sulaiman NF, Zainal Abidin N, Hanafi MA, Zarei M, et al.

Food Funct, 2018 Mar 01;9(3):1657-1671.
PMID: 29469915 DOI: 10.1039/c7fo01769c

Winged bean seed (WBS) is an underutilized tropical crop. The current study evaluates its potential to reduce blood pressure (BP) in spontaneously hypertensive rats and finds that it reduces BP significantly, in a dose-dependent manner. Five peptides with the sequences, RGVFPCLK, TQLDLPTQ, EPALVP, MRSVVT and DMKP, have been characterized in terms of their stability against ACE via in vitro and in silico modelling. All peptides exhibited IC50 values between 0.019 and 6.885 mM and various inhibitory modes, including substrate, prodrug and true inhibitor modes. The toxicity status of non-Current Good Manufacturing Practice (non-CGMP) peptides is evaluated and the results show that such peptides are toxic, and thus are not suitable to be tested in animals, particularly in repeated-dose studies. In short, WBS hydrolysate demonstrated in vitro ACE inhibitory properties and in vivo blood pressure lowering efficacy in rat models, fostering its potential as a functional food ingredient. Non-CGMP grade peptides are toxic and unfit for testing in animal models.

Matched MeSH terms: Rats, Inbred SHR
Cardiac kallikrein in hypertensive and normotensive rats with and without diabetes

Sharma JN, Kesavarao U

Immunopharmacology, 1996 Jun;33(1-3):341-3.
PMID: 8856181 DOI: 10.1016/0162-3109(96)00104-x

This study examined the effects of streptozotocin-induced diabetes on blood pressure and cardiac tissue kallikrein levels in WKYR and SHR. Streptozotocin-induced diabetes caused significant (p < 0.001) increase in SBP and DBP in WKYR and SHR as compared with their respective controls. We also observed that the active cardiac tissue kallikrein levels reduced greatly (p < 0.001) in diabetic WKYR and SHR than the normal rats. These findings suggest for the first time that the cardiac tissue kallikrein formation may have a greater role in the regulation of blood pressure and cardiac function.

Matched MeSH terms: Rats, Inbred SHR
Cardiovascular effects of aspidofractinine-type alkaloids from Kopsia

Mok SL, Yoganathan K, Lim TM, Kam TS

J Nat Prod, 1998 Mar;61(3):328-32.
PMID: 9544563

Intravenous injection of the aspidofractinine alkaloid, kopsingine (1, 0.2-10.0 mg/kg) from Kopsia teoi, produced dose-related decreases in the mean arterial blood pressure and heart rate in anesthetized spontaneously hypertensive rats, which were similar to those seen in normotensive controls. Minor modifications in the molecular structure of kopsingine, as in kopsaporine (2, the 12-demethoxy derivative of kopsingine) and 14,15-dihydrokopsingine (4), did not significantly alter the hypotensive responses, whereas a more drastic change in the structure, as in the heptacyclic kopsidine A (3) and the 3-to-17 oxo-bridged compound 5, resulted in an increase in blood pressure. The antihypertensive effects of kopsingine (1) and its congeners (2 and 4) along with the pressor effects produced by the heptacyclic oxo-bridged compounds (5 and 3) could be ascribed to central as well as peripheral actions.

Matched MeSH terms: Rats, Inbred SHR
Fulltext Changes in the urinary metabolites in losartan-treated spontaneously hypertensive rats

Norasikin Ab Azis, Mohd Saleh Ahmad Kamal, Zurain Radjeni, Ahmed Mediani, Renu Agarwal

Journal of Clinical and Health Sciences, 2021;6(1):32-45.
MyJurnal

Introduction: This study examined the association of losartan induced changes in urinary
metabolomic profile with the changes in blood pressure (BP) and renin-angiotensinaldosterone system (RAAS) in spontaneously hypertensive rats (SHR). Methods: Male SHR
were administered with either 0.5 mL of distilled water (control group, n=6) or 10 mg.kg-1 of
losartan (group 2, n=6) daily by oral gavage for 4 weeks. Body weight, BP, food and water
intake were measured weekly. At week 4, urine was collected for urinary electrolyte analysis
and metabolite profiling, after which the animals were euthanised by decapitation and blood
was collected for analysis of components of RAAS and electrolyte concentrations. Urine
metabolite profile of SHR was determined using proton nuclear magnetic resonance (
1H-NMR)
spectrometry combined with multivariate data analysis. Results: At week 4, losartan-treated
SHR had significantly lower BP than non-treated SHR. There were no differences in water
and food intake, body weight, serum and urinary electrolyte concentrations or in their urinary
excretions between the two groups. No differences were evident in the components of RAAS
except that the angiotensinogen level was significantly higher in losartan-treated SHR
compared to non-treated SHR. Orthogonal partial least squares discriminant analysis (OPLSDA) showed clear separation of urinary metabolites between control and losartan-treated
SHR. Losartan-treated SHR group was separated from the control group by changes in the
intermediates involved in glycine, serine and threonine metabolism. Conclusion:
Antihypertensive effect of losartan in SHR seems to be associated with changes in urinary
metabolite profile, particularly involving the metabolism of glycine, serine and threonine.

Matched MeSH terms: Rats, Inbred SHR
Chronic treatment with flavonoids prevents endothelial dysfunction in spontaneously hypertensive rat aorta

Machha A, Mustafa MR

J Cardiovasc Pharmacol, 2005 Jul;46(1):36-40.
PMID: 15965352

Flavonoids are known to possess cardioprotective properties. Vascular endothelial function is a surrogate marker for cardiovascular diseases, including hypertension. We have studied the effects of chronic flavonoid treatment on vascular endothelial functions in spontaneously hypertensive rats (SHR). Starting from 6-7 weeks old, SHR were given flavonoids (baicalein, flavone, or quercetin) orally (10 mg/kg, once daily) to the SHRs for 4 weeks. Aortas from all the flavonoid-treated animals showed remarkably higher endothelium-dependent relaxations to acetylcholine, to a similar extent as those pretreated with the angiotensin-converting enzyme inhibitor, captopril. However, in contrast to other experimental groups, flavone pretreatment also enhanced the endothelium-independent relaxations to sodium nitroprusside. In addition, treatment with either flavone or quercetin induced a significant attenuation in systolic blood pressure of the hypertensive animals. The present results suggest that chronic treatment with the flavonoids (baicalein, flavone, and quercetin) preserves vascular endothelial functions in hypertensive animals through several possible actions, including increasing endothelial nitric oxide production and bioavailability and reduction in blood pressure.

Matched MeSH terms: Rats, Inbred SHR
Chronic treatment with losartan and carvedilol differentially modulates renal vascular responses to sympathomimetics compared to treatment with individual agents in normal Wistar Kyoto and spontaneously hypertensive rats

Abdulla MH, Sattar MA, Abdullah NA, Khan MA, Abdallah HH, Johns EJ

Eur J Pharmacol, 2009 Jun 10;612(1-3):69-74.
PMID: 19356722 DOI: 10.1016/j.ejphar.2009.03.064

This study set out to investigate the impact of chronic cumulative blockade of angiotensin II and adrenoceptors in WKY and SHR and to explore how the renovascular responses to adrenergic and angiotensin II receptor agonists may be interdependent. Rats were treated with either losartan, carvedilol or losartan+carvedilol for 7 days and on day eight, animals were pentobarbitone anaesthetized and prepared for renal haemodynamic study. Dose-response relationships were determined in terms of reduction/elevation in the magnitude of renal blood flow in response to intrarenal arterial injection of dopamine, phenylephrine and isoprenaline. Renal vascular responses were blunted in WKY and SHR treated with either losartan or carvedilol as compared to their untreated counterparts (P<0.05). In the combined treated rats, the vascular responses to isoprenaline and phenylephrine were restored to levels observed in the untreated rats, but the renal vasoconstrictor responses to dopamine decreased (P<0.05) in both WKY and SHR. There was a reduction of (P<0.05) in the magnitude of the isoprenaline induced renal vasodilation in all SHR as compared to WKY groups. The data obtained showed that the renal vascular action of dopamine, phenylephrine and isoprenaline depended on an intact renin-angiotensin system (RAS) in WKY and SHR. Treatment with losartan or carvedilol blunted the renal vasoconstrictor/vasodilator responses to sympathomimetics which was attenuated with the combined treatment. These observations using chronic blockade of adrenergic and angiotensin receptors demonstrated that there was a long standing interdependency between the RAS and sympathetic nervous system (SNS) in determining the responsiveness of the renal vasculature of normal and hypertensive rats.

Matched MeSH terms: Rats, Inbred SHR
Cisplatin-induced nephrotoxicity causes altered renal hemodynamics in Wistar Kyoto and spontaneously hypertensive rats: role of augmented renal alpha-adrenergic responsiveness

Hye Khan MA, Abdul Sattar M, Abdullah NA, Johns EJ

Exp. Toxicol. Pathol., 2007 Nov;59(3-4):253-60.
PMID: 17764917

The pathogenesis of cisplatin-induced renal failure is related to reduced renal blood flow due to severe tubular damage and enhanced renovascular resistance. It is also known that alpha(1)-adrenoceptors, the major subtype of alpha-adrenoceptors in renal vasculature play the pivotal role in regulating renal hemodynamics. With this background, we have hypothesized that the altered renal hemodynamics and enhanced renovascular resistance in cisplatin-induced renal failure might be caused by the altered alpha-adrenergic responsiveness with a possible involvement of alpha(1)-adrenoceptors in the renal vasculature. In a unique experimental approach with anesthetized rats, this study has therefore examined if there is any shift in the renovascular responsiveness to renal nerve stimulation and a series of alpha-adrenergic agonists in Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats with cisplatin-induced renal failure in comparison with their body weight-matched normal controls. Thirty-two male rats of both WKY (n=16) and SHR (n=16) origin with body weight 236+/-7.9 g received cisplatin (5mg/kg i.p.). The renal failure was confirmed in terms of significantly reduced renal blood flow, reduced creatinine clearance, increased fractional excretion of sodium, increased kidney index (all P<0.05) and tubular damage. After 7 days of cisplatin, the overnight fasted rats were anesthetized (sodium pentobarbitone, 60 mg/kg i.p.) and renal vasoconstrictor experiments were done. The changes in the vasoconstrictor responses were determined in terms of reductions in renal blood flow caused by electrical renal nerve stimulation or intrarenal administration of noradrenaline, phenylephrine and methoxamine. It was observed that in the cisplatin-treated renal failure WKY and SHR rats there were significant (all P<0.05) reductions in the renal blood flow along with significantly (P<0.05) higher renal adrenergic responsiveness as compared with their non-renal failure controls. The data showed that in the renal failure WKY and SHR rats, the altered renal hemodynamics might be caused by an augmented renal adrenergic responsiveness. The results obtained further led us to suggest that the augmented renal adrenergic responsiveness in the cisplatin-induced renal failure rats were possibly mediated by the alpha(1)-adrenoceptors.

Matched MeSH terms: Rats, Inbred SHR
Clonidine and a novel clonidine analog AL-12 cause sympathoinhibition in spontaneously hypertensive and diabetic spontaneously hypertensive rats

Lazahari MI, Sattar MA, Abdullah NA, Khan MA, Johns EJ

Methods Find Exp Clin Pharmacol, 2008 Apr;30(3):193-9.
PMID: 18597003 DOI: 10.1358/mf.2008.30.3.1166221

This study examined the sympathoinhibitory effects of clonidine and a novel clonidine analog, AL-12, in rat models of genetic hypertension and a combined state of genetic hypertension and diabetes. Rats in the treatment groups were given either clonidine or AL-12 while the respective control groups received either saline or Tween 80 for 6 days. Physiological data were collected during this period, which was followed by acute studies on day 7 when bolus administrations (i.v.) of graded doses of noradrenaline, phenylephrine and methoxamine were carried out. It was observed that in AL-12-treated nondiabetic spontaneously hypertensive rats (SHR), the pressure responses to all adrenergic agonists were greater (p < 0.05) in the treated group, while in the diabetic SHR rats a larger pressure response was observed only to noradrenaline (p < 0.05). In nondiabetic SHR rats treated with clonidine, a greater (p < 0.05) pressure response was observed only in the case of phenylephrine. In the diabetic SHR rats treated with clonidine, the pressure responses to the adrenergic agonists were similar (p > 0.05) in the treated and its control animals except that methoxamine caused a greater (p < 0.05) pressure response in the control group. The data obtained suggest that clonidine and AL-12 act possibly via vascular alpha1 and alpha2 adrenoceptors present at both pre- and postsynaptic locations.

Matched MeSH terms: Rats, Inbred SHR
Des-aspartate angiotensin I (DAA-I) reduces endothelial dysfunction in the aorta of the spontaneously hypertensive rat through inhibition of angiotensin II-induced oxidative stress

Loh WM, Ling WC, Murugan DD, Lau YS, Achike FI, Vanhoutte PM, et al.

Vascul. Pharmacol., 2015 Aug;71:151-8.
PMID: 25869508 DOI: 10.1016/j.vph.2015.03.011

Des-aspartate angiotensin I (DAA-I), an endogenous nonapeptide, counteracts several effects of angiotensin II on vascular tone. The aim of this study was to investigate the acute protective effect of DAA-I on endothelial function in the spontaneously hypertensive rat (SHR) as well as its effect on angiotensin II-induced contractions and oxidative stress. Aortic rings were incubated with DAA-I (0.1μM) for 30min prior to the assessment of angiotensin II-induced contractions (0.1nM-10μM) in WKY and SHR aortas. Total nitrate and nitrite levels were assessed using a colorimetric method and reactive oxygen species (ROS) were measured by dihydroethidium (DHE) fluorescence and lucigenin-enhanced chemiluminescence. The effect of DAA-I was also assessed against endothelium-dependent and -independent relaxations to acetylcholine and sodium nitroprusside, respectively. Angiotensin II-induced contractions were significantly reduced by DAA-I, losartan and tempol. Incubation with ODQ (soluble guanylyl cyclase inhibitor) and removal of the endothelium prevented the reduction of angiotensin II-induced contractions by DAA-I. Total nitrate and nitrite levels were increased in DAA-I, losartan and tempol treated-SHR tissues while ROS level was reduced by DAA-I and the latter inhibitors. In addition, DAA-I significantly improved the impaired acetylcholine-induced relaxation in SHR aortas whilst sodium nitroprusside-induced endothelium-independent relaxation remained unaffected. The present findings indicate that improvement of endothelial function by DAA-I in the SHR aorta is mediated through endothelium-dependent release of nitric oxide and inhibition of angiotensin II-induced oxidative stress.

Matched MeSH terms: Rats, Inbred SHR
Fulltext Differential responses to blood pressure and oxidative stress in streptozotocin-induced diabetic Wistar-Kyoto rats and spontaneously hypertensive rats: effects of antioxidant (honey) treatment

Erejuwa OO, Sulaiman SA, Wahab MS, Sirajudeen KN, Salleh MS, Gurtu S

Int J Mol Sci, 2011;12(3):1888-907.
PMID: 21673929 DOI: 10.3390/ijms12031888

Oxidative stress is implicated in the pathogenesis and/or complications of hypertension and/or diabetes mellitus. A combination of these disorders increases the risk of developing cardiovascular events. This study investigated the effects of streptozotocin (60 mg/kg; ip)-induced diabetes on blood pressure, oxidative stress and effects of honey on these parameters in the kidneys of streptozotocin-induced diabetic Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Diabetic WKY and SHR were randomized into four groups and received distilled water (0.5 mL) and honey (1.0 g/kg) orally once daily for three weeks. Control SHR had reduced malondialdehyde (MDA) and increased systolic blood pressure (SBP), catalase (CAT) activity, and total antioxidant status (TAS). SBP, activities of glutathione peroxidase (GPx) and glutathione reductase (GR) were elevated while TAS was reduced in diabetic WKY. In contrast, SBP, TAS, activities of GPx and GR were reduced in diabetic SHR. Antioxidant (honey) treatment further reduced SBP in diabetic SHR but not in diabetic WKY. It also increased TAS, GSH, reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio, activities of GPx and GR in diabetic SHR. These data suggest that differences in types, severity, and complications of diseases as well as strains may influence responses to blood pressure and oxidative stress.

Matched MeSH terms: Rats, Inbred SHR

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