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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: Norepinephrine/pharmacology
The effect of enalapril on tyramine induced changes in renal function in man

Rahman AR, Lang CC, Struthers AD

Int J Clin Pharmacol Ther, 1995 Jul;33(7):404-9.
PMID: 7582398

Increasing animal evidence support an important facilitatory interaction between angiotensin II and norepinephrine within the kidney. This angiotensin II/norepinephrine interaction was investigated in man by examining the effect of enalapril pretreatment (5 mg for 5 days) on the renal response to a low non-pressor dose of intravenous tyramine 4 micrograms/kg/min for 120 min in 8 healthy subjects undergoing water diuresis. Tyramine is an indirect sympathomimetic agent which causes neuronal release of norepinephrine. Enalapril and tyramine, alone and in combination, had no effect on glomerular filtration, effective renal plasma flow or sodium excretion. Tyramine caused a significant increase in urinary flow rate (p < 0.05) but this was not influenced by enalapril pretreatment. The lack of effect of enalapril on the renal response to tyramine contrasts with a previous study which examined the effect of enalapril on the renal response to circulating norepinephrine. This may suggest that enalapril affect renal function only when there is renal vasoconstriction (as with norepinephrine) and not when renal blood flow is unchanged (as with tyramine).

Matched MeSH terms: Norepinephrine/blood
Fulltext Cholecystokinin hyperresponsiveness in functional dyspepsia

Chua AS, Keeling PW

World J Gastroenterol, 2006 May 07;12(17):2688-93.
PMID: 16718754 DOI: 10.3748/wjg.v12.i17.2688

Functional dyspepsia (FD) is a common disorder of yet uncertain etiology. Dyspeptic symptoms are usually meal related and suggest an association to gastrointestinal (GI) sensorimotor dysfunction. Cholecystokinin (CCK) is an established brain-gut peptide that plays an important regulatory role in gastrointestinal function. It inhibits gastric motility and emptying via a capsaicin sensitive vagal pathway. The effects on emptying are via its action on the proximal stomach and pylorus. CCK is also involved in the regulation of food intake. It is released in the gut in response to a meal and acts via vagal afferents to induce satiety. Furthermore CCK has also been shown to be involved in the pathogenesis of panic disorder, anxiety and pain. Other neurotransmitters such as serotonin and noradrenaline may be implicated with CCK in the coordination of GI activity. In addition, intravenous administration of CCK has been observed to reproduce the symptoms in FD and this effect can be blocked both by atropine and loxiglumide (CCK-A antagonist). It is possible that an altered response to CCK may be responsible for the commonly observed gastric sensorimotor dysfunction, which may then be associated with the genesis of dyspeptic symptoms.

Matched MeSH terms: Norepinephrine/physiology
Effects of age on the glucoregulatory response following acute glucoprivation induced by 2-deoxyglucose (2DG) in the adrenal medulla of Sprague Dawley rats

Muda NA, Ramlan H, Damanhuri HA

Neuro Endocrinol. Lett., 2017 Jul;38(3):224-235.
PMID: 28759191

OBJECTIVES: Impairment in glucose homeostasis is one of the factors that may alter the feeding drive, hunger and satiety signals, which essential to maintain a sufficient level of energy for daily activities especially among the elderly. Adrenal medulla is one of the important organs that involves in glucose homeostasis through secretion of catecholamines. The catecholamines biosynthesis pathway utilizes various enzymes and protein kinases. The aims of this study are to investigate the effects of age on the biosynthetic pathway of catecholamines in adrenal medulla by determining the level of blood glucose and blood catecholamines, the gene and protein expression of biosynthetic catecholamine enzymes (TH, DBH and PNMT) as well as protein kinase substrates that involved in the phosphorylation of TH in 2DG-induced rats.
METHODS: Adrenal medulla from male Sprague Dawley rats at the age of 3-months (n=12) and 24-months (n=12) were further divided into two groups: 1) treatment group with 2DG to create glucoprivation condition and 2) the vehicle group which received normal saline as control.
RESULTS: The results showed that the level of glucose, adrenaline and noradrenaline were increased in response to acute glucoprivation conditions in both young and old rats. No age-related differences were found in the basal gene expression of the enzymes that involved in the catecholamines biosynthesis pathway. Interestingly the expressions of TH and DBH protein as well as the level of TH phosphorylation at Ser40, PKA, PKC and ERK1/2 substrates were higher in basal condition of the aged rats. However, contradicted findings were obtained in glucoprivic condition, which the protein expressions of DBH, pERK1/2 and substrates for pPKC were increased in young rats. Only substrate for pCDK was highly expressed in the old rats in the glucoprivic condition, while pPKC and pERK1/2 were decreased significantly. The results demonstrate that adrenal medulla of young and old rats are responsive to glucose deficit and capable to restore the blood glucose level by increasing the levels of blood catecholamines.
CONCLUSION: The present findings also suggest that, at least in rats, aging alters the protein expression of the biosynthetic catecholamine enzymes as well as protein kinase substrates that may attenuate the response to glucoprivation.

Matched MeSH terms: Norepinephrine/metabolism*
Anxiolytic- and antidepressant-like activities of a methanolic extract of Morinda citrifolia Linn. (noni) fruit in mice: Involvement of benzodiazepine-GABAAergic, serotonergic and adrenergic systems

Narasingam M, Vijeepallam K, Mohamed Z, Pandy V

Biomed Pharmacother, 2017 Dec;96:944-952.
PMID: 29217165 DOI: 10.1016/j.biopha.2017.11.148

This study presents anxiolytic- and antidepressant-like effects of a methanolic extract of Morinda citrifolia Linn. (noni) fruit (MMC) in well-established mouse models of anxiety and depression. The administration of MMC (1 g/kg, p.o.) and diazepam (1 mg/kg, i.p.) significantly attenuated anxiety-like behaviour in mice by increasing the percentage of time spent and number of entries in the open arms in the elevated plus maze (EPM), and significantly enhanced the exploration in the light box in the light/dark test (LDT). The pre-treatment with flumazenil (6 mg/kg, i.p.) or bicuculline (3 mg/kg, i.p.) or WAY 100635 (1 mg/kg, i.p.) antagonized the anxiolytic-like effect elicited by MMC (1 g/kg, p.o.). These results suggest the possible involvement of benzodiazepine-GABAAergic and serotonergic mechanisms in the anxiolytic-like effect of noni fruit. Meanwhile, in the antidepressant study, the administration of MMC (0.5 and 0.75 g/kg, p.o.) and desipramine (30 mg/kg, i.p.) significantly reduced the duration of immobility in the tail suspension test (TST). Furthermore, pre-treatment of mice with 4-chloro-DL-phenylalanine methyl ester hydrochloride (PCPA; 100 mg/kg, i.p., an inhibitor of serotonin synthesis) for four consecutive days or a single dose of WAY 100635 (1 mg/kg, i.p., 5HT1A receptor antagonist) or α-methyl-DL-tyrosine (AMPT; 100 mg/kg, i.p., an inhibitor of noradrenaline synthesis) significantly reversed the anti-immobility effect of MMC (0.5 g/kg, p.o.) in TST by indicating the specific involvement of the serotonergic and noradrenergic systems in the antidepressant-like effect of noni fruit. Taken together, these findings suggest that MMC has both anxiolytic- and antidepressant-like activities to be resorted as a valuable alternative therapy for comorbid anxiety and depressive conditions.

Matched MeSH terms: Norepinephrine/metabolism
Fulltext Renoprotective and haemodynamic effects of adiponectin and peroxisome proliferator-activated receptor agonist, pioglitazone, in renal vasculature of diabetic Spontaneously hypertensive rats

Afzal S, Abdul Sattar M, Johns EJ, Eseyin OA

PLoS One, 2020;15(11):e0229803.
PMID: 33170841 DOI: 10.1371/journal.pone.0229803

Pioglitazone, a therapeutic drug for diabetes, possesses full PPAR-γ agonist activity and increase circulating adiponectin plasma concentration. Plasma adiponectin concentration decreases in hypertensive patients with renal dysfunctions. Present study investigated the reno-protective, altered excretory functions and renal haemodynamic responses to adrenergic agonists and ANG II following separate and combined therapy with pioglitazone in diabetic model of hypertensive rats. Pioglitazone was given orally [10mg/kg/day] for 28 days and adiponectin intraperitoneally [2.5μg/kg/day] for last 7 days. Groups of SHR received either pioglitazone or adiponectin in combination. A group of Wistar Kyoto rats [WKY] served as normotensive controls, whereas streptozotocin administered SHRs served as diabetic hypertensive rats. Metabolic data and plasma samples were taken on day 0, 8, 21 and 28. In acute studies, the renal vasoconstrictor actions of Angiotensin II [ANGII], noradrenaline [NA], phenylephrine [PE] and methoxamine [ME] were determined. Diabetic SHRs control had a higher basal mean arterial blood pressure than the WKY, lower RCBP and plasma adiponectin, higher creatinine clearance and urinary sodium excretion compared to WKY [all P<0.05] which were normalized by the individual drug treatments and to greater degree following combined treatment. Responses to intra-renal administration of NA, PE, ME and ANGII were larger in diabetic SHR than WKY and SHRs [P<0.05]. Adiponectin significantly blunted responses to NA, PE, ME and ANG II in diabetic treated SHRs by 40%, whereas the pioglitazone combined therapy with adiponectin further attenuated the responses to adrenergic agonists by 65%. [all P <0.05]. These findings suggest that adiponectin possesses renoprotective effects and improves renal haemodynamics through adiponectin receptors and PPAR-γ in diabetic SHRs, suggesting that synergism exists between adiponectin and pioglitazone. A cross-talk relationship also supposed to exists between adiponectin receptors, PPAR-γ and alpha adrenoceptors in renal vasculature of diabetic SHRs.

Matched MeSH terms: Norepinephrine
A Case of Paraganglioma with Cyanotic Congenital Heart Disease

Wahab NA, Chien BH, Omar MR, Aziz AA, Mustafa N, Sukor N, et al.

Acta Med Indones, 2021 Jan;53(1):77-81.
PMID: 33818409

Co-occurrence of cyanotic congenital heart disease (CCHD) and phaeochromocytoma (PCC) and paraganglioma (PGL) are rare, although some cases have been reported. We report a case of left paraganglioma in a 20-year-old lady with an underlying CCHD who underwent palliative Glenn shunt, subsequently developed polycythaemia and cavernous sinus thrombosis presented with palpitation, sweating, headache and hypertension of 3-months duration at the age of 17. The abdominal CT scan revealed an enhancing left paraaortic mass measuring 5.2 cm x 4.4 cm x 3.8 cm. A 24-hour urine catecholamine demonstrated raised noradrenaline level to six times upper limit of normal and hence diagnosis of left sympathetic (sPGL) was made. In view of the delayed diagnosis and significant morbidity associated with her condition, surgical treatment is no longer an option. Therefore, vigilant screening and early treatment of PCC-PGL in patients with CCHD are crucial in order to avoid significant morbidity and ensure a good quality of life.

Matched MeSH terms: Norepinephrine
Fulltext Erectogenic Effects of Clerodendron capitatum: Involvement of Phosphodiesterase Type-5 Inhibition

Abdelwahab SI, Mohamed AH, Mohamed OY, Oall M, Taha MM, Mohan S, et al.

Evid Based Complement Alternat Med, 2012;2012:137386.
PMID: 21747892 DOI: 10.1155/2012/137386

Clerodendron capitatum (Willd) (family: verbenaceae) is locally named as Gung and used traditionally to treat erectile dysfunction. Therefore, the current study was designed to investigate the erectogenic properties of C. capitatum. The relaxation effect of this plant was tested on phenylephrine precontracted rabbit corpus cavernosum smooth muscle (CCSM). The effects of C. capitatum were also examined on isolated Guinea pig atria alone, in the presence of calcium chloride (Ca(2+) channel blocker), atropine (cholinergic blocker), and glibenclamide (ATP-sensitive K(+) channel blocker). These effects were confirmed on isolated rabbit aortic strips. The extract, when tested colorimetrically for its inhibitory activities on phosphordiesterase-5 (PDE-5) in vitro towards p-nitrophenyl phenyl phosphate (PNPPP), was observed to induce significant dose-dependent inhibition of PDE-5, with an ID(50) of 0.161 mg/ml (P < .05). In conclusion, our results suggest that C. capitatum possesses a relaxant effect on CCSM, which is attributable to the inhibition of PDE-5, but not mediated by the release calcium, activation of adrenergic or cholinergic receptors, or the activation of potassium channels.

Matched MeSH terms: Norepinephrine
Fulltext Metabolic Response in Rats following Electroacupuncture or Moxibustion Stimulation

Xu J, Lin X, Cheng KK, Zhong H, Liu M, Zhang G, et al.

Evid Based Complement Alternat Med, 2019;2019:6947471.
PMID: 31186665 DOI: 10.1155/2019/6947471

Electroacupuncture and moxibustion are traditional Chinese medicine practices that exert therapeutic effects through stimulation of specific meridian acupoints. However, the biological basis of the therapies has been difficult to establish; thus the current practices still rely on ancient TCM references. Here, we used a rat model to study perturbations in cortex, liver, and stomach metabolome and plasma hormones following electroacupuncture or moxibustion treatment on either stomach meridian or gallbladder meridian acupoints. All treatment groups, regardless of meridian and mode of treatment, showed perturbation in cortex metabolome and increased phenylalanine, tyrosine, and branched-chain amino acids in liver. In addition, electroacupuncture was found to increase ATP in cortex, creatine, and dimethylglycine in stomach and GABA in liver. On the other hand, moxibustion increased plasma enkephalin concentration, as well as betaine and fumarate concentrations in stomach. Furthermore, we had observed meridian-specific changes including increased N-acetyl-aspartate in liver and 3-hydroxybutyrate in stomach for gallbladder meridian stimulation and increased noradrenaline concentration in blood plasma following stimulation on stomach meridian. In summary, the current findings may provide insight into the metabolic basis of electroacupuncture and moxibustion, which may contribute towards new application of acupoint stimulation.

Matched MeSH terms: Norepinephrine
Fulltext Palm vitamin E reduces catecholamines, xanthine oxidase activity and gastric lesions in rats exposed to water-immersion restraint stress

Mohd Fahami NA, Ibrahim IA, Kamisah Y, Mohd Ismail N

BMC Gastroenterol, 2012;12:54.
PMID: 22639913 DOI: 10.1186/1471-230X-12-54

This study examined the effects of Palm vitamin E (PVE) and α-tocopherol (α-TF) supplementations on adrenalin, noradrenalin, xanthine oxidase plus dehydrogenase (XO + XD) activities and gastric lesions in rats exposed to water-immersion restraint stress (WIRS).

Matched MeSH terms: Norepinephrine/blood
High-fructose feeding impacts on the adrenergic control of renal haemodynamics in the rat

Abdulla MH, Sattar MA, Johns EJ, Abdullah NA, Hye Khan MA, Rathore HA

Br J Nutr, 2012 Jan;107(2):218-28.
PMID: 21733307 DOI: 10.1017/S0007114511002716

The present study explored the hypothesis that a prolonged 8 weeks exposure to a high fructose intake suppresses adrenergic and angiotensin II (Ang II)-mediated vasoconstriction and is associated with a higher contribution of α1D-adrenoceptors. A total of thirty-two Sprague-Dawley rats received either 20 % fructose solution (FFR) or tap water (control, C) to drink ad libitum for 8 weeks. Metabolic and haemodynamic parameters were assessed weekly. The renal cortical vasoconstrictor responses to noradrenaline (NA), phenylephrine (PE), methoxamine (ME) and Ang II were determined in the presence and absence of BMY7378 (α1D-adrenoceptor antagonist). FFR had increased blood pressure, plasma levels of glucose, TAG and insulin. FFR expressed reduced renal vascular responses to adrenergic agonists and Ang II (NA: 50 %, PE: 50 %, ME, 65 %, Ang II: 54 %). Furthermore in the C group, the magnitude of the renal cortical vasoconstriction to all agonists was blunted in the presence of the low or high dose of BMY7378 (NA: 30 and 31 %, PE: 23 and 33 %, ME: 19 and 44 %, Ang II: 53 and 77 %), respectively, while in the FFR, vasoconstriction was enhanced to adrenergic agonists and reduced to Ang II (NA: 8 and 83 %, PE: 55 %, ME, 2 and 177 %, Ang II: 61 and 31 %). Chronic high fructose intake blunts vascular sensitivity to adrenergic agonists and Ang II. Moreover, blocking of the α1D-adrenoceptor subtype results in enhancement of renal vasoconstriction to adrenergic agonists, suggesting an inhibitory action of α1D-adrenoceptors in the FFR. α1D-Adrenoceptors buffer the AT1-receptor response in the renal vasculature of normal rats and fructose feeding suppressed this interaction.

Matched MeSH terms: Norepinephrine/metabolism
Evidence for the role of α1A-adrenoceptor subtype in the control of renal haemodynamics in fructose-fed Sprague-Dawley rat

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

Eur J Nutr, 2011 Dec;50(8):689-97.
PMID: 21373947 DOI: 10.1007/s00394-011-0180-9

AIM: To explore the hypothesis that high fructose intake results in a higher functional contribution of α1A-adrenoceptors and blunts the adrenergically and angiotensin II (Ang II)-induced renal vasoconstriction.
METHODS: Twelve Sprague-Dawley rats received either 20% fructose solution [FFR] or tap water [C] to drink ad libitum for 8 weeks. The renal vasoconstrictor response to noradrenaline (NA), phenylephrine (PE), methoxamine (ME) and Ang II was determined in the presence and absence of 5-methylurapidil (5-MU) (α1A-adrenoceptor antagonist) in a three-phase experiment (pre-drug, low- and high-dose 5-MU). Data, mean ± SEM were analysed by ANOVA or Student's unpaired t-test with significance at P < 0.05.
RESULTS: FFR exhibited insulin resistance (HOMA index), hypertension and significant increases in plasma levels of glucose and insulin. All agonists caused dose-related reductions in cortical blood perfusion that were larger in C than in FFR while the magnitudes of the responses were progressively reduced with increasing doses of 5-MU in both C and FFR. The degree of 5-MU attenuation of the renal cortical vasoconstriction due to NA, ME and Ang II was significantly greater in the FFR compared to C.
CONCLUSIONS: Fructose intake for 8 weeks results in smaller vascular response to adrenergic agonists and Ang II. The α1A-adrenoceptor subtype is the functional subtype that mediates renal cortical vasoconstriction in control rats, and this contribution becomes higher due to fructose feeding.

Matched MeSH terms: Norepinephrine/pharmacology
Influence of high dietary sodium intake on the functional subtypes of alpha-adrenoceptors in the renal cortical vasculature of Wistar-Kyoto rats

Kazi RN, Munavvar AS, Abdullah NA, Khan AH, Johns EJ

Auton Autacoid Pharmacol, 2009 Jan;29(1-2):25-31.
PMID: 19302553 DOI: 10.1111/j.1474-8673.2009.00428.x

1 Increased renal vascular resistance is one renal functional abnormality that contributes to hypertension, and alpha(1)-adrenoceptors play a pivotal role in modulating this renal vascular resistance. This study investigates the functional contribution of alpha(1)-adrenoceptor subtypes in the renal cortical vasculature of Wistar-Kyoto rats on a normal sodium diet (WKYNNa) compared with those given saline to drink for 6 weeks (WKYHNa). 2 The renal cortical vascular responses to the adrenergic agonists noradrenaline (NA), methoxamine (ME) and phenylephrine (PE) were measured in WKYHNa and WKYNNa rats either in the absence (the control phase) or presence of chloroethylclonidine (CEC), an alpha(1B)-adrenoceptor antagonist, 5-methylurapidil (5-MeU), an alpha(1A) antagonist, or BMY7378, an alpha(1D) antagonist. 3 Results showed a greater renal cortical vascular sensitivity to NA, PE and ME in the WKYHNa compared with WKYNNa rats (P < 0.05). Moreover, 5-MeU and BMY7378 attenuated adrenergically induced renal cortical vasoconstriction in WKYHNa and WKYNNa rats; this response was largely blunted in CEC-treated WKYHNa rats (all P < 0.05) but not in CEC-treated WKYNNa rats. 4 The data suggest that irrespective of dietary sodium content, in Wistar-Kyoto rats alpha(1A)- and alpha(1D)-subtypes are the major alpha(1)-adrenoceptors in renal cortical vasculature; however, there appears to be a functional involvement of alpha(1B)-adrenoceptors in the WKYHNa rats.

Matched MeSH terms: Norepinephrine/pharmacology
Alpha1A- and alpha1D-adrenoceptors are the major functional subtypes of renal alpha1-adrenoceptors in streptozotocin-induced diabetic and normal Sprague-Dawley rats

Armenia, Sattar MA, Abdullah NA, Khan MA, Johns EJ

Auton Autacoid Pharmacol, 2008 Jan;28(1):1-10.
PMID: 18257746 DOI: 10.1111/j.1474-8673.2007.00412.x

1 The present study investigated the effect of streptozotocin-induced diabetes on alpha(1)-adrenoceptor subtypes in rat renal resistance vessels. 2 Studies on renal haemodynamics were carried out 7 days after the last streptozotocin. Changes in renal blood flow were recorded in response to electrical stimulation of the renal nerve (RNS) and a range of adrenergic agonists; noradrenaline (NA), phenylephrine (PE) and methoxamine (MTX), either in the absence or the presence of nitrendipine (Nit), 5-methylurapidil (MEU), chlorethylclonidine (CEC) or BMY 7378. 3 In non-diabetic animals, Nit, MEU and BMY 7378 significantly attenuated renal vasoconstriction induced by adrenergic agonists, while CEC showed a significant accentuation in RNS-induced responses without having a significant effect on responses to adrenergic agonists. In diabetic rats, renal vasoconstriction was also significantly reduced in Nit-, MEU- and BMY 7378-treated groups and CEC potentiated RNS-induced contractions caused a change similar to that observed in non-diabetic rats. BMY 7378 significantly (P < 0.05) attenuated the PE- and MTX-induced vasoconstrictions but did not cause any significant (P > 0.05) alteration in the RNS- and NA-induced responses. 4 The results showed functional co-existence of alpha(1A)- and alpha(1D)-adrenoceptors in the renal vasculature of SD rats irrespective of the presence of diabetes. A possible minor contribution of prejunctional alpha-adrenoceptor subtype has also been suggested in either experimental group, particularly possible functional involvement of alpha(1B)-adrenoceptor subtypes in non-diabetic SD rats.

Matched MeSH terms: Norepinephrine/pharmacology
Effect of acute unilateral renal denervation on renal hemodynamics in spontaneously hypertensive rats

Abdulla MH, Sattar MA, Salman IM, Abdullah NA, Ameer OZ, Khan MA, et al.

Auton Autacoid Pharmacol, 2008 Apr-Jul;28(2-3):87-94.
PMID: 18598290 DOI: 10.1111/j.1474-8673.2008.00421.x

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.

Matched MeSH terms: Norepinephrine/pharmacology
Influence of cisplatin-induced renal failure on the alpha(1)-adrenoceptor subtype causing vasoconstriction in the kidney of the rat

Khan AH, Sattar MA, Abdullah NA, Johns EJ

Eur J Pharmacol, 2007 Aug 13;569(1-2):110-8.
PMID: 17559832

This study investigated whether the alpha(1)-adrenoceptor subtype(s) mediating the vasoconstrictor actions of the renal sympathetic nerves were altered in rats with cisplatin-induced renal failure. Male Wistar Kyoto rats were used and half received cisplatin (5 mg/kg i.p.) to induce renal failure and were taken for study 7 days later. The renal blood flow reductions caused by electrical renal nerve stimulation and close intra-renal administration of noradrenaline, phenylephrine and methoxamine were determined before and after amlodopine (AMP), 5-methylurapidil (MeU), chloroethylclonidine (CEC) or BMY 7378. Water intake and creatinine clearance were decreased (P<0.05) by 40-50% while fractional excretion of sodium was increased two-fold in the cisplatin treated rats. Mean arterial pressure was higher, 110+/-2 versus 102+/-3 mmHg and renal blood flow was lower, 10.7+/-0.9 versus 18.9+/-0.1 ml/min/kg in the renal failure rats (both P<0.05). AMP, MeU and BMY 7378 decreased (all P<0.05) the adrenergically induced renal vasoconstrictor responses in the renal failure groups by 30 to 50% and in normal rats by 20 to 40%. In the presence of CEC, renal nerve stimulation and noradrenaline and methoxamine induced renal vasoconstrictor responses were enhanced (all P<0.05) in the renal failure but not in the normal rats. These data showed that alpha(1A)- and alpha(1D)-adrenoceptors were the major subtypes in mediating adrenergically induced renal vasoconstriction but there was no substantial shift in subtype in renal failure. The contribution of alpha(1B)-adrenoceptor subtypes either pre- or post-synaptic appeared to be raised in the renal failure rats.

Matched MeSH terms: Norepinephrine/pharmacology
Interaction between irbesartan, peroxisome proliferator-activated receptor (PPAR-γ), and adiponectin in the regulation of blood pressure and renal function in spontaneously hypertensive rats

Afzal S, Sattar MA, Johns EJ, Abdulla MH, Akhtar S, Hashmi F, et al.

J Physiol Biochem, 2016 Dec;72(4):593-604.
PMID: 27405250

Adiponectin exerts vasodilatory effects. Irbesartan, an angiotensin receptor blocker, possesses partial peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist activity and increases circulating adiponectin. This study explored the effect of irbesartan alone and in combination with adiponectin on blood pressure, renal hemodynamic excretory function, and vasoactive responses to angiotensin II and adrenergic agonists in spontaneously hypertensive rat (SHR). Irbesartan was given orally (30 mg/kg/day) for 28 days and adiponectin intraperitoneally (2.5 μg/kg/day) for last 7 days. Groups of SHR received either irbesartan or adiponectin or in combination. A group of Wistar Kyoto rats (WKY) served as controls. Metabolic data and plasma samples were taken on days 0, 21, and 28. In acute studies, the renal vasoconstrictor actions of angiotensin II (ANGII), noradrenaline (NA), phenylephrine (PE), and methoxamine (ME) were determined. SHR control rats had a higher mean blood pressure than the WKY (132 ± 7 vs. 98 ± 2 mmHg), lower plasma and urinary adiponectin, creatinine clearance, urine flow rate and sodium excretion, and oxidative stress markers compared to WKY (all P

Matched MeSH terms: Norepinephrine/pharmacology
Fulltext Functional subtypes of renal alpha1-adrenoceptor in diabetic and non-diabetic 2K1C Goldblatt renovascular hypertension

Armenia A, Sattar MA, Abdullah NA, Khan MA, Johns EJ

Acta Pharmacol Sin, 2008 May;29(5):564-72.
PMID: 18430364 DOI: 10.1111/j.1745-7254.2008.00788.x

This study investigates the subtypes of the alpha1-adrenoceptor mediating the adrenergically-induced renal vasoconstrictor responses in streptozotocin-induced diabetic and non-diabetic 2-kidney one clip (2K1C) Goldblatt hypertensive rats.

Matched MeSH terms: Norepinephrine/pharmacology
Functional subtypes of renal alpha1-adrenoceptor in spontaneously hypertensive rats with streptozotocin-induced experimental diabetic nephropathy

Khan MA, Sattar MA, Abdullah NA, Abdulla MH, Salman IM, Kazi RN, et al.

Kidney Blood Press Res, 2009;32(5):349-59.
PMID: 19844130 DOI: 10.1159/000249149

This study investigated the impact of hypertension combined with diabetic nephropathy on rat renal alpha(1)-adrenoceptor subtype composition.

Matched MeSH terms: Norepinephrine/pharmacology
Fulltext Brain Cortical and Hippocampal Dopamine: A New Mechanistic Approach for Eurycoma longifolia Well-Known Aphrodisiac Activity and Its Chemical Characterization

Ezzat SM, Ezzat MI, Okba MM, Hassan SM, Alkorashy AI, Karar MM, et al.

Evid Based Complement Alternat Med, 2019;2019:7543460.
PMID: 31275418 DOI: 10.1155/2019/7543460

Eurycoma longifolia Jack (Fam.: Simaroubaceae), known as Tongkat Ali (TA), has been known as a symbol of virility and sexual power for men. Metabolic profiling of the aqueous extract of E. longifolia (AEEL) using UPLC-MS/MS in both positive and negative modes allowed the identification of seventeen metabolites. The identified compounds were classified into four groups: quassinoids, alkaloids, triterpenes, and biphenylneolignans. AEEL is considered safe with oral LD50 cut-off >5000 mg/kg. Oral administration of 50, 100, 200, 400, or 800 mg/kg of AEEL for 10 consecutive days to Sprague-Dawley male rats caused significant reductions in mounting, intromission, and ejaculation latencies and increased penile erection index. AEEL increased total body weight and relative weights of seminal vesicles and prostate. Total and free serum testosterone and brain cortical and hippocampal dopamine content was significantly elevated in treated groups with no significant effects on serotonin or noradrenaline content.

Matched MeSH terms: Norepinephrine

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