Displaying publications 1 - 20 of 32 in total

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  1. Afzal S, Sattar MA, Eseyin OA, Attiq A, Johns EJ
    Eur J Pharmacol, 2022 Feb 15;917:174703.
    PMID: 34973951 DOI: 10.1016/j.ejphar.2021.174703
    Hypoadiponectinemia is associated with renal dysfunctions. Irbesartan and pioglitazone activate Peroxisome proliferator-activated gamma receptor (PPAR-γ) as partial and full agonists. We investigated a crosstalk interaction and synergistic action between adiponectin receptors, PPAR-γ agonists in attenuating renal hemodynamics to adrenergic agonists in diabetic Wistar Kyoto rats (WKY). Streptozotocin (40 mg/kg) was used to induce diabetes, whereas, pioglitazone (10 mg/kg/day), irbesartan (30 mg/kg/day) administered orally for 28 days and adiponectin intraperitoneally (2.5 μg/kg/day) for last 7 days. Metabolic and plasma samples were analyzed on days 0, 8, 21, and 28. During the acute study (day 29), renal vasoconstrictor actions to adrenergic agonists and angiotensin-II were determined. Diabetic WKYs had lower plasma adiponectin, higher creatinine clearance, urinary and fractional sodium excretion but were normalized to a greater extent in pioglitazone and adiponectin combined treatment. Responses to intra-renal administration of adrenergic agonists including noradrenaline (NA), phenylephrine (PE), methoxamine (ME), and angiotensin-II (ANG-II) were larger in diabetic WKY, but significantly blunted with adiponectin treatment in diabetic WKYs to 35-40%, and further reduced by 65-70% in combination with pioglitazone. Attenuation to ANG-II responses in adiponectin and combination with irbesartan was 30-35% and 75-80%, respectively (P 
    Matched MeSH terms: Vasoconstriction/drug effects
  2. Lau YS, Kwan CY, Ku TC, Hsieh WT, Wang HD, Nishibe S, et al.
    J Ethnopharmacol, 2012 Sep 28;143(2):565-71.
    PMID: 22835814 DOI: 10.1016/j.jep.2012.07.012
    The leaves extract of Apocynum venetum (AVLE), also known as "luobuma", have long been used in traditional Chinese medicine to treat hypertension and depression in parts of China and it has been shown to possess anti-oxidant and anti-lipid peroxidation effects. AVLE (10 μg/ml) has been reported to have a long-lasting endothelium-dependent relaxant effect and this effect has been proposed to be due to its nitric oxide(NO)-releasing and superoxide anion(SOA)-scavenging properties.
    Matched MeSH terms: Vasoconstriction/drug effects*
  3. Muir CK, Lim YM
    Med J Malaysia, 1980 Jun;34(4):387-90.
    PMID: 7219269
    The effects of phentolamine and propranolol on contractural responses of guinea-pig superior mesenteric-portal vein to adrenaline and isoprenaline were investigated. Phentolamine was capable of completely abolishing the response to adrenaline and to isoprenaline while propranolol had no effect on responses to either agonist. It is suggested that Alpha receptors are the only type of adrenoceptor involved in adrenergic control of contraction of this vein and that isoprenaline is capable of stimulating these receptors.
    Matched MeSH terms: Vasoconstriction/drug effects
  4. Hye Khan MA, Sattar MA, Abdullah NA, Johns EJ
    Br J Pharmacol, 2008 Mar;153(6):1232-41.
    PMID: 18246093 DOI: 10.1038/bjp.2008.13
    This study investigated whether the alpha(1)-adrenoceptor responsiveness of the renal vasculature was altered in the state of hypertension combined with renal failure.
    Matched MeSH terms: Vasoconstriction/drug effects
  5. Abdulla MH, Sattar MA, Abdullah NA, Khan AH, Anand Swarup KR, Rathore HA, et al.
    Ups. J. Med. Sci., 2011 Mar;116(1):18-25.
    PMID: 21047287 DOI: 10.3109/03009734.2010.526723
    This study examined the effect of renal sympathetic innervation on adrenergically and angiotensin II (Ang II)-induced renal vasoconstriction in Wistar-Kyoto (WKY) rats.
    Matched MeSH terms: Vasoconstriction/drug effects*
  6. Machha A, Achike FI, Mohd MA, Mustafa MR
    Eur J Pharmacol, 2007 Jun 22;565(1-3):144-50.
    PMID: 17442302
    Acute exposure to the flavonoid baicalein inhibited endothelium-dependent relaxation in physiological arteries, although the mechanisms are not fully understood. We investigated the effect of baicalein on vascular tone in Wistar-Kyoto (WKY) rat isolated aortic rings in the presence and absence of oxidative stress to further determine the underlying mechanisms. Exposure to baicalein (10 microM) completely abolished endothelium-dependent relaxation induced by acetylcholine and attenuated significantly the endothelium-independent relaxation induced by sodium nitroprusside. Baicalein, similar to Nomega-nitro-L-arginine methyl ester (L-NAME, 10 microM), potentiated significantly the contractile response of aortic rings to alpha1-adrenoceptor agonist phenylephrine. In the presence of L-NAME the baicalein effect on phenylphrine contraction or acetylcholine relaxation was unaltered, suggesting that these effects of baicalein are (like L-NAME effect) endothelial nitric oxide synthase (eNOS)/endothelium-derived nitric oxide-dependent. Inhibition of cyclooxygenase activity with indomethacin (10 microM) or scavenging of superoxide anions with superoxide dismutase (150 units/ml), but not scavenging of hydrogen peroxide with catalase (800 units/ml), enhanced significantly by an essentially similar extent the relaxation to acetylcholine in baicalein-pretreated aortic rings. Relaxant effect to acetylcholine was significantly attenuated in control aortic rings, but was completely abolished in baicalein-pretreated aortic rings in the presence of reduced form of beta-nicotinamide adenine di-nucleotide (beta-NADH, 300 microM). Baicalein blocked beta-NADH (300 microM)-induced transient contractions, suggesting that baicalein may have inhibited activity of NADH/NADPH-oxidase. Baicalein did not alter the failure of acetylcholine to induce relaxation in the presence of pyrogallol (300 microM). In summary, acute exposure to baicalein impairs eNOS/endothelium-derived nitric oxide-mediated vascular tone in rat aortas through the inhibition of endothelium-derived nitric oxide bioavailability coupled to reduced bioactivity of endothelium-derived nitric oxide and to cyclooxygenase-mediated release of superoxide anions.
    Matched MeSH terms: Vasoconstriction/drug effects
  7. 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: Vasoconstriction/drug effects
  8. 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: Vasoconstriction/drug effects
  9. Csato V, Kadir SZSA, Khavandi K, Bennett H, Sugden S, Gurney AM, et al.
    Physiol Rep, 2019 Nov;7(22):e14260.
    PMID: 31782255 DOI: 10.14814/phy2.14260
    We investigated the biomechanical relationship between intraluminal pressure within small mesenteric resistance arteries, oxidant activation of PKG, Ca2+ sparks, and BK channel vasoregulation. Mesenteric resistance arteries from wild type (WT) and genetically modified mice with PKG resistance to oxidative activation were studied using wire and pressure myography. Ca2+ sparks and Ca2+ transients within vascular smooth muscle cells of intact arteries were characterized using high-speed confocal microscopy of intact arteries. Arteries were studied under conditions of varying intraluminal pressure and oxidation. Intraluminal pressure specifically, rather than the generic stretch of the artery, was necessary to activate the oxidative pathway. We demonstrated a graded step activation profile for the generation of Ca2+ sparks and also a functional "ceiling" for this pressure --sensitive oxidative pathway. During steady state pressure - induced constriction, any additional Ca2+ sensitive-K+ channel functional availability was independent of oxidant activated PKG. There was an increase in the amplitude, but not the Area under the Curve (AUC) of the caffeine-induced Ca2+ transient in pressurized arteries from mice with oxidant-resistant PKG compared with wild type. Overall, we surmise that intraluminal pressure within resistance arteries controls Ca2+ spark vasoregulation through a tightly controlled pathway with a graded onset switch. The pathway, underpinned by oxidant activation of PKG, cannot be further boosted by additional pressure or oxidation once active. We propose that these restrictive characteristics of pressure-induced Ca2+ spark vasoregulation confer stability for the artery in order to provide a constant flow independent of additional pressure fluctuations or exogenous oxidants.
    Matched MeSH terms: Vasoconstriction/drug effects
  10. Jaarin K, Mustafa MR, Leong XF
    Clinics (Sao Paulo), 2011;66(12):2125-32.
    PMID: 22189740
    OBJECTIVES: The goal of this study was to determine the possible mechanism that is involved in the blood pressure-raising effect of heated vegetable oils.

    METHODS: Adult male Sprague-Dawley rats were divided into 11 groups; the control group was fed with rat chow, and the other groups were fed with chow that was mixed with 15% weight/weight palm or soy oils, which were either in a fresh form or heated once, twice, five, or ten times. Blood pressures were measured at the baseline and throughout the 24-week study. Plasma nitric oxide levels were assessed prior to treatment and at the end of the study. Following 24 weeks, the rats were sacrificed to investigate their vascular reactivity using the thoracic aorta.

    RESULTS: Palm and soy oils had no detrimental effects on blood pressure, and they significantly elevated the nitric oxide contents and reduced the contractile responses to phenylephrine. However, trials using palm and soy oils that were repeatedly heated showed an increase in blood pressure, enhanced phenylephrine-induced contractions, reduced acetylcholine- and sodium nitroprusside-induced relaxations relative to the control and rats that were fed fresh vegetable oils.

    CONCLUSIONS: The blood pressure-raising effect of the heated vegetable cooking oils is associated with increased vascular reactivity and a reduction in nitric oxide levels. The chronic consumption of heated vegetable oils leads to disturbances in endogenous vascular regulatory substances, such as nitric oxide. The thermal oxidation of the cooking oils promotes the generation of free radicals and may play an important contributory role in the pathogenesis of hypertension in rats.

    Matched MeSH terms: Vasoconstriction/drug effects
  11. Leong XF, Najib MN, Das S, Mustafa MR, Jaarin K
    Tohoku J Exp Med, 2009 Sep;219(1):71-8.
    PMID: 19713687
    Oxidization of dietary cooking oil increases the risk of cardiovascular diseases such as hypertension by increasing the formation oxidative oxygen radicals. The aim of study was to investigate the effects of repeatedly heated palm oil on blood pressure, plasma nitrites, and vascular reactivity. Nitrites were measured, as an indirect marker for nitric oxide production. Male Sprague-Dawley rats were divided into four groups: control group fed with basal diet and other three groups fortified with 15% weight/weight fresh palm oil (FPO), palm oil heated five times (5HPO) or palm oil heated ten times (10HPO) for 24 weeks. The oil was heated to 180 degrees C for 10 min. Blood pressure was measured at baseline and at intervals of four weeks for 24 weeks using non-invasive tail-cuff method. Following 24 weeks, the rats were sacrificed and thoracic aortas were dissected for measurement of vascular reactivity. Blood pressure was elevated significantly (p < 0.05) in 5HPO and 10HPO groups, with the 10HPO group showing higher values. Aortic rings from animals fed with heated oil showed diminished relaxation in response to acetylcholine or sodium nitroprusside, and greater contraction to phenylephrine. Acetylcholine and sodium nitroprusside cause endothelium-dependent and endothelium-independent relaxation, respectively. Relaxation responses remained unaltered in the FPO group, with the attenuated contractile response to phenylephrine, compared to control group. FPO increased plasma nitrites by 28%, whereas 5HPO and 10HPO reduced them by 25% and 33%, respectively. Intake of repeatedly heated palm oil causes an increase in blood pressure, which may be accounted for by the attenuated endothelium-dependent vasorelaxant response.
    Matched MeSH terms: Vasoconstriction/drug effects
  12. Ajay M, Mustafa MR
    Vascul Pharmacol, 2006 Aug;45(2):127-33.
    PMID: 16807125 DOI: 10.1016/j.vph.2006.05.001
    Impaired vascular reactivity is a hallmark of several cardiovascular diseases that include hypertension and diabetes. This study compared the changes in vascular reactivity in age-matched experimental hypertension and diabetes, and, subsequently, tested whether these changes could be affected directly by ascorbic acid (10 microM). Endothelium-derived nitric oxide (NO) modulation of ascorbic acid effects was also investigated. All the experiments were performed in the presence of a cyclooxygenase inhibitor, indomethacin (10 microM). Results showed that the endothelium-dependent and -independent relaxations induced by acetylcholine (ACh) and sodium nitroprusside (SNP), respectively, were blunted to a similar extent in isolated aortic rings from age-matched spontaneously hypertensive (SHR) (R(max): ACh = 72.83+/-1.86%, SNP = 96.6+/-1.90%) and diabetic (Rmax: ACh = 64.09+/-5.14%, SNP = 95.84+/-1.41%) rats compared with aortic rings of normal rats (Rmax: ACh = 89%, SNP = 104.0+/-1.0%). The alpha1-receptor-mediated contractions induced by phenylephrine (PE) were augmented in diabetic (Cmax = 148.8+/-9.0%) rat aortic rings compared to both normal (Cmax = 127+/-6.9%) and SHR (Cmax = 118+/-4.5%) aortic rings. Ascorbic acid pretreatment was without any significant effects on the vascular responses to ACh, SNP and PE in aortic rings from normal rats. Ascorbic acid significantly improved ACh-induced relaxations in SHR (Rmax = 89.09+/-2.82%) aortic rings to a level similar to that observed in normal aortic rings, but this enhancement in ACh-induced relaxations was only partial in diabetic aortic rings. Ascorbic acid lacked any effects on SNP-induced relaxations in both SHR and diabetic aortic rings. Ascorbic acid markedly attenuated contractions induced by PE in aortic rings from both SHR (Cmax = 92.9+/-6.68%) and diabetic (Cmax = 116.9+/-9.4%) rats. Additionally, following inhibition of nitric oxide synthesis with l-NAME, ascorbic acid attenuated PE-induced contractions in all aortic ring types studied. These results suggest that (1) vascular hyper-responsiveness to alpha(1)-receptor agonists in diabetic arteries is independent of endothelial nitric oxide dysfunction; (2) ascorbic acid directly modulates contractile responses of hypertensive and diabetic rat aortas, likely through mechanisms in part independent of preservation of endothelium-derived nitric oxide.
    Matched MeSH terms: Vasoconstriction/drug effects*
  13. Khan AU, Mustafa MR, Khan AU, Murugan DD
    PMID: 22883710 DOI: 10.1186/1472-6882-12-121
    Gentiana floribunda was investigated for the possible hypotensive and vasodilator activities in an attempt to rationalize its traditional use in hypertension.
    Matched MeSH terms: Vasoconstriction/drug effects
  14. 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: Vasoconstriction/drug effects
  15. Subramaniam G, Achike FI, Mustafa MR
    Regul. Pept., 2009 Jun 5;155(1-3):70-5.
    PMID: 19362578 DOI: 10.1016/j.regpep.2009.04.008
    The effect of acidosis on insulin-induced relaxation was studied in thoracic aortic rings (from Wistar-Kyoto (WKY) rats) with (+ED) or without (-ED) endothelium. The rings were mounted in normal (pH 7.4) or acidotic (pH 7.2) Krebs solution for isometric tension recording. Phenylephrine (PE, 3.0 microM)-contracted tissues were exposed to insulin in the presence or absence of various inhibitors. Insulin exerted similar concentration-dependent relaxation of +ED tissues in normal and acidotic pH. Endothelium denudation, significantly (p<0.05) reduced insulin effect in normal, but not acidotic pH. Under normal pH, treatment with L-NAME or methylene blue significantly (p<0.05) reduced insulin responses in the +ED (but not the -ED) tissues. The insulin effect was also significantly (p<0.05) inhibited by tetraethylammonium (TEA; BK(Ca) blocker), 4-Aminopyridine (4-AP; K(V) channel blocker), combined treatments (L-NAME+4-AP+TEA, in +ED tissues) or (4-AP+TEA, in -ED tissues). In either +ED or -ED tissues, indomethacin (cyclo-oxygenase inhibitor), glibenclamide (K(ATP) channel blocker), barium chloride (K(ir) channel blocker) or Ouabain (a Na(+)/K(+)-ATPase inhibitor) had no effect. Except for methylene blue (effect on +ED tissues), none of the drug treatments inhibited insulin vasodilator effect in acidosis (+ED or -ED tissues). These data indicate that insulin exerts an endothelium-dependent and -independent vasodilatation in rat aorta which in normal pH is mediated via BK(Ca) and K(v) channels, including the EDNO-cGMP cascade. Acidosis abolishes the endothelium-dependent relaxation mechanism unraveling a novel mechanism that is as efficacious and is cGMP-, but not EDNO-, BK(Ca)- or K(v)-mediated.
    Matched MeSH terms: Vasoconstriction/drug effects
  16. 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: Vasoconstriction/drug effects
  17. Abdulla MH, Sattar MA, Khan MA, Abdullah NA, Johns EJ
    Acta Physiol (Oxf), 2009 Mar;195(3):397-404.
    PMID: 19183357 DOI: 10.1111/j.1748-1716.2008.01895.x
    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).
    Matched MeSH terms: Vasoconstriction/drug effects*
  18. 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: Vasoconstriction/drug effects
  19. 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: Vasoconstriction/drug effects
  20. 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: Vasoconstriction/drug effects
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