Prostaglandins and nitric oxide in regional kidney blood flow responses to renal nerve stimulation

Rajapakse, Niwanthi W.; Flower, Rebecca; Eppel, Gabriela Alejandra; Denton, Kate M.; Malpas, Simon C.; Evans, Roger G.

doi:10.1007/s00424-004-1320-3

Cited by 14 publications

(14 citation statements)

References 38 publications

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“…Thus this decrease in MAP results from decreased vascular resistance and not secondary to the effect of ACh on cardiac muscarinic receptors. Similar doses of ACh lower MAP in rabbits, rats, and humans (8,16,27). These dose-dependent decreases in MAP after ACh are also unrelated to the basal MAP, as previously reported in rats and rabbits (8,18,35).…”

Section: Discussionsupporting

confidence: 60%

15-Lipoxygenase metabolites contribute to age-related reduction in acetylcholine-induced hypotension in rabbits

Aggarwal

Gauthier²,

Campbell³

2008

American Journal of Physiology-Heart and Circulatory Physiology

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Aggarwal NT, Gauthier KM, Campbell WB. 15-Lipoxygenase metabolites contribute to age-related reduction in acetylcholine-induced hypotension in rabbits. Am J Physiol Heart Circ Physiol 295: H89 -H96, 2008. First published May 2, 2008 doi:10.1152/ajpheart.00054.2008.-Arachidonic acid (AA) metabolites from the 15-lipoxygenase-1 (15-LO-1) pathway, trihydroxyeicosatrienoic acids (THETAs) and hydroxy-epoxyeicosatrienoic acids (HEETAs), are endothelium-derived hyperpolarizing factors (EDHFs) and relax rabbit arteries. Rabbit vascular 15-LO-1 expression, THETA and HEETA synthesis, and nitric oxide and prostaglandinindependent relaxations to acetylcholine (ACh) and AA decreased with age (neonates to 16-wk-old). We characterized age-dependent ACh-hypotensive responses in vivo in 1-, 4-, 8-, and 16-wk-old rabbits and the contribution of THETAs and HEETAs to these responses. In anesthetized rabbits, blood pressure responses to ACh (4 -4,000 ng/kg) were determined in the presence of vehicle or various inhibitors. ACh responses decreased with age (P Ͼ 0.001). In the absence or presence of N -nitro-L-arginine methyl ester (L-NAME) and indomethacin (Indo), maximum responses in 1 (Ϫ54.7 Ϯ 7.4 and Ϫ37.9 Ϯ 3.9%)-and 4 (Ϫ48.8 Ϯ 2.4 and Ϫ35.5 Ϯ 7.8%)-wk-old rabbits were higher than 8 (Ϫ30.0 Ϯ 2.8 and Ϫ26.6 Ϯ 4.4%)-and 16 (Ϫ36.7 Ϯ 3.5 and Ϫ27.3 Ϯ 10%)-wk-old rabbits. A lipoxygenase inhibitor, BW755C, reduced THETA and HEETA synthesis in mesenteric arteries. In the presence of Indo and N -nitro-L-arginine, ACh relaxations were reduced by BW755C to a greater extent in the mesenteric arteries from the younger rabbits. In 4-wk-old rabbits treated with L-NAME and Indo, the maximum ACh hypotension was reduced by the potassium channel inhibitors apamin and charybdotoxin to Ϫ6.9 Ϯ 0.9%, by apamin alone to Ϫ19.5 Ϯ 1.4%, and by BW755C to Ϫ18.8 Ϯ 3.5%. The present study indicates that the age-related decrease in ACh-induced hypotension is mediated by the decreased synthesis of the 15-LO-1 metabolites THETAs and HEETAs. endothelium-derived hyperpolarizing factor; arachidonic acid; vasodilation; mean arterial pressure THE VASCULAR ENDOTHELIUM RELEASES dilators including nitric oxide (NO), prostaglandins (PG), and endothelium-derived hyperpolarizing factors (EDHF; Ref. 7). Agonists, such as acetylcholine (ACh), induce release of these mediators from the endothelium and thus relax arteries. In the presence of endothelial NO synthase (eNOS) and cyclooxygenase (COX) inhibitors, EDHFs contribute to ACh-induced relaxations. This has been documented in rabbits (22), rats (17, 26), dogs (21), and humans (16). EDHFs compensate for the impaired NO release and activity in eNOS knockout mice (3), eNOS and COX double knockout mice (10), and hypertensive patients (30).Several compounds have been described as EDHFs including arachidonic acid (AA) metabolites of cytochrome 450 (CYP450; Refs. 4, 11) and 15-lipoxygenase-1 (15-LO-1; Refs. 24, 25) and the potassium (K) ion (9, 36). AA metabolites of 15-LO-1, 11,12,15-trihydroxyeicosatrienoic acid (THETA) and 15-hyd...

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Section: Discussionsupporting

confidence: 60%

15-Lipoxygenase metabolites contribute to age-related reduction in acetylcholine-induced hypotension in rabbits

Aggarwal

Gauthier²,

Campbell³

2008

American Journal of Physiology-Heart and Circulatory Physiology

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“…As we have found previously (16,17,21,34,35), responses to RNS were highly reproducible across the course of the experiment in control rabbits (group 1). By analyzing our results mainly in a within-animal fashion, we were able to detect relatively modest effects of ANG II and PD123319 on responses to RNS, even though responses to RNS can vary somewhat in different rabbits.…”

Section: Discussionsupporting

confidence: 51%

“…We have indirect evidence that this effect is mediated by NO, since 1) NO synthase (NOS) blockade enhances responses of MLDF to RNS (16,34,35), and 2) under conditions of NOS blockade renal arterial infusion of ANG II enhances responses of MLDF to RNS (35). Our current observations suggest that the effects of exogenous ANG II on neural control of medullary blood flow are mediated by AT 2 receptors, since they were abolished by PD123319.…”

Section: Discussionmentioning

confidence: 67%

ANG II type 2 receptors and neural control of intrarenal blood flow

Rajapakse¹,

Eppel²,

Widdop³

et al. 2006

American Journal of Physiology-Regulatory, Integrative and Comp

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We tested the hypothesis that activation of angiotensin type 2 (AT 2) receptors, by both exogenous and endogenous ANG II, modulates neurally mediated vasoconstriction in the renal cortical and medullary circulations. Under control conditions in pentobarbital-anesthetized rabbits, electrical stimulation of the renal nerves (RNS; 0.5-8 Hz) reduced renal blood flow (RBF; Ϫ88 Ϯ 3% at 8 Hz) and cortical perfusion (CBF; Ϫ92 Ϯ 2% at 8 Hz) more than medullary perfusion (MBF; Ϫ67 Ϯ 6% at 8 Hz). Renal arterial infusion of ANG II, at a dose titrated to reduce RBF by ϳ40 -50% (5-50 ng ⅐ kg Ϫ1 ⅐ min Ϫ1 ) blunted responses of MBF to RNS, without significantly affecting responses of RBF or CBF. Subsequent administration of PD123319 (1 mg/kg plus 1 mg ⅐ kg Ϫ1 ⅐ h Ϫ1 ) during continued renal arterial infusion of ANG II did not significantly affect responses of RBF or CBF to RNS but enhanced responses of MBF, so that they were similar to those observed under control conditions. In contrast, administration of PD123319 alone blunted responses of CBF and MBF to RNS. Subsequent renal arterial infusion of ANG II in PD123319-pretreated rabbits restored CBF responses to RNS back to control levels. In contrast, ANG II infusion in PD123319-pretreated rabbits did not alter MBF responses to RNS. These data indicate that exogenous ANG II can blunt neurally mediated vasoconstriction in the medullary circulation through activation of AT2 receptors. However, AT2-receptor activation by endogenous ANG II appears to enhance neurally mediated vasoconstriction in both the cortical and medullary circulations. kidney medulla; renal circulation; renin-angiotensin system; sympathetic nervous system THE RENAL MEDULLARY MICROCIRCULATION (7)(8)(9)(10)20), the renal sympathetic nerves (11), and the renin-angiotensin system (37) all play key roles in long-term regulation of arterial pressure. Renal sympathetic nerves innervate juxtamedullary afferent and efferent arterioles and outer medullary descending vasa recta (17, 18), vascular elements likely important in control of medullary perfusion (20). Angiotensin type 2 (AT 2 ) and/or AT 1 receptors are also localized to these vascular elements (32). Activation of the renal nerves (18, 24) and AT receptors (13, 14) can alter renal medullary blood flow. However, medullary blood flow appears to be less sensitive than cortical blood flow to vasoconstriction evoked by either neural activation or ANG II (18,20).We recently found that renal arterial infusion of ANG II, at doses that reduce baseline total renal blood flow (RBF) and cortical laser Doppler flux (CLDF; an index of cortical blood flow) by Ͼ30% but do not significantly alter baseline medullary laser Doppler flux (MLDF), blunt reductions in MLDF induced by electrical stimulation of the renal nerves (RNS) (21). In contrast, ANG II infusion did not significantly affect responses of RBF or CLDF to RNS (21). This raised the interesting possibility that ANG II might act specifically within the medullary circulation to blunt vasoconstrictor responses to RNS. This...

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“…27 A reduction in renal NO bioavailability can increase the responsiveness of the kidney to any given level of renal sympathetic nerve activity (RSNA). For example, we and others have shown that reduced renal NO levels can induce greater reductions in renal medullary perfusion to a given level of RSNA, 29,30 which in turn can lead to sodium and water retention leading to hypertension. 31 Indeed, in fat fed rabbits, stimulation of renal nerves resulted in greater reductions in medullary perfusion and sodium retention when compared with controls.…”

Section: Reduced No Bioavailability Can Exacerbate the Prohypertensivmentioning

confidence: 92%

“…27 La disminución de la biodisponibilidad de NO renal puede aumentar la capacidad de respuesta del riñón a determinado nivel de actividad nerviosa simpática renal (ANSR). Por ejemplo, nosotros y otros colegas hemos demostrado que la disminución del nivel de NO renal puede inducir una mayor reducción de la perfusión en la médula renal a determinado nivel de ANSR, 29,30 lo que a su vez puede derivar en la retención de sodio y agua y terminar en hipertensión. 31 De hecho, en conejos con una dieta a base de grasas, la estimulación de los nervios renales dio como resultado mayor reducción de la perfusión en la médula renal y retención de sodio en comparación con los controles.…”

Section: -24unclassified

Say NO to Obesity-Related Hypertension

2016

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O besity and its complications represent one of the major emerging challenges for the developed world. 1,2 Hypertension is a common sequelae of obesity, 3,4 and the obesity pandemic is estimated to contribute to 75% of cases of hypertension in men and 65% in women.1 Frequently, subjects with obesity are resistant to standard antihypertensive medication, 4 and poor understanding of the precise mechanisms underlying the link between obesity and hypertension has presented roadblocks for the development of new and effective therapy. 4 In this context, we recently found that obesity is associated with reduced nitric oxide (NO) bioavailability caused by impaired transport of its substrate l-arginine and that augmentation of endothelial l-arginine transport prevents experimental obesity-induced hypertension.5 Findings by others also provide clear evidence that endothelial dysfunction plays an important role in the pathogenesis of hypertension 6,7 including that associated with obesity. 8In the current review, we will discuss the role of the l-arginine-NO pathway in the long-term regulation of blood pressure, its complex inter-relationship with other key neurohormonal and biochemical determinants of arterial pressure, and the way in which this system becomes deranged in obesity-related hypertension. l-Arginine-NO PathwayNO is well recognized as a pivotal endogenous modulator of vascular tone and endothelial function.9 l-Arginine is the sole substrate for NO formation and transport of extracellular l-arginine via cationic amino acid transporter-1 (CAT1) is a rate limiting factor for endothelial NO synthase (eNOS)-dependent NO formation (Figure 1). [9][10][11] This occurs despite the fact that intracellular concentration of l-arginine far exceeds the Michaelis constant K m of eNOS for l-arginine, and this phenomenon is commonly referred to as the l-arginine paradox. 9 The precise factors underlying this paradox remain to be determined, but some of the proposed mechanisms include sequestration of intracellular l-arginine into pools that are not accessible to membrane-bound eNOS, the presence of endogenous eNOS inhibitors such as asymmetrical dimethylarginine and colocalization of CAT1, and eNOS within the plasma membrane of endothelial cells, which facilitates the use of extracellular l-arginine for eNOS-dependent NO formation.9-11 Regardless of the mechanism(s) involved, the presence of the l-arginine paradox creates a crucial role for l-arginine transporters in regulating NO bioavailability and consequently endothelial function. Does Endothelial Dysfunction Precede Hypertension in the Setting of Obesity?Although there is a plethora of data to support an association between endothelial dysfunction and hypertension, [12][13][14] the precise relationship between these 2 phenomena remains complex and undefined. Weisbrod et al 15 recently demonstrated that endothelial function as measured by aortic relaxation to acetylcholine ex vivo was impaired within 2 months of placing mice on a high fat, high sucrose diet. Howeve...

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Prostaglandins and nitric oxide in regional kidney blood flow responses to renal nerve stimulation

Cited by 14 publications

References 38 publications

15-Lipoxygenase metabolites contribute to age-related reduction in acetylcholine-induced hypotension in rabbits

15-Lipoxygenase metabolites contribute to age-related reduction in acetylcholine-induced hypotension in rabbits

ANG II type 2 receptors and neural control of intrarenal blood flow

Say NO to Obesity-Related Hypertension

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