1. The aim of the present study was to examine the roles of cyclo-oxygenase (COX)- and lipoxygenase (LOX)-dependent arachidonate signalling cascades in the control of regional kidney blood flow. 2. In pentobarbitone-anaesthetized rabbits treated with NG-nitro-l-arginine and glyceryl trinitrate to 'clamp' nitric oxide, we determined the effects of ibuprofen (a COX inhibitor) and esculetin (a LOX inhibitor) on resting systemic and renal haemodynamics and responses to renal arterial infusions of vasoconstrictors. 3. Ibuprofen increased mean arterial pressure (14 +/- 5%) and reduced medullary laser Doppler flux (MLDF; 26 +/- 6%) when administered with esculetin. A similar pattern of responses was observed when ibuprofen was given alone, although the reduction in MLDF was not statistically significant. Esculetin tended to increase renal blood flow (RBF; 16 +/- 7%) and MLDF (28 +/- 13%) when given alone, but not when combined with ibuprofen. 4. After vehicle, renal arterial infusions of noradrenaline, angiotensin II and endothelin-1 reduced RBF and cortical laser Doppler flux (CLDF), but not MLDF. In contrast, renal arterial [Phe2,Ile3,Orn8]-vasopressin reduced MLDF but not RBF or CLDF. Ibuprofen alone did not significantly affect these responses. Esculetin, when given alone, but not when combined with ibuprofen, enhanced noradrenaline-induced renal vasoconstriction. In contrast, esculetin did not significantly affect responses to [Phe2,Ile3,Orn8]-vasopressin, angiotensin II or endothelin-1. 5. We conclude that COX products contribute to the maintenance of arterial pressure and renal medullary perfusion under 'nitric oxide clamp' conditions, but not to renal haemodynamic responses to the vasoconstrictors we tested. Lipoxygenase products may blunt noradrenaline-induced vasoconstriction, but our observations may, instead, reflect LOX-independent effects of esculetin.
"Both ODQ and LNA cause partial reductions in the relaxations to ACH, and these ODQ-resistant and LNA-resistant ACH relaxations were blocked by LO inhibition. In agreement with these results, LNA-resistant relaxations were inhibited completely by a number of LO inhibitors including BW755C, ebselen and baicalein (Aggarwal et al., 2008c; Oliver et al., 2003). ODQ and LNA caused similar reductions in the relaxations to ACH suggesting that NO's effects are mediated by GC and cGMP pathway exclusively. "
[Show abstract][Hide abstract] ABSTRACT: Endothelial 15-lipoxygenase-1 (15-LO-1) metabolites of arachidonic acid (AA), 11,12,15-trihydroxyeicosatrienoic acid (THETA) and 15-hydroxy-11,12-epoxyeicosatrienoic acid (HEETA) and nitric oxide (NO) mediate relaxations to acetylcholine (ACH). However, interactions between NO and the 15-LO-1 pathway have not been explored. Therefore, the effect of physiological and pharmacological concentrations of NO on 15-LO activity and relaxation was studied in rabbit aorta. In indomethacin-treated aortic rings, maximal ACH relaxations of 91.3±4.0%, decreased to 54.5±3.0% by the NO synthase inhibitor, nitro-l-arginine (LNA), to 49.8±3% by the guanylate cyclase (GC) inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, to 63.7±4.9% by the lipoxygenase (LO) inhibitor, nordihydroguaiaretic acid (NDGA) and were completely inhibited by the combination of LNA and NDGA. AA relaxations were not affected by GC inhibition but were reduced by LO inhibition. The NO donor, dipropylenetriamine-NONOate (DPTA) caused concentration-related relaxations (EC(50)=4.7×10(-6)M). Aortic metabolism of (14)C-AA to THETA and HEETA was not altered by EC(50) concentrations of DPTA but were reduced 10-fold by 10(-3)M DPTA. In LNA-treated aorta, DPTA (3×10(-6)M) caused relaxations of 38.2.5±4%. Maximum relaxations to ACH did not differ in the presence and absence 3×10(-6)M DPTA (49.5±5% and 44.2±4%, respectively). These results indicate that NO and 15-LO-1 act in parallel to mediate ACH relaxations and NO does not alter 15-LO-1 activity.
[Show abstract][Hide abstract] ABSTRACT: This study examined the effects of renal arterial infusion of a selective cytochrome P-450 epoxygenase inhibitor, N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH; 2 mg/kg plus 1.5 mg.kg(-1).h(-1)), on renal hemodynamic responses to infusions of [Phe(2),Ile(3),Orn(8)]vasopressin and ANG II into the renal artery of anesthetized rabbits. MS-PPOH did not affect basal renal blood flow (RBF) or cortical or medullary blood flow measured by laser-Doppler flowmetry (CLDF/MLDF). In vehicle-treated rabbits, [Phe(2),Ile(3),Orn(8)]vasopressin (30 ng.kg(-1).min(-1)) reduced MLDF by 62 +/- 7% but CLDF and RBF were unaltered. In MS-PPOH-treated rabbits, RBF and CLDF fell by 51 +/- 8 and 59 +/- 13%, respectively, when [Phe(2),Ile(3),Orn(8)]vasopressin was infused. MS-PPOH had no significant effects on the MLDF response to [Phe(2),Ile(3),Orn(8)]vasopressin (43 +/- 9% reduction). ANG II (20 ng.kg(-1).min(-1)) reduced RBF by 45 +/- 10% and CLDF by 41 +/- 14%, but MLDF was not significantly altered. MS-PPOH did not affect blood flow responses to ANG II. Formation of epoxyeicosatrienoic acids (EETs) and dihydroxyeicosatrienoic acids (DiHETEs) was 49% lower in homogenates prepared from the renal cortex of MS-PPOH-treated rabbits than from vehicle-treated rabbits. MS-PPOH had no effect on the renal formation of 20-hydroxyeicosatetraenoic acid (20-HETE). Incubation of renal cortical homogenates from untreated rabbits with [Phe(2),Ile(3),Orn(8)]vasopressin (0.2-20 ng/ml) did not affect formation of EETs, DiHETEs, or 20-HETE. These results do not support a role for de novo EET synthesis in modulating renal hemodynamic responses to ANG II. However, EETs appear to selectively oppose V(1)-receptor-mediated vasoconstriction in the renal cortex but not in the medullary circulation and contribute to the relative insensitivity of cortical blood flow to V(1)-receptor activation [corrected].
[Show abstract][Hide abstract] ABSTRACT: We examined the roles of cyclooxygenase products and of interactions between the cyclooxygenase and nitric oxide systems in the mechanisms underlying the relative insensitivity of medullary perfusion to renal nerve stimulation (RNS) in anaesthetized rabbits. To this end we examined the effects of ibuprofen and N(G)-nitro-L: -arginine (L-NNA), both alone and in combination, on the responses of regional kidney perfusion to RNS. Under control conditions, RNS produced frequency-dependent reductions in total renal blood flow (RBF; -82+/-3% at 6 Hz), cortical laser-Doppler flux (CLDF; -84+/-4% at 6 Hz) and, to a lesser extent, medullary laser-Doppler flux (MLDF; -46+/-7% at 6 Hz). Ibuprofen did not affect these responses significantly, suggesting that cyclooxygenase products have little net role in modulating renal vascular responses to RNS. L-NNA enhanced RBF (P=0.002), CLDF (P=0.03) and MLDF (P=0.03) responses to RNS. As we have shown previously, this effect of L-NNA was particularly prominent for MLDF at RNS frequencies < or = 1.5 Hz. Subsequent administration of ibuprofen, in L-NNA-pretreated rabbits, did not affect responses to RNS significantly. We conclude that counter-regulatory actions of NO, but not of prostaglandins, partly underlie the relative insensitivity of medullary perfusion to renal nerve activation.
Pflügers Archiv - European Journal of Physiology 12/2004; 449(2):143-9. DOI:10.1007/s00424-004-1320-3 · 4.10 Impact Factor
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