Neuronal NOS contributes to biphasic autoregulatory response during enhanced TGF activity

1999 ◽  
Vol 277 (1) ◽  
pp. F113-F120 ◽  
Author(s):  
Atsuhiro Ichihara ◽  
L. Gabriel Navar
Keyword(s):  
Initial Response ◽  
Renal Perfusion ◽  
Tubuloglomerular Feedback ◽  
Afferent Arterioles ◽  
Series Of Experiments ◽  
Oxide Synthase ◽  
Increased Activity ◽  
Arteriolar Diameter ◽  
Distal Delivery

To assess the afferent arteriolar autoregulatory response during increased activity of the tubuloglomerular feedback (TGF) mechanism and to delineate the contribution of neuronal nitric oxide synthase (nNOS) to this response, afferent arteriolar diameter responses to changes in renal perfusion pressure (RPP) were monitored in vitro using the blood-perfused rat juxtamedullary nephron preparation. At RPP of 100 mmHg, basal afferent arteriolar diameter averaged 21.1 ± 1.4 μm ( n = 9). The initial and sustained constrictor responses of afferent arterioles to a 60-mmHg increase in RPP averaged 14.8 ± 1.4% and 13.3 ± 1.3%, respectively. Acetazolamide treatment, which enhances TGF responsiveness by increasing distal nephron volume delivery, significantly decreased basal afferent arteriolar diameter by 8.2 ± 0.5% and enhanced the initial response (25.5 ± 2.3%) to a 60-mmHg increase in RPP but did not alter the sustained response (14.3 ± 1.5%). In another series of experiments, nNOS inhibition with 10 μM S-methyl-l-thiocitrulline (l-SMTC) significantly decreased afferent arteriolar diameter from 20.3 ± 1.3 to 18.3 ± 1.1 μm ( n = 7) and enhanced both the initial (34.4 ± 3.5%) and sustained constrictor responses (27.6 ± 2.9%) to a 60-mmHg increase in RPP. Treatment with acetazolamide further enhanced both initial (56.4 ± 3.0%) and sustained responses (54.6 ± 2.7%). Interruption of distal delivery by transection of the loops of Henle prevented the enhanced responses to increases in RPP elicited with either acetazolamide orl-SMTC. These results indicate that nNOS contributes to the counteracting resetting process of biphasic afferent arteriolar constrictor responses to increases in RPP through a TGF-dependent mechanism.

Direct assessment of renal microvascular responses to P2-purinoceptor agonists

1998 ◽  
Vol 274 (4) ◽  
pp. F718-F727 ◽  
Author(s):  
Edward W. Inscho ◽  
Anthony K. Cook ◽  
Vy Mui ◽  
Jason Miller
Keyword(s):  
Vessel Diameter ◽  
Renal Perfusion ◽  
Receptor Subtypes ◽  
Selective Agonist ◽  
Juxtamedullary Nephron ◽  
Afferent Arterioles ◽  
Arcuate Artery ◽  
Arteriolar Diameter

Studies were performed to determine the responsiveness of rat juxtamedullary afferent arterioles to receptor-selective P2-purinoceptor agonists. Experiments were performed in vitro using the blood perfused juxtamedullary nephron technique, combined with videomicroscopy. Renal perfusion pressure was set at 110 mmHg and held constant. Basal afferent arteriolar diameter averaged 22.0 ± 0.6 μm ( n = 69). Stimulation with 0.1, 1.0, 10, and 100 μM ATP ( n = 10) elicited a concentration-dependent vasoconstriction averaging 8 ± 2, 17 ± 2, 21 ± 4, and 23 ± 5%, respectively. A nearly identical afferent arteriolar vasoconstriction was observed in response to the P2X-selective agonist β,γ-methylene ATP ( n = 10); however, another P2X agonist, α,β-methylene ATP, evoked marked receptor desensitization ( n = 10). Vessel diameter decreased by ∼7 ± 2, 16 ± 2, 23 ± 3, and 22 ± 3%, respectively, over the same concentration range. The P2Y-selective agonist, 2-methylthio-ATP, evoked only a modest vasoconstriction, whereas UTP and adenosine 5′- O-(3-thiotriphosphate) (ATPγS) reduced afferent diameter markedly at concentrations >1.0 μM. Afferent arteriolar diameter decreased by 5 ± 4, 31 ± 8, and 72 ± 8% during UTP administration ( n = 7) at concentrations of 1.0, 10, and 100 μM, respectively. Similarly, ATPγS ( n = 6) decreased afferent diameter by 16 ± 2, 58 ± 8, and 98 ± 3%, respectively, over the same concentration range. Nitric oxide synthesis inhibition with N ω-nitro-l-arginine did not significantly alter the afferent arteriolar response to ATP but did potentiate ATP-mediated arcuate artery vasoconstriction. The following data suggest the presence of multiple P2 receptors on juxtamedullary afferent arterioles and are consistent with classification of those receptors as members of the P2X- and P2Y2 (P2U)-receptor subtypes.

Autoregulation of afferent arteriolar blood flow in juxtamedullary nephrons

1994 ◽  
Vol 267 (5) ◽  
pp. F879-F887 ◽  
Author(s):  
T. Takenaka ◽  
L. M. Harrison-Bernard ◽  
E. W. Inscho ◽  
P. K. Carmines ◽  
L. G. Navar
Keyword(s):  
Blood Flow ◽  
Cross Correlation ◽  
Perfusion Pressure ◽  
Tubuloglomerular Feedback ◽  
Juxtamedullary Nephron ◽  
Afferent Arterioles ◽  
The Relationship ◽  
Feedback Pathway ◽  
Arteriolar Diameter

Utilizing the in vitro blood-perfused juxtamedullary nephron preparation, we examined the effects of alterations in renal arterial pressure on afferent arteriolar blood flow. With video microscopy and cross-correlation techniques, arteriolar inside diameters and centerline erythrocyte velocity were measured to estimate single afferent arteriolar blood flow. In response to random changes in perfusion pressure, afferent arteriolar diameter (n = 8) varied inversely (-0.53 +/- 0.02%/mmHg), and erythrocyte velocity was directly related (1.4 +/- 0.1%/mmHg). Above 95 mmHg, the slope of the relationship between perfusion pressure and afferent arteriolar blood flow did not differ from zero (0.081 +/- 0.053%/mmHg), suggesting efficient autoregulation. When the tubuloglomerular feedback pathway was interrupted by the addition of furosemide (n = 9) or papillectomy (n = 7), there was attenuation of pressure-induced afferent arteriolar constriction, with impairment in blood flow autoregulation (0.60 +/- 0.05%/mmHg). Superfusion with diltiazem abolished autoregulatory responses in afferent arteriolar diameter and blood flow (1.5 +/- 0.2%/mmHg). These data demonstrate the autoregulation of blood flow of individual afferent arterioles in juxtamedullary nephrons and suggest that both tubuloglomerular feedback-dependent and -independent mechanisms are required for autoregulatory responses.

scholarly journals Actions of epoxygenase metabolites on the preglomerular vasculature.

1996 ◽  
Vol 7 (11) ◽  
pp. 2364-2370 ◽  
Author(s):  
J D Imig ◽  
L G Navar ◽  
R J Roman ◽  
K K Reddy ◽  
J R Falck
Keyword(s):  
Perfusion Pressure ◽  
Direct Action ◽  
Renal Perfusion ◽  
Epoxyeicosatrienoic Acids ◽  
Vasodilatory Response ◽  
Vasoconstrictor Response ◽  
Juxtamedullary Nephron ◽  
Afferent Arterioles ◽  
Arteriolar Diameter

Epoxygenase metabolites of arachidonic acid are produced by the kidney and have been implicated in the control of renal blood flow. This study examined the preglomerular actions of various epoxyeicosatrienoic acids (EET). By use of the in vitro blood-perfused juxtamedullary nephron preparation, interlobular and afferent arteriolar diameter responses to 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET were determined. Diameters of interlobular and afferent arterioles preconstricted with 0.5 microM norepinephrine averaged 24 +/- 1 microns (N = 27) and 17 +/- 1 microns (N = 32), respectively, at a renal perfusion pressure of 100 mm Hg. Superfusion with 0.01 to 100 nM 11,12-EET caused graded increases in diameters of the interlobular and afferent arterioles. At a dose of 100 nM, 11,12-EET increased the diameters of the interlobular and afferent arterioles by 18 +/- 2% (N = 10) and 20 +/- 3% (N = 9), respectively. The vasodilatory response to 11,12-EET was stereoselective because 11,12(R,S)-EET but not 11,12(S,R)-EET increased the diameters of the interlobular and afferent arterioles. 14,15-EET had a much smaller effect and increased the diameters of the these vessels by 10%; 8,9-EET did not significantly affect vascular diameters. In contrast, 5,6-EET constricted the interlobular and afferent arterioles by 16 +/- 3% (N = 6) and 21 +/- 3% (N = 7), respectively. The corresponding diols, 5,6-DIHETE and 11,12-DIHETE, had no effect on diameters of the interlobular and afferent arterioles at concentrations up to 1 microM. The vasodilatory response to 11,12-EET was not affected by removal of the endothelium or by inhibition of cyclooxygenase with indomethacin. In contrast, the vasoconstrictor response to 5,6-EET was abolished by both removal of the endothelium or cyclooxygenase inhibition. The thromboxane/ enderoperoxide receptor inhibitor, SQ 29,548, resulted in a 60% attenuation of the afferent arteriolar vasconstriction to 5,6-EET. These results indicate that the preglomerular vasoconstriction to 5,6-EET is cyclooxygenase dependent and requires an intact endothelium, whereas the vasodilation to 11,12-EET is stereoselective and is the result of direct action of the epoxide on the preglomerular vascular smooth muscle.

Direct evaluation of the microvascular actions of ANP in juxtamedullary nephrons

1988 ◽  
Vol 254 (3) ◽  
pp. F440-F444 ◽  
Author(s):  
P. J. Veldkamp ◽  
P. K. Carmines ◽  
E. W. Inscho ◽  
L. G. Navar
Keyword(s):  
Angiotensin Ii ◽  
Topical Administration ◽  
Normal Kidney ◽  
Arterial Diameter ◽  
Direct Evaluation ◽  
Juxtamedullary Nephron ◽  
Afferent Arterioles ◽  
Renal Vascular ◽  
Arteriolar Diameter

The renal vascular actions of atrial natriuretic peptide (ANP) remain incompletely understood. The purpose of this study is to evaluate the effects of ANP on microvascular structures of the normal kidney. The in vitro blood-perfused juxtamedullary nephron technique was utilized to allow visualization of arcuate arteries and afferent and efferent arterioles. Donor rats were pretreated with captopril to eliminate possible interactions between angiotensin II and atriopeptin III (AP III). The effects of topical administration of 3 nM AP III were determined by videometric analysis of vessel inside diameters. Under control conditions, arcuate arterial diameter averaged 83 +/- 14 microns (n = 7), afferent arteriolar diameter was 20 +/- 4 microns (n = 7), and efferent arteriolar diameter was 16 +/- 2 microns (n = 7). During superfusion with AP III, arcuate arteries and afferent arterioles dilated 73 +/- 9 and 23 +/- 5%, respectively. Both returned to their control values when AP III was removed from the superfusate. Further experiments on arcuate arteries (n = 5) revealed that 0.3 nM AP III also vasodilated these vessels (26 +/- 9%); however, no significant effect was elicited by 0.03 nM AP III. In contrast to the vasodilator influence of AP III on preglomerular vessels, efferent arteriolar diameter was not altered by AP III exposure. These observations reveal that AP III can induce selective preglomerular vasodilation involving arcuate arteries as well as afferent arterioles, while efferent arteriolar diameter is not perceptibly influenced.

Effects of ATP on pre- and postglomerular juxtamedullary microvasculature

1992 ◽  
Vol 263 (5) ◽  
pp. F886-F893 ◽  
Author(s):  
E. W. Inscho ◽  
K. Ohishi ◽  
L. G. Navar
Keyword(s):  
Perfusion Pressure ◽  
Renal Perfusion ◽  
Renal Perfusion Pressure ◽  
Organ Systems ◽  
Smooth Muscle Function ◽  
Juxtamedullary Nephron ◽  
Afferent Arterioles ◽  
The Right ◽  
Dose Dependent

Based on evidence that extracellular ATP can influence vascular smooth muscle function in other organ systems, experiments were conducted to characterize the responsiveness of rat juxtamedullary microvascular segments to ATP. Experiments were performed using the in vitro blood-perfused juxtamedullary nephron preparation combined with video microscopy. Pentobarbital-anesthetized rats were pretreated with enalaprilat (2 mg iv) for 30 min before the right kidney was isolated and prepared for study. Renal perfusion pressure was set at 110 mmHg and held constant. Under control conditions, afferent and efferent arteriolar diameters averaged 19.9 +/- 1.4 (n = 19) and 21.6 +/- 1.2 microns (n = 10), respectively. Superfusion with 1, 10, and 100 microM ATP solutions induced sustained dose-dependent afferent vasoconstriction of 8.3 +/- 1.4, 12.8 +/- 1.7, and 12.1 +/- 2.1%, respectively (P < 0.01). Afferent vasoconstrictor responses to ATP were also observed during adenosine receptor blockade. In contrast, efferent arterioles were unresponsive to ATP stimulation even at concentrations as high as 100 microM (P > 0.05). Arcuate and interlobular arterial diameters averaged 82.0 +/- 15.7 (n = 5) and 43.4 +/- 4.5 microns (n = 6), respectively, during control conditions and responded to ATP treatment with a transient vasoconstriction followed by a gradual return to control diameter. Interlobular arteries exhibited a sustained constriction only at the 100 microM concentration (P < 0.05). These data demonstrate that afferent arterioles are more responsive to ATP treatment than other renal microvascular segments and suggest the presence of ATP-sensitive P2x purinoceptors on pre- but not postglomerular juxtamedullary microvascular elements.

Contribution of prostaglandin EP2 receptors to renal microvascular reactivity in mice

2002 ◽  
Vol 283 (3) ◽  
pp. F415-F422 ◽  
Author(s):  
John D. Imig ◽  
Matthew D. Breyer ◽  
Richard M. Breyer
Keyword(s):  
Perfusion Pressure ◽  
Renal Perfusion ◽  
Receptor Activation ◽  
Angiotensin Converting Enzyme Inhibition ◽  
Wild Type ◽  
Endothelin 1 ◽  
Converting Enzyme Inhibition ◽  
Afferent Arterioles ◽  
Arteriolar Vasodilation ◽  
Arteriolar Diameter

The present studies were performed to determine the contribution of EP2 receptors to renal hemodynamics by examining afferent arteriolar responses to PGE2, butaprost, sulprostone, and endothelin-1 in EP2 receptor-deficient male mice (EP2−/−). Afferent arteriolar diameters averaged 17.8 ± 0.8 μm in wild-type (EP2+/+) mice and 16.7 ± 0.7 μm in EP2−/− mice at a renal perfusion pressure of 100 mmHg. Vessels from both groups of mice responded to norepinephrine (0.5 μM) with similar 17–19% decreases in diameter. Diameters of norepinephrine-preconstricted afferent arterioles increased by 7 ± 2 and 20 ± 6% in EP2+/+ mice in response to 1 μM PGE2 and 1 μM butaprost, respectively. In contrast, afferent arteriolar diameter of EP2−/− mice decreased by 13 ± 3 and 16 ± 6% in response to PGE2 and butaprost. The afferent arteriolar vasoconstriction to butaprost in EP2−/− mice was eliminated by angiotensin-converting enzyme inhibition. Sulprostone, an EP1 and EP3receptor ligand, decreased afferent arteriolar diameter in both groups; however, the vasoconstriction in the EP2−/− mice was greater than in the EP2+/+ mice. Endothelin-1-mediated afferent arteriolar diameter responses were enhanced in EP2−/− mice. Afferent arteriolar diameter decreased by 29 ± 7% in EP2−/− and 12 ± 7% in EP2+/+ mice after administration of 1 nM endothelin-1. These results demonstrate that the EP2 receptor mediates a portion of the PGE2 afferent arteriolar vasodilation and buffers the renal vasoconstrictor responses elicited by EP1and EP3 receptor activation as well as endothelin-1.

Role of connexin40 in the autoregulatory response of the afferent arteriole

2012 ◽  
Vol 303 (6) ◽  
pp. F855-F863 ◽  
Author(s):  
Charlotte Mehlin Sorensen ◽  
Isaiah Giese ◽  
Thomas Hartig Braunstein ◽  
Jens Christian Brasen ◽  
Max Salomonsson ◽  
...  
Keyword(s):  
Electrical Stimulation ◽  
Significant Role ◽  
Knockout Mice ◽  
Perfusion Pressure ◽  
Renal Perfusion ◽  
Tubuloglomerular Feedback ◽  
Wild Type ◽  
Renal Perfusion Pressure ◽  
Acute Changes ◽  
Arteriolar Diameter

Connexins in renal arterioles affect autoregulation of arteriolar tonus and renal blood flow and are believed to be involved in the transmission of the tubuloglomerular feedback (TGF) response across the cells of the juxtaglomerular apparatus. Connexin40 (Cx40) also plays a significant role in the regulation of renin secretion. We investigated the effect of deleting the Cx40 gene on autoregulation of afferent arteriolar diameter in response to acute changes in renal perfusion pressure. The experiments were performed using the isolated blood perfused juxtamedullary nephron preparation in kidneys obtained from wild-type or Cx40 knockout mice. Renal perfusion pressure was increased in steps from 75 to 155 mmHg, and the response in afferent arteriolar diameter was measured. Hereafter, a papillectomy was performed to inhibit TGF, and the pressure steps were repeated. Conduction of intercellular Ca2+changes in response to local electrical stimulation was examined in isolated interlobular arteries and afferent arterioles from wild-type or Cx40 knockout mice. Cx40 knockout mice had an impaired autoregulatory response to acute changes in renal perfusion pressure compared with wild-type mice. Inhibition of TGF by papillectomy significantly reduced autoregulation of afferent arteriolar diameter in wild-type mice. In Cx40 knockout mice, papillectomy did not affect the autoregulatory response, indicating that these mice have no functional TGF. Also, Cx40 knockout mice showed no conduction of intercellular Ca2+changes in response to local electrical stimulation of interlobular arteries, whereas the Ca2+response to norepinephrine was unaffected. These results suggest that Cx40 plays a significant role in the renal autoregulatory response of preglomerular resistance vessels.

Determinants of renal afferent arteriolar actions of bradykinin: evidence that multiple pathways mediate responses attributed to EDHF

2003 ◽  
Vol 285 (3) ◽  
pp. F540-F549 ◽  
Author(s):  
Xuemei Wang ◽  
Greg Trottier ◽  
Rodger Loutzenhiser
Keyword(s):  
Rat Kidney ◽  
Afferent Arteriole ◽  
Ang Ii ◽  
Epoxyeicosatrienoic Acid ◽  
Nitric Oxide Synthase Inhibitor ◽  
Afferent Arterioles ◽  
Synthase Inhibitor ◽  
Oxide Synthase ◽  
Arteriolar Vasodilation

The determinants of bradykinin (BK)-induced afferent arteriolar vasodilation were investigated in the in vitro perfused hydronephrotic rat kidney. BK elicited a concentration-dependent vasodilation of afferent arterioles that had been preconstricted with ANG II (0.1 nmol/l), but this dilation was transient in character. Pretreatment with the nitric oxide synthase inhibitor Nω-nitro-l-arginine methyl ester (100 μmol/l) and the cyclooxygenase inhibitor ibuprofen (10 μmol/l) did not prevent this dilation when tone was established by ANG II but fully blocked the response when tone was established by elevated extracellular KCl, which suggests roles for both NO and endothelium-derived hyperpolarizing factor (EDHF). We had previously shown that the EDHF-like response of the afferent arteriole evoked by ACh was fully abolished by a combination of charybdotoxin (ChTX;10 nmol/l) and apamin (AP; 1 μmol/l). However, in the current study, treatment with ChTX plus AP only reduced the EDHF-like component of the BK response from 98 ± 5 to 53 ± 6% dilation. Tetraethylammonium (TEA; 1 mmol/l), which had no effect on the EDHF-induced vasodilation associated with ACh, reduced the EDHF-like response to BK to 88 ± 3% dilation. However, the combination of TEA plus ChTX plus AP abolished the response (0.3 ± 1% dilation). Similarly, 17-octadecynoic acid (17-ODYA) did not prevent the dilation when it was administered alone (77 ± 9% dilation) but fully abolished the EDHF-like response when added in combination with ChTX plus AP (-0.5 ± 4% dilation). These findings suggest that BK acts via multiple EDHFs: one that is similar to that evoked by ACh in that it is blocked by ChTX plus AP, and a second that is blocked by either TEA or 17-ODYA. Our finding that a component of the BK response is sensitive to TEA and 17-ODYA is consistent with previous suggestions that the EDHF released by BK is an epoxyeicosatrienoic acid.

scholarly journals Heme oxygenase metabolites inhibit tubuloglomerular feedback (TGF)

2008 ◽  
Vol 295 (4) ◽  
pp. F1207-F1212 ◽  
Author(s):  
YiLin Ren ◽  
Martin A. D'Ambrosio ◽  
Hong Wang ◽  
Ruisheng Liu ◽  
Jeffrey L. Garvin ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Heme Oxygenase ◽  
Tubuloglomerular Feedback ◽  
Afferent Arteriole ◽  
Nacl Concentration ◽  
Before And After ◽  
Low Levels ◽  
And Function ◽  
Oxide Synthase

Tubuloglomerular feedback (TGF) is the mechanism by which the macula densa (MD) senses increases in luminal NaCl concentration and sends a signal to constrict the afferent arteriole (Af-Art). The kidney expresses constitutively heme oxygenase-2 (HO-2) and low levels of HO-1. HOs release carbon monoxide (CO), biliverdin, and free iron. We hypothesized that renal HOs inhibit TGF via release of CO and biliverdin. Rabbit Af-Arts and attached MD were simultaneously microperfused in vitro. The TGF response was determined by measuring Af-Art diameter before and after increasing NaCl in the MD perfusate. When HO activity was inhibited by adding stannous mesoporphyrin (SnMP) to the MD perfusate, the TGF response increased from 2.1 ± 0.2 to 4.1 ± 0.4 μm ( P = 0.003, control vs. SnMP, n = 7). When a CO-releasing molecule, (CORM-3; 50 μM), was added to the MD perfusate, the TGF response decreased by 41%, from 3.6 ± 0.3 to 2.1 ± 0.2 μm ( P < 0.001, control vs. CORM-3, n = 12). When CORM-3 at 100 μM was added to the perfusate, it completely blocked the TGF response, from 4.2 ± 0.4 to −0.2 ± 0.3 μm ( P < 0.001, control vs. CORM-3, n = 6). When biliverdin was added to the perfusate, the TGF response decreased by 79%, from 3.4 ± 0.3 to 0.7 ± 0.4 μm ( P = 0.001, control vs. biliverdin, n = 6). The effects of SnMP and CORM-3 were not blocked by inhibition of nitric oxide synthase. We concluded that renal HO inhibits TGF probably via release of CO and biliverdin. HO regulation of TGF is a novel mechanism that could lead to a better understanding of the control of renal microcirculation and function.

Abstract 1436: CYP2J2 Endothelial Overexpression Increases Nitric Oxide and Cyclooxygenase Independent Renal Dilation and Attenuates Endothelin-1 Vasoconstriction

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
John D Imig ◽  
Craig R Lee ◽  
Alyce Bradbury ◽  
Joan P Graves ◽  
Laura M DeGraff ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Renal Vasculature ◽  
Specific Expression ◽  
Endothelin 1 ◽  
Afferent Arterioles ◽  
Oxide Synthase ◽  
Renal Vascular ◽  
Arteriolar Diameter ◽  
Regulation Of Vascular Tone

Human CYP2J2 is expressed in endothelial cells and active in the biosynthesis of epoxyeico-satrienoic acids (EETs). However, the functional role of CYP2J2 and its products in the renal vasculature remain poorly characterized. To address this, we developed transgenic (Tr) mice with constitutive, endothelial cell-specific expression of human CYP2J2 ( Tie2 promoter and full enhancer) and enhanced EET biosynthesis. Experiments were conducted in the juxtamedullary nephron preparation to determine renal microvascular responses to acetylcholine (ACh) and endothelin-1 in Tie2 -CYP2J2 Tr mice and wild type (Wt) littermate controls. Administration of phenylephrine to kidney perfusate decreased the diameter of afferent arterioles from 20.1±0.5 to 13.9±0.6 μm (n=21) in Wt mice and 19.4±0.6 to 13.5±0.6 μm (n=23) in Tie2 -CYP2J2 Tr mice. Following phenylephrine, the afferent arteriole diameter response to ACh (0.01nM-10μM) was determined. There was a leftward shift in the logEC50 in Tie2 -CYP2J2 Tr mice (−6.5±0.2, n=13) compared to Wt mice (−6.1±0.2, n=11). However, the maximal afferent arteriolar relaxation to ACh was decreased in Tie2 -CYP2J2 Tr mice (59±6%) compared to Wt mice (70±7%, p=0.12). Endothelial expression of CYP2J2 increased the maximal renal vascular response to ACh in the presence of nitric oxide synthase (100μM L-NAME) and cyclooxygenase (10μM indomethacin) inhibition. Afferent arterioles relaxed by 27±4% (n=12) in Wt mice and 44±6% (n=10, p=0.018) in Tie2 -CYP2J2 Tr mice (10μM ACh). The afferent arteriolar dose response curve to endothelin-1 (0.001–10nM) was significantly attenuated in Tie2 -CYP2J2 Tr compared to Wt mice. Afferent arteriolar diameter decreased by 24±4% (n=6) in Wt mice and 13±2% (n=5, p=0.023) in Tie2 -CYP2J2 Tr mice (3nM endothelin-1). These results demonstrate that the nitric oxide- and cyclooxygenase-independent afferent arteriolar dilation to ACh is enhanced by endothelial overexpression of CYP2J2, and endothelin-1 mediated constriction is attenuated. In conclusion, endothelial overexpression of CYP2J2 can oppose renal vascular constrictor responses and enhance dilator responses in mice, implicating the important role of CYP2J2-derived eicosanoids in the regulation of vascular tone.

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