Redundant signaling mechanisms contribute to the vasodilatory response of the afferent arteriole to proteinase-activated receptor-2

2005 ◽  
Vol 288 (1) ◽  
pp. F65-F75 ◽  
Author(s):  
Xuemei Wang ◽  
Morley D. Hollenberg ◽  
Rodger Loutzenhiser
Keyword(s):  
Rat Kidney ◽  
Combined Treatment ◽  
Afferent Arteriole ◽  
Vasodilatory Response ◽  
Signaling Mechanisms ◽  
Afferent Arterioles ◽  
Arteriolar Vasodilation ◽  
Dependent Mechanism ◽  
Stimulation Of

We previously demonstrated that stimulation of proteinase-activated receptor-2 (PAR-2) by SLIGRL-NH2 elicits afferent arteriolar vasodilation, in part, by elaborating nitric oxide (NO), suggesting an endothelium-dependent mechanism (Trottier G, Hollenberg M, Wang X, Gui Y, Loutzenhiser K, and Loutzenhiser R. Am J Physiol Renal Physiol 282: F891–F897, 2002). In the present study, we characterized the NO-independent component of this response, using the in vitro perfused hydronephrotic rat kidney. SLIGRL-NH2 (10 μmol/l) dilated afferent arterioles preconstricted with ANG II, and the initial transient component of this response was resistant to NO synthase (NOS) and cyclooxygenase inhibition. This NO-independent response was not prevented by treatment with 10 nmol/l charybdotoxin and 1 μmol/l apamin, a manipulation that prevents the endothelium-derived hyperpolarizing factor (EDHF)-like response of the afferent arteriole to acetylcholine, nor was it blocked by the addition of 1 mmol/l tetraethylammonium (TEA) or 50 μmol/l 17-octadecynoic acid, treatments that block the EDHF-like response to bradykinin. To determine whether the PAR-2 response additionally involves the electrogenic Na+-K+-ATPase, responses were evaluated in the presence of 3 mmol/l ouabain. In this setting, SLIGRL-NH2 induced a biphasic dilation in control and a transient response after NOS inhibition. The latter was not prevented by charybdotoxin plus apamin or by TEA alone but was abolished by combined treatment with charybdotoxin, apamin, and TEA. This treatment did not prevent the NO-dependent dilation evoked in the absence of NOS inhibition. Our findings indicate a remarkable redundancy in the signaling cascade mediating PAR-2 -induced afferent arteriolar vasodilation, suggesting an importance in settings such as inflamation or ischemia, in which vascular mechanisms might be impaired and the PAR system is thought to be activated.

Afferent arteriolar adenosine A2a receptors are coupled to KATP in in vitro perfused hydronephrotic rat kidney

1999 ◽  
Vol 277 (6) ◽  
pp. F926-F933 ◽  
Author(s):  
Lilong Tang ◽  
Michael Parker ◽  
Qing Fei ◽  
Rodger Loutzenhiser
Keyword(s):  
Rat Kidney ◽  
Afferent Arteriole ◽  
Adenosine A2a Receptors ◽  
A2a Receptors ◽  
High Affinity ◽  
Vasodilatory Response ◽  
Renal Microvasculature ◽  
Adenosine A2a ◽  
Arteriolar Vasodilation

Adenosine is known to exert dual actions on the afferent arteriole, eliciting vasoconstriction, by activating A1 receptors, and vasodilation at higher concentrations, by activating lower-affinity A2 receptors. We could demonstrate both of these known adenosine responses in the in vitro perfused hydronephrotic rat kidney. Thus, 1.0 μM adenosine elicited a transient vasoconstriction blocked by 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), and 10–30 μM adenosine reversed KCl-induced vasoconstriction. However, when we examined the effects of adenosine on pressure-induced afferent arteriolar vasoconstriction, we observed a third action. In this setting, a high-affinity adenosine vasodilatory response was observed at concentrations of 10–300 nM. This response was blocked by both 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-yl-amino]ethyl)phenol (ZM-241385) and glibenclamide and was mimicked by 2-phenylaminoadenosine (CV-1808) (IC50 of 100 nM), implicating adenosine A2a receptors coupled to ATP-sensitive K channels (KATP). Like adenosine, 5′- N-ethylcarboxamidoadenosine (NECA) elicited both glibenclamide-sensitive and glibenclamide-insensitive vasodilatory responses. The order of potency for the glibenclamide-sensitive component was NECA > adenosine = CV-1808. Our findings suggest that, in addition to the previously described adenosine A1 and low-affinity A2b receptors, the renal microvasculature is also capable of expressing high-affinity adenosine A2areceptors. This renal adenosine receptor elicits afferent arteriolar vasodilation at submicromolar adenosine levels by activating KATP.

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.

PAR-2 elicits afferent arteriolar vasodilation by NO-dependent and NO-independent actions

2002 ◽  
Vol 282 (5) ◽  
pp. F891-F897 ◽  
Author(s):  
Greg Trottier ◽  
Morley Hollenberg ◽  
Xuemei Wang ◽  
Yu Gui ◽  
Kathy Loutzenhiser ◽  
...  
Keyword(s):  
Rat Kidney ◽  
Peptide Sequence ◽  
Afferent Arteriole ◽  
Proteinase Activated Receptors ◽  
Normal Rat ◽  
Afferent Arterioles ◽  
Arteriolar Vasodilation ◽  
G Protein Coupled ◽  
Arteriolar Diameter

Proteinase-activated receptors (PARs) are a novel class of G protein-coupled receptors that respond to signals through endogenous proteinases. PAR activation involves enzymatic cleavage of the extracellular NH2-terminal domain and unmasking of a new NH2 terminus, which serves as an anchored ligand to activate the receptor. At least four PAR subtypes have been identified. In the present study, we used the in vitro perfused hydronephrotic rat kidney to examine the effects of activating PAR-2 on the afferent arteriole. The synthetic peptide SLIGRL-NH2, which corresponds to the exposed ligand sequence and selectively activates PAR-2, did not alter basal afferent arteriolar diameter but caused a concentration-dependent vasodilation (3–30 μM) of arterioles preconstricted by angiotensin II (0.1 nM). A modified peptide sequence (LSIGRL-NH2, inactive at PAR-2) had no effect. This vasodilation was characterized by an initial transient component followed by a smaller sustained response. A similar pattern of vasodilation was seen when SLIGRL-NH2 was administered to isolated perfused normal rat kidney. The sustained component of the PAR-2-induced afferent arteriolar vasodilation was eliminated by nitric oxide (NO) synthase inhibition (100 μM nitro-l-arginine methyl ester). In contrast, the transient vasodilation persisted under these conditions. This transient response was not observed when afferent arterioles were preconstricted with elevated KCl, suggesting involvement of an endothelium-derived hyperpolarizing factor. Finally, RT-PCR revealed the presence of PAR-2 mRNA in isolated afferent arterioles. These findings indicate that PAR-2 is expressed in the afferent arteriole and that its activation elicits afferent arteriolar vasodilation by NO-dependent and NO-independent mechanisms.

Luminal and contraluminal action of 1–34 and 3–34 PTH peptides on renal type IIa Na-Pi cotransporter

2000 ◽  
Vol 278 (5) ◽  
pp. F792-F798 ◽  
Author(s):  
Martin Traebert ◽  
Harald Völkl ◽  
Jürg Biber ◽  
Heini Murer ◽  
Brigitte Kaissling
Keyword(s):  
Brush Border Membrane ◽  
Rat Kidney ◽  
Membrane Domains ◽  
Calphostin C ◽  
Signaling Mechanisms ◽  
Proximal Tubular ◽  
Proximal Tubular Reabsorption ◽  
Dependent Mechanism

Parathyroid hormone (PTH) inhibits proximal tubular reabsorption of Pi by retrieval of type IIa Na-Pi cotransporters (NaPi-IIa) from the brush-border membrane (BBM). We analyzed by immunohistochemistry whether PTH analogs, signaling through either protein kinase A (PKA) and C (PKC; 1–34 PTH) or only PKC (3–34 PTH), elicit in rat kidney in vivo or in the perfused murine proximal tubule in vitro a retrieval of NaPi-IIa and whether pharmacological agonists or inhibitors of these kinases are able to either mimic or interfere with these PTH effects. Treatment with either 1–34 or 3–34 PTH downregulated NaPi-IIa in rat kidney. In isolated murine proximal tubules 1–34 PTH was effective when added to either the apical or basolateral perfusate, whereas 3–34 PTH acted only via the luminal perfusate. These effects were mimicked by an activation of PKA with 8-bromoadenosine 3′,5′-cyclic monophosphate or PKC with 1,2-dioctanoylglycerol. The luminal action of both PTH peptides was blocked by inhibition of the PKC pathway (calphostin C), whereas the basolateral effect of 1–34 PTH was completely abolished by inhibiting both pathways (H-89 and calphostin C). These results suggest that 1) NaPi-IIa can be internalized by cAMP-dependent and -independent signaling mechanisms; 2) functional PTH receptors are located in both membrane domains; and 3) apical PTH receptors may preferentially initiate the effect through a PKC-dependent mechanism.

scholarly journals Potassium channel contributions to afferent arteriolar tone in normal and diabetic rat kidney

2008 ◽  
Vol 295 (1) ◽  
pp. F171-F178 ◽  
Author(s):  
Carmen M. Troncoso Brindeiro ◽  
Rachel W. Fallet ◽  
Pascale H. Lane ◽  
Pamela K. Carmines
Keyword(s):  
Potassium Channel ◽  
Rat Kidney ◽  
The Other ◽  
Diabetic Rat ◽  
Channel Blockers ◽  
Juxtamedullary Nephron ◽  
Afferent Arterioles ◽  
Arteriolar Tone ◽  
Constrictor Response

We previously reported an enhanced tonic dilator impact of ATP-sensitive K+ channels in afferent arterioles of rats with streptozotocin (STZ)-induced diabetes. The present study explored the hypothesis that other types of K+ channel also contribute to afferent arteriolar dilation in STZ rats. The in vitro blood-perfused juxtamedullary nephron technique was utilized to quantify afferent arteriolar lumen diameter responses to K+ channel blockers: 0.1–3.0 mM 4-aminopyridine (4-AP; KV channels), 10–100 μM barium (KIR channels), 1–100 nM tertiapin-Q (TPQ; Kir1.1 and Kir3.x subfamilies of KIR channels), 100 nM apamin (SKCa channels), and 1 mM tetraethylammonium (TEA; BKCa channels). In kidneys from normal rats, 4-AP, TEA, and Ba2+ reduced afferent diameter by 23 ± 3, 8 ± 4, and 18 ± 2%, respectively, at the highest concentrations employed. Neither TPQ nor apamin significantly altered afferent diameter. In arterioles from STZ rats, a constrictor response to TPQ (22 ± 4% decrease in diameter) emerged, and the response to Ba2+ was exaggerated (28 ± 5% decrease in diameter). Responses to the other K+ channel blockers were similar to those observed in normal rats. Moreover, exposure to either TPQ or Ba2+ reversed the afferent arteriolar dilation characteristic of STZ rats. Acute surgical papillectomy did not alter the response to TPQ in arterioles from normal or STZ rats. We conclude that 1) KV, KIR, and BKCa channels tonically influence normal afferent arteriolar tone, 2) KIR channels (including Kir1.1 and/or Kir3.x) contribute to the afferent arteriolar dilation during diabetes, and 3) the dilator impact of Kir1.1/Kir3.x channels during diabetes is independent of solute delivery to the macula densa.

Effects of phosphate-induced hyperparathyroidism and parathyroidectomy on rat kidney calcium in vivo

1981 ◽  
Vol 241 (2) ◽  
pp. E136-E141 ◽  
Author(s):  
A. B. Borle ◽  
I. Clark
Keyword(s):  
Calcium Metabolism ◽  
Rat Kidney ◽  
Normal Diet ◽  
Kidney Cells ◽  
Elevated Plasma ◽  
Plasma Phosphate ◽  
High Phosphate ◽  
Stimulation Of

The effects of a high-phosphate diet on the calcium metabolism of kidney cells were studied in intact and parathyroidectomized (PTX) rats. The control and the PTX rats were pair-fed a normal diet with a Ca/P of 2:1 or a high-phosphate diet with a Ca/P of 1:8 for 6 wk (chronic experiments) or 1, 3, and 6 days (acute experiments). Renal cell calcium metabolism was studied by chemical and kinetic analyses in kidney slices incubated in vitro. In the control rats the high-phosphate diet significantly increased kidney and mitochondrial calcium, the cytosolic and mitochondrial exchangeable calcium pools, and all calcium fluxes. In these controls, the plasma phosphate was not significantly elevated, but the parathyroid hormone (PTH) levels tended to be high. In PTX rats fed the same high-phosphate diet, the plasma phosphate was significantly elevated, but no change in renal calcium metabolism occurred. These results suggest that nephrocalcinosis was caused by elevated PTH levels and not by the elevated plasma phosphate and that the first step in the development of nephrocalcinosis is a stimulation of cellular calcium metabolism and transport.

Gentamicin-induced stimulation of DNA synthesis in rat kidney comparison between in vivo and in vitro models

1984 ◽  
Vol 23 (2) ◽  
pp. 205-213 ◽  
Author(s):  
G.A. Porter ◽  
G. Laurent ◽  
P. Maldague ◽  
P. Tulkens
Keyword(s):  
Dna Synthesis ◽  
Rat Kidney ◽  
In Vitro Models ◽  
Stimulation Of

scholarly journals Increased oxidation of uroporphyrinogen by an inducible liver microsomal system. Possible relevance to drug-induced uroporphyria

1988 ◽  
Vol 250 (1) ◽  
pp. 161-169 ◽  
Author(s):  
F De Matteis ◽  
C Harvey ◽  
C Reed ◽  
R Hempenius
Keyword(s):  
Chick Embryo ◽  
Drug Metabolism ◽  
Microsomal Fraction ◽  
Marked Decrease ◽  
Rat Hepatocytes ◽  
Drug Induced ◽  
Dependent Mechanism ◽  
Stimulation Of

1. The hypothesis that uroporphyria-inducing drugs stimulate the oxidation of uroporphyrinogen by a microsomal NADPH-dependent mechanism was tested. 2. 3,4,3′,4′-Tetrachlorobiphenyl, a very effective inducer of uroporphyria in chick-embryo hepatocyte cultures, stimulates the NADPH-dependent oxidation of uroporphyrinogen by chick-embryo microsomal fraction in vitro. 3. Two different actions of 3,4,3′,4′-tetrachlorobiphenyl are apparently required for this effect: (a) induction of a microsomal system by treatment in vivo and (b) interaction with the induced microsomal fraction in vitro, producing an oxidizing species. 4. The analogue 2,4,2′,4′-tetrachlorobiphenyl is relatively ineffective in both the production of porphyria in culture and the stimulation of porphyrinogen oxidation in vitro. 5. Rat hepatocytes do not develop uroporphyria when treated with polychlorinated biphenyls in culture, yet they respond to these drugs with typical induction of cytochrome P-448-dependent drug metabolism. 6. These data provide support for the hypothesis of an increased oxidation of uroporphyrinogen in drug-induced uroporphyria, but also suggest that induction of cytochrome P-448 is not the only factor involved. 7. Both I and III isomers of uroporphyrin and heptacarboxylate porphyrin accumulate when chicken hepatocytes are made uroporphyric by drugs; treatment with desferrioxamine causes a marked decrease in both isomers, suggesting that iron may be involved in the accumulation of both.

scholarly journals Ca2+-dependent and Ca2+-independent degradation of phosphatidylinositol in rabbit vas deferens

1981 ◽  
Vol 194 (1) ◽  
pp. 129-136 ◽  
Author(s):  
K Egawa ◽  
B Sacktor ◽  
T Takenawa
Keyword(s):  
Smooth Muscle ◽  
Plasma Membrane ◽  
Vas Deferens ◽  
The Other ◽  
Ionophore A23187 ◽  
K Concentration ◽  
Rabbit Vas Deferens ◽  
Dependent Mechanism ◽  
Stimulation Of

The effects of Ca2+ and acetylcholine on the degradation and synthesis of phosphatidylinositol in rabbit vas deferens was studied in vitro by a pulse–chase technique and by measuring the content of the phospholipid in the tissue. Ca2+-dependent degradation of phosphatidylinositol was found in slices and homogenates prelabelled with myo-[2-3H]inositol. The phosphatidylinositol content of the slices also decreased by a Ca2+-dependent mechanism. On the other hand, removal of intracellular Ca2+ with the ionophore A23187 and EGTA increased the amount of phosphatidylinositol. These results indicate that the intracellular Ca2+ concentration has an important role in regulating the phosphatidylinositol content of the tissue. Increasing the extracellular K+ concentration, which causes an increase in plasma-membrane Ca2+ permeability, did not enhance phosphatidylinositol breakdown nor decrease its tissue content. However, phosphatidylinositol synthesis was clearly inhibited. After stimulation of the smooth muscle with acetylcholine, degradation of phosphatidylinositol was enhanced. Furthermore, the content of phosphatidylinositol in the tissue also decreased. These phenomena were evident even in the absence of Ca2+. The acetylcholine-induced degradation of phosphatidylinositol was blocked by the muscarinic antagonist atropine, but not by the nicotinic antagonist (+)-tubocurarine. The acetylcholine-induced decrease in the phosphatidylinositol content of the tissue led to the compensatory synthesis of phosphatidylinositol. Synthesis was separated from degradation in the same tissue. Compensatory synthesis was inhibited by acetylcholine. The degradation of phosphatidylinositol induced by acetylcholine was not inhibited by 8-bromoguanosine 3′:5′-cyclic monophosphate, indicating that the degradative process was not mediated by an increase in the cyclic nucleotide.

scholarly journals A mathematical model of the myogenic response to systolic pressure in the afferent arteriole

2011 ◽  
Vol 300 (3) ◽  
pp. F669-F681 ◽  
Author(s):  
Jing Chen ◽  
Ioannis Sgouralis ◽  
Leon C. Moore ◽  
Harold E. Layton ◽  
Anita T. Layton
Keyword(s):  
Blood Pressure ◽  
Mathematical Model ◽  
Systolic Blood Pressure ◽  
Rat Kidney ◽  
Systolic Pressure ◽  
Vessel Diameter ◽  
Renal Diseases ◽  
Myogenic Response ◽  
Afferent Arteriole

Elevations in systolic blood pressure are believed to be closely linked to the pathogenesis and progression of renal diseases. It has been hypothesized that the afferent arteriole (AA) protects the glomerulus from the damaging effects of hypertension by sensing increases in systolic blood pressure and responding with a compensatory vasoconstriction (Loutzenhiser R, Bidani A, Chilton L. Circ Res 90: 1316–1324, 2002). To investigate this hypothesis, we developed a mathematical model of the myogenic response of an AA wall, based on an arteriole model (Gonzalez-Fernandez JM, Ermentrout B. Math Biosci 119: 127–167, 1994). The model incorporates ionic transport, cell membrane potential, contraction of the AA smooth muscle cell, and the mechanics of a thick-walled cylinder. The model represents a myogenic response based on a pressure-induced shift in the voltage dependence of calcium channel openings: with increasing transmural pressure, model vessel diameter decreases; and with decreasing pressure, vessel diameter increases. Furthermore, the model myogenic mechanism includes a rate-sensitive component that yields constriction and dilation kinetics similar to behaviors observed in vitro. A parameter set is identified based on physical dimensions of an AA in a rat kidney. Model results suggest that the interaction of Ca2+ and K+ fluxes mediated by voltage-gated and voltage-calcium-gated channels, respectively, gives rise to periodicity in the transport of the two ions. This results in a time-periodic cytoplasmic calcium concentration, myosin light chain phosphorylation, and cross-bridge formation with the attending muscle stress. Furthermore, the model predicts myogenic responses that agree with experimental observations, most notably those which demonstrate that the renal AA constricts in response to increases in both steady and systolic blood pressures. The myogenic model captures these essential functions of the renal AA, and it may prove useful as a fundamental component in a multiscale model of the renal microvasculature suitable for investigations of the pathogenesis of hypertensive renal diseases.

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