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E W Inscho

Publications and source records attributed to E W Inscho.

At least 19 recordsLinked to original sources
PubMed1998

Neuronal nitric oxide synthase modulates rat renal microvascular function.

This study was performed to determine the influence of neuronal nitric oxide synthase (nNOS) on renal arteriolar tone under conditions of normal, interrupted, and increased volume delivery to the macula densa segment and on the microvascular responses to angiotensin II (ANG II). Experiments were performed in vitro on afferent (21.2 +/- 0.2 microns) and efferent (18.5 +/- 0.2 microns) arterioles of kidneys harvested from male Sprague-Dawley rats, using the blood-perfused juxtamedullary nephron technique. Superfusion with the specific nNOS inhibitor, S-methyl-L-thiocitrulline (L-SMTC), decreased afferent and efferent arteriolar diameters, and these decreases in arteriolar diameters were prevented by interruption of distal volume delivery by papillectomy. When 10 mM acetazolamide was added to the blood perfusate to increase volume delivery to the macula densa segment, afferent arteriolar vasoconstrictor responses to L-SMTC were enhanced, but this effect was again completely prevented after papillectomy. In contrast, the arteriolar diameter responses to the nonselective NOS inhibitor, N omega-nitro-L-arginine (L-NNA) were only attenuated by papillectomy. L-SMTC (10 microM) enhanced the efferent arteriolar vasoconstrictor response to ANG II but did not alter the afferent arteriolar vasoconstrictor responsiveness to ANG II. In contrast, L-NNA (100 microM) enhanced both afferent and efferent arteriolar vasoconstrictor responses to ANG II. These results indicate that the modulating influence of nNOS on afferent arteriolar tone of juxtamedullary nephrons is dependent on distal tubular fluid flow. Furthermore, nNOS exerts a differential modulatory action on the juxtamedullary micro-vasculature by enhancing efferent, but not afferent, arteriolar responsiveness to ANG II.

Acetazolamide↗
PubMed1998

Direct assessment of renal microvascular responses to P2-purinoceptor agonists.

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 microns (n = 69). Stimulation with 0.1, 1.0, 10, and 100 microM 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 beta,gamma-methylene ATP (n = 10); however, another P2X agonist, alpha,beta-methylene ATP, evoked marked receptor desensitization (n = 10). Vessel diameter decreased by approximately 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) (ATP gamma S) reduced afferent diameter markedly at concentrations > 1.0 microM. 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 microM, respectively. Similarly, ATP gamma S (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 omega-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.

Adenosine Monophosphate↗
PubMed1998

Calcium mobilization contributes to pressure-mediated afferent arteriolar vasoconstriction.

Preglomerular responses to vasoactive agonists utilize calcium released from intracellular stores and activation of calcium influx pathways to elicit vasoconstriction. The current study was performed to determine the role of calcium release from intracellular stores on the afferent arteriolar response to increases in perfusion pressure. Experiments were performed, in vitro, using the blood perfused, juxtamedullary nephron technique combined with videomicroscopy. The response of afferent arterioles to 30 mm Hg increases in perfusion pressure was determined before and after depletion of intracellular calcium pools with a 10-minute preincubation with 1 micromol/L thapsigargin or 100 micromol/L cyclopiazonic acid. Afferent arteriolar diameter averaged 20.2+/-1.0 microm (n=19) at a control perfusion pressure of 100 mm Hg. Increasing perfusion pressure to 130 and 160 mm Hg reduced afferent caliber by 10.7+/-1.0% (P<.05 versus con) and by 24.7+/-1.6% (P<.05 versus diameter at 130 mm Hg); respectively. Thapsigargin significantly increased afferent diameter by 21+/-2% (n=6) at 100 mm Hg and prevented pressure-induced autoregulatory responses. Afferent diameter averaged 24.3+/-1.7, 24.5+/-1.8 and 24.3+/-1.8 microm at perfusion pressures of 100, 130 and 160 mm Hg; respectively. Cyclopiazonic acid treatment also inhibited autoregulatory behavior but did not alter resting vessel diameter. Afferent arteriolar diameter (n=6) averaged 21.4+/-1.9 microm at 100 mm Hg and 20.9+/-2.1 and 20.5+/-2.2 microm at 130 and 160 mm Hg; respectively. Additional studies were performed to assess the role of phospholipase C activity in pressure-mediated autoregulatory behavior of afferent arterioles. Step increases in perfusion pressure decreased afferent diameter by 10.7+/-3.8 and 21.7+/-4.1%; respectively. Administration of the phospholipase C inhibitor, U-73122, (5 micromoles/L) did not significantly alter baseline diameter but did attenuate the pressure-mediated vasoconstrictor response. Increasing perfusion pressure to 130 and 160 mm Hg reduced afferent diameter by only 6.5+/-1.5 and 10.0+/-2.0%; respectively. These data demonstrate that interruption of calcium mobilization with thapsigargin, cyclopiazonic acid, or phospholipase C inhibition markedly attenuates pressure-mediated afferent arteriolar vasoconstriction and suggests that autoregulatory adjustments in afferent arteriolar diameter involve calcium release from inositoltrisphosphate(IP3)-sensitive intracellular stores.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

Afferent and efferent arteriolar vasoconstriction to angiotensin II and norepinephrine involves release of Ca2+ from intracellular stores.

Renal vascular responses to angiotensin II (Ang II) and norepinephrine (NE) are reported to involve both mobilization of calcium from intracellular stores and activation of calcium influx pathways. The present study was conducted to determine the contribution of calcium release from intracellular stores to afferent and efferent arteriolar responses to Ang II and NE. Experiments were performed in vitro using the blood-perfused, juxtamedullary nephron technique combined with videomicroscopy. The responses of afferent and efferent arterioles to Ang II and NE were determined before and after depletion of intracellular calcium pools with 1 mumol/L thapsigargin. Positive control responses were obtained with 55 mmol/L KCI. Ang II concentrations of 0.1, 1.0, and 10 nmol/L decreased afferent arteriolar diameter by 10 +/- 4%, 17 +/- 4%, and 29 +/- 6%, respectively (P < .05; n = 8). NE also decreased afferent diameter by 5 +/- 1%, 13 +/- 1%, and 57 +/- 9% at concentrations of 10, 100, and 1000 nmol/L, respectively (P < .05; n = 6). Thapsigargin treatment shifted the afferent arteriolar concentration-response curves for both Ang II and NE significantly to the right. Nevertheless, KCI evoked a pronounced vasoconstriction and decreased afferent diameter by 56 +/- 7% (P < .05; n = 6). Postglomerular responses to Ang II and NE were abolished by thapsigargin. During the control period, efferent diameter decreased by 3 +/- 1%, 7 +/- 2%, and 14 +/- 4% for the three Ang II concentrations and 3 +/- 1%, 5 +/- 1%, and 15 +/- 4% in response to the three NE concentrations, respectively. These responses were completely eliminated in the presence of thapsigargin, whereas KCI evoked an efferent arteriolar vasoconstriction of 57 +/- 9% (P < .05). These data demonstrate that agonist-induced calcium release from intracellular stores represents an essential component in the afferent and efferent arteriolar response to Ang II and NE. Furthermore, they suggest that efferent arteriolar responses to these agents may rely more heavily on calcium release from this store, whereas afferent responses may include activation of other pathways.

Adrenergic alpha-Agonists↗
PubMed1997

Role of renal nerves in afferent arteriolar reactivity in angiotensin-induced hypertension.

The objective of this study was to determine the contribution of renal nerves to the enhanced afferent arteriolar reactivity observed in angiotensin II (Ang II)-induced hypertension. Uninephrectomized Sprague-Dawley rats were divided into four groups: sham rats, renal-denervated rats, Ang II-infused (at 40 ng/min for 13 days) rats, and Ang II-infused+renal-denervated rats. With the use of an implanted arterial catheter, mean arterial pressure (MAP) was monitored in conscious rats. Ang II infusion resulted in a progressive increase in MAP from 98 +/- 1 (day 0) to 166 +/- 7 mm Hg (day 13). This increase in MAP was attenuated in denervated rats and averaged 136 +/- 3 mm Hg on day 13. Kidneys were harvested on day 13 for microcirculatory experiments or measurement of intrarenal Ang II levels. Basal afferent arteriolar diameter was similar in all groups, and group averages ranged from 19.6 to 20.7 microns. Chronic Ang II infusion increased intrarenal Ang II levels. Renal denervation did not alter this effect. Increasing perfusion pressure from 100 to 160 mm Hg reduced afferent arteriolar diameter significantly by 11.2 +/- 0.6% in the sham group and by a similar degree in the remaining three groups. Superfusion with Ang II (10 nmol/L) reduced afferent arteriolar diameter by 34.3 +/- 2.0% in the sham group. This response was enhanced in Ang II-infused (62.3 +/- 3.4%) but not in renal-denervated or Ang II-infused+renal-denervated rats. Additionally, the enhanced afferent arteriolar reactivity to Ang II was not influenced by adrenergic receptor blockade. The afferent arteriolar response to norepinephrine was enhanced in renal-denervated, Ang II-infused, and Ang II-infused+renal-denervated rats compared with sham controls. Administration of the calcium ionophore A23187 decreased afferent arteriolar diameter similarly in all four groups. These results indicate that renal nerves contribute to the development of hypertension and to the enhanced afferent arteriolar responsiveness to Ang II elicited by chronic Ang II infusion.

Angiotensin II↗
PubMed1996

Purinoceptor-mediated regulation of the renal microvasculature.

1. Recent evidence supports the contention that numerous paracrine factors are released into the intrarenal interstitial environment where they can influence renal microvascular and tubular function. Studies have shown that P1 and P2 purinoceptor activation by adenosine and ATP, respectively, can selectively evoke alterations in renal microvascular diameter. 2. Vasoconstrictor responses to extracellular ATP, which are almost exclusively preglomerular, are biphasic, develop rapidly and are rapidly reversible. ATP-mediated afferent arteriolar vasoconstriction is largely dependent on the influx of extracellular calcium and the sustained vasoconstriction is maintained by calcium influx through voltage-dependent L-type calcium channels. 3. Microvascular responses to adenosine include vasoconstriction at low concentrations and vasodilation at higher concentrations. Adenosine elicits a vasoconstrictor response which develops more slowly than responses to ATP and the vasoconstriction is elicited from both the preglomerular and postglomerular arterioles. 4. Studies were performed to evaluate the possible involvement of P2 purinoceptor activation in the renal vascular autoregulatory response. Inactivation of P2 receptor-dependent preglomerular microvascular responses by purinoceptor desensitization or purinoceptor saturation completely abolished autoregulatory adjustments in afferent arteriolar calibre. 5. These studies demonstrate that the renal microvasculature is responsive to purinoceptor activation. Furthermore, the data support an important role for the involvement of intrarenal P2 receptors in the regulation of renal haemodynamics.

Adenosine↗
PubMed1996

Pressure-mediated vasoconstriction of juxtamedullary afferent arterioles involves P2-purinoceptor activation.

This study was conducted to examine the hypothesis that P2 purinoceptors contribute to pressure-induced autoregulatory adjustments of afferent arteriolar caliber. Experiments were performed in vitro using the blood-perfused juxtamedullary nephron technique. Afferent arteriolar diameter averaged 19.2 +/- 0.6 microns (n = 51) at control perfusion pressure of 100 mmHg and decreased when perfusion pressure was increased. Desensitization of P2 purinoceptors abolished the alpha, beta-methylene ATP-mediated afferent vasoconstriction and prevented pressure-dependent autoregulatory adjustments in afferent diameter. P2-purinoceptor saturation significantly decreased afferent caliber and attenuated pressure-induced autoregulatory responses. To block P2 receptors, afferent arterioles were treated with the P2-purinoceptor antagonists, pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid or suramin. P2-receptor blockade prevented the afferent arteriolar vasoconstriction evoked by increasing perfusion pressure from 100 to 130 and 160 mmHg. These data demonstrate that inhibition of P2 purinoceptor-dependent responses through receptor desensitization, receptor saturation, or purinoceptor blockade impairs normal autoregulatory behavior in rat juxtamedullary afferent arterioles. The results are consistent with the hypothesis that P2 purinoceptors participate in mediating autoregulatory adjustments in afferent arteriolar diameter.

Adenosine Triphosphate↗
PubMed1996

Paracrine regulation of the renal microcirculation.

There has been an explosive growth of interest in the multiple interacting paracrine systems that influence renal microvascular function. This review first discusses the membrane activation mechanisms for renal vascular control. Evidence is provided that there are differential activating mechanisms regulating pre- and postglomerular arteriolar vascular smooth muscle cells. The next section deals with the critical role of the endothelium in the control of renal vascular function and covers the recent findings related to the role of nitric oxide and other endothelial-derived factors. This section is followed by an analysis of the roles of vasoactive paracrine systems that have their origin from adjoining tubular structures. The interplay of signals between the epithelial cells and the vascular network to provide feedback regulation of renal hemodynamics is developed. Because of their well-recognized contributions to the regulation of renal microvascular function, three major paracrine systems are discussed in separate sections. Recent findings related to the role of intrarenally formed angiotensin II and the prominence of the AT1 receptors are described. The possible contribution of purinergic compounds is then discussed. Recognition of the emerging role of extracellular ATP operating via P2 receptors as well as the more recognized functions of the P1 receptors provides fertile ground for further studies. In the next section, the family of vasoactive arachidonic acid metabolites is described. Possibilities for a myriad of interacting functions operating both directly on vascular smooth muscle cells and indirectly via influences on endothelial and epithelial cells are discussed. Particular attention is given to the more recent developments related to hemodynamic actions of the cytochrome P-450 metabolites. The final section discusses unique mechanisms that may be responsible for differential regulation of medullary blood flow by locally formed paracrine agents. Several sections provide perspectives on the complex interactions among the multiple mechanisms responsible for paracrine regulation of the renal microcirculation. This plurality of regulatory interactions highlights the need for experimental strategies that include integrative approaches that allow manifestation of indirect as well as direct influences of these paracrine systems on renal microvascular function.

Animals↗
PubMed1995

Calcium activation mechanisms in the renal microvascular response to extracellular ATP.

Previous studies have suggested a paracrine role for extracellular ATP in the regulation of afferent arteriolar tone. The current study was conducted to determine the dependence of this response on calcium entry mechanisms. Experiments were performed in vitro using the blood-perfused juxtamedullary nephron technique combined with video microscopy. The afferent arteriolar response to alpha, beta-methylene ATP was determined before and after treatment with the calcium channel blockers, diltiazem or felodipine. alpha, beta-Methylene ATP was used to obviate concerns over responses being elicited by ATP or by ATP hydrolysis products such as adenosine. Previous studies have shown that afferent arteriolar responses to alpha, beta-methylene ATP are comparable to those elicited by ATP. alpha, beta-Methylene ATP (1.0 microM) induced a rapid initial afferent vasoconstriction of 72.5 +/- 10.6%, which partially recovered to a stable diameter 11.3 +/- 1.7% smaller than control (P < 0.01 vs control). Afferent diameter returned to control diameter on removal of ATP from the bath. Diltiazem or felodipine treatment significantly increased afferent diameter by 5.6 +/- 2.3 and 16.4 +/- 4.6%, respectively (P < 0.05). In the presence of either diltiazem or felodipine, the initial vasoconstriction to alpha, beta-methylene ATP was attenuated, and the sustained vasoconstriction was completely blocked. Removal of calcium from the extracellular medium completely abolished both the initial and sustained vasoconstrictor response.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1994

Modulation of dihydropyridine receptors in vascular smooth muscle cells by membrane potential and cell proliferation.

We have studied binding of isradipine to A7r5 vascular smooth muscle cells as a function of membrane potential and cell proliferation. Consistent with a voltage-modulated receptor model, two classes of binding sites were detected in confluent cultures: high-affinity sites under depolarizing (50 mM K+) conditions (Kd = 45 +/- 3 pM), and lower affinity sites under resting (5 mM K+) conditions (Kd = 181 +/- 20 pM). However, proliferating cells also displayed the high-affinity state at rest (Kd = 29 +/- 9 pM) in addition to a low-affinity site (Kd = 869 +/- 383 pM). Analysis of dissociation rates also revealed two receptor classes during proliferation. Proliferating cells showed a single class of high-affinity sites (Kd = 39 +/- 6 pM) when depolarized, similar to confluent cells. Receptor density in confluent monolayers increased from 15 +/- 3 fmol/10(6) cells at 5 days to 72 +/- 6 fmol/10(6) cells after 10 days. These results suggest (i) that some L-type Ca2+ channels are spontaneously active in proliferating vascular smooth muscle cells, but require depolarization to activate in a confluent monolayer, and (ii) that the density of dihydropyridine receptors increases after a monolayer becomes confluent.

Animals↗
PubMed1994

Extracellular ATP in the regulation of renal microvascular function.

Considerable attention has been focused on the purine nucleoside, adenosine, in the control of renal blood flow, epithelial transport, and renin secretion; however, surprisingly little attention has been directed toward the renal effects of purine nucleotides such as adenosine triphosphate (ATP). Recent studies utilizing in vivo micropuncture and in vitro techniques have demonstrated that renal vascular, epithelial, and mesangial cells respond to extracellular ATP via mechanisms distinct from those elicited by adenosine. ATP vasoconstricts afferent but not efferent arterioles whereas adenosine vasoconstricts both vascular segments. Adenosine-mediated afferent arteriolar vasoconstriction is abolished by adenosine receptor antagonists, whereas the response to ATP is enhanced. ATP-mediated vasoconstriction reaches a maximum within seconds of exposure while the vasoconstriction induced by adenosine develops more slowly. L-type calcium channel antagonists such as diltiazem or felodipine prevent the sustained afferent vasoconstriction produced by ATP. Data from micropuncture experiments indicate that peritubular capillary infusion of ATP reduces glomerular pressure and results in marked attenuation of the tubuloglomerular feedback mechanism, which transmits signals from the macula densa to the afferent arteriole. These data support the existence of ATP-sensitive P2 purinoceptors in the preglomerular microvasculature that contribute to the control of renal vascular function via activation of calcium channels.

Adenosine Triphosphate↗
PubMed1994

Autoregulation of afferent arteriolar blood flow in juxtamedullary nephrons.

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.

Animals↗
PubMed1994

Renal arteriolar angiotensin responses during varied adenosine receptor activation.

We performed experiments to test the hypothesis that endogenous adenosine acts as an essential cofactor required for eliciting angiotensin II (Ang II)-induced afferent and/or efferent arteriolar vasoconstriction. Enalaprilat (2 mg IV) was administered to anesthetized rats to reduce endogenous Ang II levels. Kidneys and blood were harvested from these animals and used for study of renal microvascular function using the in vitro blood-perfused juxtamedullary nephron technique. Arteriolar inside diameter was monitored videomicroscopically in (1) normal kidneys, (2) kidneys subjected to adenosine receptor blockade (100 mumol/L 1,3-dipropyl-8-p-sulfophenylxanthine), and (3) kidneys continuously exposed to 1 mumol/L adenosine. Under resting conditions, arteriolar diameters were similar in all three groups of kidneys, averaging 24.8 +/- 1.0 microns (n = 23) in afferent arterioles and 24.0 +/- 0.9 microns (n = 16) in efferent arterioles. In normal kidneys, adenosine (10 mumol/L) decreased both afferent (10.2 +/- 2.0%) and efferent (6.5 +/- 0.8%) diameters, an effect that was absent in kidneys subjected to adenosine receptor blockade. Ang II (10 pmol/L to 100 nmol/L) elicited dose-dependent vasoconstriction of both vascular segments in normal kidneys. At a concentration of 100 nmol/L, Ang II decreased afferent diameter by 36.8 +/- 8.5% and efferent diameter by 30.8 +/- 9.6%. Neither afferent nor efferent arteriolar Ang II dose-response relations were significantly different in kidneys treated with low-dose adenosine or the adenosine receptor blocker. These observations refute the hypothesis that a receptor-mediated action of adenosine is required for Ang II-induced constriction of juxtamedullary afferent or efferent arterioles.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1992

Effects of ATP on pre- and postglomerular juxtamedullary microvasculature.

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.

Adenosine↗
PubMed1992

EDRF-angiotensin II interactions in rat juxtamedullary afferent and efferent arterioles.

The in vitro blood-perfused juxtamedullary nephron technique was utilized to determine the contribution of endothelium-derived relaxing factor (EDRF) to resting renal arteriolar caliber and to evaluate the interaction between EDRF and angiotensin II (ANG II) in renal microvascular control. Video microscopy was employed to visualize rat afferent and efferent arterioles and to measure their responses to blockade of nitric oxide (NO), which has been shown to account for much of the biological action of EDRF. The NO synthesis inhibitor, N omega-nitro-L-arginine (L-NNA), elicited vasoconstriction in a concentration-dependent manner, with 1,000 microM L-NNA significantly reducing both afferent (16 +/- 3%) and efferent (13 +/- 1%) diameters. This concentration of L-NNA also blocked the vasodilator response to 10 microM acetylcholine, while responsiveness to sodium nitroprusside was maintained. Vasoconstrictor responses to 1,000 microM L-NNA were attenuated in kidneys from rats pretreated with enalaprilat or losartan, reducing afferent diameter by 7 +/- 1 (n = 8) and 3 +/- 1% (n = 10) of control, respectively. Efferent arteriolar responses to L-NNA were similarly attenuated by losartan. The constrictor response to 10 nM ANG II was not exaggerated by L-NNA, suggesting that ANG II does not stimulate EDRF synthesis. These observations indicate that EDRF is continuously released in a quantity sufficient to affect both afferent and efferent arterioles of juxtamedullary nephrons in vitro. Furthermore, ANG II blockade attenuates the vasoconstriction elicited by L-NNA, suggesting that EDRF interacts with the renin-angiotensin system to control juxtamedullary afferent and efferent arteriolar resistance.

Acetylcholine↗
PubMed1992

Attenuated afferent arteriolar response to acetylcholine in Goldblatt hypertension.

We tested the hypothesis that endothelium-dependent afferent arteriolar vasodilation is impaired in the nonclipped kidney of two-kidney, one clip Goldblatt hypertensive rats relative to sham-operated controls. Five to six weeks after positioning of a 0.25-mm clip on the left renal artery, systolic pressure averaged 173 +/- 10 mm Hg in Goldblatt rats and 118 +/- 4 mm Hg in controls (p less than 0.01). The right kidney was harvested for videometric study of the microvasculature using the in vitro blood-perfused juxtamedullary nephron technique. Kidneys from Goldblatt and control rats were perfused at renal arterial pressures of 150 and 110 mm Hg, respectively. Afferent arteriolar inside diameter did not differ between control (20.3 +/- 0.7 microns) and Goldblatt (21.1 +/- 1.7 microns) kidneys. Determination of afferent responses to increasing concentrations of the endothelium-dependent vasodilator acetylcholine (1 nM to 10 microM) in the bathing solution unveiled a shift to the right in the dose-response relation in Goldblatt rats. Afferent arterioles from control kidneys dilated significantly when exposed to 1 nM acetylcholine, whereas a 1,000-fold higher concentration was required to dilate arterioles from Goldblatt rats. Sodium nitroprusside, an endothelium-independent vasodilator, increased afferent diameter to a similar extent in both groups. In a separate group of normal kidneys, vasodilator responses to 10 microM acetylcholine were completely blocked by 1,000 microM nitro-L-arginine, an inhibitor of nitric oxide synthesis. Thus, endothelium-dependent afferent vasodilation appears to be impaired in the nonclipped kidney of Goldblatt hypertensive rats. This phenomenon could contribute to the altered renal hemodynamic status characteristic of Goldblatt hypertension.

Acetylcholine↗