Vasoconstrictor and vasodilator effects of adenosine in the kidney - 《American Journal of Physiology》美国生理学杂志干细胞之家



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发表于 2009-4-21 13:47 |只看该作者 |倒序浏览 |打印

作者：Pernille B. Hansen and Jurgen Schnermann作者单位：National Institute of Diabetes and Digestive and Kidney Diseases,National Institutes of Health, Bethesda, Maryland 20892 4 e: S3 _+ p6 k2 R

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      【摘要】6 i8 G1 }9 X: q8 A  v
   Adenosine is an ATP breakdown product that in most vessels causes vasodilatation and that contributes to the metabolic control of organperfusion, i.e., to the match between oxygen demand and oxygen delivery. Inthe renal vasculature, in contrast, adenosine can produce vasoconstriction, aresponse that has been suggested to be an organ-specific version of metabolic control designed to restrict organ perfusion when transport work increases.However, the vasoconstriction elicited by an intravenous infusion of adenosineis only short lasting, being replaced within 1-2 min by vasodilatation.It appears that the steady-state response to the increase of plasma adenosine levels above normal resulting from the infusion is global renal vasorelaxationthat is the result of A 2 AR activation in most parts of the renalvasculature, including larger renal arteries, juxtamedullary afferentarterioles, efferent arterioles, and medullary vessels.A 2 AR-mediated vasorelaxation is probably facilitated by endothelialreceptors that cause the release of nitric oxide and other endothelialrelaxing factors. In contrast, isolated perfused afferent arterioles ofsuperficial and midcortical nephrons of rabbit and mouse, especially in theirmost distal segment at the entrance to the glomerulus, respond to adenosinewith persistent vasoconstriction, indicating predominant or exclusiveexpression of A 1 AR. A 1 AR in afferent arterioles areselectively activated from the interstitial aspect of the vessel. Thisproperty can dissociate A 1 AR activation from changes in vascularadenosine concentration, a characteristic that is ideally suited for the roleof renal adenosine as a paracrine factor in the control of glomerularfunction.
      【关键词】 adenosine receptors vascular resistance renal blood flow endothelium
   THE EXTRACELLULAR ACTIONS of adenosine are mediated by binding of the nucleoside to four types of G protein-coupled membrane receptors,A 1, A 2a, A 2b, and A 3 adenosinereceptors (A 1 AR, A 2a AR, A 2b AR,A 3 AR). The expression pattern of adenosine receptor subtypesthroughout the organism is extremely widespread, commensurate with theorganismwide actions of the nucleoside. In most blood vessels, adenosineelicits marked vasodilatation, and this effect is mediated by A 2a ARand A 2b AR, G protein-coupled receptors that induce relaxationthrough the G s and protein kinase A pathway.Adenosine-induced vasodilatation reflects dominance of A 2 AR in thevasculature of most tissues and organs. In contrast, A 1 AR coupledto G i and PLC activate motor activity of smooth muscle cellsin a number of muscular tissues( 4, 44, 65, 67 ), but this receptor subtypeis not widely expressed in the vasculature. A 1 AR are, however,present in blood vessels of the kidney besides A 2 AR, and this hasmade the renal vascular actions of adenosine comparatively complex.
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Evidence obtained in the 1960s solidified an earlier observation that thekidney vasculature differs from other vascular beds in that the overall effectof exogenous adenosine may be vasoconstriction ( 17, 24, 81 ). This remarkableobservation of a constrictor effect exerted by a prototypical metabolicdilator has been the focus of numerous discussions, but its understanding is still incomplete. A renewed interest in the vasoconstrictor action ofadenosine has resulted from the recent evidence in support of the notion thatthe nucleoside is responsible for the afferent arteriolar constriction causedby increasing NaCl concentration at the macula densa, the so-calledtubuloglomerular feedback (TGF) response( 10, 76, 80 ). Although thevasoconstrictor potential of adenosine at the organ level has been the origin of the proposal of adenosine acting as the constrictor mediator of the TGFresponse ( 55 ), this reasoninghas always been weakened by an apparent, but not fully acknowledged, internalinconsistency. The main problem has been that the vasoconstriction and the accompanying decrease in renal blood flow at the organ level are only atransient phenomenon, whereas the steady-state effect of adenosine is eitherno change or an increase in renal blood flow( 23, 52, 54, 74, 77 ). Thus the temporalcharacteristics of the effects of changes in adenosine levels on global renal vasoconstriction and on TGF-induced vasoconstriction are apparently entirelydifferent, making it difficult to accept that these responses are mediated bythe same receptors ( 51 ).Because the kidney vasculature is sufficiently heterogeneous, it has beencommon to argue that adenosine causes vasoconstriction in one part of therenal vascular bed and vasodilatation in another, for example, that afferentarteriolar vasoconstriction is accompanied and overcome by efferentvasodilatation ( 77 ) or thatsuperficial vasoconstriction is accompanied and overcome by juxtamedullaryvasodilatation ( 58 ).
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In the present review, we make an attempt to reconcile the failure ofadenosine to cause a lasting global renal vasoconstriction with its ability tomarkedly and persistently elicit vasoconstriction at the arteriolar level,both pharmacologically and in its presumed physiological equivalent, the TGFresponse. Our overall conclusion is that the dominant effect of exogenousadenosine in the whole kidney is vasodilatation, which like in other vascular beds is a reflection of the wide distribution of A 2 AR in the renalvasculature and their activation by the supranormal adenosine levels resultingfrom the infusion. However, the distal afferent arteriole at the entrance tothe glomerulus constricts to adenosine over a much wider concentration rangethan any other vascular segment, perhaps reflecting predominant or exclusiveexpression of A 1 AR. Because the region of A 1 AR-mediatedvasoconstriction at high adenosine concentrations is restricted to a narrow segment, the effect of A 1 AR activation on total renal vascular resistance can be overcome when adenosine levels exceed normal concentrationsand A 2b AR in other parts of the renal vasculature are fullyengaged.! l! r) p' ]  ?

EXPRESSION OF ADENOSINE RECEPTORS IN THE KIDNEY

The scarcity of reliable antibodies and radiolabeling probes and the lowexpression levels have made it unexpectedly difficult to precisely identifythe adenosine receptor subtypes present along the renal vasculature. Globalexpression in rat renal cortical and medullary tissue has been shown for allfour adenosine receptors at both the mRNA and protein levels( 29, 40, 93 ). Studies in apreglomerular vessel preparation containing arcuate and interlobular arteriesas well as afferent arterioles have identified the presence of A 1 ARprotein and mRNA, but this approach does not resolve the expression profilealong the longitudinal axis of the preglomerular vasculature( 29 ). By in situhybridization, cortical A 1 AR mRNA was found exclusively at theglomerular vascular pole but not over the glomerulus itself( 83 ). Although it is unclearwhether the signal originated in granular, extraglomerular mesangial, orvascular smooth muscle cells, one may conclude that some cells at theglomerular vascular pole express A 1 AR at much higher levels thanany other vessel. RT-PCR assessment of A 1 AR mRNA expression hasconfirmed its presence in dissected glomeruli( 88 ). More recently,immunohistochemical evidence has suggested the presence of A 1 ARexpression in glomerular vessels, presumably in afferent arterioles, andinside the glomerulum, presumably in mesangial cells( 71 ). However, of twoantibodies directed against different epitopes, only one showed positivestaining, an observation that cautions against overinterpretation ofantibody-based evidence. In regard to A 2 receptors, it has beenreported that preglomerular vessels express only the low-affinityA 2b AR at high levels but not the high-affinity A 2a ARreceptor protein ( 29 ). In situhybridization failed to detect either A 2a AR or A 2b ARmRNA in the renal cortex ( 83 ).The profile of adenosine receptor expression in efferent arterioles has notbeen determined with any degree of certainty. In outer medullary descendingvasa recta, RT-PCR analysis revealed expression of A 1 AR,A 2a AR, and A 2b AR, which was verified by Southernblotting ( 33 ).Receptor-binding studies using the well-defined panel of stable and selectiveligands for adenosine receptor subtypes have not been performed in renalvascular tissue. In conclusion, the functional clues that can be derived fromexpression studies are relatively limited, but it seems clear thatA 1 AR are predominantly expressed in afferent arterioles. A 2 AR, mostly A 2b AR, are present in all preglomerularvessels and in descending vasa recta. No reliable information is available forefferent arterioles.  c- t% x' Z3 k, t- c% K

ADENOSINE-INDUCED RENAL VASOCONSTRICTION
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Effect of Adenosine at the Organ Level$ u+ Q" |2 `0 A; T

There is abundant evidence to show that bolus injections of adenosine causean immediate reduction in renal blood flow reflecting the response toactivation of high-affinity A 1 AR ( 24, 56, 77, 81 ). Because this blood flowresponse was seen when adenosine was injected in the renal artery, it is not mediated by systemic consequences of adenosine such as a reduction in bloodpressure ( 24, 54 ). A reduction in renalblood flow was also observed during continuous administration of adenosine, but this decrease was only short lasting and waned within 1-2 min. Thetransient constrictor effect was blocked by nonspecific andA 1 AR-specific antagonists, and it is absent in A 1 ARknockout mice, indicating that it is mediated by activation of A 1 AR ( 3, 54 ). This is supported by thepersistent reduction in renal blood flow and glomerular filtration rate (GFR)induced by the infusion of the A 1 AR-specific agonistcyclohexyladenosine (CHA; see Ref. 13 ). In the isolated perfusedkidney, CHA causes increasing vasoconstriction in the dose range between10 - 9 and 10 - 7 10 - 6 M cause vasodilatation no doubt because of spillover onto A 2 AR with undefined vascular localization( 43, 46 ). On the basis of hemodynamic modeling, the reduction in renal blood flow was attributed to apreglomerular, presumably afferent, arteriolar vasoconstriction( 43, 77 ). The administration ofA 1 AR antagonists does not usually cause major increases in renalblood flow, suggesting either that A 1 AR activation does notcontribute to renal vascular resistance under resting conditions or that theeffect of the inhibitors is incomplete( 3, 34 ). GFR, on the other hand,is typically increased by A 1 AR antagonists ( 5, 41, 86 ).
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Effect of Adenosine in Glomerular Arterioles
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Superficial afferent arterioles. Micropuncture studies in dogs have shown that an intrarenal adenosine infusion caused a doubling ofpreglomerular arteriolar resistance( 58 ). In rats, adenosine caused a fall in glomerular capillary and welling point pressures and a fallin superficial nephron GFR (SNGFR), results consistent with preglomerulararteriolar vasoconstriction( 22 ). In contrast to thetransient reduction in renal blood flow, the effects of adenosine on SNGFRwere persistent. Thus the constrictor response in superficial nephrons occursin the absence of changes in renal plasma flow and with only small or nochanges in kidney GFR ( 57, 58 ). These observations appearto be internally inconsistent, but it is possible that there is an unusualoverrepresentation of A 1 AR in afferent arterioles of the verysuperficial nephron population. Concordant with a tonic constrictor effect ofadenosine in these nephrons are observations showing that inhibition of A 1 AR with 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) or CVT-124 caused afferent arteriolar vasodilatation and an increase in both SNGFR andkidney GFR ( 5, 41, 86 ).6 r- K  J/ [( }0 u% s0 C
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The effect of adenosine on arteriolar tone has been studied more directlyin preparations that permit visualization of vessel diameters and that are notrestricted to a selected population of vessels. Furthermore, in these in vitropreparations, the testable adenosine concentrations include the subnormal range, thereby facilitating the detection of A 1 AR-mediated effects. In afferent arterioles of neonatal hamster kidneys transplanted in the cheekpouch of adult animals, adenosine, topically applied through micropipettes,caused dose-dependent vasoconstriction of afferent arterioles, whereas itdilated the arterioles of the cheek pouch itself( 30 ). In isolated perfusedafferent arterioles from the rabbit, addition of adenosine to the bath causedvasoconstriction in a dose-dependent fashion( 84 ). Effects consisted of a30% reduction in vessel diameter in proximal parts of the arteriole withmaximum effects being reached at 10 - 6 M andsmaller effects at higher concentrations, indicating that in this part of thearteriole A 1 AR-mediated vasoconstriction is partially counteractedby A 2b AR-dependent vasodilatation as adenosine concentrationsincrease. It is consistent with this interpretation that the vasoconstriction caused by the A 1 AR agonist CHA was slightly greater than that caused by adenosine and that it increased over the entire concentration rangefrom 10 - 9 to 10 - 4 M( 84 ). However, in the afferentarteriole in the immediate vicinity of the glomerulus, adenosine caused amonotonic vasoconstriction consisting of a 45% reduction in vessel diameter at10 - 4 M, the highest concentration tested( Fig. 1 ). The absence of adiscernible vasodilator effect at concentrations at which A 2b ARshould be activated indicates that the short section of the afferent arterioleclose to and inside the glomerulus is unique in that A 1 AR-inducedconstriction does not appear to be opposed by A 2 AR to a detectableextent. Recent experiments in isolated afferent arterioles from the mouseindicate a similar effectiveness of abluminal adenosine to vasoconstrict thevessel, particularly at its glomerular entrance segment. The origin of thearterioles used in both the rabbit and mouse studies was the midcortical andouter cortical region, so that arterioles from true juxtamedullary nephronswere not included. Our results are apparently different from the netvasodilator effect of CHA in the isolated perfused kidney that was seen atperfusate concentrations of 10 - 5 M and higher( 43, 46 ). Thus the A 2 ARactivated by high CHA concentrations and determining total renal vascularresistance in the whole kidney are localized on vascular segments other thanafferent arterioles.- n7 \  J4 b$ X1 s, X
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Fig. 1. Photomicrograph showing the effect of adenosine (Ado;10 - 8 M) on the diameter of a perfused afferentarteriole from rabbit kidney. Note that there is a marked reduction in theluminal diameter of the arteriole at a narrow region at the entrance of thevessel into the glomerulus, just before the first branching of the arteriole,and that the region of highest sensitivity to adenosine is close to the maculadensa (MD) cell plaque. This region showed vasoconstriction up to aconcentration of 10 - 4 M adenosine. In contrast,the arteriole further upstream did not show measurable constriction at the10 - 8 M concentration. Because of specimenpositioning, this segment of high sensitivity is not visible in mostpreparations. Photograph taken by H. Weihprecht( 84 ). Black bars define innervascular diameters at indicated locations.

In the hydronephrotic kidney preparation, another technique permittingdirect observation of arteriolar responses, the effect of adenosine appears tobe transient. With topical application, adenosine caused a dose-dependentvasoconstriction over the 10 - 6 to10 - 4 M dose range that faded within 1-2 min,and a similar effect was seen in an in vitro perfused hydronephrotic kidneywith luminal application ( 20, 78 ). There was no noticeablesteady-state effect of adenosine in the afferent arterioles, whereasinterlobular arteries and efferent arterioles showed steady-statevasodilatation at a concentration of 10 - 5 M( 20 ). The abluminaladministration of CHA, in contrast, had effects comparable to those found inisolated vessels. These effects consisted of a stable diameter reduction that was dose dependent in the range between 10 - 8 and10 - 6 M and that was most pronounced in the distalpart of the arteriole where it caused a maximum effect of about -50%.The reduction in vascular diameter was accompanied by a reduction inglomerular blood flow by 30-40% at 10 - 7 50% at 10 - 5 M( 15, 27 ). Although NECA vasodilatedall preglomerular vascular segments up to the arcuate arteries, it caused no change or even a small constriction in the distal afferent arteriole ( 16, 27 ). Although NECA is not aspecific A 2 agonist, this finding provides additional support forthe notion that the distal afferent arteriole is unique in its predominantexpression of A 1 AR. In view of the normal actions of CHA, thewaning effect of adenosine in this preparation may reflect an increasedexpression of dilatory A 2 AR. It is also of note that at least inthe in situ hydronephrotic kidney model the starting level for the adenosineaddition studies are the prevailing tissue and plasma adenosine levels, not anadenosine-free condition.
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Juxtamedullary afferent arterioles. Studies of the effect of adenosine in juxtamedullary arterioles are important in view of the notionthat medullary blood flow may be regulated by adenosine in a way that isopposite to cortical blood flow regulation. Juxtamedullary afferentarterioles, studied in a blood-perfused preparation, respond to abluminalapplication of adenosine at 10 - 6 and10 - 5 M with a marked transient and a smallersteady-state reduction of vessel diameter that was prevented by theA 1 AR antagonist KW-3902 and magnified by A 2a ARinhibition ( 11, 28, 47 10 - 5 M, the effect of adenosine wasvasodilatation of juxtamedullary afferent arterioles that was partiallyinhibited by the A 2a AR antagonist KF-19837( 47 ). Diameter evaluations inthese studies were made at a distance of 100 µm from the glomerulus and didnot distinguish between proximal and distal regions of afferent arterioles.Although the steady-state effect of adenosine in these studies was relativelysmall, it may be relevant to point out that a 10% reduction in vessel diameter translates into a 50% increase in vessel resistance.
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The response of afferent arterioles of juxtamedullary nephrons to CHA inthe hydronephrotic kidney preparation consisted of a dose-dependent diameterreduction in the tested concentration range of10 - 8 to 10 - 6 M thatwas about one-half that seen in more superficial arterioles( 16 ). Concomitantly, glomerular blood flow was reduced by 40% at10 - 6 M, a response that was smaller than seen insuperficial nephrons. In contrast to superficial arterioles, NECA had a smalldilator effect in juxtamedullary afferent arterioles. These studies indicatethat afferent arterioles of juxtamedullary nephrons may be less responsive toadenosine than arterioles from superficial or midcortical nephrons but thatthey respond qualitatively similar. Based on the functional informationfurnished by CHA and NECA, one would conclude that afferent arterioles ofjuxtamedullary nephrons have a lower expression level of functionalA 1 AR and a higher level of A 2 AR compared withsuperficial arterioles ( 16 ).Nevertheless, the dilator action of A 1 AR inhibition indicates that,in juxtamedullary afferent arterioles, the dominant effect of adenosine up toa concentration of 10 µM is vasoconstriction.# M# s0 d" R9 L# F. J1 g7 q# _+ V4 A

It is unclear to what extent a loss of A 1 AR-mediated constrictor efficiency is responsible for the fleeting reduction in total renal blood flowcaused by systemic adenosine, but the following aspects seem pertinent. Themaintenance of constriction in afferent arterioles for extended periods oftime noted in the observational studies indicates that A 1 AR inafferent arterioles do not undergo rapid desensitization, the waning of afunctional response during prolonged or repeated exposure of a receptor to itsligand ( 27, 30, 47 ). Most notably, in recentexperiments in isolated afferent arterioles from the mouse, vasoconstriction caused by adenosine was observed to last for up to 30 min (Hansen PB,unpublished observations). The persistent nature of the A 1 AR-induced vasoconstriction of afferent arterioles is consonant with the evidence from a number of studies indicating that the desensitizationof native A 1 AR in response to prolonged exposure to an agonistoccurs in a time frame of hours to days( 60 ). Furthermore, theinhibition of forskolin-stimulated adenylate cyclase activity in CHO cellsexpressing the human recombinant A 1 AR was unaffected by a 30-mintreatment with an A 1 AR agonist ( 59 ). We consider it unlikelythat the propensity of A 1 AR to desensitize varies between differentpreparations and between A 1 AR expressed in different segments ofthe renal vasculature.( @  U1 Y9 q$ w5 z2 z
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Because the adenosine effects in vivo are assessed in a more complexenvironment than those encountered in vitro, it is possible that differencesin the presence of some modulating factor account for the apparent differencein the constrictor potential of adenosine seen in vivo and in vitro. The most intensely studied modulator of A 1 AR-mediated constrictor actions isANG II. There is abundant evidence to show that a reduction in ambient ANG IIlevels and the prevention of ANG II formation and action cause a markedattenuation of the vasoconstrictor response of the intact kidney to adenosine( 15, 23, 56, 73, 85 ). Conversely, an elevationof ambient ANG II concentrations enhances the constrictor effect ofA 1 AR activation by adenosine or A 1 AR-specific ligands( 56, 85 ). Nevertheless, it is not clear that differences in ambient ANG II levels can explain the differentresponses of intact kidneys and isolated preparations. One would expectambient ANG II concentrations to be lower in the artificial environment, andadenosine responses should therefore be blunted, the opposite of what isactually observed. The possibility that A 1 AR-mediatedvasoconstriction is dependent on the state of arteriolar innervation is notsupported by studies showing an unaltered constrictor response to anA 1 AR agonist in denervated compared with innervated kidneys( 61 ). These results do notlend support to the possibility that the absence of nervous input in theisolated preparations importantly modifies their adenosine response.* r# G- [; b, x3 W/ X

Because the studies examining the effect of adenosine on renal blood flowin the whole kidney have been performed during systemic administration ofadenosine, whereas the in vitro experiments were typically done duringabluminal adenosine application, the possibility exists that the strength ofthe constrictor response varies with the route of administration. In support of a sidedness in the vascular actions of adenosine, we recently observedusing laser-Doppler flowmetry in mice that adenosine given intravenouslycaused an increase in superficial renal blood flow, whereas the infusion ofadenosine in the interstitial region below the flow probe caused a reductionin blood flow (Hashimoto S, unpublished observations). Furthermore, thevasoconstriction of isolated perfused afferent arterioles from the mousecaused by the bath addition of adenosine was not seen when adenosine was addedto the luminal perfusate (Hansen PB, unpublished observations). In a studycomparing the effects of intravenous infusion of high- andlow-molecular-weight polyadenylic acids on renal blood flow in dogs, it hasbeen noted that the low-molecular-weight compound (mol wt 5,000) causedtransient vasoconstriction like adenosine, whereas the high-molecular-weightcompound (mol wt 100,000) caused an exclusive and long-lasting vasodilator response that was inhibited by theophylline( 79 ). The authors concludedthat adenosine causes A 2 AR-mediated vasodilatation through anintravascular site, whereas the A 1 AR causing vasoconstriction arenormally accessed from the interstitial aspect of the vessel. The causes forthis sidedness of the effect of adenosine need to be explored further. It isconceivable, although unproven, that A 1 AR are present inendothelial cells along the renal vasculature and that adenosine causes therelease of nitric oxide (NO) and perhaps other endothelial vasodilators when administered from the vascular but not from the interstitial aspect of thevessel. The resulting A 1 AR-induced constriction would therefore beblunted by endothelial factors only when adenosine is given intravascularly.In a study in dogs, the administration of nitric oxide synthesis (NOS)inhibitors caused a marked augmentation in the constrictor response of renal blood flow to bolus injections of adenosine while the dilator effect of theA 2 agonist CGS-21680 was unaffected, indicating that adenosine maycause NOS activation through an A 1 AR-mediated mechanism( 52 ). Enhancement ofA 1 AR agonist induced vasoconstriction by N G -nitro- L -arginine methyl ester, and a markedleft shift of the dose-response relationship between adenosine concentration and vasoconstrictor response has also been observed in the rat ( 7, 63 ). Studies showing a similarleft shift in the adenosine dose-response curve during application ofindomethacin suggest that a vasodilator prostaglandin may be anotherendothelial factor opposing A 1 AR-mediated constriction( 62 ). The results of thesestudies do not establish that A 1 AR activation is directly coupledto the release of NO or prostaglandins since they are also compatible with thepossibility that the constrictor effect of adenosine is merely enhanced by theremoval of a constitutive vasodilator influence. It is also of note thatadenosine administered in the vascular space must cross the endothelial celllayer to interact with smooth muscle cells. In addition to being a potentialphysical barrier to the movement of adenosine, endothelial cells from coronaryblood vessels have been shown to rapidly metabolize adenosine withincorporation into various nucleotide pools( 45 ). These authors suggestthat, in coronary vessels, transvascular adenosine movement may be impededmore by this metabolic barrier function of the endothelium than by itsphysical properties. If the endothelium restricts the movement of adenosine, one would expect differences in receptor accessibility dependent on the routeof administration.3 F7 P: L  u, I! s4 o

In summary, adenosine administered from the vessel outside causes a marked,nontransient vasoconstriction in afferent arterioles from all regions of thekidney, although vessels of superficial nephrons appear to be more sensitivethan arterioles of juxtamedullary nephrons. In the afferent arteriole at theglomerular entrance, the diameter reduction is monotonically dose dependent,indicating the absence of adenosine receptors opposing vasoconstriction. Inthe more proximal part of the arteriole, the vasoconstrictor effect ofadenosine is blunted (at lower concentrations by A 2a AR and athigher concentrations by A 2b AR), but net vasodilatation does notoccur. In the hydronephrotic kidney preparation, the adenosine-inducedvasoconstriction is transient, an effect that may reflect changes in thevascular response pattern resulting from chronic elimination of the tubularepithelium. For reasons that are not entirely clear, A 1 ARactivation appears to cause a more pronounced constriction of afferentarterioles when added to the interstitial aspect of the vessel.
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ADENOSINE AND RENAL VASODILATATION7 s% w) S* {2 M

Effect of Adenosine at the Organ Level
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In contrast to bolus injections, adenosine administered by constant infusion is associated with an unchanged or usually even increased renal bloodflow ( 23, 54, 58, 77 ). The causes for thesteady-state vasodilatation have been ascribed to preferential relaxation ofthe efferent arteriolar or medullary vascular beds, but a convincing argumentfor either explanation cannot be made on the basis of studies at the organlevel. Nevertheless, the selective A 2 AR agonist CGS-21680A elicitsa monophasic reduction in renal vascular resistance, clearly indicating thatactivation of A 2 AR is the cause for the transient nature of therenal constrictor response to adenosine( 35 ). Furthermore,vasodilatation was seen in isolated perfused kidneys with the somewhatA 2 AR-specific agonist NECA( 43, 46 ). It is noteworthy that GFRis typically suppressed by adenosine in a more persistent fashion so that areduction of filtration fraction is an invariable consequence of prolongedadenosine administration.5 c) j& P1 h: \4 F1 U0 z0 J
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Even though obvious, it is relevant to point out that the infusion studiesdiscussed above examine the effect of an addition of adenosine to the existingendogenous nucleoside levels and therefore limit the analysis to thesupranormal concentration range. A consideration of the baseline adenosineconcentrations in plasma and in the renal interstitial fluid may therefore behelpful to predict the expected changes in receptor engagement with adenosineinfusions, taking into account the known affinity and dissociation constantsof the different adenosine receptors. Plasma adenosine levels have beenreported to be somewhere between 100 nM and 1 µM, i.e., in the10 - 7 to 10 - 6 M range( 12, 18, 32, 89, 91 ). Renal interstitialconcentrations of adenosine as determined by microdialysis have been found tobe between 50 and 200 nM in the cortex and between 160 and 210 nM in themedulla ( 6, 48 - 50, 70, 92 ). Thus these levels are inthe same order of magnitude as plasma concentrations. The classical earlyanalysis of ligand binding kinetics to the various adenosine receptors hasestablished that A 1 AR and A 2a AR have affinity constantsfor adenosine in the order of 10 - 8 M, whereas theaffinity of A 2b AR is much lower, around10 - 5 M( 14, 19, 37, 82 ). Thus, at the prevailing extracellular adenosine concentrations of 10 - 7 M, one would expect A 1 AR andthe high-affinity A 2a AR to be partly occupied, whereasA 2b AR are probably not. The absence of a major effect ofnonspecific AR inhibitors such as theophylline or aminophylline on renalhemodynamics is consistent with the notion that resting renal vascular tonerepresents a state of balanced A 1 AR and A 2a AR activation( 9, 54, 64 ). The increments inadenosine concentration resulting from the infusion should mostly be targetedto the A 2b AR receptor pool. For this simple reason, it is perhapsnot surprising that adenosine infusions result in relaxation of all vesselsexpressing A 2b AR, the majority of the renal vasculature, andtherefore cause global renal vasodilatation. In view of the evidence discussedabove that the afferent arteriole near the glomerulus may not vasodilate evenat elevated levels of adenosine, at least when adenosine is administered fromthe interstitial side, it is relevant to point out that the afferent arterioleis not the only resistance vessel in the kidney. Aside from the significantcontribution of the efferent arterioles, interlobular arteries in the rat kidney have been estimated to represent as much as 50% of renal preglomerularresistance ( 8, 26 ) and have also been shown to contribute importantly to autoregulatory adjustments of renal vascularresistance ( 25 ). Furthermore,the renal artery has been shown to regulate renal vascular resistance by therelease and downstream action of endothelium-derived vasodilators( 31 ). Therefore, global renalvasodilatation may well occur in the absence of overt vasodilatation inafferent arterioles.+ g7 w8 Q; C7 U' j- B' ?4 @
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It is now well recognized that the majority of vasodilator agents act bybinding to their receptors on endothelial cells and by eliciting thegeneration and release of endothelial relaxing factors, most notably NO,endothelial hyperpolarizing factor, and prostaglandins. The presence ofA 2 AR in endothelial cells of the renal vasculature has not beenestablished directly, but a number of studies in various excised vesselpreparations indicate that adenosine-induced vasodilatation is probably to some extent endothelium dependent. In the majority of these studies, adenosineappears to augment NOS activity and NO release through anA 2 AR-mediated process, an action that would enhance the dilatorcomponent rather than diminish the constrictor component of the adenosineactions ( 1, 21, 38, 75, 90 ). In addition, adenosinehas also been reported to dilate rabbit renal arteries through an endothelialrelaxing factor that does not appear to be NO( 66 ). Finally, adenosine hasbeen shown to consistently stimulate the production of NO in cultured endothelial cells, usually through an A 2 AR-dependent mechanism ( 36, 53, 87 ). Thus, in addition to thepossible blunting of A 1 AR-induced vasoconstriction as discussedabove, endothelial dilator factors generated in response to A 2 ARactivation may enhance renal vasodilatation, thereby contributing to thewaning renal constriction in the kidney during intravenous administration.

The overall conclusion from these studies at the organ level would be thatthe intravenous administration of exogenous adenosine, i.e., an elevation ofplasma adenosine concentrations above normal, causes a short-lasting netvasoconstriction mediated by high-affinity A 1 AR. However, thiseffect is overcome, at the elevated plasma adenosine levels resulting from theaddition of exogenous nucleoside, by the simultaneous activation of lower-affinity A 2 AR so that the dominating and lasting effect isnet vasodilatation in most cases.

Effect of Adenosine in Efferent Arterioles3 D* d( @8 o7 y6 f0 s  ]
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Dilatation of efferent arterioles has been suggested as one of the reasonsfor the return of renal blood flow to normal or supranormal values during anadenosine infusion, a notion that is mainly based on the observed reduction infiltration fraction ( 42, 77 ). However, it has beendifficult to establish an unequivocal vasodilator action of adenosine inpreparations in which the arteriole can be observed directly. In theblood-perfused juxtamedullary nephron preparation, the effect of adenosine onthe diameter of efferent arterioles was qualitatively similar to that seen inafferent arterioles consisting of a stable diameter reduction by 6% at aconcentration of 10 - 5 M, a constrictor effect thatwas smaller than that seen in afferent arterioles( 11, 47 ). Vasodilatation in thepresence of an A 1 AR blocker, and enhanced constriction in thepresence of an A 2a AR blocker, resembled the effects noted inafferent arterioles. On the other hand, in the hydronephrotic kidney,adenosine at 10 - 5 M caused a steady-state diameterincrease of 14% that was not changed much by the A 1 ARantagonist DPCPX but was abolished by the A 2 AR antagonist3,7-dimethyl- L -propargylxanthine ( 20 ). These results suggestthe absence of A 1 AR in efferent arterioles in this preparation, anotion supported by previous reports using the same preparation in which theA 1 AR agonist CHA caused only small or no diameter reductions inefferent arterioles up to a concentration of 10 - 5 M ( 16, 27 ). In contrast, NECA induceda small efferent vasodilatation and an increase in glomerular blood flow( 27 ). Thus adenosine effects in the efferent arteriole are not very pronounced and appear to consist ofsmall constrictions at lower and small dilations at higher concentrations. Thesmall magnitude of both constrictor and dilator effects suggests rather lowlevels of expression for all receptor subtypes. Overall, we conclude that adilator effect of efferent arterioles may contribute to the loss of netvasoconstriction at elevated adenosine levels but that it is unlikely toaccount for the full dilator action of adenosine.) Z: y# J7 I2 v8 Q

Adenosine and medullary blood flow. Vasodilatation of the vessels controlling renal medullary blood flow has been proposed as being responsiblefor the net vasodilatation of the kidney in response to continuous intravenousinfusion of adenosine. Renal blood flow distribution measured withmicrospheres showed an increase in inner cortical blood flow, whereas outercortical blood flow was unchanged( 72 ). The magnitude of thisincrease varied between 23 and 94%, depending on the renin status of the dogs.Interstitial infusion of adenosine induced an increase in medullary blood flowmeasured with laser-Doppler flowmetry by 40%( 2 ). Direct infusion ofadenosine in the renal medulla caused an 25-30% increase in bothouter and inner medullary blood flows( 92 ). Direct assessment ofblood flow in single inner medullary vasa recta by videomicroscopy showed anincrease in red cell velocity without a diameter change only during intrarenal adenosine infusion at the highest dose tested( 39 ). The infused amounts didnot induce significant changes in inulin or p -aminohippuric acidclearances. In isolated perfused outer medullary vasa recta, theadministration of increasing concentrations of adenosine induced a biphasicresponse, consisting of a vasoconstriction in the dose range between10 - 11 and 10 - 7 M and avasodilatation at 10 - 6 to10 - 5 M( 68 ). In contrast to corticalresistance vessels, administration of adenosine to vasa recta preconstrictedby ANG II leads to vasodilatation ( 68, 69 ). The concentration ofadenosine in the interstitial fluid of the medulla is between10 - 7 and 10 - 6 M, alevel where one may expect not much impact on resting tone but where anincrease of adenosine concentration should cause vasodilatation( 70, 92 ). In summary, most studiesagree that the administration of adenosine causes an increase in medullary blood flow by relaxing both juxtamedullary afferent and perhaps efferentarterioles and outer medullary vasa recta pericytes. Nevertheless, forquantitative reasons, we consider it unlikely that this increase in medullaryblood flow can be the only reason responsible for the overall increase intotal renal blood flow seen with constant infusions of adenosine. Medullary blood flow represents only 10% of total renal blood flow. Thus areduction in cortical blood flow by 50% would require a more than fivefoldincrease in medullary flow for compensation. The magnitude of the observedincrease in medullary blood flow, variable as it may be, is not even close tothis expectation. Thus much of the compensatory increase in total renal blood flow in response to continuous adenosine infusions must take place in therenal cortex.

In conclusion, the intravenous infusion of adenosine, i.e., an increase ofplasma adenosine levels above normal, causes a renal vasodilator response thatis the result of A 2 AR-mediated vasorelaxation in most parts of therenal vasculature, including larger renal arteries, juxtamedullary afferentarterioles, efferent arterioles, and medullary vessels( Fig. 2 ). A combination ofthese effects, rather than one single action, is responsible for therelaxation caused by exogenous adenosine in the whole kidney.A 2 AR-mediated vasorelaxation may be facilitated by intravascularreceptors, most likely on endothelial cells, causing the release of NO andother endothelial relaxing factors. In contrast, the afferent arteriole,especially in the segment closest to the glomerulus, responds to adenosinewith vasoconstriction over a wide concentration range. Afferent arteriolarA 1 AR are selectively activated from the interstitial aspect of thevessel, a characteristic that is ideally suited for the presumed physiological role of these receptors, the mediation of the TGF response.! {/ M0 l! f9 M- [. P

Fig. 2. Relationship between the concentration of adenosine and the 辌rease inthe diameter of afferent arterioles near the glomerulus (AA-Glom), proximalafferent arterioles (AA), juxtamedullary afferent arterioles (JM-AA),juxtamedullary efferent arterioles (JM-EA), and outer medullary descendingvasa recta (OMDVR). There are no data for the missing vessels. Diameterdecrements are a measure of vessel resistance. Data are from Refs. 47, 68, and 84.
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DISCLOSURES

Work from the authors' laboratory was supported by intramural funds fromthe National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).P. B. Hansen was the recipient of a Visiting Fellowship of the NIDDK.
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