Influence of Acute Renal Failure on Coronary Vasoregulation in Dogs
John G. Kingma, Jr.,
Chantal Vincent,
Jacques R. Rouleau and
Iris Kingma
Coronary Physiology Research Group, Institut Universitaire de Cardiologie et Pneumologie, Department of Medicine, Laval University, Quebec City, Quebec, Canada
Address correspondence to: Dr. John G. Kingma, Jr., Research Center, Laval Hospital, 2725 Chemin Sainte-Foy, Quebec, G1V 4G5 Canada. Phone: +418-656-8711 ext. 5388; Fax: +418-656-4509; john.kingma{at}med.ulaval.ca
Received for publication October 18, 2005.
Accepted for publication February 21, 2006.
Impaired renal function is associated with an increased riskfor cardiovascular events and death, but the pathophysiologyis poorly defined. The hypothesis that coronary blood flow regulationand distribution of ventricular blood flow could be compromisedduring acute renal failure (ARF) was tested. In two separategroups (n = 14 each) of dogs with ARF, (1) coronary autoregulation(pressure-flow relations), vascular reserve (reactive hyperemia),and myocardial blood flow distribution (microspheres) and (2)coronary vessel responses to intracoronary infusion of selectendothelium-dependent and -independent vasodilators were evaluated.In addition, coronary pressure-flow relations and vascular reserveafter inhibition of nitric oxide and prostaglandin release wereevaluated. Under resting conditions, myocardial oxygen consumptionincreased in dogs with ARF compared with no renal failure (NRF;11.8 ± 9.2 versus 5.0 ± 1.5 ml O2/min per 100g; P = 0.01), and the autoregulatory break point of the coronarypressure-flow relation was shifted to higher diastolic coronarypressures (60 ± 17 versus 52 ± 8 mmHg in NRF;P = 0.003); the latter was shifted further rightward after inhibitionof both nitric oxide and prostaglandin release. The endocardial/epicardialblood flow ratio was comparable for both groups, suggestingpreserved ventricular distribution of blood flow. In dogs withARF, coronary vascular conductance also was reduced (P = 0.001versus NRF), but coronary zero-flow pressure was unchanged.Vessel reactivity to each endothelium-dependent/independentcompound also was blunted significantly. In conclusion, underresting conditions, coronary vascular tone, reserve, and vesselreactivity are markedly diminished with ARF, suggesting impairedvascular function. Consequently, during ARF, small increasesin myocardial oxygen demand would induce subendocardial ischemiaas a result of a limited capacity to increase oxygen supplyand thereby contribute to higher risk for adverse coronary eventsand mortality.
Mortality rates in acute renal failure (ARF) have remained unchangedin the past five decades (1). Several major clinical trialshave documented that reduced renal function is associated withincreased risk for cardiovascular events and death (2,3) inpatients with acute or chronic renal disease (4). Renal diseasealso is an important risk factor for cardiovascular complicationsafter myocardial infarction and cardiogenic shock (5). Renalfailure modifies most factors that regulate cardiovascular functionvia direct hemodynamic effects, neurogenic reflexes, and circulatinghormones (6). The loss of cardiovascular reserve as a resultof renal disease may explain the high morbidity and mortalityin patients with end-stage renal failure (4,7,8). Coronary autoregulationis an important homeostatic mechanism for maintenance of nutrientand oxygen delivery to the myocardium (9–11). Intrinsicautoregulatory mechanisms adjust tone within the microvasculatureto maintain distribution of myocardial blood flow over a rangeof oxygen supply and demand requirements (9). Factors that areinvolved include intra- and extravascular compressive forces(12,13), left ventricular (LV) preload and afterload (14), LVvolume, coronary collateral blood flow (15), neuronal status(16,17), arterial structure (18), and endothelial function (19);these factors can be modulated significantly under physiologicor pathologic conditions. Although it is established that underlyingcardiac disease compromises kidney function in humans, it isnot clear how impaired renal function affects coronary bloodflow regulation, myocardial blood flow distribution, and cardiovascularreserve. We hypothesized that myocardial blood flow regulationcould be compromised after onset of kidney dysfunction and therebycontribute to mortality in these patients. Studies were doneusing an in situ canine model of renal ischemia-reperfusioninjury; total coronary blood flow (flow probe) and transmural(microspheres) myocardial blood flow regulation were evaluated.In addition, coronary vessel reactivity was assessed in responseto intracoronary infusion of endothelium-dependent and -independentvasodilators before and after inhibition of nitric oxide (NO)and prostaglandin release.
Male mongrel dogs that weighed 20 to 25 kg were used in thisstudy; animals were acclimatized for 7 d before the day of firstsurgical procedure. Dogs were fed a standard diet and providedaccess to water ad libitum. All dogs received humane care incompliance with the Guide to the Care and Use of ExperimentalAnimals (vols. 1 and 2) of the Canadian Council on Animal Care;the Laval University Animal Ethics Committee approved thesestudies.
Renal Ischemia-Reperfusion Injury Preparation
Dogs were premedicated with acepromazine maleate (Atravet, 0.5mg/kg, intramuscularly); cefazolin sodium (Kefzol, 22 mg/kg,intravenously) and butorphanol (0.2 mg/kg, intramuscularly)were given 30 min before surgery and every 2 h during the surgicalintervention for antibiotic prophylaxis and analgesia, respectively.Anesthesia was induced with sodium pentobarbital (Somnotol,30 mg/kg, intravenously); maintenance doses were administeredas needed. Dogs were intubated and mechanically ventilated (HarvardApparatus, Boston, MA). ARF was produced using a modified Goldblattmodel. Briefly, through a lower abdominal section, the spleenwas removed (20); the kidneys were exposed and dissected freeof perirenal tissue. All branches of the right renal arterywere stripped and ligated; small branches of the left renalartery were similarly stripped and ligated and an inflatablevascular occluder (4 to 5 mm; In Vivo Metrics, Healdbourg, CA)was positioned on the main artery. The silastic tubing was tunnelledsubcutaneously into a pouch in the dorsal interscapular region,and the abdominal wound was closed in layers. Buprenorphine(0.2 mg/kg, intramuscularly) was given to relieve postoperativepain. After 24 h of recovery, the vascular occluder on the leftrenal artery was inflated (glycerine was used to ensure completeocclusion) for 45 min; glycerine subsequently was removed fromthe tubing to allow reperfusion of ischemic tissues. Butorphanol(0.1 mg/kg, intramuscularly) was administered to all dogs torelieve potential discomfort during these manipulations. Dogswith no renal failure (NRF; controls) underwent the same surgicalprocedure described above, but the left renal artery was notoccluded.
Extent of renal failure was confirmed by increases in plasmaurea nitrogen (mmol/L) and creatinine (µmol/L) in venousblood samples that were drawn daily (a.m.). Blood was collectedin precooled vials that contained EDTA at baseline and on day8 for determination of plasma renin activity; samples were centrifugedfor 15 min at 1200 rpm at 4°C and kept at –20°Cfor later analysis.
General Experimental Preparation
When plasma urea nitrogen and creatinine levels were >40mmol/L and 800 µmol/L, dogs (± 8 d of postrenalartery occlusion) were sedated with acepromazine maleate (Atravet,0.5 mg/kg intramuscularly) and butorphanol (0.1 mg/kg intramuscularly).Dogs were anesthetized using sodium pentobarbital (30 mg/kgintravenously), intubated, and mechanically ventilated; atelectasiswas prevented by maintaining an end-expiratory pressure of 5to 7 cmH2O. Arterial blood pH, Po2, and Pco2 were monitoredregularly and kept within normal physiologic limits. Body temperaturewas kept at 38 ± 1°C by a water-jacketed Micro-Tempheating blanket (Zimmer, Dover, OH) and was monitored with probesplaced in the abdomen and trachea. A left thoracotomy was performedin the fifth intercostal space. Heparin-filled catheters wereinserted into the internal thoracic artery (for reference arterialblood withdrawal), the left atrium (for injection of microspheres),the coronary sinus (for venous blood withdrawal), and both femoralarteries and veins. A 5F microtipped pressure transducer (MillarMPC500) was placed in the LV cavity through the apex to measureLV pressure and its first derivative; a 7F Pigtail catheterwas placed in the aortic root via the left femoral artery tomeasure aortic pressure. A segment of the left main coronaryartery was dissected free proximal to first major marginal branchand a Doppler probe (Transonic Systems Inc., New York, NY) waspositioned to measure changes in coronary blood flow. A snare(for reactive hyperemia) was placed distal to the probe alongwith a micrometric screw occluder (for construction of coronarypressure flow relations [PFR]). Piezoelectric crystals (5 MHz;Triton Technologies, San Diego, CA) were positioned in the posteriorventricular wall to assess myocardial wall thickening as describedpreviously (21). Two catheters were inserted into the coronaryartery distal to the screw occluder to allow infusion of drugsand measurement of coronary perfusion pressure (22). Heparinsodium (200 U/kg intravenously) was administered every 2 h duringthe experimental protocol. The chest cavity was covered withplastic film to prevent undue cooling.
Left atrial, circumflex artery, coronary sinus, and ascendingaorta catheters were connected to Statham P23Db strain gaugemanometers; zero was set at mid-chest level. The Millar MPC500micro-manometer transducer was calibrated with systolic aorticand diastolic left atrial pressures. Standard lead II of thescalar electrocardiogram was used to determine heart rate. Allof the data, including heart rate, arterial pressures, and coronaryblood flow, were recorded continuously during the experimenton a 12-channel direct-writing oscillograph (Yokogawa OR1200A;Electro-Meters, Dorval, QC, Canada) and on magnetic tape usinga TEAC XR-510 recorder.
Coronary PFR and Distribution of Myocardial Blood Flow
Under resting conditions (n = 14 dogs), a reactive hyperemicresponse to 20 s of total occlusion of the left circumflex arterywas recorded to assess coronary vascular reserve; circumflexartery diastolic pressure was recorded at both zero flow andpeak flow. After return to baseline, coronary PFR were constructedby incremental (5- to 10-mmHg increments) lowering of arterialpressure; the autoregulatory break point (LPL) for each curvewas determined as described previously (23). Coronary pressureswere not allowed to fall below the LPL to avoid potential preconditioningeffects. Distribution of myocardial blood flow was determinedusing radiolabeled microspheres (15 µm; NEN, Boston, MA)at baseline (i.e., intact coronary tone) and at the LPL as describedin earlier experiments from our laboratory (16). Immediatelyafter each microsphere injection, arterial and coronary sinusblood samples were drawn simultaneously to evaluate blood gases,pH, hematocrit, percentage of oxygen saturation, and oxygencontent. The same experimental protocol was repeated in eachdog during treatment with N-nitro-L-arginine methyl ester (L-NAME)(50 µg/kg per min, intracoronary [IC] at a rate of 1 ml/minfor 12-min with an infusion pump) and L-NAME (as above) + indomethacin(INDO) (5 mg/kg intravenous bolus) to evaluate potential contributionof NO and prostanoids on blood flow regulation in these dogsas described previously (24,25).
In Vivo Coronary Dose-Response Experiments
Peak reactive hyperemic responses to a 20-s coronary occlusionwere recorded to assess coronary vascular reserve (n = 14 dogs),as described above. For assessment of the effects of ARF onendothelium-dependent and -independent vasoreactivity acetylcholinechloride (0.1 to 10 µg/min IC; Sigma, St. Louis, MO),bradykinin acetate (0.03 to 1.0 µg/min IC; Sigma), adenosine(1.0 to 100.0 µg/min IC; Sigma), and l-arginine (0.0 to30.0 mg/min IC; Sigma) dissolved in normal saline (solutionsprepared fresh daily) were infused into the circumflex coronaryartery with a precision pump injector (1 ml/min; Harvard Apparatus,Holliston, MA) for 2 min (24); data were recorded when coronaryblood flow was stable. Normal saline was infused at the samerate to determine the effects of vehicle on coronary blood flow.The response to a single dose of nitroglycerin (100 µg/minIC; SABEX, Boucherville, QC, Canada) also was evaluated. Thesame experimental protocol was repeated in each dog during combinedtreatment with L-NAME (50 µg/kg per min, IC at a rateof 1 ml/min for 12 min with an infusion pump) and INDO (5 mg/kgintravenous bolus); however, only a single dose of each agonistwas injected: Adenosine (30 µg/min IC), acetylcholine(5 µg/min IC), and bradykinin (0.33 µg/min IC).The sequence of drug administration was randomly selected withthe exception that nitroglycerin was always administered atthe end of each study because of long-lasting effects. At least5 min was allowed between injections for return to steady-statehemodynamic values.
Postmortem Preparation
At the end of each experiment, the left main circumflex arterywas ligated and Monastral blue dye was injected into the circumflexartery to delineate its vascular bed. Under deep anesthesia,cardiac arrest was induced by intra-atrial injection of saturatedpotassium chloride. For assessment of regional blood flow distribution(see Coronary PFR and Distribution of Myocardial Blood Flowsection), the heart was excised, fixed in 10% buffered formaldehyde(pH 7.4), and subsequently processed as described previously(21). The left kidney also was removed and fixed in formalin;tissue samples were obtained from the cortex. Radioactivityin reference arterial blood and cardiac and renal tissue sampleswas measured in a multichannel NaI(TI) -well counter (Auto-Gamma5003 Cobra II; Packard Instruments, Meriden, CT) with standardwindow settings. All samples were counted for 2 min, and nuclideactivity was corrected for background and decay. Overlap correctionswere made using the inversion matrix technique; the matrix wasderived from radioisotope standards made from small aliquotsof the microsphere stock and assayed simultaneously with theblood and tissue samples. Blood flow (ml/min per 100 g) wascalculated using PCGERDA computer software (version 1.02; PackardInstruments).
Statistical Analyses
Hemodynamic, coronary blood flow, and myocardial contractilefunction data were obtained directly from strip chart recordings.Overall comparisons of blood flow data under control (no treatment),L-NAME, or L-NAME+INDO conditions were made using ANOVA forrepeated measures. The Student-Newman-Keuls multiple range test,with 0.05, was performed on all main-effect means to identifysignificant differences between interventions. A similar approachwas used to assess differences between vascular responses toadenosine, acetylcholine, bradykinin, and l-arginine. End-diastolicwall thickness (EDT; onset of positive dP/dt) and end-systolicwall thickness (EST; approximately 20 ms before peak negativedP/dt) also were evaluated (26); because contractile functionvaries with the respiratory cycle, all measurements were determinedat end expiration. Percentage of systolic myocardial wall thickening(SWT) was calculated using the equation SWT (%) = EST –EDT/EDT x 100. Values from five consecutive, artifact-free beatswere averaged and normalized to preocclusion values.
All statistical procedures were performed using the SAS statisticalsoftware package (SAS Inc., Cary, NC) (27). P < 0.05 wasused to indicate a significant difference in mean values.
Thirty-four dogs were entered into these studies; six dogs (oneNRF and five ARF) died during the 8-d postsurgical period andwere excluded from the study. Twenty-eight dogs were used inthe data analysis. Body weights were not significantly differentbetween NRF and ARF dogs. Coronary PFR and distribution of myocardialblood flow were evaluated in 14 dogs; in an additional 14 dogs,endothelial function was assessed directly by intracoronaryinjection of endothelium-dependent and -independent vasodilators.
Biochemical Variables and Blood Gases
Plasma levels of plasma urea nitrogen, creatinine, and reninactivity were markedly augmented in all ARF dogs; plasma potassiumand calcium levels were not changed, as shown in Table 1. Bloodgas values for arterial and coronary sinus blood are summarizedin Table 2. Partial pressure of oxygen in coronary sinus bloodwas lower (P = 0.005) in dogs with ARF compared with controls;arterial and coronary sinus carbon dioxide levels were similar.Arterial blood pH was more alkaline in dogs with ARF (P = 0.008versus NRF), but oxygen saturation and hematocrit were not different.
Table 2. Summary of hematocrit, blood gas, oxygen saturation and pH dataa
Cardiac Hemodynamics and Wall Thickening
Heart rate, LV pressure (systolic/diastolic), and SWT in theposterior ventricular wall are summarized in Table 3. Developmentof ARF was associated with a significant increase in systolicLV pressure (125 ± 25 versus 104 ± 9 mmHg in NRF);mean heart rate was similar between the two experimental groups.Heart rate–arterial BP index (15.8 ± 4.6 versus12.7 ± 2.3 bpmxmmHg per 10–3; P = 0.032) and myocardialoxygen consumption (11.8 ± 9.2 versus 5.0 ± 1.5ml O2/min per 100 g; P = 0.001) were significantly elevatedin ARF dogs. Treatment with L-NAME and L-NAME+INDO resultedin a further increase of myocardial oxygen consumption in NRFdogs, but this effect was not observed in animals with ARF.SWT did not change for either experimental group under controlconditions but was markedly reduced in both groups after treatmentwith L-NAME and L-NAME+INDO.
Table 3. Summary of myocardial oxygen demand parameters and oxygen consumptiona
Coronary Pressure-Flow Relations, Reactive Hyperemia, and Distribution of Blood Flow Figure 1 summarizes the effects of ARF on coronary pressure-flowrelations during autoregulation. Baseline coronary blood flow(cf. Table 4) was higher in ARF dogs (57 ± 20 versus38 ± 12 ml/min; P = 0.006 versus NRF); diastolic circumflexartery pressure was 93 ± 8 and 111 ± 25 mmHg (P= 0.003), respectively, in NRF and ARF dogs. There was littlechange in coronary blood flow as perfusion pressure was incrementallyreduced over the autoregulatory plateau (this shows intact autoregulation).The autoregulatory break point (LPL) was higher in ARF dogs(60 ± 17 versus 52 ± 8 mmHg; P = 0.003 versusNRF dogs); inhibition of NO and prostaglandin release produceda further rightward shift of the LPL in ARF dogs. During reactivehyperemia, blood flow increased from 38 ± 12 to 209 ±18 ml/min in NRF and from 57 ± 20 to 178 ± 20ml/min in ARF dogs; flow repayment duration was significantlylonger in ARF dogs (156 ± 49 versus 126 ± 32 sin NRF; P = 0.001). Reduced peak blood flow levels in ARF dogsoccurred even though diastolic coronary perfusion pressureswere much higher in these animals (reduced vascular conductance).The endocardial/epicardial blood flow ratio (determined frommicrosphere blood flow data) was not different between the twoexperimental groups over the autoregulatory range; this suggeststhat distribution of blood flow across the LV wall was preserved.Diastolic coronary artery pressures at zero flow were similarfor both experimental groups at baseline (11 ± 4 mmHgin NRF versus 12 ± 4 mmHg in ARF dogs); these valuesincreased significantly in both groups during treatment withL-NAME and L-NAME+INDO (cf. Table 5). Vascular conductance (i.e.,slope of the flow-pressure relation) also was significantlylower in ARF dogs; further reductions in vascular conductancewere observed for this group during treatment with L-NAME andL-NAME+INDO.
Figure 1. Blood flow responses after a 20-s coronary occlusion in dogs with no renal failure (NRF) and acute renal failure (ARF); diastolic coronary pressure was measured at zero and peak flow. Vascular conductance was markedly reduced in ARF dogs (P = 0.001 versus NRF) and was diminished further after administration of N-nitro-L-arginine methyl ester (L-NAME) and L-NAME + indomethacin (INDO) (data not shown). Coronary pressure at zero flow was comparable for the two experimental groups. Coronary blood flow during autoregulation was higher and the autoregulatory break point shifted rightward (60 ± 6 mmHg) in ARF dogs. Endocardial/epicardial (endo/epi) blood flow ratios (bottom) were similar for both groups over the range of autoregulation under these resting conditions. Values are means ± SEM; n = 7 dogs per group.
Table 5. Evaluation of diastolic coronary pressure-flow relationsa
In the left kidney, cortical blood flow was reduced in ARF dogs(2.7 ± 1.8 versus 8.4 ± 0.9 ml/min per g in NRF;P = 0.001). Treatment with L-NAME decreased cortical blood flowvalues (1.7 ± 0.6 in ARF versus 4.4 ± 0.6 ml/minper g in NRF; P = 0.001) in both experimental groups; this effectwas exacerbated further with L-NAME+INDO (1.5 ± 0.8 versus3.4 ± 0.9 ml/min per g; P = 0.02).
Dose-Response Relations to Endothelium-Dependent and -Independent Vasoactive Drugs
Adenosine, acetylcholine, and bradykinin produced dose-dependentincreases in coronary blood flow in all dogs without significantlyaffecting heart rate or mean arterial pressure; however, vasodilatoryresponses to each of these compounds was markedly reduced inARF dogs (P < 0.05 versus NRF; Figure 2). Intracoronary infusionof l-arginine increased coronary blood flow in NRF dogs buthad no effect in ARF dogs even at the higher dosages (P <0.05 versus NRF). Percentage change in circumflex artery bloodflow in response to a single dose of adenosine, acetylcholine,and bradykinin was substantially reduced in both experimentalgroups after combined treatment with L-NAME+INDO (Table 6).Vascular responses to intracoronary nitroglycerin (endotheliumindependent) also were substantially reduced in ARF dogs (177± 14% versus 260 ± 25 in NRF; P = 0.01) beforeand after combined treatment with L-NAME+INDO.
Figure 2. Coronary blood flow (expressed as % increase from baseline values) in NRF and ARF dogs induced by intracoronary infusions of adenosine, acetylcholine, bradykinin, and l-arginine under resting conditions. Values are means ± SEM (*P 0.05; n = 7 dogs per group).
This study presents several new findings regarding the effectsof ARF on blood flow regulation in the heart. Results show that(1) coronary autoregulation is preserved but the lower autoregulatorybreak point shifts to a higher coronary perfusion pressure;(2) coronary vascular reserve and coronary vascular conductanceare markedly diminished; and (3) coronary vessel reactivityto either endothelium-dependent or -independent vasodilatorsis substantially reduced, suggesting loss of vascular functionin ARF dogs. All of these effects are exacerbated during combinedblockade of NO and prostaglandin release.
Vascular endothelium plays a crucial role in regulation of vasculartone, inflammation, and thrombosis; endothelial dysfunctioncontributes to pathophysiology of atherosclerosis (28) and acutecardiovascular syndromes (29). Coronary reserve is markedlyreduced in patients with congestive heart failure, diabetes,and nephropathy (30). These changes are attributed mostly toincreases in LV mass, circulating neurohumoral factors, andanemia. In our study, peak reactive hyperemic responses weresimilar for both study groups, but coronary vascular reservewas blunted in ARF dogs. Under resting conditions, coronaryautoregulation and myocardial blood flow distribution were maintainedin both ARF and NRF dogs; however, the autoregulatory breakpoint in ARF dogs was shifted to a higher diastolic coronarypressure as a result of the reduction of coronary vascular conductancebecause coronary pressure at zero flow was similar in theseexperimental groups both at baseline and during combined treatmentwith L-NAME+INDO. Increases in myocardial oxygen demand combinedwith a higher LPL markedly diminish the ability to maintainuniform distribution of blood flow across the LV wall (13,31).With ARF, higher levels of myocardial oxygen demand would triggermaldistribution of ventricular blood flow and result in subendocardialischemia.
The endothelium produces many compounds that modulate coronaryvascular tone in relation to myocardial oxygen demand. The balancebetween oxygen supply and demand in the heart is postulatedto be controlled by the coronary venous oxygen tension (32);a relation has been shown between coronary venous oxygen levelsand mediators of vascular dilation in normal dogs. During exercise,blockade of adenosine (including KATP channels) and NO synthesisproduces a parallel downward shift of the coronary venous Po2versus myocardial oxygen consumption relationship. Inhibitionof prostaglandins alone did not affect this relationship; however,this does not exclude a potential effect of prostaglandins duringdisease (32). With ARF, the observed reduction in coronary venousPo2 may reflect diminished efficacy of local coronary metabolicmediators: (1) Reduced bioavailability of NO to vascular smoothmuscle cells as a result of structural alterations in the vesselor microvessel wall, (2) increased destruction of NO as a resultof overproduction of reactive oxygen intermediates in the vesselwall (33), and (3) impaired dilation to NO donors (e.g., nitroglycerin)as a result of defective vascular smooth muscle cell functionat the level of the soluble guanylate cyclase/cyclic guanosinemonophosphate signaling pathway. During ARF, we documented thatcombined blockade of NO synthase and cyclooxygenase furtherreduced vessel reactivity and coronary vascular conductance,indicating a role for prostaglandins. The overall impact ofthese factors is a mismatch between myocardial oxygen supplyand demand that could explain the increased cardiovascular riskobserved with renal failure. In an earlier study, Ruschitzkaet al. (34) reported significant endothelial dysfunction inrenal arteries of rats 24 h after acute renal ischemia-reperfusioninjury. Our results, although consistent with these findings,support the view that vascular smooth muscle cell dysfunctioncan contribute to overall vascular dysfunction (35).
Renal ischemia is associated with significant increases of vasoactivecompounds in plasma (e.g., angiotensin II, bradykinin) (36);treatment with angiotensin-converting enzyme inhibitors facilitatesrelease of NO and prostanoids in these patients (19,37). Plasmaand tissue levels of endothelin also are augmented in ARF (34,38)as a result, in part, of limited clearance by the lungs andkidneys; although endothelin may be partly responsible for thereduced vessel function, other, unknown uremic toxins also mayplay a role. In our study, renal blood flow was significantlyreduced in ARF dogs; combined treatment with L-NAME+INDO furtherreduced renal perfusion that could trigger a greater releaseof vasoactive compounds that may have contributed to the lowercoronary conductance. Increased production of reactive oxygenintermediates after renal ischemia-reperfusion injury may promoteendothelial dysfunction as elevated levels of reactive oxygenspecies quench synthesis of NO and limit bioavailability. Exogenousantioxidants have been shown to augment bioavailability of NOin animal models of ARF (39). In our study, vascular responsesto agonists that stimulate both NO-dependent and independentmechanisms were markedly diminished in ARF dogs; reduced bioavailabilityof NO may be responsible, but plasma NO levels were not measureddirectly. That intracoronary infusion of l-arginine was unableto elicit a blood flow response suggests that other pathwaysthat are involved in production of NO could be suppressed inARF dogs.
Like most studies, this one has limitations. First, experimentswere carried out in an experimental model of renal failure;plasma creatinine levels increased >10-fold in most animalsand is indicative of severe renal impairment. In humans, whenplasma creatinine levels double, clearance is reduced to 50%;a 10-fold increase in plasma creatinine levels likely wouldreduce clearance levels to approximately 10% of normal values.ESRD is considered when GFR is 15 ml/min or less (normal of120) in humans. As such, dogs that were used in our study wereconsidered to be in moderate to severe renal failure. With plasmacreatinine levels >1000 µmol/L, dogs succumbed as aresult of severe electrolyte abnormalities. Although the biochemicalparameters used here to indicate renal dysfunction are consideredto be relatively insensitive in humans (3), more conventionaltechniques, including the Modification of Diet in Renal Disease(40) and the Cockcroft and Gault equations (41), have not beenvalidated in canines.
Acquired coagulopathy in patients with renal disease can resultin thrombosis, bleeding, or a combination of both (42). Coagulationparameters could have influenced blood rheology or vessel reactivityin these studies; however, the similarity of hematocrit levelsbetween the two experimental groups reduced the possibilitythat a change in blood viscosity was responsible for coronaryblood flow alterations in ARF dogs.
Our data demonstrate that under resting conditions, coronaryvasodilatory reserve is reduced (diminished coronary vascularconductance), vascular reactivity to endothelium-dependent or-independent compounds is compromised, and the autoregulatorybreak point is increased after acute renal ischemia-reperfusioninjury. These factors would contribute to the higher risk foradverse coronary events in patients with renal failure if increasesin myocardial oxygen demand cannot be met because of limitedcoronary vascular reserve.
Acknowledgments
These studies were supported by an operating grant from theKidney Foundation of Canada (J.G.K. and J.R.) and the Heartand Stroke Foundation of Quebec (J.G.K.).
We appreciate the expert surgical (André Blouin), technical(Lynn Atton), and animal care (Guy Noel and Justin Robillard)assistance of the staff at the Laval Hospital Research Center.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
Ympa YP, Sakr Y, Reinhart K, Vincent JL: Has mortality from acute renal failure decreased? A systematic review of the literature.
Am J Med 118
: 827
–832, 2005[CrossRef][Medline]
Freeman RV, Mehta RH, Al BW, Cooper JV, Kline-Rogers E, Eagle KA: Influence of concurrent renal dysfunction on outcomes of patients with acute coronary syndromes and implications of the use of glycoprotein IIb/IIIa inhibitors.
J Am Coll Cardiol 41
: 718
–724, 2003[Abstract/Free Full Text]
Anavekar NS, McMurray JJ, Velazquez EJ, Solomon SD, Kober L, Rouleau JL, White HD, Nordlander R, Maggioni A, Dickstein K, Zelenkofske S, Leimberger JD, Califf RM, Pfeffer MA: Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction.
N Engl J Med 351
: 1285
–1295, 2004[Abstract/Free Full Text]
USRDS 2004 annual data report.
Am J Kidney Dis 45
: 8
–280, 2005
Koreny M, Karth GD, Geppert A, Neunteufl T, Priglinger U, Heinz G, Siostrzonek P: Prognosis of patients who develop acute renal failure during the first 24 hours of cardiogenic shock after myocardial infarction.
Am J Med 112
: 115
–119, 2002[CrossRef][Medline]
Zanchetti A, Stella A: Cardiovascular disease and the kidney: An epidemiologic overview.
J Cardiovasc Pharmacol 33[Suppl 1]
: S1
–S6, 1999
London GM, Marchais SJ, Guerin AP, Metivier F, Adda H: Arterial structure and function in end-stage renal disease.
Nephrol Dial Transplant 17
: 1713
–1724, 2002[Free Full Text]
Munagala VK, Hart CY, Burnett JC Jr, Meyer DM, Redfield MM: Ventricular structure and function in aged dogs with renal hypertension: A model of experimental diastolic heart failure.
Circulation 111
: 1128
–1135, 2005[Abstract/Free Full Text]
Rouleau JR, Boerboom LE, Surjadhana A, Hoffman JIE: The role of autoregulation and tissue diastolic pressures in the transmural distribution of left ventricular blood flow in anesthetized dogs.
Circ Res 45
: 804
–815, 1979[Free Full Text]
Mosher P, Ross J Jr, McFate PA, Shaw RF: Control of coronary blood flow by an autoregulatory mechanism.
Circ Res 14
: 250
–259, 1964[Abstract/Free Full Text]
Canty JM Jr: Coronary pressure-function and steady-state pressure-flow relations during autoregulation in the unanesthetized dog.
Circ Res 63
: 821
–836, 1988[Abstract/Free Full Text]
Sellke FW, Myers PR, Bates JN, Harrison DG: Influence of vessel size on the sensitivity of porcine coronary microvessels to nitroglycerin.
Am J Physiol 258
: H515
–H520, 1990
Rouleau JR, Simard D, Kingma JG Jr: Myocardial blood flow regulation relative to left ventricle pressure and volume in anesthetized dogs.
Can J Physiol Pharmacol 77
: 902
–908, 1999[CrossRef][Medline]
Hoffman JIE, Spaan JAE: Pressure-flow relations in coronary circulation.
Physiol Rev 70
: 331
–390, 1990[Abstract/Free Full Text]
Messina LM, Hanley FL, Uhlig PN, Baer RW, Grattan MT, Hoffman JIE: Effects of pressure gradients between branches of the left coronary artery on the pressure axis intercept and the shape of steady state circumflex pressure-flow relations in dogs.
Circ Res 56
: 11
–19, 1985[Abstract/Free Full Text]
Rouleau JR, Simard D, Rodrigue N, Blouin A, Kingma JG Jr: Myocardial blood flow after chronic cardiac decentralization in anesthetized dogs: Effects of ACE-inhibition.
Auton Neurosci 97
: 12
–18, 2002[CrossRef][Medline]
Ferguson DW: Sympathetic mechanisms in heart failure. Pathophysiological and pharmacological implications.
Circulation 87
: VII-68
–VII-75, 1993
Benetos A, Albaladejo P, Levy BI, Safar ME: Acute and long-term effects of angiotensin-converting enzyme inhibition on larger arteries and cardiac hypertrophy: Mechanical and structural parameters.
J Hypertens 12
: S21
–S29, 1994
Zanzinger J, Zheng X, Bassenge E: Endothelium dependent vasomotor responses to endogenous agonists are potentiated following ACE inhibition by a bradykinin dependent mechanism.
Cardiovasc Res 28
: 209
–214, 1994[Abstract/Free Full Text]
Sato N, Shen Y-T, Kiuchi K, Shannon RP, Vatner SF: Splenic contraction-induced increases in arterial O2 reduce requirement for CBF in conscious dogs.
Am J Physiol Heart Circ Physiol 269
: H491
–H503, 1995[Abstract/Free Full Text]
Kingma JG Jr, Plante S, Bogaty P: Platelet GPIIb/IIIa receptor blockade reduces infarct size in a canine model of ischemia-reperfusion.
J Am Coll Cardiol 36
: 2317
–2324, 2000[Abstract/Free Full Text]
Rouleau JR, Simard D, Blouin A, Kingma JG Jr: Angiotensin inhibition and coronary autoregulation in a canine model of LV hypertrophy.
Basic Res Cardiol 97
: 384
–391, 2002[CrossRef][Medline]
Rouleau JR, Simard D, Kingma JG: Effect of angiotensin inhibition on the coronary artery lower pressure limit in anesthetized dogs.
Can J Physiol Pharmacol 78
: 892
–896, 2000[CrossRef][Medline]
Parent R, Hamdad N, Ming Z, Lavallee M: Contrasting effects of blockade of nitric oxide formation on resistance and conductance coronary vessels in conscious dogs.
Cardiovasc Res 31
: 555
–567, 1996[CrossRef][Medline]
Sudhir K, Chou TM, Hutchison SJ, Chatterjee K: Coronary vasodilation induced by angiotensin-converting enzyme inhibition in vivo: Differential contribution of nitric oxide and bradykinin in conductance and resistance arteries.
Circulation 93
: 1734
–1739, 1996[Abstract/Free Full Text]
Gallagher KP, Matsuzaki M, Koziol JA, Kemper WS, Ross J Jr: Regional myocardial perfusion and wall thickening during ischemia in conscious dogs.
Am J Physiol Heart Circ Physiol 247
: H727
–H738, 1984[Abstract/Free Full Text]
Repeated measures ANOVA using the SAS GLM Procedure. In:
SAS User’s Guide: Statistics, 5th ed., Cary, NC, SAS Institute, 1985
, pp 475
–485
Ross R: The pathogenesis of atherosclerosis: A perspective for the 1990s.
Nature 362
: 801
–809, 1993[CrossRef][Medline]
Levine GN, Keaney JF Jr, Vita JA: Cholesterol reduction in cardiovascular disease. Clinical benefits and possible mechanisms.
N Engl J Med 332
: 512
–521, 1995[Free Full Text]
Ragosta M, Samady H, Isaacs RB, Gimple LW, Sarembock IJ, Powers ER: Coronary flow reserve abnormalities in patients with diabetes mellitus who have end-stage renal disease and normal epicardial coronary arteries.
Am Heart J 147
: 1017
–1023, 2004[CrossRef][Medline]
Traverse JH, Chen Y, Crampton M, Voss S, Bache RJ: Increased extravascular forces limit endothelium-dependent and -independent coronary vasodilation in congestive heart failure.
Cardiovasc Res 52
: 454
–461, 2001[Abstract/Free Full Text]
Morrow JD, Frei B, Longmire AW, Gaziano JM, Lynch SM, Shyr Y, Strauss WE, Oates JA, Roberts LJ: Increase in circulating products of lipid peroxidation (F2-isoprostanes) in smokers. Smoking as a cause of oxidative damage.
N Engl J Med 332
: 1198
–1203, 1995[Abstract/Free Full Text]
Ruschitzka F, Shaw S, Gygi D, Noll G, Barton M, Luscher TF: Endothelial dysfunction in acute renal failure: Role of circulating and tissue endothelin-1.
J Am Soc Nephrol 10
: 953
–962, 1999[Abstract/Free Full Text]
Jeremy JY, Rowe D, Emsley AM, Newby AC: Nitric oxide and the proliferation of vascular smooth muscle cells.
Cardiovasc Res 43
: 580
–594, 1999[Free Full Text]
Mackie FE, Meyer TW, Campbell DJ: Effects of antihypertensive therapy on intrarenal angiotensin and bradykinin levels in experimental renal insufficiency.
Kidney Int 61
: 555
–563, 2002[CrossRef][Medline]
McGiff JC, Terragno NA, Malik KU, Lonigro AJ: Release of a prostaglandin E-like substance from canine kidney by bradykinin.
Circ Res 31
: 36
–43, 1972[Abstract/Free Full Text]
Lariviere R, Lebel M: Endothelin-1 in chronic renal failure and hypertension.
Can J Physiol Pharmacol 81
: 607
–621, 2003[CrossRef][Medline]
Wang W, Jittikanont S, Falk SA, Li P, Feng L, Gengaro PE, Poole BD, Bowler RP, Day BJ, Crapo JD, Schrier RW: Interaction among nitric oxide, reactive oxygen species, and antioxidants during endotoxemia-related acute renal failure.
Am J Physiol Renal Physiol 284
: F532
–F537, 2003[Abstract/Free Full Text]
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D: A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Modification of Diet in Renal Disease Study Group.
Ann Intern Med 130
: 461
–470, 1999[Abstract/Free Full Text]
Cockcroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine.
Nephron 16
: 31
–41, 1976[Medline]
Schetz MR: Coagulation disorders in acute renal failure.
Kidney Int Suppl 66
: S96
–S101, 1998[Medline]
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Abstract
Introduction
-nitro-L-arginine methyl ester (L-NAME) (50 µg/kg per min, intracoronary [IC] at a rate of 1 ml/min for 12-min with an infusion pump) and L-NAME (as above) + indomethacin (INDO) (5 mg/kg intravenous bolus) to evaluate potential contribution of NO and prostanoids on blood flow regulation in these dogs as described previously (24,25). 
-well counter (Auto-Gamma 5003 Cobra II; Packard Instruments, Meriden, CT) with standard window settings. All samples were counted for 2 min, and nuclide activity was corrected for background and decay. Overlap corrections were made using the inversion matrix technique; the matrix was derived from radioisotope standards made from small aliquots of the microsphere stock and assayed simultaneously with the blood and tissue samples. Blood flow (ml/min per 100 g) was calculated using PCGERDA computer software (version 1.02; Packard Instruments). 
0.05, was performed on all main-effect means to identify significant differences between interventions. A similar approach was used to assess differences between vascular responses to adenosine, acetylcholine, bradykinin, and l-arginine. End-diastolic wall thickness (EDT; onset of positive dP/dt) and end-systolic wall thickness (EST; approximately 20 ms before peak negative dP/dt) also were evaluated (26); because contractile function varies with the respiratory cycle, all measurements were determined at end expiration. Percentage of systolic myocardial wall thickening (SWT) was calculated using the equation SWT (%) = EST – EDT/EDT x 100. Values from five consecutive, artifact-free beats were averaged and normalized to preocclusion values. 
