Impact of Chronic Kidney Disease on Myocardial Blood Flow Regulation in Dogs

Kingma, John G.; Simard, Denys; Voisine, Pierre; Rouleau, Jacques R.

doi:10.1159/000362090

Cited by 8 publications

(8 citation statements)

References 33 publications

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“…In the present study dogs developed a kidney disease phenotype corresponding to Stage 2 criteria according to the International Renal Interest Society (IRIS) staging system. In SNx dogs, under normoxemic conditions arterial oxygen content decreased in relation to hematocrit levels; in an earlier study from our laboratory with the same experimental model oxygen extraction levels and distribution of myocardial blood flow were not changed under resting conditions [27]. Those findings supported the concept of a tissue autoregulatory mechanism for oxygen [37,38].…”

Section: Discussionsupporting

confidence: 73%

“…We recently documented a marked alteration of coronary vasoregulation and coronary vascular reserve in canines with the renocardiac syndrome phenotype [27]; in these dogs the coronary autoregulatory threshold was more readily exhausted with incremental increases in cardiac work. An overall loss of coronary autoregulation puts the subendocardium at risk of injury and can induce cardiac contractile dysfunction.…”

Section: Effect Of Subtotal Renal Nephrectomy On Cyp450-mediated Metamentioning

confidence: 99%

“…Dogs were intubated and ventilated with a volume-regulated respirator. CKD dogs underwent a two-stage subtotal nephrectomy (SNx) [27,28]; for the first step (Surg1), the left kidney was isolated via a flank incision and several dorsal and ventral branches of the left renal artery were ligated. A target of 50-60 percent infarction of the left kidney (established by visual verification of topical cyanosis) was applied.…”

Section: Surgical Proceduresmentioning

confidence: 99%

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Effect of Subtotal Renal Nephrectomy on CYP450-Mediated Metabolism of Arachidonic Acid: A Potential Player in Pathogenesis of Renocardiac Syndrome?

Kingma¹,

Rouleau²,

Patoine³

et al. 2016

Cardiovasc Pharm Open Access

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Background/Aims: Cardiovascular events are common in patients with renocardiac syndrome. A direct link between endothelial dysfunction and increased cardiovascular events has not been established for this syndrome; however, a causal role could be attributed to modulations of Cytochrome P450-mediated (CYP450) eicosanoid metabolites including Epoxyeicosatrienoic (EETs), Dihydroxyeicosatrienoic (DHET) and 20-Hydroxyeicosatetraenoic acids (20-HETE). In this study we investigated inter-organ variations in CYP450-mediated eicosanoids in key organs from dogs with renal insufficiency. Methods: Renal insufficiency was induced by two-stage subtotal nephrectomy (SNx). Biochemical markers (serum creatinine, blood urea nitrogen) and cardiac hemodynamics were measured weekly. After 5 weeks, arachidonic acid CYP450-metabolites in heart, remnant kidney and liver biopsies were analyzed. Results: Serum creatinine and blood urea nitrogen were significantly higher in the SNx group (versus timematched sham controls); hematocrit, body weight and creatinine clearance were significantly reduced. The lymphocyte:monocyte ratio, a biomarker of vascular risk, was lower (p=NS) in SNx dogs. Cardiac hemodynamics were similar for both groups. Cardiac levels of 20-HETE were markedly lower (p=0.014) in SNx dogs; however, 14, 15-DHET, a biomarker of soluble epoxide hydrolase levels were unchanged. The 20-HETE/14, 15-DHET ratio was lower in these dogs (p=0.003) and could help to explain a loss of autoregulation in this experimental model. In kidney and liver biopsies from SNx dogs 20-HETE tended to be higher and 14, 15-DHET lower (p=NS) versus time-matched controls; no change was observed for 20-HETE/14, 15-DHET. Conclusion: A marked reduction of cardiac 20-HETE and 20-HETE/14, 15-DHET levels occurred in dogs with kidney injury but no change in these CYP450-metabolites was observed in kidney or liver biopsies. As such, kidney injury appears to trigger significant alterations in CYP450-metabolites that may initiate endothelial dysfunction and vascular inflammation even in distant organs. Manipulating these pathways may eventually constitute a potential pharmacologic target to limit vessel dysfunction in the setting of renocardiac syndrome.

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Section: Discussionsupporting

confidence: 73%

Section: Effect Of Subtotal Renal Nephrectomy On Cyp450-mediated Metamentioning

confidence: 99%

Section: Surgical Proceduresmentioning

confidence: 99%

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Effect of Subtotal Renal Nephrectomy on CYP450-Mediated Metabolism of Arachidonic Acid: A Potential Player in Pathogenesis of Renocardiac Syndrome?

Kingma¹,

Rouleau²,

Patoine³

et al. 2016

Cardiovasc Pharm Open Access

View full text Add to dashboard Cite

show abstract

“…Histologic evaluations of LV geometry were not done in the present study; interestingly heart weight and total LV cross-sectional area were not significantly changed during the experimental timeline but we would expect these results to change with longer durations of prolonged uremia. Body weight, another indicator of renal insufficiency was not measured in this study; however, we [40] and others [9] [41] have reported little variation between control and uremic animals in different species particularly in the early stages (i.e. <6 weeks) after onset of kidney insufficiency.…”

Section: Discussionmentioning

confidence: 75%

Ischemic Tolerance in Uremic Rabbits

Kingma¹,

Sénéchal²,

Rouleau³

et al. 2015

WJCD

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Background: Cardiac complications after myocardial infarction are believed to be worse in the presence of comorbidities; we tested whether experimentally induced prolonged uremia exacerbated myocardial necrosis in a rabbit preparation of ischemia-reperfusion injury. In addition, we examined if treatment with an angiotensin converting enzyme inhibitor (Enalapril, ENA, 3 mg/Kg, IV) could reduce post-ischemic myocardial damage. Methods: Prolonged uremia was induced by a two-stage subtotal nephrectomy and confirmed by marked increases in serum creatinine and urea levels; after 5 weeks, four groups of rabbits were exposed to 45-min acute coronary occlusion followed by 180-min reperfusion. In treated animals, ENA was administered 5-min before onset of coronary reperfusion. All data from uremic animals were compared with time-matched controls. Results: Cardiac hemodynamics was similar for all groups during the development of kidney failure; heart rate in uremic rabbits was significantly lower for the duration of ischemia-reperfusion. In this animal model, the absence of coronary collateral circulation provides a stable ischemic substrate for evaluation of cellular necrosis. Infarct size (expressed as percent risk zone size) was: control, 48 ± 16; uremia, 36 ± 5; control + ENA, 51 ± 19; and uremia + ENA, 41 ± 16; risk zone size was similar for all animals. Conclusion: The present findings are inconsistent with the view that post-ischemic cardiac injury is greater in animals with pre-existent uremia. In addition, we were unable to show a significant beneficial effect with an angiotensin converting enzyme inhibitor on infarct size in either control or uremic rabbits. It remains to be proven in animal models with comorbidities such as manifest kidney disease that ischemic tolerance can be substantially reduced by either pharmacologic or non-pharmacologic interventions.

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“…In 16 dogs, bilateral flank incisions were performed to expose the left and right kidneys. Several dorsal and ventral branches of the left and right renal arteries were ligated to achieve a target of 50-60% infarction of both the kidneys (established by visual verification of topical cyanosis; Kingma et al 2014). In eight of 16 CKD dogs, both kidneys were surgically denervated by cutting all visible nerves of the adventitia of the renal arteries (CKD + RDN group), and then the arteries were moistened with a 20% phenol-ethanol solution for 10-15 min.…”

Section: Surgical Proceduresmentioning

confidence: 99%

Renal denervation decreases susceptibility of the heart to ventricular fibrillation in a canine model of chronic kidney disease

Tang

Shi

Cui

et al. 2017

Experimental Physiology

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What is the central question of this study? Renal denervation (RDN) has been shown to be effective and safe, resulting in better control of blood pressure and an improvement in left ventricular hypertrophy in chronic kidney disease (CKD) patients. Ventricular arrhythmias and sudden cardiac death are common causes of death in CKD patients, but previous studies pay almost no attention to the effects of RDN on the risk of ventricular fibrillation associated with CKD. What is the main finding and its importance? Renal denervation could decrease susceptibility of the heart to ventricular fibrillation in a canine CKD model. Improvement of left ventricular hypertrophy, sympathetic activation and inflammation by RDN may be responsible for its beneficial effects. Renal denervation (RDN) has been shown to have therapeutic value in patients with chronic kidney disease (CKD). The aim of this study was to investigate whether RDN could decrease the susceptibility of the heart to ventricular fibrillation in a canine model of CKD. Twenty-one dogs were used. Chronic kidney disease was produced by subtotal nephrectomy in 16 dogs with RDN treatment (CKD + RDN group, n = 8) or sham RDN (CKD group, n = 8). Another five dogs underwent sham operation and sham RDN to serve as controls (CTR group). Parameters of renal function, blood pressure, echocardiography, ECG, noradrenaline and inflammation were measured at baseline and 6 weeks after the surgical procedure. The ventricular fibrillation threshold (VFT) was determined at the end of the study. Subtotal nephrectomy successfully induced a canine CKD model. When compared with the CTR group, subtotal nephrectomy in the CKD group significantly elevated blood pressure; increased the left ventricular mass, end-diastolic left ventricular internal dimension, left ventricular end-diastolic posterior wall thickness and end-diastolic interventricular septum thickness; prolonged the QT interval, corrected QT interval, the interval from the peak to the end of the T wave (Tp-e) and the corrected Tp-e interval; and increased the QT dispersion and the Tp-e/QT ratio; decreased the VFT; and increased the serum concentrations of noradrenaline, C-reactive protein and interleukin-6. Renal denervation significantly attenuated these changes induced by CKD. The study demonstrated that RDN could decrease the susceptibility of the heart to ventricular fibrillation in this CKD model. Improvement of left ventricular hypertrophy, sympathetic activation and inflammation by RDN may be responsible for its beneficial effects.

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Impact of Chronic Kidney Disease on Myocardial Blood Flow Regulation in Dogs

Cited by 8 publications

References 33 publications

Effect of Subtotal Renal Nephrectomy on CYP450-Mediated Metabolism of Arachidonic Acid: A Potential Player in Pathogenesis of Renocardiac Syndrome?

Effect of Subtotal Renal Nephrectomy on CYP450-Mediated Metabolism of Arachidonic Acid: A Potential Player in Pathogenesis of Renocardiac Syndrome?

Ischemic Tolerance in Uremic Rabbits

Renal denervation decreases susceptibility of the heart to ventricular fibrillation in a canine model of chronic kidney disease

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