Roger G. Evans

Intrarenal oxygenation: unique challenges and the biophysical basis of homeostasis

The kidney is faced with unique challenges for oxygen regulation, both because its function requires that perfusion greatly exceeds that required to meet metabolic demand and because vascular control in the kidney is dominated by mechanisms that regulate glomerular filtration and tubular reabsorption. Because tubular sodium reabsorption accounts for most oxygen consumption (Vo2) in the kidney, renal Vo2 varies with glomerular filtration rate. This provides an intrinsic mechanism to match changes in oxygen delivery due to changes in renal blood flow (RBF) with changes in oxygen demand. Renal Vo2 is low relative to supply of oxygen, but diffusional arterial-to-venous (AV) oxygen shunting provides a mechanism by which oxygen superfluous to metabolic demand can bypass the renal microcirculation. This mechanism prevents development of tissue hyperoxia and subsequent tissue oxidation that would otherwise result from the mismatch between renal Vo2 and RBF. Recent evidence suggests that RBF-dependent changes in AV oxygen shunting may also help maintain stable tissue oxygen tension when RBF changes within the physiological range. However, AV oxygen shunting also renders the kidney susceptible to hypoxia. Given that tissue hypoxia is a hallmark of both acute renal injury and chronic renal disease, understanding the causes of tissue hypoxia is of great clinical importance. The simplistic paradigm of oxygenation depending only on the balance between local perfusion and Vo2 is inadequate to achieve this goal. To fully understand the control of renal oxygenation, we must consider a triad of factors that regulate intrarenal oxygenation: local perfusion, local Vo2, and AV oxygen shunting.

Haemodynamic influences on kidney oxygenation: clinical implications of integrative physiology

Renal blood flow, local tissue perfusion and blood oxygen content are the major determinants of oxygen delivery to kidney tissue. Arterial pressure and segmental vascular resistance influence kidney oxygen consumption through effects on glomerular filtration rate and sodium reabsorption. Diffusive shunting of oxygen from arteries to veins in the cortex and from descending to ascending vasa recta in the medulla limits oxygen delivery to renal tissue. Oxygen shunting depends on the vascular network, renal haemodynamics and kidney oxygen consumption. Consequently, the impact of changes in renal haemodynamics on tissue oxygenation cannot necessarily be predicted intuitively and, instead, requires the integrative approach offered by computational modelling and multiple measuring modalities. Tissue hypoxia is a hallmark of acute kidney injury (AKI) arising from multiple initiating insults, including ischaemia–reperfusion injury, radiocontrast administration, cardiopulmonary bypass surgery, shock and sepsis. Its pathophysiology is defined by inflammation and/or ischaemia resulting in alterations in renal tissue oxygenation, nitric oxide bioavailability and oxygen radical homeostasis. This sequence of events appears to cause renal microcirculatory dysfunction, which may then be exacerbated by the inappropriate use of therapies common in peri‐operative medicine, such as fluid resuscitation. The development of new ways to prevent and treat AKI requires an integrative approach that considers not just the molecular mechanisms underlying failure of filtration and tissue damage, but also the contribution of haemodynamic factors that determine kidney oxygenation. The development of bedside monitors allowing continuous surveillance of renal haemodynamics, oxygenation and function should facilitate better prevention, detection and treatment of AKI.

Mechanisms mediating pressure natriuresis: what we know and what we need to find out.

1. It is well established that pressure natriuresis plays a key role in long‐term blood pressure regulation, but our understanding of the mechanisms underlying this process is incomplete.

John Ludbrook APPS Symposium Neural Mechanisms In The Cardiovascular Responses To Acute Central Hypovolaemia

1. The haemodynamic response to acute central hypovolaemia consists of two phases. During phase I, arterial pressure is well maintained in the face of falling cardiac output (CO) by baroreceptor‐mediated reflex vasoconstriction and cardio‐acceleration. Phase II commences once CO has fallen to a critical level of 50–60% of its resting value, equivalent to loss of approximately 30% of blood volume.

Gender Differences in Pressure-Natriuresis and Renal Autoregulation: Role of the Angiotensin Type 2 Receptor

Sexual dimorphism in arterial pressure regulation has been observed in humans and animal models. The mechanisms underlying this gender difference are not fully known. Previous studies in rats have shown that females excrete more salt than males at a similar arterial pressure. The renin-angiotensin system is a powerful regulator of arterial pressure and body fluid volume. This study examined the role of the angiotensin type 2 receptor (AT2R) in pressure-natriuresis in male and female rats because AT2R expression has been reported to be enhanced in females. Renal function was examined at renal perfusion pressures of 120, 100, and 80 mm Hg in vehicle-treated and AT2R antagonist-treated (PD123319; 1 mg/kg/h) groups. The pressure-natriuresis relationship was gender-dependent such that it was shifted upward in female vs male rats (P<0.001). AT2R blockade modulated the pressure-natriuresis relationship, shifting the curve downward in male (P<0.01) and female (P<0.01) rats to a similar extent. In females, AT2R blockade also reduced the lower end of the autoregulatory range of renal blood flow (P<0.05) and glomerular filtration rate (P<0.01). Subsequently, the renal blood flow response to graded angiotensin II infusion was also measured with and without AT2R blockade. We found that AT2R blockade enhanced the renal vasoconstrictor response to angiotensin II in females but not in males (P<0.05). In conclusion, the AT2R modulates pressure-natriuresis, allowing the same level of sodium to be excreted at a lower pressure in both genders. However, a gender-specific role for the AT2R in renal autoregulation was evident in females, which may be a direct vascular AT2R effect.

Dysfunction of the Cholinergic Anti-Inflammatory Pathway Mediates Organ Damage in Hypertension

Inflammatory responses are associated with the genesis and progression of end-organ damage (EOD) in hypertension. A role for the &agr;7 nicotinic acetylcholine receptor (&agr;7nAChR) in inflammation has recently been identified. We tested the hypothesis that &agr;7nAChR dysfunction contributes to hypertensive EOD. In both spontaneously hypertensive rats (SHRs) and rats with abdominal aorta coarctation–induced hypertension, atropine-induced tachycardia was blunted compared with normotensive controls. Both models of hypertension were associated with deficits in expression of the vesicular acetylcholine transporter and the &agr;7nAChR in cardiovascular tissues. In hypertension induced by abdominal aorta coarctation, deficits in aortic vesicular acetylcholine transporter and &agr;7nAChR were present both above and below the coarctation site, indicating that they were independent of the level of arterial pressure itself. Hypertension in 40-week-old SHRs was associated with cardiac and aortic hypertrophy. Morphological abnormalities consistent with EOD, along with elevated tissue levels of proinflammatory cytokines (tumor necrosis factor-&agr;, interleukin-1&bgr;, and interleukin-6) were observed in the heart, kidney, and aorta. Chronic treatment of SHRs with the &agr;7nAChR agonist PNU-282987 relieved EOD and inhibited tissue levels of proinflammatory cytokines and activation of nuclear factor &kgr;B. Greater serum levels of proinflammatory cytokines and more severe damage in the heart, aorta, and kidney were seen in &agr;7nAChR−/− mice subjected to 2-kidney-1-clip surgery than in wild-type mice. A deficit in the cholinergic anti-inflammatory pathway appears to contribute to the pathogenesis of EOD in models of hypertension of varying etiology. This pathway may provide a new target for preventing cardiovascular disease resulting from hypertension.

Role for endothelium-derived hyperpolarizing factor in vascular tone in rat mesenteric and hindlimb circulations in vivo

The role of endothelium‐derived hyperpolarizing factor (EDHF) in the regulation of blood flow in vivo was examined in the mesenteric and hindlimb circulations of anaesthetized rats. Basal mesenteric conductance decreased from 57 ± 5 to 20 ± 6 μl min−1 mmHg−1 when nitric oxide (NO) production was inhibited, and combined blockade of intermediate‐ and small‐conductance Ca2+‐activated K+ (KCa) channels with charybdotoxin (ChTx) and apamin had no further effect. Basal hindlimb conductance was reduced from 39 ± 3 to 22 ± 2 μl min−1 mmHg−1 by NO synthesis inhibition, with no effect of the KCa channel blockers. Endothelial stimulation with acetylcholine (ACh) infusion directly into the mesenteric bed increased conductance by 20 ± 2 μl min−1 mmHg−1. Blockade of NO synthesis decreased this conductance to 15 ± 1 μl min−1 mmHg−1, leaving the response attributable to EDHF. This was reduced to 2 ± 1 μl min−1 mmHg−1 by ChTx plus apamin but not by iberiotoxin, which selectively blocks large‐conductance KCa channels. Similar results were obtained when bradykinin (BK) was used to stimulate the endothelium. Nitroprusside, which directly relaxes smooth muscle, evoked an increase in conductance that was resistant to all blockers tested. ACh‐induced increases in hindlimb conductance were reduced from 19 ± 1 to 12 ± 1 μl min−1 mmHg−1 by NO synthesis inhibition and further reduced to 2 ± 2 μl min−1 mmHg−1 by ChTx plus apamin. In contrast to NO, ChTx‐ and apamin‐sensitive EDHF appears to contribute little to basal conductance in rat mesenteric and hindlimb beds. However, EDHF accounts for a significant component of the conductance increase during endothelial stimulation by ACh and BK. In these beds, intermediate‐ and small‐conductance KCa channels underpin EDHF‐mediated vasodilatation.

Intracisternal naloxone and cardiac nerve blockade prevent vasodilatation during simulated haemorrhage in awake rabbits.

1. Acute haemorrhage was simulated in five unanaesthetized rabbits, by inflating a cuff on the inferior vena cava so that cardiac output fell by 8.3% of its resting level per minute. Simulated haemorrhage was performed after sham treatment, after graded doses of intravenous and intracisternal naloxone, and after cardiac nerve blockade with intrapericardial procaine. 2. After sham treatment, the haemodynamic response to simulated haemorrhage was biphasic. During the first phase, systemic vascular conductance fell steadily, heart rate rose steadily, and arterial pressure fell only slightly. A second decompensatory phase began abruptly when cardiac output had fallen to approximately 55% of its resting level. Vascular conductance rose steeply, heart rate fell slowly, and arterial pressure fell precipitately. 3. Treatment with naloxone (intravenous, 0.04‐0.4 mg kg‐1; intracisternal, 0.2‐2 micrograms kg‐1) did not affect either phase of the haemodynamic response to simulated haemorrhage. 4. After treatment with larger doses of naloxone (intravenous, 4‐8 mg kg‐1; intracisternal, 4‐69 micrograms kg‐1), the first phase was unaffected, but the second phase no longer occurred. Throughout simulated haemorrhage, systemic vascular conductance fell steadily, heart rate rose, and arterial pressure was well maintained. The dose of intracisternal naloxone which prevented the second phase was 90‐900 times less than the corresponding intravenous dose. The second phase was also prevented by cardiac nerve blockade. 5. We conclude that an endogenous opiate mechanism is responsible for the haemodynamic decompensation that occurs when cardiac output falls to a critical level. The mechanism is located within the central nervous system. It is triggered by a signal from the heart.

Nitric oxide and superoxide in the renal medulla: a delicate balancing act.

Purpose of reviewEndothelial nitric oxide synthase (eNOS) and nicotinamide adenine dinucleotide (phosphate) oxidase [NAD(P)H oxidase] are both expressed in tubular epithelial cells within the renal medulla, particularly the thick ascending limb of the loop of Henle (mTALH). Thick ascending limbs contribute to long-term blood pressure control, both because they reabsorb approximately 30% of filtered sodium, and because they produce paracrine factors like nitric oxide (NO) that control medullary blood flow (MBF), which in turn has a major impact on tubular sodium reabsorption. Herein, we review recent evidence for roles of NO and superoxide (O2·−) in autocrine control of tubular sodium reabsorption, and in paracrine control of MBF. Recent findingsO2·−can have a direct action to reduce MBF, and to enhance sodium reabsorption from mTALH. These actions oppose those of NO produced in mTALH, which inhibits tubular sodium reabsorption (autocrine) and increases MBF (paracrine). NO and O2·−also oppose each others actions through chemical combination to produce peroxynitrite. Thus, interactions between NO and O2·−, at both the chemical and cellular levels, likely contribute to long-term blood pressure control. This hypothesis is supported by recent data showing that sodium retention and hypertension can develop when the balance of production of these free radicals is tipped towards O2·−, such as in diabetes, atherosclerosis and renin-angiotensin-system activation. SummaryInteractions between O2·−and NO produced within the mTALH regulate tubular and vascular function in the renal medulla. Dysregulation of these systems in states of oxidative stress likely promotes salt and water retention, and thus hypertension.

Contribution of renal nerves to renal blood flow variability during hemorrhage

We have examined the role of the renal sympathetic nerves in the renal blood flow (RBF) response to hemorrhage in seven conscious rabbits. Hemorrhage was produced by blood withdrawal at 1.35 ml.min(-1).kg-1 for 20 min while RBF and renal sympathetic nerve activity (RSNA) were simultaneously measured. Hemorrhage was associated with a gradual increase in RSNA and decrease in RBF from the 4th min. In seven denervated animals, the resting RBF before hemorrhage was significantly greater (48 +/- 1 vs. 31 +/- 1 ml/min intact), and the decrease in RBF did not occur until arterial pressure also began to fall (8th min); however, the overall percentage change in RBF by 20 min of blood withdrawal was similar. Spectral analysis was used to identify the nature of oscillations in each variable. Before hemorrhage, a rhythm at approximately 0.3 Hz was observed in RSNA, although not in RBF, whose spectrogram was composed mostly of lower-frequency (< 0.25 Hz) components. The denervated group of rabbits had similar frequency spectrums for RBF before hemorrhage. RSNA played a role in dampening the effect of oscillations in arterial pressure on RBF as the transfer gain between mean arterial pressure (MAP) and RBF for frequencies > 0.25 Hz was significantly less in intact than denervated rabbits (0.83 +/- 0.12 vs. 1.19 +/- 0.10 ml.min(-1).mmHg-1). Furthermore, the coherence between MAP and RBF was also significantly higher in denervated rabbits, suggesting tighter coupling between the two variables in the absence of RSNA. Before the onset of significant decreases in arterial pressure (up to 10 min), there was an increase in the strength of oscillations centered around 0.3 Hz in RSNA. These wer accompanied by increases in the spectral power of RBF at the same frequency. Arterial pressure fell in both groups of animals, the dominant rhythm to emerge in RBF was centered between 0.15 and 0.20 Hz and was present in intact and denervated rabbits. It is speculated that this myogenic in origin. We conclude that RSNA can induce oscillations in RBF at 0.3 Hz, plays a significant role in altering the effect of oscillations in arterial pressure on RBF, and mediates a proportion of renal vasoconstriction during hemorrhage in conscious rabbits.We have examined the role of the renal sympathetic nerves in the renal blood flow (RBF) response to hemorrhage in seven conscious rabbits. Hemorrhage was produced by blood withdrawal at 1.35 ml ⋅ min-1 ⋅ kg-1for 20 min while RBF and renal sympathetic nerve activity (RSNA) were simultaneously measured. Hemorrhage was associated with a gradual increase in RSNA and decrease in RBF from the 4th min. In seven denervated animals, the resting RBF before hemorrhage was significantly greater (48 ± 1 vs. 31 ± 1 ml/min intact), and the decrease in RBF did not occur until arterial pressure also began to fall (8th min); however, the overall percentage change in RBF by 20 min of blood withdrawal was similar. Spectral analysis was used to identify the nature of the oscillations in each variable. Before hemorrhage, a rhythm at ∼0.3 Hz was observed in RSNA, although not in RBF, whose spectrogram was composed mostly of lower-frequency (<0.25 Hz) components. The denervated group of rabbits had similar frequency spectrums for RBF before hemorrhage. RSNA played a role in dampening the effect of oscillations in arterial pressure on RBF as the transfer gain between mean arterial pressure (MAP) and RBF for frequencies >0.25 Hz was significantly less in intact than denervated rabbits (0.83 ± 0.12 vs. 1.19 ± 0.10 ml ⋅ min-1 ⋅ mmHg-1). Furthermore, the coherence between MAP and RBF was also significantly higher in denervated rabbits, suggesting tighter coupling between the two variables in the absence of RSNA. Before the onset of significant decreases in arterial pressure (up to 10 min), there was an increase in the strength of oscillations centered around 0.3 Hz in RSNA. These were accompanied by increases in the spectral power of RBF at the same frequency. As arterial pressure fell in both groups of animals, the dominant rhythm to emerge in RBF was centered between 0.15 and 0.20 Hz and was present in intact and denervated rabbits. It is speculated that this is myogenic in origin. We conclude that RSNA can induce oscillations in RBF at 0.3 Hz, plays a significant role in altering the effect of oscillations in arterial pressure on RBF, and mediates a proportion of renal vasoconstriction during hemorrhage in conscious rabbits.