Gabriela A. Eppel

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.

Disparate Roles of AT2 Receptors in the Renal Cortical and Medullary Circulations of Anesthetized Rabbits

Abstract—The contributions of angiotensin II type 1 (AT1) and type 2 (AT2) receptors to the control of regional kidney blood flow were determined in pentobarbital-anesthetized rabbits. Intravenous candesartan (AT1 antagonist; 10 &mgr;g/kg plus 10 &mgr;g · kg−1 · h−1) reduced mean arterial pressure (12%) and increased total renal blood flow (29%) and cortical laser-Doppler flux (18%) but not medullary laser-Doppler flux. Neither intravenous PD123319 (AT2 antagonist; 1 mg/kg plus 1 mg · kg−1 · h−1) nor saline vehicle significantly affected these variables, and the responses to candesartan plus PD123319 were indistinguishable from those of candesartan alone. In vehicle-treated rabbits, renal-arterial infusions of angiotensin II (1 to 25 ng · kg−1 · min−1) and angiotensin III (5 to 125 ng · kg−1 · min−1) dose-dependently reduced renal blood flow (up to 51%) and cortical laser-Doppler flux (up to 50%) but did not significantly affect medullary laser-Doppler flux or arterial pressure. Angiotensin(1–7) (20 to 500 ng · kg−1 · min−1) had similar effects but of lesser magnitude. CGP42112A (20 to 500 ng · kg−1 · min−1) did not significantly affect these variables. After PD123319 administration, angiotensin II and angiotensin III dose-dependently increased medullary laser-Doppler flux (up to 84%), and reductions in renal blood flow in response to angiotensin II were enhanced. Candesartan abolished renal hemodynamic responses to the angiotensin peptides, even when given in combination with PD123319. We conclude that AT2 receptor activation counteracts AT1-mediated vasoconstriction in the renal cortex but also counteracts AT1-mediated vasodilatation in vascular elements controlling medullary perfusion. These mechanisms might have an important effect on the control of medullary perfusion under conditions of activation of the renin-angiotensin system.

Renal oxygenation in acute renal ischemia-reperfusion injury

Tissue hypoxia has been demonstrated, in both the renal cortex and medulla, during the acute phase of reperfusion after ischemia induced by occlusion of the aorta upstream from the kidney. However, there are also recent clinical observations indicating relatively well preserved oxygenation in the nonfunctional transplanted kidney. To test whether severe acute kidney injury can occur in the absence of widespread renal tissue hypoxia, we measured cortical and inner medullary tissue Po2 as well as total renal O2 delivery (Do2) and O2 consumption (Vo2) during the first 2 h of reperfusion after 60 min of occlusion of the renal artery in anesthetized rats. To perform this experiment, we used a new method for measuring kidney Do2 and Vo2 that relies on implantation of fluorescence optodes in the femoral artery and renal vein. We were unable to detect reductions in renal cortical or inner medullary tissue Po2 during reperfusion after ischemia localized to the kidney. This is likely explained by the observation that Vo2 (-57%) was reduced by at least as much as Do2 (-45%), due to a large reduction in glomerular filtration (-94%). However, localized tissue hypoxia, as evidence by pimonidazole adduct immunohistochemistry, was detected in kidneys subjected to ischemia and reperfusion, particularly in, but not exclusive to, the outer medulla. Thus, cellular hypoxia, particularly in the outer medulla, may still be present during reperfusion even when reductions in tissue Po2 are not detected in the cortex or inner medulla.

Multiple mechanisms act to maintain kidney oxygenation during renal ischemia in anesthetized rabbits

We examined the mechanisms that maintain stable renal tissue PO(2) during moderate renal ischemia, when changes in renal oxygen delivery (DO(2)) and consumption (VO(2)) are mismatched. When renal artery pressure (RAP) was reduced progressively from 80 to 40 mmHg, VO(2) (-38 ± 7%) was reduced more than DO(2) (-26 ± 4%). Electrical stimulation of the renal nerves (RNS) reduced DO(2) (-49 ± 4% at 2 Hz) more than VO(2) (-30 ± 7% at 2 Hz). Renal arterial infusion of angiotensin II reduced DO(2) (-38 ± 3%) but not VO(2) (+10 ± 10%). Despite mismatched changes in DO(2) and VO(2), renal tissue PO(2) remained remarkably stable at ≥40 mmHg RAP, during RNS at ≤2 Hz, and during angiotensin II infusion. The ratio of sodium reabsorption to VO(2) was reduced by all three ischemic stimuli. None of the stimuli significantly altered the gradients in PCO(2) or pH across the kidney. Fractional oxygen extraction increased and renal venous PO(2) fell during 2-Hz RNS and angiotensin II infusion, but not when RAP was reduced to 40 mmHg. Thus reduced renal VO(2) can help prevent tissue hypoxia during mild renal ischemia, but when renal VO(2) is reduced less than DO(2), other mechanisms prevent a fall in renal PO(2). These mechanisms do not include increased efficiency of renal oxygen utilization for sodium reabsorption or reduced washout of carbon dioxide from the kidney, leading to increased oxygen extraction. However, increased oxygen extraction could be driven by altered countercurrent exchange of carbon dioxide and/or oxygen between renal arteries and veins.

Neural control of renal medullary perfusion.

1. There is strong evidence that the renal medullary circulation plays a key role in long‐term blood pressure control. This, and evidence implicating sympathetic overactivity in development of hypertension, provides the need for understanding how sympathetic nerves affect medullary blood flow (MBF).

Factors that render the kidney susceptible to tissue hypoxia in hypoxemia

To better understand what makes the kidney susceptible to tissue hypoxia, we compared, in the rabbit kidney and hindlimb, the ability of feedback mechanisms governing oxygen consumption (Vo(2)) and oxygen delivery (Do(2)) to attenuate tissue hypoxia during hypoxemia. In the kidney (cortex and medulla) and hindlimb (biceps femoris muscle), we determined responses of whole organ blood flow and Vo(2), and local perfusion and tissue Po(2), to reductions in Do(2) mediated by graded systemic hypoxemia. Progressive hypoxemia reduced tissue Po(2) similarly in the renal cortex, renal medulla, and biceps femoris. Falls in tissue Po(2) could be detected when arterial oxygen content was reduced by as little as 4-8%. Vo(2) remained stable during progressive hypoxemia, only tending to fall once arterial oxygen content was reduced by 55% for the kidney or 42% for the hindlimb. Even then, the fall in renal Vo(2) could be accounted for by reduced oxygen demand for sodium transport rather than limited oxygen availability. Hindlimb blood flow and local biceps femoris perfusion increased progressively during graded hypoxia. In contrast, neither total renal blood flow nor cortical or medullary perfusion was altered by hypoxemia. Our data suggest that the absence in the kidney of hyperemic responses to hypoxia, and the insensitivity of renal Vo(2) to limited oxygen availability, contribute to kidney hypoxia during hypoxemia. The susceptibility of the kidney to tissue hypoxia, even in relatively mild hypoxemia, may have important implications for the progression of kidney disease, particularly in patients at high altitude or with chronic obstructive pulmonary disease.

Synchrotron-based angiography for investigation of the regulation of vasomotor function in the microcirculation in vivo.

1 Real‐time imaging of the vascular networks of any organ system in vivo is possible with synchrotron radiation (SR) angiography. In this review, we discuss the advantages of SR angiography over clinical X‐ray imaging and other non‐ionizing imaging modalities. Current limitations are also described. 2 The usefulness of dual‐energy and temporal subtraction approaches to K‐edge iodine imaging are compared. 3 High‐resolution images of the microcirculation in small animals are now being collected routinely by multiple research groups through public access research programmes at synchrotrons worldwide. Such images are permitting unrivalled insights into vasomotor regulation deep within intact organ systems, such as the brain, kidney, lung and heart. For example, recent observations indicate changes in vascular control mechanisms in pulmonary hypertension that are specific to certain branching segments of the pulmonary circulation. 4 New possibilities for non‐iodinated contrast agents in SR angiography are briefly described. 5 High‐resolution angiography in vivo using SR will now allow us to identify vessels with localized or non‐uniform vasoconstriction in states such as diabetes or to characterize the extent of endothelial dysfunction in the circulation following hypertension or ischaemic–reperfusion injury. In the near future, this research is expected to reveal the contribution of resistance vessel dysfunction to diverse pathophysiological states, such as stroke, hypertension and ischaemic heart disease.

Angiotensin II and neurohumoral control of the renal medullary circulation

1. Angiotensin (Ang) II has multiple actions in the renal medullary circulation. It can induce vasodilatation and blunt the response of medullary blood flow (MBF) to renal nerve activation through AT1 receptor‐mediated release of nitric oxide (NO) and/or vasodilator prostaglandins. These actions require high intravascular and/or intratubular AngII concentrations, so are not apparent under physiological conditions.

Measurement of Renal Tissue Oxygen Tension : Systematic Differences between Fluorescence Optode and Microelectrode Recordings in Anaesthetized Rabbits

Background/Aims: The validity of fluorescence optodes for measurement of renal cortical tissue oxygen tension was tested by comparison with Clark electrodes. Methods: We varied renal blood flow and inspired O2 content in anaesthetized rabbits while simultaneously measuring cortical tissue oxygen tension. Results: Cortical oxygen tension varied with inspired O2 content. Fluorescence optode measurements were more tightly distributed than those from a Clark electrode. Cumulative frequency distributions for fluorescence optodes were shifted to the left of those for Clark electrodes. The slope of the relationship between oxygen tension in arterial blood and cortical tissue was less for the fluorescence optode than the Clark electrode. Cortical tissue oxygen tension measurements by these two methods were correlated (r2 = 0.32; p < 0.001), with no fixed bias but considerable proportional bias. Thus, the slope of the relationship between the two measurements was less than unity (0.57 [0.50–0.69]). Conclusion: Cortical oxygen tension values from fluorescence optodes are less variable but proportionally less than those from Clark electrodes. Theoretical considerations suggest that true interstitial oxygen tension lies somewhere between values provided by the two techniques. Nevertheless, the lesser variability of the fluorescence optode technique may aid detection of physiologically significant changes in intrarenal oxygenation.

Stability of tissue PO2 in the face of altered perfusion: a phenomenon specific to the renal cortex and independent of resting renal oxygen consumption

1. Oxygen tension (PO2) in renal cortical tissue can remain relatively constant when renal blood flow changes in the physiological range, even when changes in renal oxygen delivery (DO2) and oxygen consumption (VO2) are mismatched. In the current study, we examined whether this also occurs in the renal medulla and skeletal muscle, or if it is an unusual property of the renal cortex. We also examined the potential for dysfunction of the mechanisms underlying this phenomenon to contribute to kidney hypoxia in disease states associated with increased renal VO2.