Xenon Washout Method Research Articles

Differences in renal hemodynamics and renin secretion between patients with unifocal and multifocal fibromuscular dysplasia.

Fibromuscular dysplasia (FMD) can be classified in a multifocal and a unifocal subtype. As unifocal FMD generally leads to more severe hypertension at younger age, we hypothesized that renal hemodynamics are more disturbed in unifocal renal artery FMD as compared with multifocal FMD, leading to increased renin secretion. We measured renal blood flow (Xenon washout method), renin secretion, and glomerular filtration rate per kidney in 101 patients with FMD (26 unifocal and 75 multifocal), all off medication and prior to balloon angioplasty. We found that renal blood flow and glomerular filtration were substantially lower in kidneys with unifocal FMD as compared with multifocal FMD. In the affected kidney from patients with unilateral FMD for example, mean renal blood flow was 173 ± 77 in unifocal vs. 244 ± 79 ml/100 g kidney/min in multifocal FMD (P = 0.013). Moreover, lateralization in renin secretion was only observed in a subset of patients with unifocal FMD, but not in any of the patients with multifocal FMD. These findings suggest that the impact of unifocal FMD lesions on the kidney is more severe, resulting in a classical pattern of renovascular hypertension. In multifocal FMD, however, renal blood flow is more preserved, local renin secretion is not increased, and the association between renin levels and blood pressure is inverse. These differences may explain the often more severe clinical presentation and higher success rate of revascularization in unifocal FMD, but also suggest that the pathophysiological mechanisms leading to hypertension may differ between these two disease entities.

Pathophysiological differences between multifocal fibromuscular dysplasia and atherosclerotic renal artery stenosis.

Fibromuscular dysplasia (FMD) and atherosclerotic renal artery stenosis (ARAS) are the most common causes of renovascular hypertension. So far, FMD is believed to cause hypertension via similar mechanisms as in ARAS, that is, a decrease in renal blood flow, which subsequently leads to increased renin secretion. However, given the differences in the blood pressure (BP)-lowering effect of revascularization between patients with ARAS and FMD, we questioned whether this is true. We measured renal blood flow (Xenon washout method) and renin secretion per kidney and their relationship to BP in a cohort of 64 patients with multifocal FMD and 110 patients with ARAS (off medication, prior to revascularization). We found that renal blood flow is significantly higher in FMD as compared with ARAS. In patients with unilateral ARAS, renin secretion was increased in the affected kidney as compared with the unaffected kidney. This lateralization in renin secretion, however, was not found in unilateral FMD. After correction for differences in baseline characteristics, we found that systemic renin levels and local renin secretion was lower in FMD as compared with ARAS. Moreover, the relationship between BP and renin secretion in FMD was inverse to that in ARAS. These findings argue against the hypothesis that FMD induces hypertension via similar pathophysiological mechanism as in ARAS.

Acute eprosartan-induced intrarenal vasodilation in hypertensive humans is not influenced by dietary sodium intake or angiotensin II co-infusion.

Angiotensin II (Ang II) is thought to play an important role in the development of hypertension. Nevertheless, knowledge on the angiotensin II type-1-receptors (AT1Rs) in the hypertensive kidney and the influence of sodium intake and renin-angiotensin system activity on intrarenal AT1R blockade is scarce. To improve our understanding of renal AT1Rs in hypertensive patients, we studied the effects of acute, local administration of AT1R-blocker eprosartan in kidneys of patients with essential hypertension (off medication). In 73 hypertensive patients who were scheduled for diagnostic renal angiography, we measured renal blood flow (Xenon washout method) before and during intrarenal infusion of two incremental doses of eprosartan (3 and 10 μg/kg/min for 15 min per dose). We hypothesized that the vasodilatory effects of eprosartan would be enhanced by low sodium intake and would be reduced during Ang II co-infusion. Therefore, we allocated the patients to either a high or a low sodium diet and coinfused Ang II (1 ng/kg/min) in a subgroup. Eprosartan infusion resulted in intrarenal vasodilation in all groups. No differences in the magnitude of this effect were found between the groups. No correlation was found between 24-h urinary sodium excretion (a proxy for dietary sodium intake) and the effect of eprosartan. Eprosartan-induced vasodilation is not influenced by sodium intake and/or co-infusion of Ang II. These rather unexpected findings could be explained by differences between circulating and tissue Ang II levels, variations in AT1R expression, and/or stimulation of other vasodilatory pathways.

Renal hemodynamics and renin-angiotensin system activity in humans with multifocal renal artery fibromuscular dysplasia.

Fibromuscular dysplasia (FMD) is the second most common cause of renovascular hypertension. Nonetheless, knowledge on the renal microvasculature and renin-angiotensin system (RAS) activity in kidneys with FMD is scarce. Given the fairly good results of revascularization, we hypothesized that the renal microvasculature and RAS are relatively spared in kidneys with FMD. In 58 hypertensive patients with multifocal renal artery FMD (off medication) and 116 matched controls with essential hypertension, we measured renal blood flow (Xenon washout method) per kidney and drew blood samples from the aorta and both renal veins to determine renin secretion and glomerular filtration rate per kidney. We found that renal blood flow and glomerular filtration rate in FMD were comparable to those in controls. Although systemic renin levels were somewhat higher in FMD, renal renin secretion was not elevated. Moreover, in patients with unilateral FMD, no differences between the affected and unaffected kidney were observed with regard to renal blood flow, glomerular filtration rate, or renin secretion. In men, renin levels and renin secretion were higher as compared with women. The renal blood flow response to RAS modulation (by intrarenal infusion of angiotensin II, angiotensin-(1-7), an angiotensin II type 1 receptor blocker, or a nitric oxide synthase blocker) was also comparable between FMD and controls. Renal blood flow, glomerular filtration, and the response to vasoactive substances in kidneys with multifocal FMD are comparable to patients with essential hypertension, suggesting that microvascular function is relatively spared. Renin secretion was not increased and the response to RAS modulation was not affected in kidneys with FMD.

Restoring ATBF: Dreaming the impossible dream?

Dear Sir: Knowledge of the longterm effect of weight loss on adipose tissue blood flow (ATBF) is scarce. We read with great interest the paper by Rossi et al. [3], reporting the results of a study using laser-Doppler flowmetry (LDF), where baseline thigh ATBF was lower in morbidly obese subjects compared to ageand sex-matched controls (4.8 vs. 79.9 perfusion units /PU). These results confirm several previous studies [4]. After one-year follow-up subsequent to Roux-en Y gastric bypass (RYGB) in obese patients, they observed a meaningful weight loss (−40 kg, e.g.−28%). This weight loss was associated with a slight but nevertheless significant increase in ATBF (up to 10.0 PU) although patients remained obese. The main limitations of the Rossi et al. study are linked to the inherent drawbacks of the LDF method, relating mainly to calibration, multiple Doppler shifts, tissue optical properties, motion artefacts, biological zero and impossibility to express the results in absolute values [2]. The gold-standard for ATBF measurement is the 133 xenon wash-out method, which should be combined with LDF in order to validate data obtained therewith [1]. Anemia, a frequent complication of RYGB, and antihypertensive drugs, which may influence adipose tissue perfusion [4], could also interfere with LDF measurements. However, no indication relating to these specific issues was provided in the paper. Additionally, the chosen site of measurement stands out as another scientific issue, because subcutaneous adipose tissue in the thigh is known to be much less active than in abdomen [4]. Rossi et al.’s conclusion to the effect that the slight increase in ATBF, observed one year after RYGB, is rather negligible, is sustained by another study [5] reporting on ATBF following a very low-calorie diet

Skeletal muscle vascular responses in human limbs to isometric handgrip

Studies of whole limb blood flow have shown that static handgrip elicits a vasodilatation in the resting forearm and vasoconstriction in the resting leg. We asked if these responses occur in the skeletal muscle vascular bed, and if so, what is the relative contribution of local metabolic versus other mechanisms to these vascular responses. Blood flow recordings were made simultaneously in the skeletal muscle of the resting arm and leg using the Xenon-washout method in ten subjects during 3 min of isometric handgrip at 30% of maximal voluntary contraction. In the arm, skeletal muscle vascular resistance (SMVR) decreased transiently at the onset of exercise followed by a return to baseline levels at the end of exercise. In the leg SMVR remained unchanged during the 1st min of handgrip, but had increased to exceed baseline levels by the end of exercise. During exercise electromyography (EMG) recordings from nonexercising limbs demonstrated a progressive 20-fold increase in activity in the arm, but remained at baseline in the leg. During EMG-signal modelled exercise performed to mimic the inadvertent muscle activity, decreases in forearm SMVR amounted to 57% of the decrease seen with controlateral handgrip. The present study would seem to indicate that vascular tone in nonexercising skeletal muscle in the arm and leg are controlled differently during the early stages of static handgrip. Metabolic vasodilation due to involuntary contraction could significantly modulate forearm skeletal muscle vascular responses, but other factors, most likely neural vasodilator mechanisms, must make major contributions. During the later stages of contralateral sustained handgrip, vascular adjustments in resting forearm skeletal muscle would seem to be the final result of reflex sympathetic vasoconstrictor drive, local metabolic vasodilator forces and possibly neurogenic vasodilator mechanisms.

A pitfall in the evaluation of medical therapy for occlusive arterial disease using the xenon wash-out technique

In a double-blind cross-over trial an oral thromboxane synthetase inhibitor (TSI) or placebo was given to 15 patients with severe foot ischaemia. After TSI therapy, rest pain remitted in nine out of 14 legs, while remission during placebo was seen in three out of 11 legs (NS). The ankle and toe systolic blood pressures remained constant during both study periods. Nocturnal adipose tissue blood flow in the forefoot was measured by the xenon wash-out method. A significant increase of the nocturnal perfusion rate constant during TSI therapy was found. A slight oedema developed during TSI therapy. This causes a change of the composition of the tissue under study and thus of lambda-xenon. The perfusion rate in the present study thus merely illustrates the latter and not a true increase in blood flow.

Evaluation of a method for determination of the subcutaneous blood flow in the forefoot continuously over 24 h.

A method is presented which allows for continuous registration of forefoot blood flow over 24 h. Blood flow was estimated by the radioactive Xenon washout method and a portable CdTe detector system was used to measure the tracer disappearance rate. Since the semiconductor detector is placed very close to the tracer depot the washout rates registered are a mixture of rate constants due to tracer removal by blood flow and diffusion of the tracer depot away from the detector. Rate constants only due to diffusion were obtained over 24 h from amputated feet and similarly from normal feet with circulatory arrest in several 20 min periods during 24 h. The rate constants due to blood flow could thus be calculated by subtraction of the appropriate diffusion rate constants from the recorded rate constants. Blood flow in the forefoot during 24 h was measured in 10 experimental subjects with normal peripheral circulation. Blood flow during daytime did not differ between the first and second day. Blood flow during night-time was about twice that during daytime.

The local xenon washout method applied to the study of blood flow in subcapsular cortex of the canine kidney.

The local xenon washout method applied to the study of blood flow in subcapsular cortex of the canine kidney.

The role of angiotensin in the canine renal vascular response to barbiturate anesthesia.

The influence of barbiturate anesthesia on renal blood flow was assessed by the xenon washout method in trained dogs with catheters chronically implanted in the renal artery. Anesthesia induced with either thiopental sodium or pentobarbital sodium resulted in a striking reduction in renal blood flow (4.1 +/- 0.1 vs. 2.6 +/- 0.2 ml/g per min; P less than 0.001) without a change in arterial pressure. The reduction in blood flow was prevented by a high salt intake and partially reversed by agents which interrupt the renin-angiotensin system (BPF 9a; 1-Sar,8-Ala-angiotensin II; propranolol) but not by alpha-adrenergic blocking agents (phentolamine and phenoxybenzamine). Anesthesia blunted the renal vascular response to angiotensin II (P less than 0.0005) whereas responsiveness to norepinephrine was increased (P less than 0.05). We conclude that barbiturate anesthesia induces a major, angiotensin-mediated renal vascular response which must be considered in the interpretation of experiments performed under these conditions.

Coronary blood flow in relation to angina pectoris.

The first portion of this paper represents a critical analysis of methods used in the determination of coronary blood flow in man. Coronary flow in man can be measured with the use of diffusible gases such as nitrous oxide, a procedure based on the Fick principle. In the presence of inhomogeneous perfusion, the time of equilibrium with coronary vein blood is difficult to establish, contributing to possible errors in the use of this method. Procedures which utilize substances which actively enter the cell, such as 84 rubidium, 86 rubidium, 42 potassium, and 24 sodium, are also employed. Only when the blood-tissue permeability is great in comparison to blood flow, is the exchange between blood and tissue a flow-limited process and can be used as an estimate of the nutrient circulation. Since the technic is based on the assumption that there must be equality of integrated mixed venous and coronary sinus tracer concentration after injection until the measurements are complete, any inequality in the extraction ratio of the heart and the body may introduce an error. This is the case after acute myocardial infarction. The difficulties introduced by perfusion differential are even greater when washin and washout curves are obtained following the injection of 133 xenon into the coronary artery. Technics which determine flow by interpreting the slope of an exponential decay curve in the presence of underperfused areas must be interpreted with great caution in the presence of coronary artery disease. Measurements of total coronary sinus outflow by thermodilution or by indicator dilution suffer from possible inadequate mixing of blood with the injectate. They do not measure nutritional blood flow. The determination of phasic coronary flow with the ultrasonic Doppler flowmeter is promising, but the technic is invasive, and there are inherent difficulties in correct positioning of the catheter tip. Determination of regional coronary flow is now also in clinical use. Usually gamma-emitting diffusible tracers such as 133 xenon or 43 potassium are used in addition to a scintillating camera and computers for data acquisition. Regional flow can be calculated with clearance formulae. Like other procedures used in the measurement of coronary flow, these methods suffer from the disadvantage that it is difficult to relate the rate of disappearance of the tracer substance to the degree of homogeneity of perfusion. Subsequent portions of this report deal with changes in coronary flow in ischemic heart disease. As is to be expected, results are influenced by the technic used. This applies particularly to studies employing the xenon washout method. There is general agreement however that, in the presence of coronary artery disease, the coronary flow fails to respond adequately to coronary vasodilator drugs. An explanation may lie in the so-called "coronary steal": a decrease in resistance at the precapillary level of nonoccluded vessels could result in a decrease in blood flow to muscle supplied by that artery. The importance of coronary collateral circulation was described, and the development of collaterals from preformed thin-walled blood vessels was discussed. It is unlikely that the development of extensive coronary collaterals can prevent angina pectoris. Basic principles underlying coronary microcirculation, as they affect the oxygen supply of the heart muscle, were stressed. New findings relating to this subject are countercurrent flow and asymmetric capillary arrangement. This provides favorable oxygen distribution to the heart muscle. Of importance also is the existence of recruitment of capillaries (perfusion of the increased number of capillaries as perfusion pressure rises).

Atraumatic local labeling of skin by inert gas: epicutaneous application of xenon 133.

Atraumatic local labeling of skin by inert gas: epicutaneous application of xenon 133.