The biodistribution, pharmacokinetics and multi-organ clearance of the vasodilator peptide AM (adrenomedullin) were evaluated in rats and its single-pass pulmonary clearance was measured in dogs by the indicator-dilution technique. Intravenously administered 125I-rAM(1-50) [rat AM(1-50)] was rapidly cleared following a two-compartment model with a very rapid distribution half-life of 2.0 min [95% CI (confidence interval), 1.98-2.01] and an elimination half-life of 15.9 min (95% CI, 15.0-16.9). The lungs retained most of the injected activity with evidence of single-pass clearance, since retention was lower after intra-arterial (13.5+/-0.6%) compared with intravenous (30.4+/-1.5%; P < 0.001) injection. Lung tissue levels of total endogenous AM were 20-fold higher than in other organs with no difference in plasma levels across the pulmonary circulation. In dogs, there was 36.4+/-2.1% first-pass unidirectional extraction of 125I-rAM(1-50) by the lungs that was reduced to 21.9+/-2.4% after the administration of unlabelled rAM(1-50) (P < 0.01). Extraction was not affected by calcitonin-gene-related peptide administration (40.6+/-2.9%), but was slightly reduced by the C-terminal fragment of human AM(22-52) (31.4+/-3.3%; P < 0.01). These data demonstrate that the lungs are a primary site for AM clearance in vivo with approx. 36% first-pass extraction through specific receptors. This suggests that the lungs not only modulate circulating levels of this peptide, but also represent its primary target.

We validated a noninvasive radionuclide plethysmography technique to evaluate peripheral arterial blood flow during reactive hyperemia. This method, based on the measurement of blood volume variations during repetitive venous occlusions, was compared with strain-gauge venous impedance plethysmography. The technique uses 99m Tc-labeled autologous red blood cells scintigraphy to determine the rate of change of forearm scintigraphic counts during venous occlusion. Thirteen subjects were simultaneously evaluated with radionuclide and impedance plethysmography. Six baseline flow measurements were performed to evaluate the reproducibility of each method. Twenty-seven serial measurements were then made to evaluate flow variation during forearm reactive hyperemia. After 30 min of recovery, resting forearm blood flows were again evaluated. Impedance and radionuclide methods showed excellent reproducibility with intraclass correlation coefficients of 0.96 and 0.93, respectively. There was also good correlation of flows between both methods during reactive hyperemia (r ϭ 0.87). Resting flows at 30 min after reactive hyperemia were slightly lower than at baseline with both methods. We conclude that radionuclide plethysmography could be used for the noninvasive evaluation of forearm blood flow and its dynamic variations during reactive hyperemia. endothelium; radioisotope; reactive hyperemia VENOUS PLETHYSMOGRAPHY OF the arms and legs has been extensively used to evaluate vascular function in normal and diseased states (4,14). With this method, vascular reactivity can be tested by the local infusion of pharmacological agents or by evaluation of hyperemic responses after a brief period of limb ischemia. Although it has been well validated, the use of venous plethysmography for the study of arterial reactivity has been limited to research because specialized equipment is needed and because expertise is not available in most clinical centers.Recently, there has been a growing interest in the clinical evaluation of peripheral vascular reactivity during reactive hyperemia because part of this physiological response is modulated by the integrity of the vascular endothelium (2, 8). Endothelial dysfunction is a diffuse process that occurs early in the development of atherosclerotic vascular disease (7, 9). Evidence shows that evaluation of endothelial function may be useful in risk stratification and in the assessment of response to pharmacological treatment (5). In that context, development of a simple, noninvasive, and reproducible test of the reactive hyperemic response is desirable not only for preclinical and clinical research purposes but also for its potential clinical utility.We have thus developed a noninvasive radionuclide plethysmography technique to evaluate peripheral arterial blood flow during reactive hyperemia. This method, based on the measurement of blood volume variations during repetitive venous occlusion, is analogous to impedance plethysmography (3, 12) and can also evaluate arterial blood flow into arms or leg...

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