SUMMARY Although factors influencing renin release have been studied extensively, one facet of renin release remains controversial, namely, neural regulation by arterial high-pressure receptors and cardiopulmonary low-pressure receptors. We therefore designed four studies to investigate systematically the separate and combined effects of unloading (decreased stretch) high-and low-pressure receptors on renin release in normal men. Selective unloading of cardiopulmonary receptors was induced by impeding the venous return with tourniquets around the thighs. A predominant unloading of arterial (carotid) baroreceptors was elicited with upright posture and simultaneously preventing the venous pooling in the legs. Unloading of both high-and low-pressure receptors was achieved by both upright standing and tilting. During postural experiments to predominantly unload arterial baroreceptors, the heart rate increased and the veins constricted, but renin failed to increase. The postural increase of renin occurred only if we allowed venous pooling in the legs. Selective unloading of cardiopulmonary receptors elicited substantial increases of renin. When both the cardiopulmonary and arterial baroreceptors were unloaded, renin increased more than with isolated unloading of cardipulmonary receptors. We conclude that: 1) in intact humans it is possible to demonstrate an independent role of cardiopulmonary receptors in the control of renin release; 2) there is evidence for interaction between the two receptor systems in renin control; but 3) an independent role for arterial the object of intensive research for more than two decades.' Despite this effort, the details of one facet, namely, neural regulation of renin release in humans, remains controversial. Much of the disagreement centers on the anatomic location of the afferent sensor. The question is whether an increase in renin release in normal humans can occur with unloading (decreased stretch) of either arterial high-pressure 2 or cardiopulmonary low-pressure receptors, 3 or if it is necessary that both receptor systems are simultaneously unloaded.4 There are at least three reasons for obtaining accurate information on this question: 1) understanding factors regulating an important hormone in Received December 6, 1982; revision accepted May 27, 1983. volume and pressure homeostasis is of basic physiological significance; 5 2) our understanding of abnormal renin responses in many patients with hypertension would be improved and this would possibly provide clues regarding the pathophysiology of abnormal responses; and 3) knowing the normal hemodynamic determinants that regulate the function of high-and low-pressure receptors with renin release as an easily measured humoral marker may facilitate research in various disease states where abnormalities of these receptors are suspected. Therefore, we designed the following series of experiments to evaluate the effect on renin release of separate and combined unloading of arterial high-pressure and cardiopulmonary low-pressure rec...