1. Rat kidneys were completely isolated and perfused to determine the ionic mechanism whereby isoprenaline stimulates and high perfusion pressure inhibits renin secretion. 2. Isoprenaline (2.43 microM) stimulated renin secretion, but K-free medium and ouabain also reduced perfusate flow. 3. Removing Ca from the perfusion medium increased renin secretion threefold when perfusion pressure was 100 mmHg and fourfold when pressure was raised to 150 mmHg. Simultaneously raising the perfusion pressure to 150 mmHg and the Ca concentration to 5 mM inhibited renin secretion. Verapamil (50 microM) prevented this inhibition. Raising Ca also caused vasoconstriction at a pressure of 150 mmHg, but verapamil partially prevented the vasoconstriction. 4. High concentration of K (50 mM) in the perfusion medium also stimulated renin secretion when Ca was removed and inhibited secretion when Ca concentration was raised to 5 mM. Verapamil (50 microM) prevented this inhibition. High K induced vasoconstriction in the presence of high Ca, but verapamil partially prevented the constriction. 5. High concentration of K (50 mM) and high perfusion pressure (150 mmHg) stimulated renin secretion in the absence of Ca and 20 mM-Mg potentiated this effect. This suggests that both sets of stimuli activate renin secretion by different cellular mechanisms, but that both act to lower cytoplasmic Ca in the juxtaglomerular cell. This is discussed. 6. High perfusion pressure inhibited renin secretion and reduced perfusate flow when Na was lowered from 145 to 14.5 or 0 mM whether or not Ca was present. 7. K-free medium and ouabain blocked the elevated renin secretion and reduced the high flow stimulated by high perfusion pressure when Ca was removed from the perfusion medium. 8. These observations suggest that isoprenaline stimulates renin secretion by a mechanism coupled to the Na-K pump. These observations are also consistent with the hypothesis that high renal perfusion pressure inhibits renin secretion by promoting Ca movement into the juxtaglomerular cell and stimulates secretion by a mechanism coupled to the Na-K pump. High perfusion pressure also causes renal vasoconstriction by increasing the Ca permeability of the smooth muscle cells in the afferent arteriole.