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In order to identify tissue specific regulation of angiotensin converting enzyme (ACE), the effects of dexamethasone (0.04 mg sc per day for 7 days) and triiodothyronine (T3) (0.5 mg/kg sc per day for 10 days) on ACE activity were investigated in different tissues in male Wistar rats. ACE activity was measured by fluorimetry in the plasma, heart, lung and kidney. In the kidney, ACE activity was measured in the medulla, cortex and brush border of proximal tubular cells and 3H-ramiprilat binding was used to characterise the changes in brush border ACE activity. Dexamethasone elicited a significant increase in lung ACE activity and a significant decrease in plasma ACE activity, but did not alter enzyme activity in the other tissues studied. T3 produced a significant decrease in lung ACE activity and an increase in ACE activity in the plasma and heart. In the kidney, ACE activity was not modified in the medulla whereas in the cortex and brush border ACE activity was doubled. This increase in ACE activity corresponded to a similar increase in the maximum number of binding sites of 3H-ramiprilat, suggesting that the increase in activity corresponded to an increase in the ACE level. The increased heart and kidney ACE activity in response to T3 may contribute to the cardiovascular effects of thyroid hormones through increased local angiotensin II generation. These results show that under dexamethasone or T3, ACE activity can vary from one tissue to another, suggesting that the ACE regulatory mechanism acts differently in each tissue.

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The inhibition of angiotensin converting enzyme by ramipril, ramiprilat, enalapril, enalaprilat, and captopril was studied in the plasma and various tissues (lung, heart, renal cortex, renal medulla) of normotensive rats and spontaneously hypertensive rats. Displacement curves for [ 3 H] ramiprilat were established on each tissue with the converting enzyme inhibitors, and their potencies were expressed as the concentration that inhibited 50% of the specific [ 3 H] ramiprilat binding. In the plasma, lung, and heart, the order of activities was: ramiprilat >enalaprilat> captopril > ramipril > enalapril. This order was different in the kidney (cortex and medulla): ramiprilat>enalaprilat>ramipril>captopril>enalapril. For ramiprilat, enalaprilat, and captopril, there were no differences in their respective potencies between tissues or between rat strains. However, the two prodrugs ramipril and enalapril were 10-30 times more active in the kidney than in the other tissues in both groups of rats. This was due to the deesterification of the prodrugs: in the presence of an esterase inhibitor (diethyl nitrophenyl phosphate, 10 /AM), the potencies of ramipril in the kidney were not different from that obtained in the lung, which was not affected by the presence of the esterase inhibitor. These results suggest that the variations in the tissue activities of an angiotensin converting enzyme inhibitor are probably not due to differences in tissue affinities of the angiotensin converting enzyme inhibitor but depend on the concentration of this angiotensin converting enzyme inhibitor in each tissue. (Hypertension 1991;17:492-496)

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This study examines the effects of dietary protein and of uninephrectomy on angiotensin converting enzyme (ACE) in the normotensive rat, with particular regard to the kidney. Male Wistar Kyoto rats were fed isocaloric diets containing 5, 16 or 50% protein for three weeks. Other groups of rats were subjected to either left unilateral nephrectomy or sham operations, and the rats were killed eight days after surgery. ACE activity was measured in the kidney medulla, cortex, proximal tubule brush border membrane and in the plasma, heart and lung. Renal cortex and brush border ACE activity increased in parallel with protein intake, whereas plasma and lung ACE activity decreased; heart and kidney medulla ACE activity did not vary significantly. Uninephrectomy also led to a high increase in brush border ACE activity in the contralateral kidney, with no effect in the renal medulla or in the other tissues. The increase in ACE activity in the brush border membrane corresponded to a similar increase in the maximum number of binding sites of 3H-ramiprilat. This suggested that the increase in ACE activity corresponded to an increase in ACE concentration. The increase in renal tubular ACE activity could result in higher angiotensin II levels, and could consequently play a role in the modification of sodium reabsorption and cellular growth which occurs in the proximal tubule in these experimental models.

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