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Abstract-The aim of the present study was to elucidate how transforming growth factor-␤ 1 (TGF-␤ 1 ) can stimulate collagen deposition in cardiac tissue by interstitial cells via stimulation of fibroblasts, via myofibroblasts, or via differentiation of fibroblasts to myofibroblasts. The dose-and time-dependent stimulation of collagen production and of expression of ␣-smooth muscle actin (␣-SMA), a marker of myofibroblasts, was studied in cultures of second-passage adult rat cardiac fibroblasts. The TGF-␤ 1 -stimulated collagen production is positively correlated (rϭ0.68, PϽ0.001) with the appearance of ␣-SMA. Only at high concentrations (40 to 600 pmol/L) and after a long time (24 to 48 hours) of incubation, TGF-␤ 1 increases the collagen production and stimulates the differentiation of fibroblasts to myofibroblasts. The maximal stimulation of the collagen production (2-fold, PϽ0.001) observed after incubation of cultures of fibroblasts with 600 pmol/L TGF-␤ 1 for 48 hours is accompanied by a maximal stimulation of ␣-SMA expression (3.5-fold, PϽ0.001), when cultures consist mainly of myofibroblasts. The stimulation of collagen production cannot be reversed either after additional incubation of TGF-␤ 1 -stimulated second-passage cultures for 2 days or in their offspring in the next third passage after incubation for 7 days without TGF-␤ 1 . The increased collagen production in these third-passage cultures cannot be further stimulated by TGF-␤ 1 . Our data suggest that TGF-␤ 1 -stimulated collagen production in cultures of adult rat cardiac ventricular fibroblasts cannot be explained by a direct stimulation of the collagen production either in fibroblasts or in myofibroblasts. Instead, TGF-␤ 1 induces the differentiation of fibroblasts to myofibroblasts, which have a higher activity for collagen production than fibroblasts.

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The plasma concentration of aldosterone was followed in seven hypertensive patients before and during long-term angiotensin II suppression with the orally active angiotensin-I-converting-enzyme inhibitor, captopril. The plasma concentration of aldosterone decreased initially from 74 to 21 pg/ml (P less than 0.05) after 1 month of administration of captopril. Thereafter the plasma concentration of aldosterone began to rise and after 1 year reached a level of 165 pg/ml. During long-term captopril therapy the plasma renin activity remained increased and the plasma angiotensin II concentration suppressed. The mechanism responsible for the late rise of the plasma concentration of aldosterone during long-term angiotensin II suppression with captopril remains to be elucidated. A sizeable and lasting hypotensive effect was observed in all patients.

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