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The effect of Losartan (10(-9) to 10(-6) M) on angiotensins I and II release was examined in isolated hind legs perfused with Krebs-Ringer solution from normal and bilaterally nephrectomized rats. Losartan increased dramatically both angiotensins I (Ang I) and II (Ang II) release in a dose-dependent fashion; the maximal percent increment in Ang I and Ang II release evoked by Losartan (10(-6) M) was about +380% and +160%, respectively, in normal rat hind legs. In nephrectomized animals, Losartan elicited a marked increase in both peptides dose-dependently. There was a highly positive correlation between the released amounts of Ang I and that of Ang II altered by Losartan in either normal (r = 0.954) or nephrectomized rats (r = 0.923). These results not only confirm the existence of a functional renin-angiotensin system in vascular tissues, but also suggest that the system is regulated by locally generated Ang II.

The effect of recombinant human erythropoietin (r-HuEPO, 0.1 to 2.0 U/ml) on endothelin-1 (ET-1) release was examined in isolated hind legs perfused with Krebs-Ringer solution from normal rats. r-HuEPO increased immunoreactive (ir-) ET-1 release in a dose-dependent fashion; the maximal percent increment in ir-ET-1 release evoked by r-HuEPO (2.0 U/ml) was about +210% over the basal rate of release. However, r-HuEPO showed no effect on release of angiotensin II, thromboxane B2 or vasodilatory prostaglandin I2 from the vasculature. These results not only provide direct evidence that r-HuEPO has the potential to specifically stimulate release of ET-1 from peripheral vascular beds, but, hence, suggest a contributory role of ET-1 in r-HuEPO-induced hypertension in anemic human subjects undergoing r-HuEPO therapy.

Losartan, a recently developed nonpeptide angiotensin II (Ang II) receptor antagonist, was administered orally to 10-week-old spontaneously hypertensive rats (SHR) for 2 weeks. Cardiac weight and tissue Ang II, as well as plasma renin activity (PRA) and Ang II, were determined. Treatment with Losartan (10 mg/kg per day) lowered blood pressure markedly. Losartan reduced significantly the left ventricular weight by 11% compared with control rats. The left ventricular Ang II content was lowered by Losartan (18.6 +/- 0.9 pg/tissue; 21.9 +/- 0.9 pg/tissue, control, p less than 0.05), whereas PRA and plasma Ang II concentration were increased by the treatment. With the control and Losartan-treated animals, there was a significant positive correlation between the left ventricular weight and the tissue Ang II content (r = 0.563, p less than 0.05). These results provide evidence that cardiac tissue Ang II, rather than circulating Ang II, plays an important role in the pathophysiology of left ventricular hypertrophy of this animal model of human hypertension.

High activity of angiotensin-converting enzyme was demonstrated in human pituitary tissue. This activity required the presence of chloride ion and was almost completely inhibited by a specific converting enzyme inhibitor captopril (10 nM), indicating that the activity measured is indeed angiotensin-converting enzyme. The specific activity of the enzyme was 1.68±1.20 nmol hippuric acid generated mg of protein −1 min −1 (means±SD, for 11 specimens). The biochemical features of the enzyme were closely related to the well-characterized human lung converting enzyme, such as molecular weight (290,000), optimum pH (8.0–8.5), the presence of glycoprotein residues, and dependence on chloride ion concentration. These results provide definitive evidence for the presence of angiotensin-converting enzyme in human pituitary tissue.

High activity of renin was demonstrated in human prolactinoma tissue. This activity was almost completely inhibited by specific antibody raised against human renal renin, indicating that it was not due to the nonspecific action of proteases. The specific activity of renin was 5.04 ng of angiotensin I generated/mg of protein per h, comparable to that of the pituitary tissue prepared from postmortem human subjects. The biochemical properties of the prolactinoma renin were generally similar to those of well-known kidney enzyme, such as molecular mass (Mr=46, 000), optimum pH (6.0), and glycoprotein nature. However, the isoelectric points (pI) of the prolactinoma renin pI=4.90, 5.04, 5.24 and 5.41) differed somewhat from those of plasma and kidney renins reported hitherto. These results indicate that true renin can be produced in human prolactinoma tissue.

Immunoreactive renin was demonstrated in pituitary tissues of post-mortem human subjects with different diseases. The specific immunoreactive renin activity comprised the majority of the tissue renin-like activity (mean, 83%), indicating the absence of nonspecific actions of proteases such as cathepsin D. We used three pituitary specimens with high levels of the specific renin activity for further biochemical characterization of the enzyme. Small differences were found in the molecular mass (45 K, 42 K and 37 K), binding to concanavalin A-Sepharose, and isoelectric points (pI) (4.72, 4.78, 4.86, 5.06, 5.28 and 5.44). These results seem to be interpreted as evidence for the presence of specific renin in the human pituitary with microheterogeneity.