Peculiarities of Plasma “Prorenin” Measurements in Man, Dog, and Rat, and Their Theoretical Implications

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Abstract
In human plasma, trypsin activates "prorenin" within 1 min at 23 degrees C. It is quickly neutralized by endogenous inhibitors, and the subsequent hourly expression of old and new renin activity (PRA) is relatively consistent during 15, 30, or 60 min incubation at 37 degrees. In dog plasma, prorenin activation requires much higher trypsin concentrations - 3-5 mg/ml, vs 0.5-1.5 mg in humans - implying a higher content of endogenous protease inhibitors, and/or the lack of some endogenous mediator of the action of trypsin. These could also be partly responsible for the observed lack of cryoactivation in dogs. The effect of trypsin in dog plasma does not end abruptly as in humans. A post-tryptic prorenin "convertase" continues to act at 37 degrees, steadily increasing the hourly rate of angiotensin generation as the incubation is prolonged. Neither lima bean trypsin inhibitor (LBTI) nor endogenous inhibitors fully inhibit this trypsin-induced convertase. It is transferable to normal plasma, where it raises the PRA. Pepstatin severely inhibits this effect, most probably by inhibiting the new renin, possibly also by inhibiting the convertase itself. Rat plasma appears intermediate between human and dog plasmas in some respects. Trypsin activates prorenin well at 4 mg/ml, when exposed for 30 min at 23 degrees, provided the subsequent PRA incubation stage is kept short, e.g. 10 vs 30 min. This implies a low tolerance to effective concentrations of trypsin, presumably attributable to the nature and/or quantity of endogenous protease inhibitors. The amount of prorenin, as judged by activation, equals that of dogs. However, active renin is distinctly higher in rats, possibly due to the stressful influence of anesthesia and blood collection. This greatly reduces the prorenin: renin ratio in rats relative to dogs, and brings them closer to the human ratio. Clamping off the renal blood vessels while blood is collected, lowers the basal PRA, and raises the prorenin:renin ratio. Thus, prorenin is detectable in all 3 species, but the best methods for activating it are quite different, implying marked differences in the mechanisms involved.