Can Total Prorenin in Human Plasma be Determined by Current Activation Methods?

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Abstract
A proper evaluation of the physiological significance of plasma prorenin depends on its accurate determination. However, current activation methods do not necessarily measure total prorenin, or a known proportion of it, even when carried out to apparent completion. Thus, extending cold activation of human plasma at -4°C generally revealed progressive increments of prorenin, mainly during the first 15 days, but the total and the time required to achieve it varied considerably among individuals. Similarly, the titration curves of individual plasmas varied with increments of added trypsin and achieved totals that were not necessarily greater than those obtained by cold activation. This indicates the inappropriateness of attributing greater effectiveness to one method over the other. When the two methods were paired in sequence, a synergism was apparent in that prorenin estimates increased consistently; in one case more than 10-fold. Thus, total prorenin by any single method generally fell short of the total achieved by double methods. However, this too may still not represent the unknown true total prorenin. The sequence of activation steps was important, providing clues as to the mechanism of the observed synergism. Trypsin-before-cold activation proved to be more effective than trypsin-after-cold activation, with no further advantage being gained from triple treatments involving cold before and after trypsin, or trypsin before and after cold. The inferiority of trypsin-after-cold activation was apparently due to sensitization of the plasma to the destructive effects of trypsin, shifting its titration curve to the left. This suggests that cold exposure reduced the trypsin inhibitory capacity of the plasma and/or otherwise augmented its protease content, thereby making trypsin more destructive at lower concentrations. Trypsin-before-cold enhanced cold activation, because trypsin contributed its effects before such cold-induced changes in the plasma had taken place. Thus, contrary to other reports, our data indicate that single activation methods can readily be titrated to a maximum prorenin value. However, they should not be ranked arbitrarily against each other because the efficacy of each method varies with the conditions. Furthermore, the resulting prorenin represents an unknown proportion of the true total. It follows that the present literature on human plasma prorenin, which is almost entirely based on single methods applied in various formats, necessarily provides only a preliminary understanding of its physiological significance. Direct methods are needed to establish the total prorenin independently of its activatability.

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