ABSTRACT
BACKGROUND: 'New pressor protein' was observed after tryptic activation of human and rat plasma in vitro, which is done conventionally for prorenin measurements. RESULTS: It is potently pressor, heat labile, possesses enzyme activity, and has a relative molecular mass > 30 kDa with isoelectric point(s) 4.7-4.9. New pressor protein equivalent to only 0.01 ml human, or rat, plasma injected intravenously quickly raises systolic blood pressure in 300 g anesthetized, ganglion-blocked, bioassay rats by about 15 mmHg. For unknown reasons, this is potentiated to about 45 mmHg after treatment with angiotensin I converting enzyme inhibitors (such as captopril and enalapril). New pressor protein activity in rats remains normal 24 h after bilateral nephrectomy, suggesting that it has an extrarenal origin and, furthermore, excluding the possibility of an association with renin-angiotensin system. Systolic blood pressure elevation is greater than the diastolic one, implicating cardiotonic effects. Human plasma new pressor protein was purified using standard biochemical techniques and its N-terminal sequence (19 residues) found to be homologous with the beta factor XIIa fragment of coagulation factor XII. This was supported by demonstrating inhibition of new pressor protein activity in vitro using the factor XII-specific corn trypsin inhibitor. Also, human new pressor protein activity in humans congenitally deficient in coagulation factor XII is very low. The high potency and multiphasic, cardiotonic effects of injected new pressor protein suggest that it interacts synergistically with other systems in the body. This was confirmed by showing that, within 10 min of total bilateral adrenalectomy, responses to new pressor protein decreased markedly. CONCLUSIONS: New pressor protein's action requires adrenal (medullary?) involvement, but its mechanism of action and that of its potentiation by angiotensin converting enzyme inhibitors remain unknown. The physiologic and clinical relevance of these observations depends on whether activation of new pressor protein can occur in vivo.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/pharmacology , Blood Pressure/physiology , Blood Proteins/physiology , Factor XII/physiology , Adrenal Medulla/physiology , Adrenalectomy , Amino Acid Sequence , Animals , Blood Pressure/drug effects , Blood Proteins/chemistry , Blood Proteins/genetics , Captopril/pharmacology , Enzyme Precursors/blood , Factor XII/chemistry , Factor XII/genetics , Factor XII Deficiency/blood , Humans , In Vitro Techniques , Isoelectric Point , Male , Molecular Sequence Data , Molecular Weight , Rats , Rats, Wistar , Renin/blood , Saralasin/pharmacology , Trypsin Inhibitors/pharmacologyABSTRACT
We studied a group of 50 adolescents, average age 16 years, with diagnosed IDDM present for about seven years. Twenty-five had microalbuminuria (MA) averaging 111.0 +/- 34.0 (SEM) micrograms/min albumin excretion rate versus 6.7 +/- 7.4 micrograms/min in the 25 without MA. In other respects, such as sex ratio, age, body mass index, duration of IDDM, hemoglobin A1c, and normotensive systolic, diastolic and mean blood pressures (BP), these subgroups were closely matched. We compared them with a control group of 39 normotensive adolescents, of whom 18 were carefully matched siblings of the IDDM subjects with MA and 21 were similarly matched siblings of the IDDM non-MA subjects. Plasma renin concentration was determined by a direct radioimmunoassay method (Sanofi-Pasteur) and found to be virtually the same in the control and IDDM adolescents as a whole. There was also no real difference between the MA and non-MA subgroups. In contrast, plasma prorenin was significantly higher in the combined IDDM group (197.5 +/- 9.3 vs. control, 134.0 +/- 7.9 pg/ml, P < 0.0001). It was also higher in the MA subgroup than in the non-MA subgroup (226.4 +/- 13.6 vs. 168.5 +/- 10.1 pg/ml, P < 0.001). Interestingly, the 18 control siblings matching the MA subgroup had higher plasma prorenin than the 21 control siblings matching the non-MA subgroup (P < 0.001), suggesting a familial predisposition that precedes detectable diabetes and nephropathy. Our findings confirm and extend reports by other workers that elevated plasma prorenin is associated with incipient nephropathy, manifested by MA. The exclusive renal origin of this prorenin, its role in plasma, and the mechanism responsible for its elevation in IDDM with MA, are yet to be demonstrated, as is the general applicability of these findings to different populations of diabetics, with a higher incidence and severity of complications.
