Defect in the excretion of a vasoactive polypeptide fraction A possible genetic marker of primary hypertension.

Abstract

SUMMARY A polypeptide fraction isolated from the urine of nonnotenslve subjects lowers the blood pressure (BP) in a rabbit bioassay (mean BP decrease 33.8% ± 0.6%, SEM). Patients with primary hypertension exhibit reduced or no activity (mean BP decrease 8.8% ± 1.2%). In contrast, patients with secondary forms of hypertension show activity like nonnotensives (mean BP decrease 33.4% ± 1.0%). Tbe results of the bioassay in tbe two patient groups correlate well with the family inddence of hypertension (68% and 37% for primary and secondary hypertension respectively). Cases with borderline hypertension fall into two groups; a larger one with vasoactivity in the bioassay and lower family inddence of hypertension; and a smaller group reacting like patients with primary hypertension. Only the latter group may represent an initial stage of primary hypertension. In nonnotenslve children and young men, an inactive fraction was found in 31% and 28% respectively. These inactive groups had twice the family inddence of hypertension compared to the groups with vasoactivity. These results suggest the existence of a possible genetic marker of primary hypertension and may offer the possibility to detect the disease before its manifestation. ical markers of the postulated genetic abnormality have been established. The urine of normotensive subjects contains significant amounts of low molecular weight kinins and kallikrein.8 In addition, we have previously reported the existence of a vasoactive polypeptide fraction in the urine of normotensive human beings irrespective of age and sex. 4 "* This fraction was shown to dilate the vessels of the general circulation and to retain activity in an isolated vessel preparation, while it was inactive in the pulmonary circulation, the isolated heart, or intestinal preparation.' 1 T As reported earlier, a similar, crude polypeptide fraction isolated from the urine of patients with primary hypertension did not lower the blood pressure (BP) in the bioassay. 4 ' B In view of these findings, we attempted to isolate and characterize the polypeptide fraction in a greater number of patients with different types of hypertension. In addition, we carried out studies on samples of the normal population. Since altered kallikrein excretion has been reported in patients with hypertension,"' * we also measured the kallikrein content in the urinary polypeptide fraction under study.

The Kallikrein-Kinin System as a Regulator of Cardiovascular and Renal Function

“…Decreased activity of the KKS may play a role in hypertension. Low urinary kallikrein excretion in children is one of the major genetic markers associated with a family history of essential hypertension, and children with high urinary kallikrein are less likely to be genetically predisposed to hypertension (264,289,304,321). A restriction fragment length polymorphism (RFLP) for the kallikrein gene family in SHR has been linked to high blood pressure (218), and urinary kallikrein excretion is decreased in several models of genetic hypertension.…”

The vasoactive proteins in human urine

“…The fractions were tested for activity in a rabbit bioassay as described [6]. regions represent the vasoactive fractions.…”

“…Furthermore, it was found that the urine fraction from patients with primary hypertension and from normotensive individuals with a family history of hypertension failed to lower blood pressure in a rabbit bioassay system [6]. In the previous study from this laboratory [6] it was concluded that the vasoactrve principle was distinct from kallikrein based on enzymatic measurements of kallikrein-like activity. As deficient excretion of kalhkrein also has been implemented in the pathogenesis of primary hypertension [7] it was felt of particular importance to isolate and characterize further the polypeptide fractron from the urine of normotensive individuals and to see whether, indeed, it can be distinguished from urinary kallikrem.…”

“…It is of particular interest that the vasoactivrty of this polypeptrde fraction was shown to be impaired in patients with primary hypertension [5,6]. Furthermore, it was found that the urine fraction from patients with primary hypertension and from normotensive individuals with a family history of hypertension failed to lower blood pressure in a rabbit bioassay system [6].…”

“…It is of particular interest that the vasoactivrty of this polypeptrde fraction was shown to be impaired in patients with primary hypertension [5,6]. Furthermore, it was found that the urine fraction from patients with primary hypertension and from normotensive individuals with a family history of hypertension failed to lower blood pressure in a rabbit bioassay system [6]. In the previous study from this laboratory [6] it was concluded that the vasoactrve principle was distinct from kallikrein based on enzymatic measurements of kallikrein-like activity.…”