Guanidine Excretion in Relation to Hypertension

Abstract

A series of observations haveLeen made recently, the resultscf which suggest, a relationship between arterial hypertension and guanidine metabolism. Major and Stephenscn (1) studyipg the influence of certain urinary constituents on blood pressure, noted that methyl guanidine, a product of normal metabolism and a constituent of normal urine, had marked pressor effects. These authors suggested that this compound, if produced in excess or imperfectly excreted, might account for increased blood pressure. Creatinine and creatine, substances closely allied to methyl guanidine chemically, were found inert. Later (2) observations confirmed the rise in blood pressure following experimental injection of methyl guanidine. In addition it was then noted that, in short period experiments, rise in blood pressure produced by guanidine compounds could be abolished by the use of calcium or potassium chloride. The latter is of interest, in view of the clinical results obtained from the use of these salts as reported by Addiscn (3) and Addison and Clark (4), who found that these inorganic salts, when given in large doses (about 15 grams per day) over long periods of time, produced a diuresis and accompanying this there was a decided and prolonged fall in blood pressure in a large percentage of cases of hypertension. In a further communication Major (5) reported two cases of arterial hypertension. in which the daily excretions of guanidine bases were observed. In both, during produced diuresis, a rise in urinary excretion of dimethyl-guanidine was acccmpanied by a fall in blood pressure. Experimental evidence was also presented by the same worker (6) favoring the view that the elevation in blocd pressure 587

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“…Our observations (also see Dataset S1 ) indicated that (a) dialysis/desalting through all MWCO devices, down to 2 KDa, abrogated the inhibitory effect of urine similarly ( Figure S2A ); (b) concentration of urine did not worsen its inhibitory effect, likely due to passage of the inhibitory molecules through 3–5 KDa MWCO membranes of the concentrator (data not shown); (c) acidification, alkalinization, EDTA treatment, or boiling/centrifugation of urine did not alleviate inhibition, suggesting that the inhibitor was a small (<2 KDa) molecule, not related to inherent acidic pH of normal urine (and not influenced by alkalinization), not likely a divalent cation, and not protein in nature ( Figure S2B ). Interestingly, at supra-physiological concentrations [25] – [27] , a mix of chaotropic molecules (urea, guanidine) and common ions in urine was significantly inhibitory as an EPA293 diluent (PBS vs. Mix, EC 50 comparison; p = 0.0005, F-test) ( Figure S2C ).…”

“…To further identify the chemical nature of the inhibitor, we tested several chemical treatments on urine (10 m boiling followed by centrifugation; alkalinization (pH 8) with sodium hydroxide; acidification (pH 5) with glacial acidic acid; and addition of 5, 10 or 20 mM EDTA), and used the treated urines as EPA293 diluents in sELISA. In addition, we tested known chaotropic molecules present in urine, such as urea and guanidine (guanidine hydrochloride), and divalent cations (known kosmotropes) calcium (Calcium chloride) and magnesium (Magnesium chloride), individually or combined in PBS (pH 6, 7.2 or 7.4) at physiological or supra-physiological levels (final concentration ranges: 50–800, 1–8, 1–20 and 1–20 mmol/L, respectively) [25] – [27] . All chemical reagents used were from Sigma-Aldrich, St. Louis, MO.…”