Since the discovery of the angiotensins a link was sought in vain between these polypeptides and the physiological mechanism that regulates the systemic blood pressure (1). This search, however, was rich in surprises as soon as the amazing diversity of pharmacological actions of angiotensin II was established. Besides being the most powerful vasopressor molecule known, the polypeptide is the hormone for aldosterone release (2) and has several effects on the autonomic nervous system: (a) it inhibits the uptake of catecholamines by sympathetic nerve endings (3); (b) it has a direct action on cholinergic ganglionic cells (4); (c) it accelerates the rate of biosynthesis of norepinephrine (5); and (d) it acts directly or indirectly on central sympathetic structures inducing a prolonged increase in blood pressure and heart rate (6). Even if this versatility shattered the early ideas concerning the function of the polypeptide, the classical scheme that accounted for angiotensin I production was not challenged until very recently. The liberation of the polypeptide was supposed to be restricted to the plasma, where a circulating alpha-2 globulin synthetized by the liver, angiotensinogen, is split by a proteolytic enzyme, renin, synthesized by the granular cells of the juxtaglomerular apparatus of the kidney. This proteolytic step releases a 10-residue long polypeptide from angiotensinogen, denominated angiotensin I, which is itself the substrate for a specific, Cl-activated carboxipeptidase, the converting enzyme, giving rise to the octapeptide angiotensin II. This scheme was first questioned after the finding that isolated rat renal glomeruli, devoid of plasma contamination and incubated in a simple salt medium, were able to secrete angiotensin I in great amounts (7-8). The release of the polypeptide was suppressed with protein-synthesis inhibitors. I The tissue synthesis of angiotensin I was strongly supported by the finding of a polypeptide in several tissues of the rat and the dog with pharmacological and

A pressor polypeptide was isolated from the cerebrospinal fluid of normotensive and hypertensive patients. Pharmacologically it behaves like angiotensin I. A very significant correlation (r = 0.83, P < 0.001) was found between the concentration of this polypeptide and the blood pressure of essential hypertensive patients.Early theories about the pathogenesis of essential hypertensive disease claimed that neural mechanisms were involved. The classical experiments by Goldblatt and the discovery of the renin-angiotensin system abruptly switched the emphasis to the kidney (1), which has occupied since then a central position in all hypotheses advanced to explain the mechanism of essential hypertension. A link was sought in vain between the renin-angiotensin system and hypertensive disease. No correlation was found between the concentration of angiotensin in plasma and the blood pressure of essential hypertensive patients (2). At the same time pharmacological experiments showed that angiotensin II acts on central sympathetic structures, thereby inducing a prolonged increase of arterial blood pressure (3). These results have acquired a new physiological perspective after renin (4, 5), converting enzyme (6), and angiotensins I and II (4,7,8) were found in the central nervous system of rats and dogs, suggesting that the brain renin-angiotensin system might be involved in regulation of arterial blood pressure. These observations led to the search for pressor polypeptides in the cerebrospinal fluid of normotensive and hypertensive patients. This paper contains the first results of such a study. Isolation of the Pressor Material. 10 ml of cerebrospinal fluid (CSF) were obtained from each patient, and the samples were collected in siliconed tubes containing EDTA (final concentration 3 mM). In order to destroy eventual catecholamines that could invalidate the biological assays, the CSF sample was adjusted to pH 10 with 0.1 M NaOH and boiled for 20 min. After cooling, the pH was lowered to neutrality with 0.5 M HCl. Three to four volumes of ice-cold 96% ethanol were added, and the samples were left at 40 overnight.The precipitate was discarded by centrifugation, and the clean supernatant was concentrated in a vacuum rotatory evaporator to 0.5 ml, which was then applied to a 0.6 X 7 cm Dowex X-2 column equilibrated with 0.1 M phosphate buffer (pH 7.5). The column was washed with 5 ml of the buffer followed by 2 ml of water; the retained materials were eluted with 1.5 ml of 0.1 M NaOH and 4 ml of water, and this solution was neutralized with 0.5 M HCl. After concentration to 0.5 ml, the eluate was filtered through a Sephadex G25 (fine) column previously calibrated with 5-L-[U-14C]isoleucine-angiotensin II purchased from New England Nuclear. 0.5 M formic acid was used as eluant. The formic acid in the selected fractions was eliminated before the bioassays by repeated evaporations.Bioassay. Pressor activity was assayed on nephrectomized rats. Duplicate determinations were performed for each sample and repeated on at least...

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