Inhibition of Pressor Effects of Angiotensin I and Augmentation of Depressor Effects of Bradykinin by Synthetic Peptides

Abstract

In 1965 Ferreira (1) described the isolation and properties of bradykininpotentiating factor (BPF), a crude peptidic extract from the venom of the South American snake Bothrops jararaca. Three years later Bakhle ( 2 ) demonstrated that BPF also prevented the conversion of angiotensin I to angiotensin I1 in vitro and similar effects were seen in the perfused lung (3) and in intact animals (4).These dual activities of BPF were also exhibited by the first peptide isolated and identified from BPF, Pyr-Lys-Trp-Ala-Pro, originally called BPPS5, and herein referred to as SQ 20,475 ( 5 ) . At least 8 other peptides from the venom of B. jararaca have been isolated by Ferreira, Bartelt, and Greene (6) and by Ondetti et aZ. (7). The latter investigators also determined the amino acid sequence of 6 of these.We have investigated the dual activities in vivo of these 6 peptides and of SQ 20,475, all of which were synthesized by Ondetti et a2. (8). Struotures of the 7 test peptides are shown in Table I. Materials mad Methods. Male rats of the Sprague-Dawley strain, 250 to 450 g, were anesthetized with urethane, 1.5 g/kg, im, and then tracheotomized. The trachea and the arteries and veins mentioned below were cannulated with polyethylene tubing of appropriate size. Blood pressure was monitored from a femoral artery via a Statham P23GH pressure transducer coupled to a Beckman dynograph. The rats were given atropine sulfate (1 mg/kg, iv) and heparin (250 units,/ 1Preliminary reports of parts of this work have been presented a t the NXV Int. kg, iv). Each test peptide, except the less soluble SQ 20,475, was dissolved in physiological saline and injected stat iv? 0.1 ml/dose, followed by 0.4 ml saline "wash-in" within the next 30 sec. SQ 20,475 was first dissolved in 0.1 il' NaOH, adjusted with 0.1 N HCl to about pH 8.5 and injected stat iv, 0.1 ml/dose, "washed-in" with 0.4 ml saline. Other injections of some of the test peptides were made im or sc, 0.1 ml/injection. Rats employed in experiments involving angiotensions I and I1 received a continuous infusion of pentolinium bitartrate (0.2 mg/kg/min) into a femoral vein. In experiments involving bradykinin, pentolinium was not infused.[ Ile5] -angiotensin I was purchased from Schwartz/Mann, [ Am1, Val5] -angiotensin I1 was kindly supplied by Dr. A. J. Plummer of Ciba Pharmaceutical Company, and bradykinin was purchased from Cyclo Chemical and Nutritional Biochemicals. These challenge peptides were administered stat iv, 0.1 ml/dose, in physiological saline, followed by 0.4 ml saline wash-in, in all experiments.Blood pressure responses to control doses of the challenging agent(s), i.e., to 0.10 or 0.31 pg/kg of angiotensin I and to 0.031 or 0.10 pg/kg of angiotensin I1 or to 1, 3, or 10 pg/kg of bradykinin, were first determined for each rat. The test peptide was then administered and the challenging agent (s) were injected repeatedly at 2-to 10-min initervals. Not until responses to the challenges were approximately equal to those seen in the control period was another injection of th...

Prior receptor occupancy as a determinant of the pressor activity of infused angiotensin II in the rat.

“…Recently, a synthetic nonapeptide converting enzyme inhibitor SQ 20881 (PyrTrp-Pro-Arg-Pro-Gln-Ile-Pro-Pro) (Squibb Laboratories) has been developed from the venom of Bothrops jararaca (10). This inhibitor, which produces prolonged blockade (half life > 50 minutes) of angiotensin I conversion in the rat (11), affords an opportunity to All values are means ± SE. *P < 0.01.…”

Studies on Mechanisms of Antinephritic Action of SA-446, an Angiotensin I Converting Enzyme Inhibitor (1) A Comparison with Actions of Spironolactone, Kallidinogenase and Saralacin

“…As histopathological parameters in the glomeruli, crescent formation, adhesion of capillary walls to Bowman's capsule (adhesion) and fibrinoid necrosis were observed in fifty glomeruli per section under light microscopy. The degree of changes in these three histo pathological parameters was scored as: mild (1), moderate (2) and severe (3). The number of glomeruli corresponding to each score was represented as n1, n2 and n3.…”

“…It has been speculated that the hypotensive action of ACE inhibitors may be caused by inhibition of the conversion of angiotensin I to angiotensin II and/or by inhibition of the destruction of kinins, the potent vasodepressors (2)(3)(4). We have already reported that a positive correlation exists between the crescent formation in glomeruli and the blood pressure in crescentic-type anti-glomerular basement membrane (anti-GBM) nephritis of rats and that SA-446 [(2R, 4R)-2-(2-hydroxyphenyl) 3-(3-mercaptopropionyl)-4-thiazolidine carboxylic acid], an ACE inhibitor, shows beneficial effects on histopathological changes in glomeruli and hypertension (5).…”

The Renin-Angiotensin System

“…augments the vasodepressor activity of bradykinin and lowers blood pressure in some animal models of renovascular hypertension (Engel et al, 1972). At intravenous doses of up to 1 mg/kg teprotide produces a pronounced lowering of blood pressure in patients with renovascular or malignant hypertension (Case, Wallace et al, 1980).…”