A Specific Competitive Antagonist of the Vascular Action of Angiotensin II

Abstract

The effect of 1-Asn-8-Ala-angiotensin II (Asn-Arg-Val-Tyr-Val-His-Pro-Ala) on the vascular action of angiotensin II was studied with rabbit aortic strips, pithed rats, and conscious rats. Dose-response (contraction) curves for angiotensin II on rabbit aortic strips shifted progressively to the right with increasing bath concentrations of 1-Asn-8-Ala-angiotensin II. The pA 2 value (an indication of the relative affinity of a competitive antagonist for an agonist's receptor site) was 6.84 ± 0.03. Dose-response curves for norepinephtine, serotonin, and histamine were relatively unaffected. No pA 3 values could be obtained with these agonists in the concentration range tested. Partial dose-response (pressor) curves for angiotensin II in pithed rats shifted to the right during infusions of 1-Asn-8-Ala-angiotensin II at 20 and 60 µg/kg min -1 Partial dose-response curves for vasopressin, phenylephririe, and tyramine were unaffected. Infusions of 1-Asn-8-Ala-angiotensin II counteracted the pressor effect of angiotensin II infusions in pithed and conscious rats. Infusions of 1-Asn-8-Ala-angiotensin II (200 µ/ kg min -1 ) effective in reducing the blood pressure of conscious angiotensin II-infused rats caused only small pressor effects in conscious normotensive rats but reduced the blood pressure in 75% of the conscious rats with acute unilateral renal hypertension. The data presented are consistent with the conclusion that 1-Asn-8-Ala-angiotensin II is a specific competitive antagonist of the vascular action of angiotensin II both in vitro and in vivo.

Racing To Invest? The Dynamics of Competition in Ethical Drug Discovery

“…al., 1974). This work was undertaken by researchers working in both the public sector and in commercial firms (Pals et al, 1971).…”

Renin-Angiotensin System Inhibition in Conscious Sodium-Depleted Dogs

“…This increase in 'angiotensin II concentration probably plays an important role in the maintenance of normal arterial blood pressure during salt depletion, because the arterial blood pressure decreases under these conditions after administration of saralasin (1-sarcosine-8-alanine-angiotensin II; P113) (2-7), teprotide (SQ 20,881) (7)(8)(9)(10), and SQ 14,225 (11). Saralasin is a competitive receptor antagonist of angiotensin II (4,12,13), whereas the latter two agents inhibit angiotensin-converting enzyme, which converts angiotensin I to the biologically active angiotensin II (8,(13)(14)(15)(16). Because angiotensin II is one of the most potent vasoconstrictors known (17,18), a decrease in arterial blood pressure after angiotensin inhibition presumably is due to elimination of the angiotensin-induced vasoconstriction.…”

“…Angiotensin II may affect the coronary blood flow and vascular resistance either directly by its coronary vasoconstrictor action or indirectly by systemic vasoconstriction, which increases cardiac work and myocardial oxygen consumption (20,21). Furthermore, because saralasin may exert a dose-dependent agonistic action on angiotensin receptors (12,22,23), three doses of saralasin were administered. Results of this study indicate that angiotensin II exerts an active vasoconstrictor action on the systemic and coronary vessels during salt depletion, but has no significant effect on myocardial contractility or energetics.…”

A brief history of renin

“…Another plausible target was the Ang II receptor (termed AT1 receptor). Pals, Masucci, Sipos, and Denning synthesized Sar-Ala-angiotensin, a peptide Ang II receptor blocker (ARB) better known as saralasin [15]. However, peptide ARBs proved to be not practicable.…”