Synthesis and evaluation of [des-Asp1]angiotensin I as a precursor for [des-Asp1]angiotensin II (angiotensin III)

Abstract

The nonapeptide [des-Asp1]angiotensin I (IV), synthesized by Merrifield's solid-phase procedure, was tested as a possible substrate for the converting enzymes from porcine lung and plasma. IV, [des-Asp1]angiotensin II (III), [des-(Asp1,Arg2)]angiotensin II (V), [des-(Asp1,Arg2,Val3)]angiotensin II (VI), [Sar1,Ile8]angiotensin II (VII), and [des-Asp1,Ile8]angiotensin II (VIII) possessed 0.5, 20, 2, 0 less than 0.1, and less than 0.01% of the inotropic activity (rabbit atria), 1, 15, 5, 0, 3, and 0% secretory activity of the cat adrenal medulla, and 0.0, 150, 0.5, 3, and 10% of the adrenal steroidogenic activity of angiotensin II, respectively. When tested for their antagonistic activity in the above tissues, only VII and VIII were found to inhibit responses to angiotensin II. The pA2 values for VII and VIII were 8.31 and 10.0 in the adrenal cortex and 9.31 and 9.16 in the adrenal medulla, respectively. All these peptides were also tested as product inhibitors for the plasma and lung converting enzymes. With the plasma enzyme, the ID50 values were II, 1.6 X 10(-4) M; III, 5 X 10(-5) M; V, 1.2 X 10(-4) M; VI 5 X 10(-4) M; VII 5 X 10(-5) M; VIII, 5 X 10(-4) M. Thus, IV is a good substrate for converting enzymes from lung and plasma while all other compounds were inhibitors of these enzymes. The most potent inhibitors of converting enzyme were III followed by VII and VIII. With the exception of II and III, all the other analogs had very low intrinsic activities, per se. These results suggest (a) an alternate pathway for the formation of heptapeptide III, viz., by the action of converting enzyme on the nonapeptide IV, and (b) that III may also be acting as inhibitor of the converting enzyme by the feedback mechanism.

Classification of Angiotensin Receptors in Rat Isolated Uterus, Portal Vein, and Aorta with the Novel Competitive Antagonist Sarmesin

“…However, re cent studies have revealed that tissue levels of ANG III may be higher than ANG II, and much higher than those in plasma [Naruse et al, 1985]. In addition, the existence of an intracellular RAS has been demonstrated [Okamura, 1981] and it has been shown that ANG III can be produced from ANG I with out ANG II as an intermediate [Tsai et al, 1975], Given these facts, it is possible that local ANG III concentrations could become sufficient to contribute to the overall tone of certain vascular smooth muscles. Harding et al [ 1987] have recently shown that ANG III produces electrophysiological events in rat hypothalamus which are not produced by ANG II, suggesting a possible central role for the heptapeptide.…”

Characterization of Immunoreactive Angiotensin in Canine Cerebrospinal Fluid as Des-Asp1-Angiotensin II

“…The Des-Asp'-angiotensin II in cerebrospinal fluid may be a metabolite excreted from brain tissue by a conventional angiotensin II-forming system, but the finding of biological activity for Des-Asp'-angiotensin II on the subfornical organ (Schlegel & Felix, 1976) raises the interesting possibility that Des-Asp'-angiotensin II may be the biologically active end product of an alternative biosynthetic pathway (Tsai, Peach, Khosla & Bumpus, 1975) in brain tissue.…”

Stimulation of collagen gel contraction by angiotensin II and III in cardiac fibroblasts

“…17 Ang III is a naturally-occurring heptapeptide, 28 which is formed as a result of N-terminal degradation of Ang II by 29 An alternate pathway consists of conversion of angiotensin I to des-Asp 1 -angiotensin I by aminopeptidase A, 30 followed by subsequent conversion of des-Asp 1 -angiotensin I to Ang III by converting enzyme. 31,32 In the present study we have shown that Ang II, as well as Ang III, stimulates collagen gel contraction by adult rat cardiac fibroblasts; the effect of Ang II is blocked by telmisartan but not by desAsp -angiotensin II and by telmisartan. The stimulation of collagen gel contraction by rat cardiac fibroblasts by Ang II as well as by Ang III is blocked by the AT 1 -receptor antagonist, telmisartan.…”