Angiotensin III: A Potent Inhibitor of Enkephalin‐Degrading Enzymes and an Analgesic Agent

Abstract

Various angiotensins, bradykinins, and related peptides were examined for their inhibitory activity against several enkephalin-degrading enzymes, including an aminopeptidase and a dipeptidyl aminopeptidase, purified from a membrane-bound fraction of monkey brain, and an endopeptidase, purified from the rabbit kidney membrane fraction. Angiotensin derivatives having a basic or neutral amino acid at the N-terminus showed strong inhibition of the aminopeptidase. Dipeptidyl aminopeptidase was inhibited by angiotensins II and III and their derivatives, whereas the endopeptidase was inhibited by angiotensin I and its derivatives. The most potent inhibitor of aminopeptidase and dipeptidyl aminopeptidase was angiotensin III, which completely inhibited the degradation of enkephalin by enzymes in monkey brain or human CSF. The Ki values for angiotensin III against aminopeptidase, dipeptidyl aminopeptidase, endopeptidase, and angiotensin-converting enzyme, which degraded enkephalin, were 0.66 X 10(-6), 1.03 X 10(-6), 2.3 X 10(-4), and 1.65 X 10(-6) M, respectively. Angiotensin III potentiated the analgesic activity of Met-enkephalin after intracerebroventricular coadministration to mice in the hot plate test. Angiotensin III itself also displayed analgesic activity in that test. These actions were blocked by the specific opiate antagonist naloxone.

Shedding Light on the Pharmacological Interactions between μ-Opioid Analgesics and Angiotensin Receptor Modulators: A New Option for Treating Chronic Pain

“…Following the discovery of the neuronal RAS, numerous studies have reported on the implication of AT1R/AT2R agonists on nociception [27,30,33,[68][69][70][71][72][73][74][75][76]. In spite of the high number of studies conducted, literature data remain highly controversial.…”

“…In spite of the high number of studies conducted, literature data remain highly controversial. Some publications describe the analgesic activity of AngII, AngIII, or renin on acute pain tests following central (intracerebroventricular [27,69,71,72,76] or intrathecal [33]) administration. These reports proposed different possible mechanisms of action behind the observed effects.…”

Inhibition of Cell Migration via G Protein‐Coupled Receptors to Opioid Peptides and Angiotensin

“…Angiotensin III is the heptapeptide breakdown product of angiotensin II, lacking the aminoterminal asparagic acid. This peptide inhibits the degradation of met‐enkephalin and potentiates its analgesic activity 25…”

“…This peptide inhibits the degradation of met-enkephalin and potentiates its analgesic activity. 25 There are two known GPCRs for angiotensin II, AT 1 and AT 2 , and both are connected to inhibitory G i proteins. 26 Angiotensin II has been shown to be involved in tumor angiogenesis, and the pharmacological inhibition of the ACE suppressed vascular endothelial growth factor (VEGF) expression.…”

Interaction of [Ile7]angiotensin III with dodecylphosphocholine micelles: NMR and molecular dynamics studies

“…Angiotensin III has been reported to be the most potent inhibitor. 7 The two-step model of the action of hormones on membrane-bound receptors involves partitioning followed by di †usion of the hormone in the membrane.…”