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(Hypertension. 1998;31:854-860.)
© 1998 American Heart Association, Inc.

Scientific Contributions

Augmentation of Aortic Ring Contractions by Angiotensin II Antisense Peptide

Patrick F. Dillon; Robert S. Root-Bernstein; ; Daniel D. Holsworth

From the Department of Physiology, Michigan State University (East Lansing) (P.F.D., R.S.R.-B.); and the Department of Research Chemistry, Amylin Pharmaceuticals, Inc, San Diego, Calif (D.D.H.).

Abstract—Previous biochemical experiments have revealed two antisense peptide antagonists to human angiotensin II (Ang II), one encoded in the cDNA in the antiparallel reading, the other in the parallel reading. Neither peptide's ability to produce physiological antagonism has been demonstrated previously. Both peptides were tested for their ability to antagonize Ang II–induced contractions on rabbit aorta smooth muscle. Neither peptide had any direct contractile activity. The antiparallel Ang II peptide had physiological antagonism to Ang II contractions at a lower sensitivity than reported in biochemical studies, and its antagonist activity was partially blocked by Ang II antiserum, suggesting that it is not an antipeptide but an Ang II homologue. The parallel Ang II antipeptide also required high concentrations for physiological inhibition. Its contractile inhibition was not affected by Ang II antiserum and diminished the Ang II contraction at high micromolar concentrations, findings consistent with physicochemical data showing that it is an Ang II complement. The concentration of either peptide required to produce an antagonistic physiological effect was too high to predict any pharmacological usefulness. The parallel antipeptide, however, significantly increased the force of muscle contractions at high nanomolar concentrations, thus displaying a unique dual augmentation/antagonist activity. This antipeptide seems to have highly sequence-specific activity because other similar parallel antipeptides had no activity. The parallel antipeptide augmentation mimics the shift in the Ang II dose-response curve produced in hypertension studies of the slow pressor effect of Ang II and may be useful in deducing the currently unknown cause of the slow pressor effect. It may also have some uses in migraine studies.

Key Words: antisense elements • peptides • angiotensin II • muscle, smooth, vascular

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