Jaw-Kang Chang

In vivo and in vitro release of ACTH by synthetic CRF

The 41-residue corticotropin releasing factor (CRF) was synthesized by the solid phase method. The synthetic CRF and arginine vasopressin (AVP) were examined for ACTH releasing activity and effects on the release of 5 other pituitary hormones in vivo and in vitro. Injection of the CRF into pharmacologically blocked rats increased plasma corticosterone levels in a dose-related manner. The minimum effective dose was 1.6 x 10(-12) mol/100 g body weight. CRF also significantly stimulated release of ACTH-like immunoreactivity in a dose-related manner from rat pituitary quarters beginning at a concentration of 10(-9) M. AVP, a peptide known to have CRF activity, exhibited slightly lower corticotropin releasing activity than the CRF at equimolar dose levels. Secretion of other pituitary hormones was not appreciably altered by either the CRF or AVP.

NOCICEPTIN : AN ENDOGENOUS AGONIST FOR CENTRAL OPIOID LIKE1 (ORL1) RECEPTORS POSSESSES SYSTEMIC VASORELAXANT PROPERTIES

The purpose of the present study was to investigate the effects of nociceptin on peripheral arterial rings from the cat. When feline renal, mesenteric, carotid and femoral rings with intact endothelium were precontracted with phenylephrine (100 nanomolar), nociceptin (3 x 10(-11)-3 x 10(-6) M) decreased tension in a concentration-dependent manner. The present data suggest nociceptin possesses biologic activity outside the CNS and may contribute to the regulation of systemic blood pressure and regional blood flow.

In vitro potentiation of the activity of synthetic ovine corticotropin-releasing factor by arginine vasopressin ☆

The ability of arginine vasopressin (AVP) to potentiate the actions of synthetic ovine corticotropin-releasing factor (CRF) was examined using anterior pituitary fragments. Marked potentiation of ACTH release was observed upon incubating the fragments with a combination of 2 nM AVP and 1 nM CRF. Potentiation of CRF-induced ACTH release was also observed when the fragments were incubated with a combination of 1 nM AVP and 0.5 nM CRF. These results suggest that AVP may play a role in the release of ACTH from the adenohypophysis.

The effect of adrenomedullin on the isolated heart

A novel peptide found in human blood, adrenomedullin (ADM), has been shown to have systemic vasodepressor activity in the rat. However, the direct effects of ADM on cardiac function are unknown. Results of the present study demonstrate that ADM13-52 possesses marked systemic vasodepressor activity in the anesthetized rat. Although ADM13-52 modestly decreased peak systolic pressure (PSP) indicating mild negative inotropic activity, the present data suggest that bolus administration of ADM decreases systemic arterial pressure by dilating the systemic vasculature. The present data also suggest that only a portion of the ADM molecule is necessary to produce systemic vasodilation.

ADRENOTENSIN : AN ADM GENE PRODUCT WITH THE OPPOSITE EFFECTS OF ADM

The purpose of the present study was to investigate the effects of putative products of the ADM gene, other than ADM including, prodepin, proADM45-92 and proADM153-185 on cat pulmonary arterial (PA) rings with or without precontraction with U46619. Addition of proADM153-185 (3 x 10(-10)-10(-6) M) increased tension in a concentration-dependent manner in cat PA rings without precontraction. When vessels were precontracted with U46619, ADM(3 x 10(-10)-10(-6) M) produced a concentration-dependent vasorelaxant response, whereas proADM153-185 produced a weak concentration-dependent contractile response. Prodepin and proADM45-92 up to 10(-6)M had no activity on PA rings. Since proADM153-185, similar to ADM, would be expected to be released in free form following endopeptidase-induced cleavage, the present data suggest proADM undergoes proteolytic processing to release peptides with divergent vascular effects. Thus, the present data also suggest that proADM153-185 may represent a novel product of the ADM gene and term this putative new substance adrenotensin.

An adrenomedullin fragment retains the systemic vasodepressor activity of rat adrenomedullin.

The present study was undertaken to investigate the effects of human adrenomedullin, a newly discovered peptide present in normal human plasma, as well as a fragment of adrenomedullin, on systemic hemodynamics in the anesthetized rat. Intravenous (i.v.) bolus injections of rat adrenomedullin, rat adrenomedullin-(11-50), human adrenomedullin-(13-52) decreased mean systemic arterial pressure in a dose-dependent manner. Since rat adrenomedullin and human adrenomedullin did not decrease cardiac output, the decreases in systemic arterial pressure reflect dose-dependent reductions in systemic vascular resistance. The systemic vasodepressor responses to similar doses of the adrenomedullin fragments studied and to their respective parent adrenomedullin peptides were similar. The present data demonstrate that the entire adrenomedullin molecule is not required for full systemic vasodilator activity in vivo suggesting that rat adrenomedullin-(11-50) or a structurally similar peptide, if formed endogenously, could mediate the hemodynamic properties of adrenomedullin in vivo. Since rat adrenomedullin had significantly greater systemic vasodilator activity than human adrenomedullin at similar doses in the rat, the present data suggest that adrenomedullin has greater systemic vasodilator activity in its native species and that limited changes in the peptides sequence confer markedly different vascular activity in vivo.

Adrenotensin: An adrenomedullin gene product contracts pulmonary blood vessels

The purpose of the present study was to determine the effects of adrenotensin, a newly described product of the ADM gene, on cat pulmonary arterial (PA) rings. Under resting conditions, adrenotensin increased tension of PA rings in a concentration-dependent manner. Although addition of diphenhydramine, ONO-3708, phentolamine, methysergide, atropine, and meclofenamate did not alter the contractile response to adrenotensin, removal of the endothelial cell layer significantly reduced this response. Moreover, precontraction of PA rings with adrenotensin selectively attenuated the pulmonary vasorelaxant response to ADM but not to other vasodilator substances, including isoproterenol, pinacidil, nifedipine, and adenosine. The present data suggest that adrenotensin acts in an endothelium-dependent manner to contract PA rings. Moreover, the present data suggest that adrenotensin may act in a modulatory manner to influence vasorelaxation in response to ADM, a sister proADM product.

Prodepin: A new product of the adrenomedullin (ADM) gene has systemic vasodilator activity

The purpose of the present study was to investigate the effects of products of the ADM gene other than ADM on systemic hemodynamics in the anesthetized rat, rabbit, piglet, cat and dog. Bolus intravenous (i.v.) injections of rat proADM22-41 (3-30 micrograms) significantly decreased systemic arterial pressure (SAP) and systemic vascular resistance in the anesthetized rat. Unlike ADM, rat proADM22-41 markedly increased cardiac output in the rat. Bolus i.v. injections of human proADM22-41 up to 500 micrograms had not effect in all species studied and rat proADM22-41 had no effect in species other than the rat. The present data suggest that rat proADM22-41 is a novel product of the ADM gene other than ADM and possesses marked systemic vasodilator activity. The present data also suggest that the hemodynamic activity of this peptide is species specific.