Mechanism of Action
Vasodilation and Cardiac Effects
Intermedin activates CLR/RAMP complexes on vascular smooth muscle and endothelial cells, stimulating adenylate cyclase to increase cAMP. This causes smooth muscle relaxation and vasodilation via PKA-mediated MLCP activation. On endothelial cells, intermedin stimulates eNOS-derived NO production, adding a NO-dependent vasodilatory component. In the heart, it reduces preload and afterload, decreases heart rate in some preparations, and may improve cardiac contractility at lower doses through cAMP-mediated inotropy.
Cardioprotection and Ischemia
Intermedin activates pro-survival kinases (Akt, ERK1/2) in cardiomyocytes, protecting against ischemia-reperfusion injury. It reduces mitochondrial permeability transition pore opening, preserves ATP levels, and decreases ROS generation during reperfusion. In rodent MI models, intermedin infusion reduces infarct size and improves post-MI cardiac function. It also reduces cardiomyocyte apoptosis via PI3K/Akt and PKA-CREB pathways.
Fluid Homeostasis and Renal Effects
Intermedin is produced in the kidney and acts locally on tubular cells to regulate sodium and water reabsorption. It reduces aldosterone secretion and antagonizes angiotensin II-mediated vasoconstriction and salt retention, suggesting a natriuretic/diuretic role. In models of renal ischemia, intermedin reduces tubular injury and inflammation, making it a protective autocrine/paracrine signal in the kidney.
Research Summary
Cardiac Ischemia Protection
PreclinicalIntermedin pretreatment and post-treatment in rodent ischemia-reperfusion models consistently reduces infarct size and improves cardiac function. The therapeutic window appears favorable, with benefits seen even when given 15 minutes after ischemia onset. Mechanistic studies implicate cAMP, Akt, and eNOS as key mediators. These preclinical results position intermedin as a candidate for acute MI management.
Pulmonary Hypertension
PreclinicalIntermedin gene transfer or protein administration reduces right ventricular pressure and pulmonary vascular remodeling in hypoxia-induced and monocrotaline-induced pulmonary hypertension models. It reduces pulmonary arterial smooth muscle proliferation and promotes vasodilation, complementing adrenomedullin's known effects in this disease context.
Preeclampsia and Vascular Disease
Clinical AssociationPlasma intermedin is reduced in preeclampsia, a hypertensive disorder of pregnancy characterized by deficient vasodilatation. This parallels adrenomedullin findings and suggests the cgrp/" class="wiki-internal-link">CGRP/CLR/RAMP family is a critical vasodilatory system in pregnancy. Intermedin supplementation in preeclampsia animal models improves fetal outcomes and maternal blood pressure control.
Calculate your Intermedin dose Vial strength, BAC water, exact syringe draw in IU. Free, no signup. Open Calc →
Research Protocols
| Goal | Dose | Frequency | Route |
|---|---|---|---|
| Cardiovascular protection | 1-10 pmol/kg/min IV infusion | Acute 60-min infusion | IV |
| Cardioprotection (MI model) | 100 pmol/kg IV bolus | Pre- or post-ischemia | IV |
| Renal protection study | 10-50 pmol/kg/min | 2-4 hours infusion | IV infusion |
No established human dosing. All parameters from animal preclinical models. Intermedin is not in clinical development as a standalone agent.
Interactions
Safety Profile
Intermedin is endogenous and structurally related to adrenomedullin, which has been studied in clinical trials with acceptable safety. The primary adverse effect anticipated is hypotension due to vasodilation, particularly at higher doses. Reflex tachycardia may occur. No human clinical data exists for exogenous intermedin. Given its overlap with adrenomedullin's mechanism, lessons from adrenomedullin clinical trials (sepsis, PE) are instructive. Short half-life limits cumulative effects.
References
- [1]Roh J, et al. Intermedin is a calcitonin/calcitonin gene-related peptide family peptide acting through the calcitonin receptor-like receptor/receptor activity-modifying protein receptor complexes. J Biol Chem. 2004.
- [2]Bell D, et al. Intermedin (adrenomedullin 2): cardiovascular actions and translational implications. Drug Discov Today. 2016.
- [3]Chaston DJ, et al. Intermedin (adrenomedullin-2) mediates arterial vasodilation. Eur J Pharmacol. 2008.