Structural modifications of apelin-12 molecule differently affect cardiac function

Purpose: Apelin-12, the short active fragment of natural apelin-77, and its synthetic analog apelin-12-2 have been shown to exert beneficial effects in experimental heart failure. The aim of this study was to explore effects of other analogs of apelin-12 molecule. Methods: The cardiac function of ketamine-anesthetized Wistar rats has been studied using catheterization of the left ventricle (LV) with Millar micromanometer and thoracic electrical impedance. Electric and pressure signals were sent to a computer via an analog-to-digital converter. Bolus injections of apelins were applied with subsequently increasing rate (0.05-5.0 mg/kg) at 10-min intervals. Results: Substitution of methionine in apelin-12 molecule on norleucine (apelin-12-1 analog) shortened duration of hypotensive effect due to more rapid recovery of LV systolic pressure and LV dP/dtmax associated with an increase dP/dtmax/P index and the shortening of duration of preejection time. Further modifications were made on the basis of apelin-12-1 molecule. Replacement of arginine at N-end on methylarginine (apelin-12-2 analog) was associated with removal of hypotensive effect, increased enddiastolic and systolic LV pressures as well as the rate of increment of impedance signal suggesting increased ejection speed. Replacement of hydroxyl group at C-end of this molecule by amide group (apelin-12-3 analog) reduced the extent of positive inotropic effect, but increased the relaxation constant. Finally, replacement in the latter molecule of methylarginine at the N-end by nitroarginine (apelin-12-4 analog) while retaining relaxation acceleration, exerted hypotensive effect with a reduction of LV systolic pressure, but slightly increased ejection speed and dP/dtmax/P index. Conclusions: Hypotensive effect of apelin analogs is associated with the presence of arginine and not methylarginine at N-end of molecule. The combination of methylarginine at N-end and OH-group at C-end facilitate positive inotropic effect of an analog. The presence of NH2-group instead of OH-group at C-end results in fastened relaxation. Thus, these modifications are capable to influence different targets in myocardial and vascular cells.