Recombinant Human Relaxin (rhRLX) Modifies Systemic Arterial Properties in Conscious Rats Irrespective of Gender, but in a Dose-dependent Fashion

Daniel O. Debrah
University of Pittsburgh

Because relaxin is a potent renal vasodilator that mediates the renal vasodilation and hyperfiltration of pregnancy in conscious rats, we reasoned that it might also contribute to the broader cardiovascular changes of pregnancy. We began investigating this concept by testing whether relaxin can modify systemic arterial hemodynamics and load when chronically administered to nonpregnant female and male rats. Specifically, we aimed to determine whether chronic administration of recombinant human relaxin (rhRLX) by osmotic minipump (4µg/h) to nonpregnant rats, yielding serum concentrations corresponding to early to mid-gestation (~10-20ng/ml), modifies cardiac output (CO) and systemic arterial load, and whether these modifications occur irrespective of gender. We also aimed to determine whether higher infusion rates of rhRLX (50µg/h) administered to nonpregnant female rats yielding serum concentrations corresponding to late pregnancy (~80ng/ml) will further modify CO and systemic arterial properties comparable to late gestation.
CO was measured using the thermodilution technique and instantaneous aortic pressure was acquired using a blood pressure telemetry system. Systemic arterial load was quantified in terms systemic vascular resistance (SVR) and global arterial compliance (ACg) which were calculated from the measured aortic pressure and CO.
Chronic administration of rhRLX to conscious, female, nonpregnant rats reduced from baseline the steady arterial load by decreasing SVR (15.5±2.4%), increased CO (19.2±4.8%), and reduced the pulsatile arterial load by increasing ACg (21.4+3.6%). Comparable to female, rats rhRLX administration to male rats increased from baseline both CO (20.5±4.2%) and ACg (19.4±6.9%), and reduced SVR (12.7±3.9%). In a separate group of female rats, relaxin administration also regulated the passive mechanics of small renal arteries indicating that, in addition to reduction in vascular smooth muscle tone, modification of the vascular structure (e.g., extracellular matrix) contributes to the increase in global AC. The higher dose of rhRLX administered to conscious female rats resulted in minimal and insignificant changes in CO, ACg and SVR.
We conclude: (1) rhRLX administration to conscious, nonpregnant rats increases CO and ACg, and reduces SVR irrespective of gender, and (2) at high serum concentrations of rhRLX, significant alterations in CO and systemic arterial load fail to occur. These observations are similar to those previously reported for the renal circulation (J Appl Physiol, 95:1509-1514, 2003) and suggest a role for relaxin in the systemic cardiovascular changes of pregnancy, as well as novel therapeutic potential for relaxin in modifying arterial stiffness and cardiac afterload
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