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1 Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM, USA
2 Department of Obstetrics, Gynecology and Reproducrive Sciences, and of Cell Biology and Physiology, Magee- Womens Research Institute and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
* To whom correspondence should be addressed. E-mail: rsikpc{at}mwri.magee.edu.
The pregnancy hormone relaxin mediates the renal vasodilation, hyperfiltration and osmoregulatory changes of pregnancy in rats. The hormone also elicits marked vasodilation of the renal circulation and decreases in plasma osmolality when administered to nonpregnant rats. The objective here was to further investigate the renal vasodilatory and osmoregulatory effects of relaxin in conscious rats, i.e., to determine the dose response and time course of hormone action, as well as the time required for recovery upon stopping relaxin administration. The threshold dose for rhRLX (recombinant human relaxin) was 0.15 µg/h when given by subcutaneous osmotic minipump for 2 days--an infusion rate that achieved circulating levels of ~6 ng/ml. The peak response for renal vasodilation and reduction in plasma osmolality was observed during the 0.4 µg/h infusion rate that produced serum levels of ~11 ng/ml, and was comparable to our previous work using a 4.0 µg/h infusion which reached serum concentrations of ~ 20 ng/ml. In contrast, a dose of 40 µg/h did not affect the renal circulation or plasma osmolality (serum rhRLX ~ 80 ng/ml). When 4 µg/h rhRLX was administered by osmotic minipump for shorter periods of time (
24 h), renal vasodilation and hyperfiltration and reduced plasma osmolality were observed by 6 h. Following removal of the osmotic minipump, these changes in renal function and osmoregulation were still observed after 12 h, but they were fully restored by 24 h. Even more short-term administration of 4.0 µg/h rhRLX by intravenous infusion showed an onset of action in the kidney by 1-2 hours. In contrast, the 40 µg/h dose of rhRLX showed only modest effects at best, and comparable to our earlier report, 4 µg/h purified porcine relaxin was also relatively ineffective during short-term administration. In conclusion, (1) the effect of relaxin on the renal circulation and osmoregulation is biphasic, insofar as high doses are relatively inactive, and (2) the onset of action is considerably more rapid than previously believed. These findings may be important to consider when evaluating relaxin in the treatment of renal disease.
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