Time course and dose response of relaxin-mediated renal vasodilation, hyperfiltration, and changes in plasma osmolality in conscious rats

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Abstract
The pregnancy hormone relaxin elicits renal vasodilation, hyperfiltration, and osmoregulatory changes when chronically administered to conscious, nonpregnant rats. The objective in this study was to determine the dose response and time course of hormone action, as well as the time required for recovery on stopping its administration. The threshold dose of recombinant human relaxin (rhRLX) for renal vasodilation and reduction in plasma osmolality 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 was observed during the 0.4 μg/h infusion rate (serum rhRLX of ∼11 ng/ml), which was comparable to our previous work using a 4.0 μg/h (serum rhRLX of ∼20 ng/ml). In contrast, a dose of 40 μg/h was ineffective (serum rhRLX of ∼80 ng/ml). When 4.0 μg/h rhRLX was administered by osmotic minipump for shorter periods (≤24 h), renal circulatory and osmoregulatory changes were observed by ≤6 h. After removal of the osmotic minipump, these changes persisted for at least 12 h, but they were fully restored by 24 h. Even briefer administration of 4.0 μg/h rhRLX by intravenous infusion showed an onset of action in the kidney by 1-2 h. In contrast, the 40 μg/h dose of rhRLX elicited minimal effects, and comparable to our earlier report, 4.0 μg/h purified porcine relaxin was also relatively ineffective during short-term intravenous administration. In conclusion, the effect of relaxin on the renal circulation and osmoregulation is biphasic, insofar as high doses are relatively inactive, and the onset of action is more rapid than previously believed. These findings may be important to consider when evaluating relaxin in the treatment of renal disease.