MECHANISM OF ACTION OF HEXARELIN AND GHRP-6 - ANALYSIS OF THE INVOLVEMENT OF GHRH AND SOMATOSTATIN IN THE RAT

We have recently reported oral and parenteral bioactivity for a new GH -releasing peptide, hexarelin. In the present study, we have examined the neuroendocrine mechanism by which hexarelin and GHRP-6, two GH-rel easing peptides, mediate their actions. Although previous studies have looked at the role of growth hormone-releasing hormone (GHRH) and som atostatin in regulating the action of GHRP-6 in culture and in stresse d animals, our study looked at the role of both somatostatin and GHRH in regulating the action of hexarelin as well as GHRP-6 in conscious a nd freely-moving, nonstressed rats. Adult male rats, prepared with ind welling jugular catheters, were pretreated i.v. with either control an tiserum (CTLas), growth hormone-releasing hormone antiserum (GHRHas), somatostatin antiserum (SSas), or both GHRHas and SSas. Animals were t hen treated i.v. with 25 mu g/kg of either hexarelin or GHRP-6 4 h aft er i.v. antisera pretreatment. Blood samples were collected every 20 m in for the 3 h prior to peptide treatment and at 5, 10, 15, 20, 40 and 60 min following hexarelin or GHRP-6 injection. The peak plasma GH re sponses in rats pretreated with CTLas were 552 +/- 125 ng/ml following hexarelin administration and 386 +/- 132 ng/ml following GHRP-6 admin istration. Rats pretreated with SSas exhibited peak GH responses follo wing hexarelin or GHRP-6 of 702 +/- 115 and 312 +/- 42 ng/ml, respecti vely. These plasma GH responses were similar to those observed in the CTLas-pretreated animals. Hexarelin injection resulted in a peak GH re sponse of 372 +/- 106 ng/ml in GHRHas-pretreated rats, while GHRP-6 in jection resulted in a peak response of 135 +/- 40 ng/ml. Rats pretreat ed with bath GHRHas and SSas responded to hexarelin administration wit h a GH peak of 322 +/- 66 ng/ml and to GHRP-6 with a response of 134 /- 39 ng/ml. GH responses noted in these animals were similar to the r esponses noted in GHRHas-pretreated rats. The GH responses elicited fo llowing either GHRHas or both GHRHas and SSas pretreatment were signif icantly lower than those responses observed in rats pretreated with ei ther CTLas or SSas alone. Repeated measures analysis of the variance o f peak plasma GH responses as well as of the area under the GH respons e curves allowed us to reach the following conclusions: (1) hexarelin was more effective in eliciting GH release than was GHRP-6 at the dose tested; (2) GHRHas inhibited the GH response to both hexarelin and GH RP-6, and (3) SSas pretreatment did not affect the GH response to the GH-releasing peptides. Therefore, we conclude that these two GH-releas ing peptides elicit GH release via a GHRH-dependent pathway. In additi on, because both hexarelin and GHRP-6 are bioactive regardless of circ ulating somatostatin tone, these GH-releasing peptides must also act t o suppress somatostatin release from the hypothalamus or somatostatin effectiveness at the pituitary.