The endothelial vasodilation mechanism(s) has been investigated in aortic rings of hypophysectomized male rats as well as hypophysectomized rats treated for 7 days with growth hormone (GH, 400 microg/kg, s.c.) or hexarelin (80 microg/kg, s.c.). Tissue preparations from intact animals were taken as controls. The results obtained indicate that the release of 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha) from aortic rings of hypophysectomized rats was markedly reduced (51%; p<0.01) as compared with that of control preparations; the peak response to cumulative concentration of endothelin-1 (ET-1, from 10(-11) to 10(-5) M) was increased 2.4-fold (p<0.01) versus controls; the relaxant activity of acetylcholine (ACh, from 10(-10) to 10(-4) M) in norepinephrine-precontracted aortic rings was reduced by 39.5+/-4.4%. Pretreatment of hypophysectomized rats with GH or hexarelin markedly antagonized the hyperresponsiveness of the aortic tissue to ET-1 and allowed a consistent recovery of both the relaxant activity of ACh and the generation of 6-keto-PGF1alpha. Collectively these findings support the concept that dysfunction of vascular endothelial cells may be induced by a defective GH function. Because a replacement regimen of GH restored the somatotropic function and increased plasma insulin-like growth factor-I (IGF-I) concentrations in the hypophysectomized rats, it is suggested that IGF-I may have protected the vascular endothelium acting as a biologic mediator of GH action. In contrast to GH, hexarelin replacement neither increased body weight nor affected the plasma concentrations of IGF-I, indicating that its beneficial action on vascular endothelium was divorced from that on somatotropic function and was likely due to activation of specific endothelial receptors.

We previously reported that induction of selective GH deficiency in the rat exacerbates cardiac dysfunction induced by experimental ischemia and reperfusion performed on the explanted heart. In the same model, short-term treatment with hexarelin, a GH-releasing peptide, reverted this effect, as did GH. To ascertain whether hexarelin had non-GH-mediated protective effects on the heart, we compared hexarelin and GH treatment in hypophysectomized rats. Hexarelin (80 g/kg sc), given for 7 days, prevented exacerbation of the ischemiareperfusion damage induced by hypophysectomy. We also demonstrate that hexarelin prevents increases in left ventricular end diastolic pressure, coronary perfusion pressure, reactivity of the coronary vasculature to angiotensin II, and release of creatine kinase in the heart perfusate. Moreover, hexarelin prevents the fall in prostacyclin release and enhances recovery of contractility. Treatment with GH (400 g/kg sc) produced similar results, whereas administration of EP 51389 (80 g/kg sc), another GH-releasing peptide that does not bind to the heart, was ineffective.In conclusion, we demonstrate that hexarelin prevents cardiac damage after ischemia-reperfusion, and that its action is not mediated by GH but likely occurs through activation of specific cardiac receptors. (Endocrinology 140: 4024 -4031, 1999)

In a previous work, we reported that passive immunization with anti-growth hormone-releasing hormone (GHRH) antibodies (GHRH-Ab) in neonatal rats caused disruption of somatotropic function that was still present 60 d posttreatment. We studied the reversibility of this condition by growth hormone (GH) replacement therapy. Neonatal rats received GHRH-Ab (50 ~U r d t , s.c.) or normal rabbit serum every second day from birth up to postnatal d 10 and received hGH (0.4 &g body weight, s.c., b i d . ) or vehicle in a 2 x 2 factorial design. Animals were studied on d 11 of age. In GHRH-Abtreated rats, GH therapy 1 ) counteracted the reduced body weight and low plasma IGF-I levels; 2) failed to modify the reduced pituitary weight and GH content; 3) further reduced the low plasma GH levels; 4) partially restored the defective GH responsiveness to GHRH; 5) failed to modify the reduced hypothalamic somatostatin and increased GHRH gene expression in the hypothalamus; and 6) reverted the decreased pituitary somatostatin binding. Morphologic and morphometric evaluation of the pituitary gland from GHRH-Ab+GH pups showed that the number of GH-labeled structures was lower than in normal rat serum-GH-treated pups, whereas the total GH immunoreact~ty per unit surface, an index of intracellular hormone concentration, was slightly higher than in vehicle-GH or GHRH-Ab pups. As determined by electron microscopy, somatotropes from GHRH-Ab+GH pups had morphologic features of high cellular activity. It appears that in GHRH-deprived pups GH replacement therapy can normalize most but not all altered indices of the somatotropic function. The effects of GH are mainly directed at the pituitaly, whereas the sensitivity of the hypothalamus to GH replacement is lower. (Pediatr Res 36: 315-322, 1994) Abbreviations GH, growth hormone GHRH, growth hormone-releasing hormone GHRH-Ab, anti-GHRH-antibodies NRS, normal rabbit serum dCTP, deoxycytidine triphosphate PRL, prolactin SS, somatostatin Recent studies by us (1,2) and by other groups (3,4) have shown that rat pups treated with GHRH-Ab may represent a suitable animal model for the study of the human growth disorders caused b y a primary hypothalamic dysfunction. Neonatal administration of GHRH-Ab permanently inhibits the growth rate and alters several indices of the hypophyseal somatotropic function (I). Received November 11, 1993: accepted March 21, 1994. Correspondence and reprint requests: Eugenio E. Muller, MD. Department of Pharmacology. Chemotherapy and Toxicology. University of Milan, via VanviIt is presently unknown whether these changes are due t o the G H R H deficiency itself o r to the consequent reduction of G H secretion. Therefore, we studied the effects of concomitant G H and GHRH-Ab treatment. W e have administered G H daily to GHRH-deprived and control pups from postnatal d 1 to 10 and subsequently evaluated in vivo and in vitro several hypothalamic and pituitary indices of somatotropic activity. METHODStelli 32.