EFFECTS OF CONTINUOUS AND REPETITIVE ADMINISTRATION OF A POTENT ANALOG OF GH-RH(1-30)NH2 ON THE GH RELEASE IN RATS

We examined the desensitization and/or sensitization phenomenon in the pituitary GH responsiveness induced by continuous infusion and multip le pulses at different frequencies of a potent GH-RH analog [D-Ala2, L eu15, Nle27, GABA30-GH-RH(1-30)amide]. Further, we investigated the co rrelation between doses and GH responses, as well as between pulse fre quency and GH responses in male rats in vivo and in vitro. Long-term, continuous administration was attained by osmotic minipumps releasing low and high doses of the analog for 14 days. The effects of repetitiv e administration of the GH-RH analog on the pituitary GH release was i nvestigated by injecting 4-6 pulses of the analog at different doses a nd pulse frequencies. The in vitro experiments were performed in the s uperfused rat anterior pituitary cell system. Pituitary cells were cha llenged with continuous, repetitive and simultaneous continuous and re petitive perfusion of the analog. Continuous infusion with low doses o f the GH-RH analog in vivo induced sensitization of the pituitary GH-s ecretory responsiveness and resulted in moderately increased GH releas es (129% of the control) to additional bolus injections of the same an alog, whereas continuous stimulation of the pituitary with high doses of the GH-RH analog evoked desensitization and resulted in blunted GH responses (29% of the control). Despite the desensitization of the pit uitary GH-secretory responsiveness, high doses of the analog elevated the serum GH concentration to 3 10% and induced acceleration of body w eight gain (I 60% of the control). Repetitive pulsatile administration of the GH-RH analog evoked both sensitization and desensitization of the pituitary GH-secretory responsiveness, depending on the dose and p ulse frequency administered. Low doses administered at low frequency i nduced a sensitization phenomenon, which appeared after the 3rd inject ion, and no desensitization could be seen even after the 6th injection . In contrast, the same low doses applied at high frequency did not sh ow sensitizing effects but induced desensitization after the 3rd injec tion. When the frequency of impulses was further increased, desensitiz ation appeared already after the 2nd injection. High doses of the anal og resulted in desensitization after the 4th injection given at low fr equency and after the 2nd injection given at high frequency. These res ults demonstrate that the appearance of the desensitization to repetit ive pulses of our GH-RH analog is dependent rather on the frequency th an the dose of pulses. Our results from the in vitro experiments show that desensitization can develop without depletion of the intracellula r GH pool and that the combination of the continuous and repetitive ad ministration of our GH-RH analog might be more effective than one of t hem alone. In summary, our results demonstrate the therapeutic effecti veness of our GH-RH analog in continuous administration and permit a b etter understanding of the mechanism of desensitization of the GH-secr etory responsiveness.