Adrenocorticotrophin dose-response relationships in the rat: haemodynamic, metabolic and hormonal effects

To determine adrenocorticotrophin dose-response relationships for increase of blood pressure and metabolic parameters of the Sprague-Dawley rat.

We injected 120 male Sprague-Dawley rats twice daily subcutaneously for 10 days with 0.5, 1, 5, 50, 100, 200 or 500 microg/kg synthetic adrenocorticotrophin per day (all n = 10) or subjected them to sham injection (0.9% NaCl; n = 50). Systolic blood pressure, 24 h food intake, water intake, urine volume and body weight were measured. Data from a further 45 rats treated with 500 microg/kg per day adrenocorticotrophin in previous studies were included in the blood pressure analyses. After we had killed these rats, their organ weights (kidney, heart, adrenal) and plasma electrolyte, adrenocorticotrophin and serum corticosterone concentrations were measured.

On the final day of treatment systolic blood pressure of sham-injection control rats was 123 +/- 1 mmHg (n = 50). Compared with sham treatment, a low dose of adrenocorticotrophin (1 microg/kg per day) increased systolic blood pressure from 122 +/- 1 to 130 +/- 2 mmHg (P < 0.001) without any metabolic effects, whereas a high dose of adrenocorticotrophin (500 microg/kg per day) increased systolic blood pressure from 121 +/- 1 to 150 +/- 2 mmHg (P < 0.001, n = 55) with increases in intake of water and urine volume (P < 0.001, n = 10) and a decrease in body weight (P < 0.001, n = 10). Plasma adrenocorticotrophin and serum corticosterone concentrations for the sham-injection control group were 162 +/- 12 pg/ml (36 +/- 3 pmol/l) and 376 +/- 18 ng/ml (1038 +/- 50 nmol/l), respectively. Plasma adrenocorticotrophin concentration was elevated by injections of 100 (P < 0.05), 200 (P < 0.01) and 500 microg/kg adrenocorticotrophin per day (P = 0.001). Serum corticosterone concentration was not significantly different from that of sham-injection rats with 0.5-5 microg/kg adrenocorticotrophin per day but was increased by injection of 50-500 microg/kg adrenocorticotrophin per day (P < 0.001).

These results define 1 microg/kg adrenocorticotrophin per day, administered subcutaneously, as the threshold dose for causing a rise in blood pressure in the rat Thus administration of adrenocorticotrophin increases systolic blood pressure at doses that induce minimal adrenocorticotrophin metabolic effects. Administration of a low dose of adrenocorticotrophin to the rat is a suitable model for stress-induced hypertension.