Chronic ACTH Administration and the Development of Hypertension in Rats

Abstract

Experimental hypertension can be induced by t h e administration of pharmacologic doses of adrenal mineralocorticoids (1, 2); there is considerable species variation in response, however, and the animal model studied most extensively is the saline-loaded, uninephrectomized rat given deoxycorticosterone (DOC) acetate. Based on previous observations in sheep by Scoggins et al. (3, 4) that ACTH administration induced hypertension, it was reasoned that chronic administration of ACTH to rats might stimulate endogenous adrenal steroidogenesis and induce hypertension in this species also. In the present study, the effects of continuous ACTH infusion on blood pressure and electrolyte and water metabolism were evaluated in the rat.Methods. All rats (Sprague -Dawley males) were housed individually in stainless s t e e l m e t a b o l i c c a g e s a n d k e p t in temperature-controlled rooms which were maintained on a 12-hr light-dark cycle beginning at 5 AM. Distilled water and powdered Purina rat chow (sodium content: 1.37-1.50 meq/lO g; potassium content: 2.45-2.68 meq/l0 g) were available ad libitum. Daily sodium and potassium balances were estimated from measurements of ingested and excreted (urinary) sodium and potassium. Urine volume and body weight also were measured daily. Systolic blood pressures were measured daily by the tail artery occlusion method; the recorded value was the average of three or four successive determinations.Hypertensive studies. Both a control group ( n = 7) and an experimental group ( n = 7) were studied. Systolic blood pressures were measured for 3 consecutive days in each rat. Immediately after determining blood pressure on the third day, seven of the rats were lightly anesthetized with ether, a small skin incision was made on the dorsal region of the neck, and a minipump (Alza, Model 1701) containing a saline solution of ACTH (Acthar, Armour Pharmaceutical Co.) was inserted subcutaneously. The concentration of ACTH in the infusate was adjusted so that a pharmacologic dose of 1 .O unit per day of ACTH was delivered in a volume of 24 pl (1.0 pl/hr); ACTH was infused subcutaneously for a total of 7 consecutive days. Systolic blood pressures were measured daily in both the control (no drug; n = 7) and the ACTH-treated rats ( n = 7) for the 7 days of ACTH infusion and for an additional 7 days of recovery.Hormonal studies. Both a control group ( n = 8) and an experimental group ( n = 8) of male rats were used in this part of the study also. After 2 days of systolic blood pressure measurements in each rat, eight rats were prepared with minipumps containing ACTH as described above. Blood pressures were followed daily for 5 days of ACTH infusion (1 .O unit per day). The rats were decapitated on the morning of the sixth day (8 AM) after 5 days of ACTH infusion; plasma renin activity (PRA) was determined from blood collected during the first 5 sec after decapitation while plasma concentrations of aldosterone (PAC) and corticosterone (PCC) were determined from a second sample collected during the ...

Natriuretic and hypertensive activities reside in a fragment of ACTH.

“…In addition, in at least one report the renin-angiotensin system was found to be normal or suppressed in states of high circulating ACTH. 8 Recently, Lohmeier and Carroll 20 extensively investigated the chronic effects of ACTH administration on blood pressure and suggested that the hypertensive effects might be due to increased secretion of an unknown pressor factor. Attempts to totally duplicate the hypertensive effects of ACTH infusions by glucocorticoid and/or mineralocorticoid in- fusions were not successful.…”

Aldosterone infusion into the rat and dose-dependent changes in blood pressure and arterial ionic transport.

“…The plasma aldosterone levels both in control and hypertensive rats reported in our study are comparable to those previously reported by others in experimentally induced high aldosterone states. Freeman et al 20 reported plasma aldosterone levels of 37.9 ± 8.0 ng/dl in rats made hypertensive by a 5-day constant infusion of ACTH, compared to 8.7 ± 1.4 ng/dl in their control animals. Plasma aldosterone levels in renal hypertensive rats (two-kidney, one clip) reported by the same group 2 1 were 19.5 ±5.5 ng/dl in 5-week hypertensive animals and 54.0 ± 28.5 ng/dl for 10-week hypertensive rats compared to 11.6 ± 1.4 ng/dl in control animals.…”

Effects of prolonged ACTH treatment on adrenal steroidogenesis and blood pressure in rats

“…This paper therefore re-examines some of the functional aspects of adrenocortical zonation after prolonged ACTH treatment. Furthermore, since this is known to induce hypertension in several species (Scoggins et al 1974;Haack et al 1978;McCaa 1978;Henderson & McCaa 1979;Freeman et al 1980), changes in blood pressure in ACTH-treated rats were monitored in an at¬ tempt to relate them to changes in adrenal func¬ tion.…”