Metabolic effects of ACTH in the sheep

The regional hemodynamic effects of 5 days of intravenous infusion of corticotropin (ACTH) (5 /xg/kg per day) were examined in conscious sheep (n=8). Mean arterial pressure increased from 81 ±2 to 93±3 mm Hg (/><.001) on day 2 of ACTH and remained at this level during the infusion. Cardiac output increased from 5.13±0.19 to 6.06±0.33 L/min (/ ) <.O1) because of an increase in stroke volume from 65±4 to 79±8 mL per beat (P<.01); heart rate remained unchanged. ACTH did not alter total peripheral conductance but had differential effects on regional conductances. Mesenteric conductance fell from 5.8±0.2 to a minimum of 4.9±0.3 (mL/min)/mm Hg (P<.05), and renal conductance increased from 3.5±0.3 to 4.6±0.3 (mL/min)/ mm Hg (P<.001). There was a small increase in iliac conductance (f<.05) and no change in coronary conductance. Mesenteric and iliac conductances fell progressively over 24 to 48 hours, whereas renal conductance increased rapidly after 3 hours of ACTH, reaching a maximum after 6 hours. Renal blood flow was increased during ACTH infusion from 278±18 to 403±23 mL/min (P<.001); mesenteric C orticotropin (ACTH) administration increases blood pressure in both humans 1 -3 and experimental animals. 46 In conscious sheep intravenous infusion of ACTH results in an increase in arterial blood pressure within 24 hours, which is sustained as long as ACTH is infused over a 5-to 10-day period. 7 ACTH hypertension can be reproduced by infusion of a combination of adrenocortical steroids and is dependent on the presence of the adrenal glands but not on intact adrenal innervation. 48 The hypertension is associated with an increase in plasma volume, without a significant change in extracellular fluid volume.9 A volume component of the hypertension is also suggested by the finding that the ACTH-induced rise in blood pressure can be modulated by alterations in sodium status. Long-term sodium loading magnifies the pressure rise produced by ACTH, and long-term dietary sodium restriction blunts the rise.10 " The hemodynamic profile of ACTH hypertension in conscious sheep is characterized by an elevated cardiac output (CO), with no change in total peripheral resistance. peripheral resistance to remain constant in the presence of renal vasodilatation, vasoconstriction must be occurring in other vascular beds. In the present study the effect of ACTH infusion on regional hemodynamics was examined in conscious sheep instrumented with electromagnetic flow probes to measure CO and with transittime flow probes to measure regional arterial blood flows. The aim of the study was to examine the regional hemodynamic effects of ACTH and to determine whether ACTH acts selectively to cause vasoconstriction in one vascular bed or whether the vasoconstriction is a more generalized phenomenon. MethodsMerino cross ewes (35-to 45-kg body weight), oophorectomized and with carotid artery loops, were housed in metabolism cages in association with other sheep. They were not used for at least 4 weeks after surgery until they were accustomed to ...

Section: Differential Regional Hemodynamic Effects Of Corticotropin Imentioning

confidence: 98%

Differential regional hemodynamic effects of corticotropin in conscious sheep.

Bednarik

May

1994

“…In these studies ACTH was injected intramuscularly (Synacthen depot, Ciba-Geigy, Basel, Switzerland) or infused intravenously (Synacthen, Ciba-Geigy) at 20 /xg/kg/day, a rate that has been shown to produce maximal adrenocortical steroid output. 2 The aim of the present study was to investigate the threshold and dose-response relationships for the effects of ACTH on blood pressure and other metabolic parameters. Corticotropin was infused at five different rates (range, 0.5-10 Mg/kg/day) f°r 3 days into conscious sheep.…”

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confidence: 99%

Onset and dose relationships of ACTH effects on blood pressure in sheep.

Scoggins¹,

Allen²,

Coghlan³

et al. 1985

SUMMARY The threshold and dose-response relationships for the blood pressure and metabolic effects of adrenocorticotropic hormone (corticotropin, ACTH) were examined in conscious sheep. Corticotropin was infused at five rates (0.5 jig/kg/day, n -4; 1 /ig/kg/day, n = 4; 2 /xg/kg/day, n = 6; 5 jxg/kg/day, n = 5; and 10 ^tg/kg/day, n = 5) for 3 days, and the time of onset of the rise in blood pressure was assessed with a computer-based system. The effects of equimolar infusion of /3-endorphin and ACTH at 5 ^ig/kg/hour also were examined. Corticotropin infusion at 0.5 ^g/kg/day had no effect on mean arterial pressure. An ACTH infusion of 1.0 /xg/kg/day significantly increased mean arterial pressure (p < 0.001), but the rise was less than that at the three higher doses, all of which produced similar effects. Changes in heart rate were significant at the 10 /xg/kg/day level only (p < 0.01). Initial urinary sodium retention was present at the three higher but not the two lower rates of infusion. Corticotropin infusion had no effect on urinary potassium excretion at any rate but produced hypokalemia at rates of 1.0 /xg/kg/day and above, wTiich appeared to be dose related. Plasma sodium concentration was increased significantly only at the three higher rates (p < 0.001). Urine volume and water intake were increased at ACTH infusion rates of 2.0 to 10 /xg/kg/day. Blood cortisol concentration was increased in the 1 /xg/kg/day group and was maximal in the 2 /xg/kg/day group. Blood corticosterone levels were maximal at infusion rates of 1 /xg/kg/day. A well-defined diurnal rhythm of mean arterial pressure was apparent during the 3 control days. At 10 /xg/kg/day ACTH produced an increase in mean arterial pressure within 8 hours. Infusion of equipotent amounts of ACTH and /3-endorphin did not modify ACTH-induced hypertension. These results indicate that (1) increases in blood pressure can be produced with ACTH infusion at rates that produce plasma ACTH concentrations in the physiological range; (2) the rise in blood pressure occurs within 8 hours of ACTH infusion; (3) ACTH-induced hypertension is unlikely to be due to inhibition of /3-endorphin secretion. (Hypertension 7: 287-291, 1985) KEY WORDS • corticotropin • hypertension • /3-endorphin • corticosteroids T HE administration of adrenocorticotropic hormone (ACTH or corticotropin) to sheep has been shown to produce an adrenally dependent increase in blood pressure within 24 hours, which is associated with hypokalemia and hypernatremia.1 After an initial fall in sodium excretion for 24 to 48 hours, sodium excretion returned to preinfusion values. Urine volume and water intake were increased. In these studies ACTH was injected intramuscularly (Synacthen depot, Ciba-Geigy, Basel, Switzerland) or infused intravenously (Synacthen, Ciba-Geigy) at 20 /xg/kg/day, a rate that has been shown to produce maximal adrenocortical steroid output. 2The aim of the present study was to investigate the threshold and dose-response relationships for the effects of ACTH on blood pressure and ot...

“…Schreiberet al 6 have shown that ACTH 1 -24 is natriuretic. Other investigators 7 " 10 have produced hypertension by chronic administration of ACTH, although the underlying hypothesis in their work is that the hormone was working through an adrenocortical mechanism. Since natriuretic and pressor activities have been attributed to an NH, we hypothesized that all of these properties might be found in a small fragment of ACTH or /3LPH.…”

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confidence: 99%

“…14 -' 7 We now report the natriuretic and cardiovascular effects of ACTH Methods and Materials ACTH 4 -10 or (D-Phe 7 ) ACTH 4 -10 (Bachem, Inc., Torrance, California) was dissolved in 75 mM saline at a concentration of 10~3 M, and the pH adjusted to 7 with NaH 2 PO 4 . Peptide solutions were made fresh daily, since in our hands degradation and loss of biological activity occurred in 1 to 3 days in frozen solutions even when they were acidic.…”

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confidence: 99%

Natriuretic and hypertensive activities reside in a fragment of ACTH.

Gruber¹,

Kleín²,

Hutchins³

et al. 1984

The hypertensive and natriuretic effects of chronic administration of adrenocorticotrophic hormone (ACTH) cannot be duplicated by the administration of glucocorticoids and/or mineralocorticoids. We investigated the effects of a fragment of this hormone (ACTH4-10) and an analog of the fragment (D-Phe7) ACTH4-10 and found them to have pressor and cardioaccelerator actions in rats as determined by bolus intravenous (i.v.) injections of 30 to 1000 nmol/kg. The pressor and cardioaccelerator effects of (D-Phe7) ACTH4-10 were attenuated by alpha-receptor (phentolamine) and beta-receptor (metoprolol) antagonists. The cardiovascular actions of ACTH4-10 were produced in adrenalectomized or ganglionic-blocked (with mecamylamine) rats. At a lower dose (7 nmol/kg i.v.), ACTH4-10 was natriuretic and had a pattern of activity similar to that of a larger ACTH fragment, alpha-melanocyte-stimulating hormone. Extraadrenal effects of the intact ACTH molecule or the in vivo production of an ACTH4-10-like fragment from ACTH may contribute to the hypertensive and natriuretic actions associated with this hormone.