Development Of Adrenal Regeneration Hypertension Research Articles

Natriuretic Properties of Melanocyte-Stimulating Hormones

Proopiomelanocortin (POMC) is a protein that contains the amino acid sequences of numerous peptide hormones, including the melanocyte-stimulating hormones (MSH). MSH peptides of alpha, beta, and gamma primary structure are present in plasma, and all exhibit natriuretic activity. Intravenous infusion of alpha or beta-MSH leads to a time- and dose-dependent natriuresis, whereas gamma-MSH is reported to be natriuretic at low doses but antinatriuretic at high doses. The natriuretic activity of MSH peptides occurs without change in arterial pressure or renal hemodynamics, suggesting a possible direct tubular inhibition of sodium reabsorption. Intravenously infused gamma-MSH is associated with an increase in the plasma concentration of atrial natriuretic peptide. In addition, gamma-MSH also has a direct intrarenal natriuretic action that is dependent on the renal nerves. In rats, gamma-MSH-related peptides are involved in the reflex control of sodium excretion in situations such as the natriuresis that occurs (a) from the remaining kidney after acute unilateral nephrectomy, (b) from the contralateral kidney shortly after unilateral ureteral pressure elevation, and (c) after unilateral carotid artery traction. POMC-derived peptides (including MSH) are modulated in response to salt loading, and alterations in POMC metabolism and plasma peptide concentrations have been observed in genetically hypertensive rats and during the development of adrenal regeneration hypertension. In addition, plasma gamma-MSH levels are elevated in patients with severe congestive heart failure, and in primary hyperaldosteronism. These observations suggest a possible involvement of MSH-related peptides in sodium homeostasis as well as in certain forms of hypertension.

Natriuretic Properties of Melanocyte-Stimulating Hormones

Summary: Proopiomelanocortin (POMC) is a protein that contains the amino acid sequences of numerous peptide hormones, including the melanocyte-stimulating hormones (MSH). MSH peptides of α, β, and γ primary structure are present in plasma, and all exhibit natriuretic activity. Intravenous infusion of α or β-MSH leads to a time-and dose-dependent natriuresis, whereas γ-MSH is reported to be natriuretic at low doses but antinatriuretic at high doses. The natriuretic activity of MSH peptides occurs without change in arterial pressure or renal hemodynamics, suggesting a possible direct tubular inhibition of sodium reabsorption. Intravenously infused γ-MSH is associated with an increase in the plasma concentration of atrial natriuretic peptide. In addition, γ-MSH also has a direct intrarenal natriuretic action that is dependent on the renal nerves. In rats. γ-MSH-related peptides are involved in the reflex control of sodium excretion in situations such as the natriuresis that occurs (a) from the remaining kidney after acute unilateral nephrectomy, (b) from the contralateral kidney shortly after unilateral ureteral pressure elevation, and (c) after unilateral carotid artery traction. POMC-derived peptides (including MSH) are modulated in response to salt loading, and alterations in POMC metabolism and plasma peptide concentrations have been observed in genetically hypertensive rats and during the development of adrenal regeneration hypertension. In addition, plasma γ-MSH levels are elevated in patients with severe congestive heart failure, and in primary hyperaldosteronism. These observations suggest a possible involvement of MSH-related peptides in sodium homeostasis as well as in certains forms of hypertension.

Cytochromes P-45011 beta, P-450scc and adrenodoxin gene expression during adrenocortical regeneration in the rat.

Circulating levels of 11-deoxycorticosterone are increased during the development of adrenal-regeneration hypertension. The present studies were undertaken to examine the mechanisms involved in this increase. Plasmids containing cDNA inserts coding for cytochrome P-45011 beta, cytochrome P-450scc and adrenodoxin were used to determine, by Northern blot analysis, mRNA levels at 1, 2 and 3 weeks of adrenal regeneration. There was a striking decrease in mRNA transcripts for all three enzymes during the first week of regeneration when compared with intact adrenal tissue. Over the next 2 weeks the mRNA levels increased to 64% for P-45011 beta, to 80% for P-450scc and to 82% for adrenodoxin. Actin mRNA levels were 70% of control levels in the first week but were back to control levels by the second week. The present findings suggest that decreased expression of steroid 11 beta-hydroxylase could contribute to the increased secretion of 11-deoxycorticosterone during the early stages of adrenal regeneration.

The relative importance of glucocorticoids and mineralocorticoids in the development of adrenal regeneration hypertension in rats.

The adrenocortical tissue which regenerates after adrenal enucleation, and contralateral uninephrectomy and adrenalectomy, resembles histologically zona fasciculata tissue which normally synthesises glucocorticoids. However, increases in blood pressure after enucleation (adrenal regeneration hypertension-ARH] were preceded by a rise in exchangeable body sodium similar to that found with mineralocorticoid-induced hypertension (e.g. DOC/salt rat model). Glucocorticoid involvement in ARH rats was tested, firstly by infusing dexamethasone into control and ARH rats to see whether ACTH suppression would lower blood pressure by reducing adrenocortical activity and, secondly, by infusing dexamethasone into rats with intact adrenals to see whether conditions for ARH (i.e. uninephrectomy and/or saline consumption) pre-disposed rats to the hypertensinogenic properties of glucocorticoids. Low-dose dexamethasone infusions (10 micrograms/day for 5 days) in ARH rats did not affect blood pressure but in control animals caused a significant (P less than 0.01) increase from 128 +/- 3 to 151 +/- 5 mmHg. Corticosterone, 18-hydroxycorticosterone and deoxycorticosterone plasma concentrations were suppressed in both groups by dexamethasone treatment; plasma renin concentrations were lower in ARH rats than in controls. Uninephrectomy or 1% NaCl as drinking fluid did not affect the blood pressure rise induced by sc infusion of 10 micrograms dexamethasone/day for 14 days in rats with intact adrenals. The temporal relationship between blood pressure changes and exchangeable body sodium in ARH rats resembles that in mineralocorticoid-induced hypertension. Glucocorticoid, unlike mineralocorticoid, induced hypertension is not affected by a reduction in renal mass or increased sodium intake.

Sodium excretion after adrenal enucleation and during adrenal regeneration hypertension.

AbstractRenal function following saline infusion (10% body wt) has been studied in four groups of rats 3 to 5 days after operation: Sham (S), Adrenal Enucleation (AE), Unine-phrectomy (N), and AE + N. The purpose of the study was to clarify the mechanisms of the effect of N on sodium excretion in AE. AE excreted significantly less sodium, 6.7 ± 1.3 μEq/min, than S, 29.7 ± 2.7 μEq/min. Sodium excretion by N, 25.4 ± 5.3 μEq/min and AEN, 19.4 ± 3.2 μEq/min were not different from each other or S, but greater than AE (P < 0.01). When AE (two kidneys) was compared with AEN (one kidney), the filtered sodium was not significantly different. Thus, it is concluded that the greater natriuresis in AEN versus AE is most likely secondary to a difference in tubular sodium reabsorption. Renal function following saline infusion (10% body wt) has been studied after the development of adrenal regeneration hypertension (6 weeks postsurgery) in AEN rats and their control groups N. Mean blood pressure was significantly elevat...

Sodium balance after adrenal enucleation

To better define the relationship between adrenal enucleation (AE), sodium retention and adrenal regeneration hypertension (ARH), we measured daily sodium balance in rats after bilateral adrenal enucleation with (AEN) and without uninephrectomy (AE), and before and after development of ARH, along with the appropriate control groups. We found that both AE and AEN groups retained sodium during 7 days after surgery; AE 1.16 +/- 0.24 and AEN 1.32 +/- 0.33 meq/100 g body wt. Sham-operated, uninephrectomized rats and AE rats treated with spironolactone were in zero sodium balance. In the AEN rats after the development of ARH (BP greater than 150 Torr), zero sodium balance was also noted. Only AEN rats developed hypertension while sham-operated, uninephrectomized rats and AE rats with both kidneys remained normotensive for 28 wk. In summary, we have demonstrated that for 1 wk after AE, rats are in positive sodium balance and this is reversed by spironolactone but not by uninephrectomy.

Effects of prostaglandin E2 and prostaglandin inhibitors on adrenal regeneration hypertension.

The effects of prostaglandin E2 (PGE2) and a prostaglandin inhibitor, indomethacin, on the development of adrenal regeneration hypertension (ARH) were investigated. Weanling female rats underwent right adrenonephrectomy and left adrenal enucleation. PGE2 was injected subcutaneously daily in dosages of 0, 20, 40 and 80 mug/day. Indomethacin, 1 mg/kg, was administered twice daily by gavage. Blood pressures were determined by a tail and cuff plethysmographic method at 3, 5, and 7 wk after surgery. Increases in dosage of PGE2 produced a progressive reduction in mean blood pressures, heart, and kidney weights. Indomethacin produced significant increases in mean blood pressure, heart, kidney, and adrenal weights. The effects of aspirin and indomethacin on the blood pressures of rats with right adrenalectomy, left adrenal enucleation, and intact kidneys were studied. Administration of asprin twice daily (25 or 50 mg/kg) produced a fall in blood pressure, body and heart weight. Administration of 1 mg/kg twice daily of indomethacin resulted in a significant increase in blood pressure at 3 wk, and 0.1 or 1 mg/kg caused significant increases at 5 wk. The heart, kidney, and adrenal weights also showed increases with indomethacin administration. This study suggests that a deficiency of renal PGE2 may be involved in the etiology of ARH.

Adrenal Mitochondrial and Serum Corticosteroid Studies in RatsResistant to Adrenal-Regeneration Hypertension (ARH)

Female rats of the Wistar-Furth (W/Fu) strain appear to be resistant to the development of adrenal regeneration hypertension. At a time period, after adrenal enucleation, when Holtzman female rats had elevated serum 11-deoxycorticosterone levels and were hypertensive, none of the W/Fu rats became hypertensive. In vitro adrenal studies after quiescent kills of W/Fu rats indicated that cholesterol side chain cleavage activity was greater in mitochondria from regenerating adrenals than from controls. Both serum deoxycorticosterone and corticosterone levels were significantly greater in the adrenal-enucleated group. These studies were repeated in animals which were given a standard ether anesthetic stress. Ether stress increased cholesterol side chain cleavage activity comparably in control and adrenal-enucleated rats and also increased their serum deoxycorticosterone and corticosterone levels. Adrenal-enucleated Wistar-Furth rats had higher serum deoxycorticosterone levels than controls, whereas controls had higher serum corticosterone levels than the adrenal-enucleated group after the ether stress. These results indicate that although the adrenal-enucleated W/Fu rats have increased serum deoxycorticosterone levels, none of these rats develop frank hypertension. This suggests a resistance to deoxycorticosterone-induced hypertension in this strain of rat.

Excretion of Na and H2 O and hypertension after adrenal enucleation or compression.

An attempt was made to analyze the participation of the several independent variables that must contribute to the reproted inability of large male adrenal-enucleate rats withintact kidneys to normally excrete sodium following a light oral sodium load. This was prompted by a desire to understand whether the phenomenon was improtant to development of adrenal-regeneration hypertension (ARH). The results indicated that sdoium retention required the presence of both kidneys as it was not evident in unilaterally nephrectomized rats. The failure of ARH to develop in rats having both kidneys argues against a cause-and-effect relationship between the two phenomena. Sex does not appear to be important to sodium retention. Various fasting periods were employed, but with none of them did rats with a single kidney exhibit sodium retention. Since the conditions necessary to elicit imparied sodium excretion are incompatible with the induction of ARH and those essential to development of ARH prevent significant sodium retention, the two must be considered as independent manifestations of distrubed glandular function.

Effect of aminoglutethimide in adrenal regeneration hypertension.

Aminoglutethimide, when given by stomach tube daily to rats for 7 weeks beginning immediately after adrenal enucleation, reduced markedly the development of adrenal regeneration hypertension. This effect was not due to a reduction of intake of salt drinking solutions. Relative to controls, the drug did not influence renal, cardiac, or thyroid weights. It is postulated that the drug inhibited the secretion of an as yet unidentified steroid that causes adrenal regeneration hypertension.

Effect of ventromedial hypothalamic lesions on development of adrenal-regeneration hypertension in weaning female rats.

Ventromedial hypothalame Lasionen hemmen die NNR-Regenerations-Hypertonie. Dabei ist nicht eine Verschiebung in der Nahrungs- oder Elektrolyt-Aufnahme verantwortlich19,20.

EFFECT OF TIME OF REDUCTION OF RENAL MASS ON DEVELOPMENT OF ADRENAL-REGENERATION HYPERTENSION.

Summary1. Salt-treated, uninephrecto-mized-adrenalectomized and contralaterally adrenal enucleated female rats in which those operative steps are performed shortly after weaning (zero time) show a higher mean terminal blood pressure and greater enlargement of heart, kidney, brain and spleen than do similar rats that are operated on 2 weeks after zero time. 2. Performance of the uni-nephrectomy 2 weeks after uniadrenalectomy and adrenal enucleation results in significantly lower terminal mean blood pressure and correspondingly lower lesion severity indices. This suggests that the enucleation step proper is the crucial operation in bringing about the full severity of the hypertensive syndrome. 3. Uninephrectomy and uniadrenalectomy on day zero and contralateral enucleation of the compensatorily-hypertrophied adrenal 2 weeks later results in mean terminal blood pressure and lesion severity indices comparable to those rats in which these operations are carried out at zero time. Blood pressure only rises steep...

Increased sensitivity to corticosterone as a possible factor in the development of adrenal regeneration hypertension.

The suggestion that the pathogenesis of adrenal-regeneration hypertension might involve sensitization to the hypertensive properties of corticosterone by the period of cortical insufficiency which follows adrenal enucleation has been investigated. Nonhypertensive doses of corticosterone were given to uninephrectomized, salt-treated and adrenalectomized rats after periods of insufficiency of variable length and to similar rats bearing regenerating adrenals, beginning such treatment at intervals after enucleation. The following conclusions have been drawn from the data obtained: (1) Adrenal cortical insufficiency for as long as 2 weeks did not sensitize to the hypertension-inducing property of corticosterone; (2) Corticosterone administration to rats bearing regenerating adrenals, beginning treatment up to 3 weeks after operation, did not enhance the development of hypertension or increase the severity of vascular lesions.

CONFERENCE on electrolyte and adrenal factors in human and experimental renal hypertension.

In addition to reviewing evidence bearing on the broad relationship of adrenal and electrolyte changes to the pathogenesis of hypertension, this conference considered more specifically the changes in vascular reactivity and electrolyte excretion in hypertension. Supporting the theory of an adrenal mechanism in hypertension was evidence that the development of adrenal-regeneration hypertension in different species may bear a direct relationship to the degree of adrenal regeneration (Dr. Skelton), and that a steroid having electrolyte action opposite to that of desoxycorticosterone is hypotensive in action both in DCA and renal ischemic hypertension, but not in normotensive animals (Dr. Sturtevant). On the other hand, it was observed that adrenalectomy does not alter the development of hypertension produced by kidney encapsulation in the rat (Dr. Fregly). Although it is probable that constrictor agents cause a greater increment in vascular resistance in hypertension than in normotension, the interpretation of this relationship in terms of responsiveness of vascular smooth muscle is fraught with difficulties: 1. The base line of vascular resistance in hypertension is different from that in normotension, and it is possible that the increment in resistance for a given amount of smooth muscle shortening is greater in the constricted than in the normal vessel (Dr. Tobian). 2. It is possible that the increase in resistance in hypertension is due to the encroachment of the edematous blood vessel wall into the lumen without an increase in tone of vascular smooth muscle (Dr. Tobian). 3. The responsiveness to epinephrine of aortic strips from hypertensive animals is less than (Dr. Bohr) or no greater than (Dr. Tobian) that from the nor mal animal. The pertinence of the aortic strip studies was questioned, both because the aorta differs in function (Dr. Sancetta) and responsiveness (Dr. Bohr) from the arteriole and because epinephrine was used in these studies (Dr. Skeggs). The problem of tachyphylaxis of the isolated artery strip in response to angiotonin may not yet be resolved (Drs. Bohr and Helmer). In hypertension there is an increase in sodium excretion by the kidney which is accentuated by the administration of a sodium chloride load. This abnormality reflects an impairment of the tubular reabsorption of sodium which is related to an impaired reabsorption of water (Dr. Sapirstein) and is a direct function of the arterial blood pressure (Drs. Hollander and Weller).

The influence of age on the development of adrenal-regeneration hypertension.

RECENT experiments (1,2) have shown that uninephrectomized rats, given 1% sodium chloride to drink develop hypertension and widespread vascular disease following adrenal-enucleation. The rise in blood pressure occurs as the adrenal cortex regenerates from the capsule and cortical cells adherent to the capsule (3–7) which remain in situ following the operative procedure, and, hence, has been designated “adrenalregeneration hypertension.” The initial observations were made on young rats, and since Timiras, Faribault and Selye (8) have shown that the hypertensive and vasculotoxic actions of desoxycorticosterone acetate were particularly severe in young animals, the present experiment was performed to study the influence of age on the development of adrenal-regeneration hypertension and the accompanying morphologic lesions.