Paula M. Williamson

CORTISOL AND HYPERTENSION

1. In humans, the hypertensive effects of adrenocorticotropic hormone (ACTH) infusion are reproduced by intravenous or oral Cortisol. Oral Cortisol increases blood pressure in a dose‐dependent fashion. At a dose of 80–200 mg/day, the peak increases in systolic pressure are of the order of 15mmHg. Increases in blood pressure are apparent within 24 h.

Mechanisms of cortisol-induced hypertension in humans

There is emerging evidence that cortisol plays a significantly greater role in human hypertension than previously thought. Apart from the well recognized role of cortisol in the hypertension of Cushings syndrome, local cortisol excess has been recognized as responsible for rare forms of hypertension such as apparent mineralocorticoid excess and licorice abuse and more recently implicated in the hypertension of chronic renal failure, hypertension related to low birth weight and essential hypertension. Although cortisol-induced hypertension is characterized by sodium retention and volume expansion, studies with synthetic glucocorticoids or sodium restriction suggest that the hypertension is, to a substantial degree, independent of sodium and volume. Increase in cardiac output is not essential for cortisol-induced blood pressure rise but the precise role of increases in total or regional peripheral resistance as a primary mechanism has nto been determined. Increased pressor responsiveness, particularly to catechols, is a prominent feature but whether these changes are sufficient to account for the hypertension remains unclear. There is no evidence for increased sympathetic nervous activity as judged by measurements of plasma catcholamines, neuropeptide-Y, or resting noradrenaline spillover rate. Responses to mental stress or maximal hand-grip are unchanged and baroreflex sensitivity is increased. Octreotide profoundly reduced the elevated plasma insulin concentrations seen with cortisol administration but had no effect on the rise in blood pressure.

THE NITRIC OXIDE SYSTEM AND CORTISOL-INDUCED HYPERTENSION IN HUMANS

1. The aim of the present study was to assess the role of the nitric oxide (NO) system in cortisol‐induced hypertension in humans.

Effects of oral L-arginine on plasma nitrate and blood pressure in cortisol-treated humans.

Objective The aim of this study was to determine whether cortisol-induced hypertension can be reversed by co-administration of oral l-arginine. Study design Three studies were undertaken in healthy male human subjects. The first study addressed the effect of oral l-arginine loading on plasma arginine concentration. Study 2 addressed the effect of co-administration of cortisol with l-arginine on plasma l-arginine concentrations. Study 3 was a randomized placebo crossover control comparing the effects of cortisol 80 mg/day co-administered with a placebo to cortisol 80 mg/day co-administered with l-arginine 21 g/day. Methods Blood pressure was measured by a random Hawksley sphygmomanometer. Plasma nitrate/nitrite concentrations were measured by a modified Greiss reaction. Plasma arginine and citrulline concentrations were measured by an automated amino acid analyser. Results Plasma arginine concentrations were doubled by oral doses of 15 g/day and 21 g/day of l-arginine (study 1). Co-administration of cortisol did not alter plasma arginine concentrations in subjects taking 21 g of l-arginine per day (study 2). Co-administration of l-arginine 21 g/day with cortisol 80 mg/day did not prevent cortisol-induced increases in blood pressure or cortisol-induced falls in plasma nitrate/nitrite concentrations. Conclusion Cortisol-induced hypertension is accompanied by a fall in plasma nitrate/nitrite concentrations. Oral l-arginine administration does not prevent cortisol-induced falls in plasma nitrate/nitrite concentrations or increases in blood pressure. We propose that cortisol-induced reductions in nitrate/nitrite production occur at a point distal to l-arginine availability in the nitric oxide synthase pathway.

Muscle sympathetic vasoconstrictor activity in hydrocortisone-induced hypertension in humans.

AIM This study was undertaken to test the hypothesis that increased sympathetic vasomotor drive is responsible for cortisol-induced hypertension. METHODS Ten healthy male subjects on a fixed sodium diet (150 mmol/day) were randomized to five days of treatment with cortisol (200 mg/day) or placebo in a double-blind crossover study. On day 5 of each treatment, multi-unit muscle sympathetic activity was recorded from the common peroneal nerve. Resting muscle sympathetic activity (MSA) was measured in the recumbent position and stimulated MSA was measured in the final 20 sec of end-inspiratory capacity apnoea and end-expiratory apnoea and in the second minute of a cold pressor stimulus. A subgroup of six subjects also underwent identical MSA measurements following 5 days treatment with dexamethasone (3 mg/day). MAJOR FINDINGS Cortisol, but not placebo, significantly increased systolic (115+/-2 vs 129+/-3 mmHg precortisol vs cortisol day 5, p < 0.001) and diastolic blood pressure (53+/-3 vs 61+/-3, p < 0.05). Resting MSA was significantly reduced by cortisol (23.9+/-2.3 to 5.0+/-2.0 bursts/min, placebo vs cortisol, p < 0.01). Cortisol significantly attenuated the increase in MSA observed at end-inspiratory apnoea (56.3+/-3.9 vs 35.4+/-6.6, p < 0.05) and end-expiratory apnoea (50.5+/-3.5 vs 26.3+/-6.2 bursts/min, n = 8, p < 0.05), and during the cold pressor response (55.0+/-12.7 vs 21.4+/-7.6, n = 5, p < 0.05). Dexamethasone significantly increased systolic blood pressure and suppressed resting and stimulated MSA. No changes in body weight, haematocrit or angiotensin II concentrations occurred during dexamethasone treatment. CONCLUSION MSA is significantly suppressed by cortisol treatment. As suppression of MSA is also observed during treatment with the pure glucocorticoid dexamethasone, suppressed MSA cannot be attributed to increased plasma volume or to changes in angiotensin II concentration. We conclude that cortisol-induced hypertension is not due to increased muscle sympathetic vasomotor drive.

Reflex Sympathetic Function in Cortisol-Induced Hypertension in Humans

Nine healthy male subjects underwent measurement of reflex sympathetic function, pressor responsiveness and baroreflex sensitivity to phenylephrine (PE) and glyceryltrinitrate (GTN) before (C1) and following six days of treatment (E6) with cortisol (F), 200 mg/day. Seven subjects had washout studies (W) performed at least two weeks following the end of treatment. The BP responses to head tilt, isometric exercise and mental arithmetic were unaltered by F, however, there was a significant diminution of the diastolic BP response to cold pressor stimulus (delta DBP: 19 +/- 3 vs 25 +/- 5 vs 27 +/- 5 mmHg; E6 vs C1 vs W, p < 0.05 C1 vs E6 and W). Baroreflex sensitivity to PE was increased (28 +/- 3 vs 19 +/- 2 ms/mmHg, E6 vs C1, p = 0.03). These data demonstrate that increased BP during F treatment is not attributable to increased SNS activity, and suggest that SNS activity may be decreased by F.

11β-Hydroxysteroid Dehydrogenase and Its Inhibitors in Hypertensive Pregnancy

Preeclampsia is accompanied by amplification of the sodium retention that is a feature of normal pregnancy. Recent evidence suggests that mineralocorticoid receptor activation is increased in preeclampsia, but classic mineralocorticoids (aldosterone, 11-deoxycorticosterone) are not present in excess. Cortisol can act as a mineralocorticoid receptor agonist only when its renal inactivation to cortisone by 11 beta-hydroxy-steroid dehydrogenase is impaired, for example, in congenital enzyme deficiency and after administration of exogenous inhibitors (eg, licorice). Endogenous inhibitors of this enzyme have been detected in human urine and are increased in pregnancy. To establish whether cortisol causes mineralocorticoid excess in hypertensive pregnancy and whether endogenous inhibitors of 11 beta-hydroxysteroid dehydrogenase are responsible, we studied 25 hypertensive pregnant patients (13 with preeclampsia and 12 with gestational hypertension), 16 normotensive pregnant subjects, and 13 nonpregnant control subjects. Concentrations of plasma renin and aldosterone were increased in pregnancy, but less so in hypertensive pregnancy. Plasma potassium and urinary electrolytes were not different between the groups. Plasma cortisol was increased in pregnancy but not different in hypertensive pregnancy, and urinary cortisol, plasma and urinary cortisone, and urinary tetrahydrocortisol and tetrahydrocortisone were not different between the groups. Endogenous inhibitors of 11 beta-hydroxysteroid dehydrogenase were more active in urine from pregnant women but were not increased further in hypertensive pregnancy. There were no differences in these parameters between patients with preeclampsia and gestational hypertension. We conclude that deficient inactivation of cortisol to cortisone does not contribute to the sodium retention of normotensive or hypertensive pregnancy and that endogenous inhibitors of 11 beta-hydroxysteroid dehydrogenase have no evident pathophysiological significance in pregnancy.

Glucocorticoids and the kidney

SUMMARY:  Glucocorticoids are widely used by nephrologists for their immunomodulatory and anti‐inflammatory effects. The present review considers three aspects of glucocorticoids with which nephrologists may be less familiar: (i) renal metabolism; (ii) effects on renal haemodynamics; and (iii) effects on blood pressure as they relate to the kidney.

Glucocorticoids and hypertension in man.

Abnormalities of cortisol production or metabolism are involved in the genesis of hypertension in Cushings syndrome, apparent mineralocorticoid excess and liquorice abuse and possibly in chronic renal failure and essential hypertension. We have studied the physiological mechanisms by which cortisol raises blood pressure in short term studies of cortisol administration in normal men. Cortisol induced hypertension cannot be explained by increases in vasopressor or decreases in vasodepressor hormone concentrations, or by any increase in sympathetic nervous activity. The hypertension is accompanied by substantial sodium retention but a significant component of the blood pressure rise is sodium independent. The hypertension is characterized by an increase in cardiac output but a rise in output is not essential for the rise in blood pressure. Our working hypothesis is that cortisol induced hypertension is a consequence of increases in renal vascular resistance.

Effects of cortisol on blood pressure and salt preference in normal humans

1. Adrenocorticotrophic hormone (ACTH) and corticosteroids stimulate salt appetite in laboratory animals. The hypothesis tested was that cortisol administration increases salt preference in humans.