ENDOCRINOLOGY OF BLOOD PRESSURE CONTROL

The control of blood pressure (BP) is complex, involving neural, cardiac, hormonal and many other mechanisms.

BP is dependent upon cardiac output and peripheral resistance. Although cardiac output can be increased in endocrine disease (e.g. hyperthyroidism), the main role of hormonal mechanisms is control of peripheral resistance and of circulating blood volume

The oral contraceptive pill is a common endocrine cause of mild hypertension.

Endocrine causes of hypertension

The renin-angiotensin-aldosterone axis

Angiotensinogen, an alpha2-globulin of hepatic origin, circulates in plasma. The enzyme, renin, is secreted by the kidney in response to decreased renal perfusion pressure or flow; it cleaves the decapeptide angiotensin I from angiotensinogen.

Angiotensin I is inactive but is further cleaved by angiotensin-converting enzyme (ACE; present in lung and vascular endothelium) into the active peptide, angiotensin II, which has two major actions (mediated by two types of receptor, AT1 and AT2).

The AT1 subtype which is found in the heart, blood vessels, kidney, adrenal cortex, lung and brain mediates the vasoconstrictor effect. AT2 is probably involved in vascular growth. Angiotension II:
causes rapid, powerful vasoconstriction stimulates the adrenal zona glomerulosa to increase aldosterone production (over hours or days).

As BP increases and sodium is retained, the stimuli to renin secretion are reduced. Dietary sodium excess also suppresses renin secretion, whereas sodium deprivation or urinary sodium loss will increase it.

The renin-angiotensin system can be blocked at several points with renin inhibitors, angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor antagonists (A-IIRA).

The latter two are useful agents in treatment of hypertension and heart failure but have differences in action: ACEIs also block kinin production while A-IIRAs are specific for the AT-II receptor

Atrial and brain natriuretic factors/peptides (ANP and BNP)

Atrial natriuretic peptides, a family of varying length forms, are secreted from atrial granules in response to atrial stretch. They produce marked effects on the kidney, increasing sodium and water excretion and glomerular filtration rate and lowering BP, plasma renin activity and plasma aldosterone

Brain natriuretic peptide is found in the ventricle as well as the brain and has moderate sequence homology with ANP; normally its circulating level is much less than for ANP but may exceed it in congestive cardiac failure

ANP and BNP appear to play a significant role in cardiovascular and fluid homeostasis, but there is no evidence of primary defects in their secretion causing disease

RENIN (AND ANGIOTENSIN) DEPENDENT HYPERTENSION

Many forms of unilateral and bilateral renal diseases are associated with hypertension. The classic example is renal artery stenosis: the major hypertensive effects of this and other situations such as renin-secreting tumours are directly or indirectly due to angiotensin II.

Angiotensin II receptor antagonists (e.g. losartan, valsartan, candesartan and irbesartan) are effective in hypertension and congestive cardiac failure, similar to angiotensin-converting enzyme inhibitors (ACEI). They produce much the same clinical effects, though with fewer side-effects (e.g. no cough and less hyperkalaemia).

THE ADRENAL MEDULLA

The major catecholamines, noradrenaline (norepinephrine) and adrenaline (epinephrine) are produced in the adrenal medulla, although most noradrenaline is derived from sympathetic neuronal release.

Phaeochromocytoma Phaeochromocytomas, tumours of the sympathetic nervous system, are very rare (less than 1 in 1000 cases of hypertension). Ninety per cent arise in the adrenal, while 10% occur elsewhere in the sympathetic chain

Pathology Oval groups of cells occur in clusters and stain for chromogranin A. Twenty-five percent are multiple and 10% malignant, the latter being more frequent in the extra-adrenal tumours. Malignancy cannot be determined on simple histological examination alone.

Clinical features
Symptoms
Anxiety or panic attacks Palpitations Tremor Sweating Headache Flushing Nausea and/or vomiting Weight loss Constipation or diarrhoea Raynaud's phenomenon Chest pain Polyuria/nocturia

Signs
Hypertension - intermittent or constant Tachycardia plus arrhythmias Bradycardia Orthostatic hypotension Pallor or flushing Glycosuria Fever (Signs of hypertensive damage)

The clinical features are those of catecholamine excess and are frequently, but not necessarily, intermittent. The diagnosis should particularly be considered when cardiovascular instability has been demonstrated, and in severe hypertension in pregnancy.

Diagnosis
Measurement of urinary catecholamines and metabolites Resting plasma catecholamines CT scans MRI

Treatment
Tumours should be removed if this is possible; 5-year survival is about 95% when not malignant. Medical preoperative and perioperative treatment is vital and includes complete alpha- and beta-blockade with phenoxybenzamine (20-80 mg daily initially in divided doses), then propranolol (120-240 mg daily), plus transfusion of whole blood to reexpand the contracted plasma volume