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Absent a Misdiagnosis, What Causes Treatment-Resistant Hypertension?
Treatment-resistant hypertension is defined as a blood pressure that is higher than the goal of less than 130/80 mm Hg in patients who are receiving at least three medications, including a diuretic. The synthesis of aldosterone, a pharmacologic target for the treatment of hypertension, is regulated by the proteins renin and angiotensin. In response to stimuli, the juxtaglomerular cells of the kidney secrete renin, which cleaves angiotensinogen into two fragments, one of which is angiotensin I. Angiotensin I is converted to angiotensin II, primarily in the lungs, by angiotensin-converting enzyme (ACE). Angiotensin II, a potent vasoconstrictor, stimulates cells in the zona glomerulosa of the adrenal gland to synthesize and secrete aldosterone. Corticotropin released by the pituitary gland also stimulates adrenal aldosterone production, albeit to a lesser degree than angiotensin II. Drug classes that are commonly used to treat hypertension and their sites of action in the renin–angiotensin–aldosterone system are shown. Baxdrostat blocks aldosterone synthase (also known as CYP11B2), thereby inhibiting the synthesis of aldosterone. Other drugs used to block the actions of aldosterone (e.g., spironolactone, eplerenone, and nonsteroidal mineralocorticoid receptor antagonists [MRAs]) inhibit the activation of the mineralocorticoid receptor by aldosterone.
Treatment-resistant hypertension may be attributable to volume overload, untreated obstructive sleep apnea, and renovascular disease. It may also occur in patients with hormonal dysregulation associated with hyperparathyroidism, thyroid disease, or rare conditions such as pheochromocytoma, paraganglioma, or reninoma. Treatment-resistant hypertension also occurs in patients with undiagnosed primary aldosteronism (Conn’s syndrome) or hypercortisolism (Cushing’s syndrome). Some patients with treatment-resistant hypertension have been found to have increased aldosterone production, even though they do not have primary aldosteronism ([Figure 1][12]).
Outline
- In response to stimuli, the juxtaglomerular cells of the kidney secrete renin, which cleaves angiotensinogen into two fragments, one of which is angiotensin I.
- Angiotensin II, a potent vasoconstrictor, stimulates cells in the zona glomerulosa of the adrenal gland to synthesize and secrete aldosterone.
- Corticotropin released by the pituitary gland also stimulates adrenal aldosterone production, albeit to a lesser degree than angiotensin II.
- Drug classes that are commonly used to treat hypertension and their sites of action in the renin–angiotensin–aldosterone system are shown.
- Baxdrostat blocks aldosterone synthase (also known as CYP11B2), thereby inhibiting the synthesis of aldosterone.
- Other drugs used to block the actions of aldosterone (e.g., spironolactone, eplerenone, and nonsteroidal mineralocorticoid receptor antagonists [MRAs]) inhibit the activation of the mineralocorticoid receptor by aldosterone.
- Treatment-resistant hypertension may be attributable to volume overload, untreated obstructive sleep apnea, and renovascular disease.
- It may also occur in patients with hormonal dysregulation associated with hyperparathyroidism, thyroid disease, or rare conditions such as pheochromocytoma, paraganglioma, or reninoma.
- Treatment-resistant hypertension also occurs in patients with undiagnosed primary aldosteronism (Conn’s syndrome) or hypercortisolism (Cushing’s syndrome).
- Some patients with treatment-resistant hypertension have been found to have increased aldosterone production, even though they do not have primary aldosteronism ([Figure 1][12])..