Thiazide diuretics, hypokalemia and cardiac arrhythmias.

Thiazide diuretics are widely accepted as the cornerstone of antihypertensive treatment programs. Hypokalemia is a commonly encountered metabolic consequence of chronic thiazide therapy. We treated 38 patients (22 low renin, 16 normal renin) with moderate diastolic hypertension with hydrochlorothiazide (HCTC) administered on a twice daily schedule. Initial dose was 50 mg and the dose was increased at monthly intervals to 100 mg, 150 mg and 200 mg daily until blood pressure normalized. The serum K during the control period was 4.5 +/- 0.2 mEq/l an on 50, 100, 150 and 200 mg HCTZ daily 3.9 +/- 0.3, 3.4 +/- 0.2, 2.9 +/- 0.2, and 2.4 +/- 0.3 mEq/l, respectively. Corresponding figures for whole body K were 4107 +/- 208, 3722 +/- 319, 3628 +/- 257, 3551 +/- 336, and 3269 +/- 380 mEq, respectively. In 13 patients we observed the effects of HCTZ therapy (100 mg daily) on the occurrence of PVC's during rest as well as during static and dynamic exercise. During rest we observed 0.6 +/- 0.08 PVC beats/min +/- SEM and during static and dynamic exercise 0.6 +/- 0.06 and 0.8 +/- 0.15, respectively. Corresponding figures during HCTZ therapy 100 mg daily were 1.4 +/- 0.1, 3.6 +/- 0.7 and 5.7 4/- 0.8, respectively. The occurrence of PVC's correlated significantly with the fall in serum K+ observed r = 0.72, p less than 0.001. In conclusion we found that thiazide diuretics cause hypokalemia and depletion of body potassium. The more profound hypokalemia, the greater the propensity for the occurrence of PVC's.

The C19-mineralocorticoids in hypertension.

The excretion rates of the C19-mineralcorticoids, 16beta-hydroxy-DHEA and 16-oxo-androstenediol, were measured in subjects with low-renin essential hypertension and toxemia of pregnancy. C19-mineralocorticoid excretion in low-renin essential hypertension ranged from 70-790 microgram per day. No significant difference in 16beta-hydroxy-DHEA and 16-oxo-androstenediol excretion was found between these subjects and normal controls. Subjects with toxemia of pregnancy excreted between 350 and 2500 microgram per day of these steroids. There was no significant difference between toxemic and normal pregnancy. Thus, 16beta-hydroxy - DHEA and 16-oxo-androstenediol probably do not play an important role in either low-renin essential hypertension or toxemia of pregnancy.

Saralasin infusion in the recognition of renovascular hypertension.

Saralasin, an angiotensin II antagonist, was infused into 49 patients with renal artery stenosis, 10 patients with essential hypertension and normal renal arteriograms, and five patients with "low-renin essential hypertension." Renal venous renin and differential renal function studies were used to assess the functional significance of arterial stenoses. "Response" to saralasin, evidenced by a fall in blood pressure during infusion, occurred in no patients with "low renin" hypertension and in only 20% of patients with normal renal arteriograms. In contrast, saralasin "response" occurred in more than 80% of patients with renal artery stenosis and lateralizing functional studies and 100% of cases of "proven" renovascular hypertension (cure or improvement of hypertension after operative treatment). We suggest that saralasin infusion might be a valuable screening test for the recognition of renovascular hypertension.

Are there unknown mineralocorticoids in low-renin essential hypertension?

The blood pressure elevation of primary aldosteronism is caused by excessive production of the known mineralocorticoid, aldosterone. The blood pressure elevation of low-renin essential hypertension may also be caused by mineralocorticoid excess, but which which mineralocorticoid is responsible is uncertain. Normal levels of aldosterone, found in this disorder despite suppressed plasma renin, and the presence of an unknown mineralocorticoid have been hypothesized to explain low-renin essential hypertension. We contrasted the blood pressure responses and changes in aldosterone seen in patients with low-renin essential hypertension and primary aldosteronism during treatment with two adrenal enzyme inhibitors. The results demonstrate the similarity between decrease in blood pressure and in aldosterone during early adrenal inhibition in both primary aldosteronism and in low-renin essential hypertension. During treatment with a distal adrenal blocker, patients with primary aldosteronism demonstrated decreases in both aldosterone and blood pressure, whereas patients with low-renin essential hypertension showed a decrease in aldosterone without significant change in blood pressure. This suggested that aldosterone was not the major mineralocorticoid responsible for low-renin essential hypertension. Unknown mineralocorticoid excretion decreased (along with blood pressure) during early inhibition but failed to decrease (along with blood pressure) during late inhibition at a time when aldosterone excretion decreased. This suggests that unknown mineralocorticoids play significant roles in the blood pressure elevation of low-renin essential hypertension.

Evidence for a new mineralocorticoid in patients with low-renin essential hypertension.

Patients with low-renin essential hypertension have certain features consistent with excessive mineralocorticoid activity. Because known mineralocorticoids are normal in the majority of low-renin essential hypertension patients, an unknown mineralocorticoid was sought in the urine of such patients. Urine extracts from patients with low-renin essential hypertension were assayed for mineralocorticoid activity in adrenalectomized rats and found to contain more such activity than could be accounted for by the known mineralocorticoids in the extracts. The factor responsible for the unexplained mineralocorticoid activity was purfied and then identified by mass spectral analysis as 16beta-hydroxydehydroepiandrosterone (16beta-OH-DHEA). Synthetic 16beta-OH-DHEA was found to have a mineralocorticoid potency one-fortieth that of aldosterone in the rat bioassay. The mineralocorticoid effects of both the urine extracts and the synthetic steroid were blocked in the rat by spironolactone, a mineralocorticoid antagonist. A specific assay for 16beta-OH-DHEA was developed, and its level in the urine was found to be elevated in patients with low-renin essential hypertension.