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Urinary kallikrein activity and renal vascular resistance in the antihypertensive response to thiazide diuretics
Insights
Thiazide diuretics lower blood pressure in hypertension by increasing urinary kallikrein excretion, not by altering blood volume. This suggests a key role for the renal kallikrein system in thiazide
Area of Science:
- Nephrology
- Cardiovascular Medicine
- Pharmacology
Background:
- Essential hypertension is a common condition often managed with thiazide diuretics.
- The precise mechanisms underlying the chronic effects of thiazides on blood pressure remain incompletely understood.
- Previous studies suggest volume depletion as a primary mechanism, but this is debated.
Purpose of the Study:
- To investigate the chronic effects of hydrochlorothiazide on blood pressure regulation in essential hypertensive men.
- To elucidate the role of intravascular volume, renal hemodynamics, and urinary kallikrein excretion in thiazide's hypotensive action.
Main Methods:
- A randomized, placebo-controlled, crossover study involving 19 essential hypertensive men.
- Treatment periods of 1 month each with placebo and hydrochlorothiazide.
- Measurements included mean arterial pressure, intravascular volume, renal plasma flow, glomerular filtration rate, renovascular resistance, and urinary kallikrein excretion.
Main Results:
- Hydrochlorothiazide significantly reduced mean arterial pressure without altering intravascular volume.
- Renal plasma flow and glomerular filtration rate remained unchanged, while renovascular resistance decreased.
- Urinary kallikrein excretion increased significantly, returning to normal levels from subnormal baseline values.
- Increased kallikrein excretion correlated with blood pressure reduction, independent of plasma aldosterone levels.
Conclusions:
- Chronic thiazide therapy lowers blood pressure in hypertension through mechanisms beyond volume depletion.
- Reduced renovascular resistance and increased urinary kallikrein excretion are key components of thiazide's hypotensive effect.
- The renal kallikrein system likely plays a significant role in mediating the blood pressure-lowering effects of thiazide diuretics.
Abstract:
To evaluate the mechanism of chronic thiazide diuretic action in hypertension, we treated 19 essential hypertensive white men for 1-month periods on placebo alone and hydrochlorothiazide alone. During therapy, mean arterial pressure (MAP) fell, but radioisotopically determined intravascular volume remained unchanged, suggesting other mechanisms of thiazide action upon blood pressure. In the renal circulation, thiazides did not change renal plasma flow or glomerular filtration rate, but renovascular resistance was diminished, probably at the afferent arteriole. Concomitant with the decline in blood pressure and renovascular resistance, urinary kallikrein excretion increased, from subnormal (hypertensive) levels back into the normal range. The kallikrein increase did not correlate with changes in plasma aldosterone. In addition, patients with blood pressure responses (reduction greater than or equal to 10%) to thiazides (n = 12) had greater increases in kallikrein excretion than those without such a blood pressure decrement (n = 7), suggesting a role for renal kallikrein in the hypotensive response to thiazide diuretics.