Hydralazine Mechanism of Action
Hydralazine lowers blood pressure by directly relaxing vascular smooth muscle, causing peripheral vasodilation predominantly in arterioles rather than veins, which decreases systemic vascular resistance and arterial blood pressure. 1
Primary Mechanism
Hydralazine acts as a direct vasodilator by relaxing vascular smooth muscle through interference with calcium metabolism within smooth muscle cells, specifically disrupting the calcium movements responsible for initiating and maintaining the contractile state. 1
The drug exerts its effect primarily on arterioles rather than veins, which explains why it causes minimal postural hypotension and promotes increased cardiac output. 1
This preferential arteriolar dilation increases arteriolar caliber and decreases peripheral vascular resistance with little effect on aortic wave reflections. 2
Hemodynamic Consequences
The peripheral vasodilation results in decreased arterial blood pressure (with diastolic pressure dropping more than systolic), decreased peripheral vascular resistance, and compensatory increases in heart rate, stroke volume, and cardiac output. 1
In heart failure patients specifically, hydralazine produces increased cardiac output and stroke volume with decreased vascular resistance, without significant changes in pulmonary or systemic venous pressures. 3
Secondary Compensatory Effects
Hydralazine typically increases plasma renin activity, likely due to increased renin secretion by renal juxtaglomerular cells responding to reflex sympathetic discharge triggered by blood pressure reduction. 1
This renin increase leads to angiotensin II production, which stimulates aldosterone secretion and subsequent sodium reabsorption. 1
The drug maintains or increases renal and cerebral blood flow despite lowering systemic blood pressure. 1
Clinical Implications of Mechanism
The direct arterial vasodilation with minimal venous effects explains why hydralazine is therapeutically combined with isosorbide dinitrate in heart failure treatment—hydralazine dilates arteries while isosorbide dinitrate dilates veins, providing complementary hemodynamic benefits. 4
The American Heart Association suggests hydralazine may help prevent nitrate tolerance when combined with nitrates due to potential antioxidative properties. 4
Important Caveats
Despite extensive study, the precise molecular mechanism remains incompletely understood, though calcium metabolism interference is the leading explanation. 1
Research suggests hydralazine's vascular relaxation is independent of endothelium and is not related to guanylate cyclase activation, distinguishing it from other vasodilators. 5
The reflex tachycardia and increased cardiac output are direct consequences of the mechanism—arterial vasodilation triggers baroreceptor-mediated sympathetic activation. 1, 6