Mechanism of Action of Hydralazine
Hydralazine works by directly relaxing vascular smooth muscle, causing preferential arteriolar vasodilation that decreases peripheral vascular resistance and lowers blood pressure, primarily through interference with calcium movements within vascular smooth muscle cells. 1
Primary Mechanism
Hydralazine exerts its effect by altering cellular calcium metabolism, interfering with the calcium movements within vascular smooth muscle that are responsible for initiating or maintaining the contractile state. 1
The drug acts as a direct-acting vasodilator with peripheral vasodilating effects through direct relaxation of vascular smooth muscle, independent of endothelial function. 1, 2
Importantly, the vascular relaxation produced by hydralazine is endothelium-independent and is not related to guanylate cyclase activation, distinguishing it from other vasodilators. 2
Hemodynamic Profile
Hydralazine preferentially dilates arterioles compared to veins, which increases arteriolar caliber and decreases peripheral vascular resistance with little effect on venous capacitance or aortic wave reflections. 3
This preferential arteriolar dilation minimizes postural hypotension and promotes increased cardiac output. 1
The hemodynamic effects include decreased arterial blood pressure (diastolic more than systolic), decreased peripheral vascular resistance, and increased heart rate, stroke volume, and cardiac output. 1
Compensatory Responses
Hydralazine increases renin activity in plasma, presumably from increased secretion by renal juxtaglomerular cells in response to reflex sympathetic discharge. 1
This increased renin activity leads to angiotensin II production, which stimulates aldosterone secretion and consequent sodium reabsorption. 1
The drug causes reflex tachycardia due to baroreceptor-mediated sympathetic activation in response to blood pressure reduction, though this effect may be blunted when combined with beta-blockers. 4
Clinical Rationale for Combination Therapy
The direct arterial vasodilation with minimal venous effects explains why hydralazine is therapeutically combined with isosorbide dinitrate in heart failure—hydralazine dilates arteries (reducing afterload) while isosorbide dinitrate dilates veins (reducing preload), providing complementary hemodynamic benefits. 3, 4
Hydralazine may help prevent nitrate tolerance when combined with nitrates due to potential antioxidative properties. 3
In heart failure patients, hydralazine produces increased cardiac output and stroke volume with decreased vascular resistance without significant changes in pulmonary and systemic venous pressure. 5