Mechanism of Action of Hydralazine
Hydralazine acts primarily as a direct arterial vasodilator by relaxing vascular smooth muscle through interference with intracellular calcium metabolism, specifically by inhibiting calcium movements responsible for maintaining the contractile state of smooth muscle cells. 1
Primary Mechanism: Direct Vascular Smooth Muscle Relaxation
Hydralazine directly relaxes vascular smooth muscle by altering cellular calcium metabolism, interfering with the calcium movements within vascular smooth muscle that initiate or maintain contraction 1
The drug inhibits IP₃-induced calcium release from the sarcoplasmic reticulum in vascular smooth muscle cells, which is the main mechanism underlying its vasodilatory effect 2
This calcium interference results in direct relaxation of vascular smooth muscle independent of endothelial function, as the effect persists even after endothelium removal 3
Hemodynamic Effects: Preferential Arterial Dilation
Hydralazine preferentially dilates arterioles compared to veins, which minimizes postural hypotension and promotes increased cardiac output 1
This preferential arteriolar dilation increases arteriolar caliber and decreases peripheral vascular resistance with little effect on venous tone 4
The resulting hemodynamic changes include decreased arterial blood pressure (diastolic more than systolic), decreased peripheral vascular resistance, and increased heart rate, stroke volume, and cardiac output 1
Secondary Compensatory Mechanisms
Hydralazine increases renin activity in plasma as a result of increased renin secretion by renal juxtaglomerular cells responding to reflex sympathetic discharge 1
This increased renin activity leads to angiotensin II production, which stimulates aldosterone and consequent sodium reabsorption 1
The drug triggers baroreceptor-mediated reflex sympathetic activation, resulting in reflex tachycardia rather than bradycardia 5
Additional Mechanisms and Clinical Implications
Hydralazine maintains or increases renal and cerebral blood flow despite lowering systemic blood pressure 1
The American Heart Association suggests that hydralazine may help prevent nitrate tolerance when combined with isosorbide dinitrate due to potential antioxidative properties 6, 4
Research has identified that hydralazine inhibits prolyl hydroxylase domain (PHD) enzymes, leading to HIF-1α stabilization and pro-angiogenic effects, though this represents a novel mechanism distinct from its primary vasodilatory action 7
Clinical Caveats
Hydralazine produces an unpredictable blood pressure response with a prolonged duration of action (2-4 hours), making it less desirable as a first-line agent for acute hypertensive treatment 8, 5
The drug's onset of action is delayed (10-30 minutes), and dose titration can be challenging in acute settings 8
Hydralazine is subject to polymorphic acetylation; slow acetylators have higher plasma levels and require lower doses for blood pressure control 1