Neurohormonal Activation and Nitrate Tolerance: Implications for Concomitant Therapy With Angiotensin-Converting Enzyme Inhibitors or Angiotensin Receptor Blockers

Abstract The hemodynamic and anti-ischemic effects of nitroglycerin are rapidly blunted due to the development of nitrate tolerance. With initiation of nitroglycerin therapy, one can detect an increase in plasma renin activity (reflecting increased circulating angiotensin II levels), increases in circulating vasopressin, catecholamine, and aldosterone levels, and signs of intravascular volume expansion. These so-called pseudotolerance mechanisms may compromise nitroglycerin’s vasodilating effects. Long-term treatment with nitroglycerin is also associated with a decreased responsiveness of the vasculature to nitroglycerin’s vasorelaxant potency suggesting changes in the intrinsic mechanisms of the tolerant vasculature itself. The issue of tolerance is even more complicated due to the differences in the susceptibility of arterial resistance versus conductance vessels and veins to develop tolerance. More recent experimental work defined new tolerance mechanisms such as increased vascular superoxide production and increased sensitivity to vasoconstrictors secondary to an activation of protein kinase C. Both phenomena are prevented by concomitant treatment with angiotensin-1 (AT 1 )-receptor blockers or angiotensin-converting enzyme (ACE) inhibitors suggesting a causal involvement of the renin–angiotensin system in mediating these phenomena. Despite these encouraging results in animals studies, the clinical reports concerning concomitant treatment of nitrates with ACE inhibitors are quite conflicting. With the present review, we want to summarize new aspects concerning the vasodilator mechanism of nitroglycerin, the role of circulating vasoconstrictor forces in mediating tolerance, and in particular we want to give a brief review about positive and negative results concerning the efficacy of ACE inhibitors in preventing nitrate tolerance.