Neurohormonal activation during nitrate therapy: a possible mechanism for tolerance

The hemodynamic and antianginal effects of the organic nitrates are greatly reduced during therapy designed to provide 24-hour protection throughout each day. Although the mechanisms of tolerance are not clearly understood, it is likely that tolerance is related to a combination of reduced sulfhydryl groups in vascular smooth muscle and neurohormonal activation. These changes would reduce nitrate-induced vasodilation and induce sodium and water retention with an increase in plasma volume. These reflex neurohormonal changes would reduce the hemodynamic effect of any given degree of nitrate-induced vasodilation. Although preliminary studies suggest that diuretic therapy or the use of converting enzyme inhibitors may reduce or abolish tolerance, further clinical studies are required to confirm these findings.