Low-renin hypertension with relative aldosterone excess is associated with impaired NO-mediated vasodilation

Abstract

Recent studies suggest that hypertension associated with low renin status and hyperaldosteronism is associated with increased risk for end-organ damage and cardiovascular events compared with other forms of hypertension. Additionally, experimental studies have demonstrated impaired nitric oxide-mediated bioactivity in these states. To investigate the relation between renin/aldosterone status and resistance vessel function, we examined plasma renin activity, serum aldosterone level, and forearm blood flow responses to the endothelium-dependent vasodilator methacholine and the endothelium-independent vasodilators sodium nitroprusside and verapamil using venous occlusion plethysmography in 130 volunteers (43 hypertensive, 87 normotensive). Low renin status was associated with impaired responses to methacholine and nitroprusside in patients with hypertension. Peak methacholine response was 8.7+/-5.6 mL/min per dL in the lowest renin quartile (0.1 to 0.3 ng/mL per hour) versus 14.3+/-7.3 mL/min per dL in the highest 3 renin quartiles combined (0.4 to 4.6 ng/mL per hour; P<0.001). Peak nitroprusside response was 5.6+/-2.3 mL/min per dL in the lowest renin quartile versus 13.3+/-4.1 mL/min per dL in the highest 3 renin quartiles combined (P<0.001). Blood pressure and other clinical characteristics were similar in all 4 quartiles. Vasodilator responses to verapamil did not relate to renin activity. Methacholine and nitroprusside responses did not relate to renin status in normotensive controls (P=0.34). Importantly, hypertensive patients with a high aldosterone/renin ratio also had impaired responses to methacholine. This study demonstrates that low-renin hypertension is associated with marked impairment of nitric oxide-mediated vasodilation of resistance vessels in the forearm vasculature of humans. This impairment could contribute to adverse outcomes in patients with low-renin hypertension and relative aldosterone excess.

Figure 1

Vascular function by quartile of plasma renin activity in hypertensives. Endothelium-dependent and endothelium-independent function was assessed in response to methacholine and sodium nitroprusside (SNP), respectively. Hypertensive patients in the lowest quartile of plasma renin activity had markedly impaired responses to both nitric oxide-mediated vasodilators, P<0.001.

Figure 2

Vascular function by quartile of plasma renin activity in normotensive controls. Endothelium-dependent and endothelium-independent function was assessed in response to methacholine and SNP, respectively. Normotensive participants had preserved responses to both nitric oxide-mediated vasodilators, irrespective of plasma renin activity.

Figure 3

Vasodilator responses to verapamil by plasma renin activity dichotomized above and below 1 ng/mL per hour. Endothelium-independent responses were assessed to the non-nitric oxide-mediated vasodilator verapamil in 20 patients with hypertension and 40 normotensive controls. Verapamil responses were preserved in both cohorts irrespective of plasma renin activity.

Figure 4

Vascular function by quartile of aldosterone/renin ratio in hypertensives. Endothelium-dependent and endothelium-independent function was assessed in response to methacholine and SNP, respectively. Hypertensive patients in the highest aldosterone-renin ratio quartile (4th aldosterone-renin quartile) had impaired endothelial function but preserved responses to nitroprusside, P<0.001.