Nitric oxide in hypertension

Abstract

Hypertension is a major risk factor for cardiovascular disease, and reduction of elevated blood pressure significantly reduces the risk of cardiovascular events. Endothelial dysfunction, which is characterized by impairment of nitric oxide (NO) bioavailability, is an important risk factor for both hypertension and cardiovascular disease and may represent a major link between the conditions. Evidence suggests that NO plays a major role in regulating blood pressure and that impaired NO bioactivity is an important component of hypertension. Mice with disruption of the gene for endothelial NO synthase have elevated blood pressure levels compared with control animals, suggesting a genetic component to the link between impaired NO bioactivity and hypertension. Clinical studies have shown that patients with hypertension have a blunted arterial vasodilatory response to infusion of endothelium-dependent vasodilators and that inhibition of NO raises blood pressure. Impaired NO bioactivity is also implicated in arterial stiffness, a major mechanism of systolic hypertension. Clarification of the mechanisms of impaired NO bioactivity in hypertension could have important implications for the treatment of hypertension.

Figure 1

Endothelium‐derived vasoactive substances. Nitric oxide (NO) is released from endothelial cells in response to shear stress and activation of a variety of receptors. NO exerts vasodilating and antiproliferative effects on smooth muscle cells and inhibits thrombocyte aggregation and leukocyte adhesion. Endothelin‐1 (ET‐1) exerts its major vascular effects—vasoconstriction and cell proliferation—through activation of specific endothelin‐A (ET_A) receptors on vascular smooth muscle cells. In contrast, endothelin B (ET_B) receptors mediate vasodilation via release of NO and prostacyclin. In addition, ETB receptors in the lung were shown to be a major pathway for the clearance of ET‐1 from plasma. AI indiBcates angiotensin I; AII, angiotensin II; Thr, thrombine; TGFBβ₁, transforming growth factor β; AcCh, acetylcholine; 5‐HT, 5‐hydroxytryptamine (serotonin); ADP, adenosine diphosphate; BK, bradykinin; ACE, angiotensin‐converting enzyme; AT1, angiotensin II type 1 receptor; T, thromboxane receptor; bET‐1, big ET‐1; ECE, endothelin‐converting enzyme; M, muscarinergic receptor; S₁, serotoninergic receptor; B₂, bradykinin receptor; NOS, NO synthase; L‐Arg, L‐arginine; EDHF, endothelium‐derived hyperpolarizing factor; TXA₂, thromboxane; PGH₂, prostaglandin H₂; PGI₂, prostacyclin; cAMP, cyclic adenosine monophosphate; and cGMP, cyclic 3′,5′‐guanosine monophosphate. Adapted from Lülscher et al. ¹⁰⁷

Figure 2

Bar graphs showing radial artery flow (mL/min) and radial artery diameter (mm) measured at baseline (Base) and during reactive hyperemia before and after infusion of N^g‐monomethyl‐l‐arginine (l‐NMMA). All results are expressed as mean ± SEM of 8 subjects. *P<.01 vs base. †P<.05. ‡P<.01 vs corresponding control value. Reproduced with permission from Joannides et al. ¹⁰⁸

Figure 3

In 34 normotensive subjects (mean age, 23 years) with a family history of essential hypertension, brachial artery vasodilation in response to acetylcholine, as represented by forearm blood flow (FBF) measured with strain‐gauge plethysmography, was significantly blunted compared with normotensive subjects with no family history of hypertension. FBF increased from 3.9 mL/min to a maximum of 18.9 mL/min with the highest dose of acetylcholine in hypertensive subjects, compared with an increase of 3.8 mL/min to 26.2 mL/min with the highest dose in normotensive subjects (P<.01). The FBF response to sodium nitroprusside, a nonendothelium‐dependent vasodilator, was similar between the 2 groups. *P<.01 hypertensive vs normotensive subjects. Reproduced with permission from Taddei et al. ³⁴

Figure 4

Cardiovascular regulation occurs with the interaction of the sympathetic nervous system (SNS) and the renin‐angiotensin system (RAS) with the vascular endothelium. AT indicates angiotensin II type 1 receptor; ET, endothelin; AT II, angiotensin II; ACEI, angiotensin‐converting enzyme inhibitor; Ach, acetylcholine; M, muscarinergic receptor; ET_B, endothelin B receptor; ARB, angiotensin receptor blocker; NO, nitric oxide; PGI₂, prostacyclin; ET_A, endothelin A receptor; and Bβ₂, bradykinin receptor. Reproduced with permission from Wenzel et al. ¹⁰⁵

Figure 5

Under resting conditions, infusion of N^g‐monomethyl‐l‐arginine (l‐NMMA) in 5 normotensive male volunteers increased mean arterial pressure (MAP) significantly by about 10% but had no effect on muscle sympathetic nerve activity (MSNA), measured by microelectrodes inserted selectively into muscle nerve fasciculi of the peroneal nerve posterior to the fibular head. By contrast, infusion of phenylephrine (PE), a nitric oxide‐independent vasoconstrictor, increased MAP to a similar extent but also decreased MSNA by about 50%. Coinfusion of nitroprusside (NP) with l‐NMMA resulted in reversal of the increase in MAP observed with l‐NMMA alone, but also resulted in a significant increase in MSNA. *P<.05 vs baseline. Reproduced with permission from Owlya et al. ⁹⁸

Figure 6

Muscle sympathetic nerve activity (MSNA) as assessed by microneurography was significantly decreased in hypertensive patients after 12 weeks of treatment with losartan (from 52±3.5 to 46±4.2 bursts/min; P=.022) (A). Baroreceptor sensitivity was significantly enhanced after 12 weeks of treatment with losartan (from 3.2±1.3 to 4.9±1.8 ms/mm Hg; P=.007) (B).

Figure 7

Interaction of the sympathetic nervous system (SNS) with the renin‐angiotensin system (RAS). ACE indicates angiotensin‐converting enzyme; AII, angiotensin II; NO, nitric oxide; and ET‐1, endothelin‐1. Adapted from Wenzel et al. ¹⁰⁵