Vascular endothelium and nitric oxide in childhood hypertension

Abstract

Vascular endothelium releases nitric oxide (NO), an important vasodilator that is continuously synthesised by the constitutive enzyme, endothelial nitric oxide synthase (NOS). This maintains a constant vasodilator tone which is diminished in adult hypertension, due to reduced endothelium-dependent vascular relaxation, which is NO dependent. In childhood, however, hypertension is often secondary, and normalisation of blood pressure by removal of cause (e.g. renal artery stenosis, catecholamine-producing tumour) suggests reversibility of endothelial dysfunction, if it is present. Raised plasma levels of endogenous inhibitors have been found, especially in children with secondary hypertension due to renal parenchymal and renovascular disease, and may contribute to hypertension by more than just inhibition of vascular NO release; e.g. by reduction of glomerular filtration rate and promotion of salt and water retention. These inhibitors also modulate renin release, which may be of relevance in cardiovascular physiology, and may also interfere with the anti-platelet properties of NO, increasing the likelihood of vascular thrombotic events. NO inhibitors also promote endothelial activation, with increased expression of adhesion molecules that may form seedlings of atherosclerosis. In chronic renal impairment, accumulation of NO inhibitors may contribute to hypertension. Efficient long-session dialysis helps better interdialysis control of blood pressure in these subjects, independent of salt and water removal, suggesting that removal of such vasoactive agents may be important for efficient blood pressure control. There are a few studies assessing NO generation in hypertensive children via plasma nitrite and nitrate, the NO end products, which suggest normal or increased production as opposed to a reduction, perhaps as a compensatory phenomenon. In the treatment of hypertension, nitroprusside and nitrates exert their actions via NO donation. Excessive production of NO (usually via inducible NOS) or excessive administration (nitrovasodilators) can be cytotoxic and may cause hypotension and shock, as in severe sepsis. NOS inhibitors and NO therefore appear to play a crucial role in aetiology, complications and therapy of childhood hypertension.

Elevated Blood Pressure in Offspring Born Premature to Hypertensive Pregnancy

“…Indeed, studies have shown that reduced NO availability 45 and increased endothelial derived constrictor factors 44 secondary to endothelial dysfunction or raised endogenous inhibitors of NO synthase play a role in the pathogenesis of hypertension even in children. 46 Carotid intima-media thickness is a well-established, independent predictor of future cardiovascular risk in asymptomatic adults. In a meta-analysis, Lorenz et al 47 reported that an absolute difference in intima-media thickness of 0.1 mm was associated with a relative risk of myocardial infarction and stroke of 1.15 and 1.18, respectively, in adults over the age of 40 years.…”

Target-organ damage in adolescent hypertension. Analysis of potential influencing factors, especially nitric oxide and endothelin-1

“…Despite of the numerous observational and epidemiological studies proving the prognostic significance of IMT in hypertension and a marker of atherosclerosis, there are some uncertainties regarding the pathophysiological background of the increased intimamedia thickness. Recently, the role of nitric oxideendothelin-1 imbalance has been demonstrated as one of the leading pathophysiologic factors determining essential hypertension [18][19][20] and there are also observations available pointing out the possible role of the NO/ endothelin imbalance in determination of intima-media thickness among hypertensives [21,22]. As the majority of the previous studies assessed the relationship of NO/ endothelin imbalance with intima-media thickness mainly in adult essential hypertensives, in the present study we wanted to test whether such a correlation exists between these endothelial factors and intima-media thickness of the carotid arteries already in adolescents.…”

The renin angiotensin system in childhood hypertension: Selective increase of angiotensin-(1-7) in essential hypertension

“…1,2 Despite a number of epidemiologic data, 2,3,4,5 there are only a few reports about the physiopathologic mechanisms involved in childhood hypertension. 6,7 Experimental models of hypertension and the efficacy of angiotensin converting enzyme (ACE) inhibition as treatment indicate that the renin angiotensin system (RAS) is probably involved in many hypertensive states. 6 Classically, the RAS is considered a peptidergic hormone system in which precursor peptides are transformed into active products through a stepwise enzymatic processing assumed to sequentially convert angiotensinogen into angiotensin II (Ang II).…”

“…8,9 Among these putative RAS mediators, angiotensin-(1-7) [Ang- (1)(2)(3)(4)(5)(6)(7)] is particularly interesting because it can be formed directly from angiotensin I (Ang I) by neutral-endopepdidase (NEP) 24.11 or prolyl-endopeptidase (PEP), or from Ang II via PEP, prolyl carboxypeptidase, 8,9 or the enzyme ACE2, a homolog of ACE in humans, mice, and rats. 10 A growing body of evidence suggests that Ang- (1)(2)(3)(4)(5)(6)(7) participates in the control of hydroelectrolyte balance 11,12 and plays a counterregulatory role within the RAS. 8,13 Ang-(1-7) generally opposes the vascular and proliferative effects of Ang II 8,13,14 and exerts complex renal actions.…”