Disproportionally impaired microvascular structure in essential hypertension.

BACKGROUND: Increased microvascular resistance and small artery remodelling are key abnormalities in the pathophysiology of essential hypertension. We investigated the relation between the impairment of coronary and forearm minimum vascular resistances (C-Rmin and F-Rmin) and the degree of hypertension. METHOD: Seventy-five never-treated essential hypertension patients with 24-h systolic blood pressure (BP) at least 130 mmHg or diastolic BP at least 80 mmHg were assigned into grade 1 (office BP 140/90-159/99 mmHg) and grade 2 (office BP 160/100-179/109 mmHg) hypertension and compared to normotensive controls (n = 25). The patients were (48 years, 60% men) without cardiovascular disease. C-Rmin and coronary flow reserve (CFR) were derived from flow measurements in the left anterior descending artery using transthoracic echocardiography. F-Rmin was measured using venous occlusion plethysmography. Resting systemic vascular resistance index (SVRI) was measured with a gas rebreathing technique. RESULTS: Compared to normotensive controls: 24-h mean BP was raised 14% in grade 1 essential hypertension and 28% in grade 2 essential hypertension, whereas F-Rmin and C-Rmin were elevated by 58 and 87% in grade 1 essential hypertension and 72 and 125% in grade 2 essential hypertension. C-Rmin and F-Rmin were thus both increased more than expected from the BP level. SVRI and left-ventricular mass were increased proportionally to the BP. CFR was decreased by approximately 30% in both essential hypertension groups. CONCLUSION: The results demonstrate excessive microvascular structural abnormalities in hypertension suggesting microvascular alterations occur early and not just as an adaptation to the BP level. Thus the level of BP elevation does not give an accurate indication of the microvascular involvement and impairment in essential hypertension.

A mechanism for arteriolar remodeling based on maintenance of smooth muscle cell activation.

Structural adaptation in arterioles is part of normal vascular physiology but is also seen in disease states such as hypertension. Smooth muscle cell (SMC) activation has been shown to be central to microvascular remodeling. We hypothesize that, in a remodeling process driven by SMC activation, stress sensitivity of the vascular wall is a key element in the process of achieving a stable vascular structure. We address whether the adaptive changes in arterioles under different conditions can arise through a common mechanism: remodeling in a stress-sensitive wall driven by a shift in SMC activation. We present a simple dynamic model and show that structural remodeling of the vessel radius by rearrangement of the wall material around a lumen of a different diameter and driven by differences in SMC activation can lead to vascular structures similar to those observed experimentally under various conditions. The change in structure simultaneously leads to uniform levels of circumferential wall stress and wall strain, despite differences in transmural pressure. A simulated vasoconstriction caused by increased SMC activation leads to inward remodeling, whereas outward remodeling follows relaxation of the vascular wall. The results are independent of the specific myogenic properties of the vessel. The simulated results are robust in the face of parameter changes and, hence, may be generalized to vessels from different vascular beds.

Treatment of young subjects at high familial risk of future hypertension with an angiotensin-receptor blocker.

UNLABELLED: Offspring of hypertensive parents are at high risk of future hypertension and subsequent cardiovascular diseases. We investigated whether early treatment with an angiotensin-receptor blocker in young normotensive offspring of hypertensive parents persistently lowered blood pressure after treatment withdrawal, a possibility supported by animal studies. The study is an investigator-initiated, double-blind study of 110 healthy normotensive subjects aged 18 to 36 years where both parents have essential hypertension randomly assigned to 1 of 2 treatment groups: candesartan (Atacand, Astra Zeneca), 16 mg o.d. or placebo. The intervention period was 12 months, with 24 months of follow-up. PRIMARY OUTCOME was mean 24-hour ambulatory blood pressure recordings (mean AMBP) after 12 and 24 months follow-up and was based on intention to treat (n=110). SECONDARY OUTCOMES were changes during treatment in mean AMBP, left ventricular mass, renal hemodynamics, and adverse events during intervention and were based on those completing the intervention period (n=105). PRIMARY OUTCOME: At 12 and 24 months follow-up, mean AMBP was not different to placebo. SECONDARY OUTCOMES: After 12 months of intervention, mean AMBP was reduced: -3.9/-3.4 mm Hg for candesartan versus 0.3/0.6 mm Hg for placebo, P<0.0001. Renal vascular resistance and left ventricular mass were also reduced (P=0.0007, P=0.019, respectively). There were no significant differences in adverse advents between the 2 groups. In conclusion, temporary treatment of subjects at high familial risk of future hypertension with an angiotensin receptor blocker is feasible, but the treatment had no persistent effect on blood pressure when treatment was withdrawn.

Renal haemodynamics are not related to genotypes in offspring of parents with essential hypertension.

UNLABELLED: INTRODUCTION. The pathogenesis of essential hypertension (EH) has a major genetic component and is associated with renal abnormalities. Normotensive offspring of hypertensive parents are likely to develop EH and are a suitable population for identifying possible relations between genetic and renal abnormalities. METHODS: We investigated if renin-angiotensinaldosterone system associated genotypes (angiotensinogen [M235T] and ACE [I/D]) are related to blood pressure (BP), renal haemodynamics and sodium excretion in sex and age-matched (1835 years) healthy Caucasian offspring of either two parents with EH (n=101, EH-offspring) or two normotensive parents (n=50, controls). The alpha-adducin polymorphism (G460W) was also investigated. RESULTS: Compared to controls, BP, heart rate, renal vascular resistance (RVR) and urinary sodium excretion were, respectively, 5%, 7%, 15% and 20% higher in EHoffspring. In controls, the TT-genotype of the M235T angiotensinogen polymorphism was associated with higher BP and higher plasma angiotensinogen. By contrast, in EHoffspring the TT-genotype was associated with lower BP and unchanged plasma angiotensinogen. Plasma angiotensinogen correlated positively with BP in EH-offspring, with a similar tendency (p=0.08) in controls. The distributions of the three candidate polymorphisms were similar in EH-offspring and controls. There were no associations between any of the polymorphisms and any of the renal parameters measured. CONCLUSION: The markedly greater RVR, proportionally larger than the greater BP, supports a role for RVR in the pathogenesis of EH. The lack of association between the candidate polymorphisms and the investigated parameters, even in this homogenous and for hypertension strongly predisposed group, suggests that the polymorphisms investigated do not play important roles in the pathogenesis of hypertension.

The superoxide dismutase mimetic, tempol, blunts right ventricular hypertrophy in chronic hypoxic rats.

1. The purpose of this study was to investigate whether a membrane-permeable superoxide dismutase mimetic, tempol, added either alone or in combination with the nitric oxide (NO) donor molsidomine, prevents the development of pulmonary hypertension (PH) in chronic hypoxic rats. 2. Chronic hypobaric hypoxia (10% oxygen) for 2 weeks increased the right ventricular systolic pressure (RVSP), right ventricle and lung wet weight. Relaxations evoked by acetylcholine (ACh) and the molsidomine metabolite SIN-1 were impaired in isolated proximal, but not distal pulmonary arteries, from chronic hypoxic rats. 3. Treatment with tempol (86 mg x kg(-1) day(-1) in drinking water) normalized RVSP and reduced right ventricular hypertrophy, while systemic blood pressure, lung and liver weights, and blunted ACh relaxation of pulmonary arteries were unchanged. 4. Treatment with molsidomine (15 mg x kg(-1) day(-1) in drinking water) had the same effects as tempol, except that liver weight was reduced, and potassium and U46619-evoked vasoconstrictions in pulmonary arteries were increased. Combining tempol and molsidomine did not have additional effects compared to tempol alone. ACh relaxation in pulmonary arteries was not normalized by these treatments. 5. The media to lumen diameter ratio of the pulmonary arteries was greater for the hypoxic rats compared to the normoxic rats, and was not reversed by treatment with tempol, molsidomine, or the combination of tempol and molsidomine. 6. We conclude that tempol, like molsidomine, is able to correct RVSP and reduce right ventricular weight in the rat hypoxic model. Functional and structural properties of pulmonary small arteries were little affected. The results support the possibility that superoxide dismutase mimetics may be a useful means for the treatment of PH.

Adrenergic mechanisms and remodeling of subcutaneous small resistance arteries in humans.

BACKGROUND: Vascular structural alterations in small resistance arteries of patients with essential hypertension (EH) are mostly characterized by inward eutrophic remodeling. In fact, no difference in the smooth muscle cell volume (CV) between normotensive subjects (NT) and essential hypertensive patients was observed. However, experimental models of hypertension with chronic infusion of agonists of adrenergic receptors were characterized by the presence of smooth muscle cell hypertrophy or hyperplasia. Recently, we have observed the presence of vascular smooth muscle cell hypertrophy in patients with renovascular hypertension. OBJECTIVE: The aim of the study to investigate the structural characteristics of subcutaneous small resistance arteries of NT, of EH, and of patients with phaeochromocytoma (Phaeo). PATIENTS AND METHODS: Thirty Phaeo, 30 NT and 30 EH were included in the study. A biopsy of subcutaneous fat was taken from all subjects. Small resistance arteries (relaxed diameter 160-280 microm) were dissected and mounted on a micromyograph and the media : lumen ratio was calculated. In nine Phaeo, nine NT and 13 EH the cell volume was measured by an unbiased stereological principle, the 'disector' method. RESULTS No difference in smooth muscle cell volume was observed between groups. However, inward remodeling in Phaeo was less marked than in EH, although the increase in media : lumen ratio was similar compared with NT. However, the lack of changes in media cross-sectional area, compared with NT, suggest that there has been little hypertrophy, the changes observed thus being eutrophic. CONCLUSIONS: Our data show, based on a reasonably large sample, that a pronounced activation of the adrenergic system is not associated with vascular smooth muscle cell hypertrophy or hyperplasia in humans. It is therefore possible that adrenergic mechanisms may have a relevant role in the development of eutrophic remodeling in small vessels.