Structural Changes In Resistance Vessels Research Articles

P4993Tissue sodium concentration emerged as a determinant of hypertrophic vascular remodeling in type 2 diabetes

Abstract Background Studies describe a linkage between greater sodium intake and higher incidence of organ damage and cardiovascular end points. Sodium intake is usually assessed by measuring 24-hour urinary sodium excretion, which is prone to high fluctuation. For the assessment of tissue sodium a new technique (23Na-MRI) has been developed. We analyzed whether tissue sodium is linked to vascular remodeling of small resistance vessels in patients with type-2 diabetes. Methods In patients with type 2 diabetes we assessed tissue sodium content and vascular structural parameters of the retinal arterioles, since structural changes of resistance vessels (150–300 μm) can be non-invasively and reliably assessed in the retinal circulation by Scanning Laser Doppler Flowmetry (SLDF). Patients with antidiabetic medication were off the therapy (antihypertensives were kept constant) for 4 weeks. The structural parameters of retinal arterioles assessed were outer- and inner diameter (OD & ID), wall thickness (WT), wall-to-lumen ratio (WLR) and wall cross sectional area (WCSA). Tissue sodium content was assessed non-invasively with a 3.0 T clinical MRI system in each patient. Subject placed their lower legs in the center of a 23Na knee coil and sodium content in skin and muscle (musculus triceps surae) were measured. Results In patients with type 2 diabetes (N=52) we observed a significant correlation between tissue sodium content (muscle and skin) and OD, WT and WCSA and a trend has been noticed between muscle sodium content and ID and WLR. Multiple linear regression analysis demonstrated that tissue sodium content is a significant determinant of hypertrophic vascular remodeling as indicated by increased WT and WCSA, independent of age, gender and 24-hour ambulatory diastolic blood pressure. Correlation coefficients Muscle sodium content (mmol/l) Skin sodium content (mmol/l) OD (μmol) r=0.402, p=0.003 r=0.299, p=0.033 ID (μmol) r=0.265, p=0.058 r=0.202, p=0.154 WT (μm) r=0.402, p=0.003 r=0.313, p=0.026 WLR r=0.247, p=0.078 r=0.171, p=0.230 WCSA (μm2) r=0.417, p=0.002 r=0.322, p=0.021 Conclusion With the novel 23Na-MRI technology, we could demonstrate that high tissue sodium concentration is linked to with hypertrophic vascular remodeling of retinal arterioles. Thus, the reduction of tissue sodium content may emerge as a therapeutic target.

Endothelial Cell Tetrahydrobiopterin Modulates Sensitivity to Ang (Angiotensin) II-Induced Vascular Remodeling, Blood Pressure, and Abdominal Aortic Aneurysm.

GTPCH (GTP cyclohydrolase 1, encoded by Gch1) is required for the synthesis of tetrahydrobiopterin; a critical regulator of endothelial NO synthase function. We have previously shown that mice with selective loss of Gch1 in endothelial cells have mild vascular dysfunction, but the consequences of endothelial cell tetrahydrobiopterin deficiency in vascular disease pathogenesis are unknown. We investigated the pathological consequence of Ang (angiotensin) II infusion in endothelial cell Gch1 deficient (Gch1fl/fl Tie2cre) mice. Ang II (0.4 mg/kg per day, delivered by osmotic minipump) caused a significant decrease in circulating tetrahydrobiopterin levels in Gch1fl/fl Tie2cre mice and a significant increase in the Nω-nitro-L-arginine methyl ester inhabitable production of H2O2 in the aorta. Chronic treatment with this subpressor dose of Ang II resulted in a significant increase in blood pressure only in Gch1fl/fl Tie2cre mice. This finding was mirrored with acute administration of Ang II, where increased sensitivity to Ang II was observed at both pressor and subpressor doses. Chronic Ang II infusion in Gch1fl/fl Tie2ce mice resulted in vascular dysfunction in resistance mesenteric arteries with an enhanced constrictor and decreased dilator response and medial hypertrophy. Altered vascular remodeling was also observed in the aorta with an increase in the incidence of abdominal aortic aneurysm formation in Gch1fl/fl Tie2ce mice. These findings indicate a specific requirement for endothelial cell tetrahydrobiopterin in modulating the hemodynamic and structural changes induced by Ang II, through modulation of blood pressure, structural changes in resistance vessels, and aneurysm formation in the aorta.

Association Between Graded Exercise Test Indicators of Cardiovascular Disease Risks and Peripheral Vascular Stiffness

Exaggerated systolic blood pressure (SBP) responses to graded exercise testing in normotensive adults have been associated with risk of future hypertension. Venous occlusion plethysmography (VOP) non-invasively characterizes endotheliumdependent vasodilatory capacity in peripheral arteries (reactive hyperemia: RH). Endothelial dysfunction has been hypothesized to lead to functional and structural changes in resistance vessels and also contribute to increased risk for future hypertension. Limited research has been done to assess the relationship between exaggerated SBP in exercise testing and vascular status by the VOP/RH test in young normotensive adults. PURPOSE: To determine if an association exists between exaggerated SBP responses to graded exercise and peripheral vascular vasodilatory capacity. METHODS: Subjects were 50 young males (Mean ± SD: age = 22.4 ± 2.6 yr; body fat = 24.3 ± 6.1 %; BMI = 27.7 ± 5.7). Post-occlusive RH was assessed after a 5-min brachial artery occlusion using VOP and standard procedures recommended by the manufacturer (Hokanson EC-6, Bellevue, WA). Each subject performed maximal cycle ergometer exercise tests with a 15 watts/min ramping protocol. Blood pressures (BP) were measured at rest, every 2 min during, and at 15 sec intervals after exercise. Subjects recovered in the seated position, with minimal-load pedaling. Exaggerated BP was defined as any one of the following: SBP at METpk >195 mm Hg; Δ SBP >60 mm Hg at 35% METpk; Δ SBP >70 mm Hg at 65% METpk and (4) Δ diastolic BP >10 mm Hg at METpk. RESULTS: Resting SBP showed modest (r ∼ 0.33) but statistically significant (p<0.02) associations with RH scores from 30–60 sec post-occlusion. However, during exercise no relationship was found between any of the exaggerated SBP indices and the measures of peripheral artery status by VOP. DBP at 4 min post-exercise was significantly associated with RH immediately post-occlusion (r = 0.28, p = 0.04). Furthermore, when individual SBP responses from peak exercise at the highest (200–246 mmHg) vs. lowest tertiles (138–176 mmHg) were contrasted, no differences in the VOP measures of vascular status were found. CONCLUSION: Regulations of blood pressure at rest and during exercise are complex and the mechanisms by which vascular status may contribute to risk of hypertension remain poorly understood, especially with respect to younger vs. older adults. Within the limitations of this study, exaggerated SBP response to graded exercise in young adult males seems to be regulated largely by factors other than peripheral vascular status, as assessed by VOP/RH. Supported by a grant from ResMed Sleep Disordered Breathing Foundation, Poway, CA.

Racial differences in minimum lower leg vascular resistance in normotensive young adults with positive and negative parental histories of hypertension.

To determine whether peripheral hemodynamic differences exist in young adult normotensive African Americans and white Americans with a positive and negative parental history of hypertension. The participants were healthy men of whom 13 were African Americans and nine white Americans with a positive parental history and 19 were African Americans and 13 white Americans with a negative parental history. Lower leg blood flows were obtained at rest and during reactive hyperemia. Lower leg minimum vascular resistance (Rmin) was computed from reactive hyperemic blood flow measured by venous occlusion plethysmography, and mean arterial blood pressure was determined by auscultation of the brachial artery. Resting blood flow and mean arterial pressure were similar in all groups. A significant race x parental history interaction effect was observed for lower leg Rmin. In the white men the lower leg Rmin was significantly greater in the positive than the negative parental group (P < 0.05). Lower leg Rmin was significantly greater in African Americans than in white men without a parental histoy (P < 0.05). Mean arterial blood pressure and heart rate were similar among the groups. This study demonstrates that lower leg Rmin is greater in young white men with a positive parental history of hypertension than those with a negative parental history. In African Americans with either positive or negative parental histories, lower leg Rmin is not different. This finding suggests that heredity may have a greater influence in white populations than in African Americans on the structural changes in resistance vessels. The study also suggests that African Americans have an earlier structural change in the resistance vessels compared with white people, regardless of a parental history of hypertension. This suggests that factors other than heredity are of importance in changing the structure of the resistance vessels.

Influence of Isradipine and Spirapril on Left Ventricular Hypertrophy and Resistance Arteries

Left ventricular hypertrophy is a common clinical feature in hypertensive patients and may be associated with structural changes in vessel morphology. In an open prospective trial, we evaluated 14 patients with previously untreated hypertension (163 +/- 2/104 +/- 2 mm Hg) and an echocardiographically determined left ventricular mass index of 141.6 +/- 5.2 g/m2, indicating left ventricular hypertrophy. We obtained a gluteal skin biopsy sample before starting treatment to investigate subcutaneous small-artery (approximately 200 to 400 microns diameter) morphology and function. Patients then received antihypertensive treatment with a combination of spirapril (3 or 6 mg) and isradipine (2.5 or 5 mg). Echocardiographic recordings were made after 6 months and 1 year, and a final biopsy was taken after 1 year. After 1 year, blood pressure was significantly reduced to 142 +/- 3/ 90 +/- 1 mm Hg (P < .001), and left ventricular mass index decreased significantly to 105.3 +/- 5.8 g/m2 (P < .001). Baseline media-lumen ratio (7.64 +/- 0.48%) was not markedly reduced (7.21 +/- 0.55%), although a decrease occurred in 7 of 12 evaluable patients. Norepinephrine-induced vasoconstriction was markedly reduced after 1 year. In conclusion, a significant regression of left ventricular hypertrophy was obtained after 1 year of treatment with spirapril and isradipine, whereas a similar reduction in medial thickness relative to lumen diameter of subcutaneous small arteries could not be observed in all patients. Reversal of structural changes in resistance vessels may require a longer treatment period in patients with proven left ventricular hypertrophy.

Histometric assessment of renal arterioles during DOCA and post-DOCA hypertension and hydralazine treatment in rats

It is now well established that structural changes in resistance vessels contribute to the long-term maintenance of many forms of hypertension. This study measured the time course of structural change in smaller resistance vessels during the development of deoxycorticosterone acetates (DOCA) hypertension and after cessation of DOCA in Wistar rats by histometric assessment of cross-sections of renal arterioles. The relationship of structural change to blood pressure was assessed by preventing hypertension during DOCA treatment with hydralazine. Blood pressure rose progressively during DOCA treatment reaching 192 +/- 3 mmHg compared with 132 +/- 2 mmHg in controls after 10 weeks. Five and 10 weeks after cessation of DOCA, following 10 weeks of DOCA treatment, post-DOCA reversal of hypertension was only partial. Medial area to internal elastic lamina (IEL) radius ratio, wall to lumen ratio and intimal area to IEL radius ratio of renal arterioles increased progressively during 10 weeks of DOCA treatment with partial reversal of the increased medial area and wall to lumen ratio 5 weeks post-DOCA. Hydralazine completely prevented hypertension in DOCA rats and also largely prevented structural change.

Does cytosolic free calcium concentration in platelets reflect tone and structural changes of resistance vessels?

To investigate tone and vascular changes of resistance vessels as related to cytosolic free calcium concentration [( Ca2+]i) in platelets, we measured forearm vascular resistance and free calcium concentration in platelets from 10 essential hypertensives and 15 normotensives. The [Ca2+]i in platelets was significantly higher in essential hypertensives than in normotensives (184 +/- 43 versus 146 +/- 23 nmol/l, P less than 0.01). The [Ca2+]i levels in platelets were significantly correlated with both systolic (r = 0.50, P less than 0.05) and diastolic blood pressures (r = 0.57, P less than 0.01). Resting vascular resistance and minimal vascular resistance were significantly higher in essential hypertensives than in normotensives (30.6 +/- 12.6 and 2.57 +/- 1.30 versus 16.3 +/- 8.0 and 1.47 +/- 0.63 mmHg/ml per min per 100 ml, P less than 0.05 and P less than 0.01, respectively). Both resting and minimal vascular resistance were significantly correlated with [Ca2+]i in platelets (r = 0.40 and P less than 0.05, r = 0.55 and P less than 0.01, respectively). These results suggest that [Ca2+]i in platelets reflects [Ca2+]i in vascular smooth muscle cells and may be a significant determinant of not only tone but also structural changes of resistance vessels.

Functional versus structural changes of forearm vascular resistance in hypertension.

Structural changes in resistance vessels have been considered an important factor in triggering and maintaining chronic hypertension in humans and in experimental animals. To determine whether the increased forearm vascular resistance observed following vasodilator maneuvers in hypertensive patients is predominantly due to structural or to functional changes, we examined the influence of different vasodilator stimuli on forearm blood flow and blood pressure in 22 male patients with established essential hypertension and in 22 age-matched normotensive men (age range, 28-52 years). Blood pressure was measured directly, and blood flow was measured by venous occlusion plethysmography. The maneuvers applied were 1) arterial occlusion combined with handgrip exercise and local heating, 2) intra-arterial infusion of the calcium entry blocker nifedipine, 3) intra-arterial infusion of the nonspecific vasodilator sodium nitroprusside, 4) arterial occlusion initiated after intra-arterial infusion of nifedipine. Vascular resistance during vasodilation induced by arterial occlusion or infusion of nifedipine or sodium nitroprusside remained significantly higher in the hypertensive than in the normotensive subjects. However, the maximal vasodilation achieved by the combination of arterial occlusion and nifedipine resulted in a similar resistance in both groups (1.6 +/- 0.2 in the hypertensive vs 1.4 +/- 0.2 mm Hg/ml/min/100 ml tissue in the normotensive subjects. These data suggest that there is an important functional component of the elevated resistance in patients with essential hypertension.

Maximal hand blood flow in hypertensive and normal subjects

The present study examined whether patients with systemic hypertension have evidence of structural vascular changes, whether such changes can be detected in early stages of hypertension and whether they are reversible with treatment. Hypertensive and normal subjects were studied under conditions of maximal vasodilation in which flow at a given driving pressure was considered to give an index of structural changes in resistance vessels. Thirty-two subjects were separated into 4 groups: 8 with sustained hypertension, 8 with intermittent hypertension, 8 treated hypertensive subjects maintained at systolic pressures of less than 125 mm Hg with drugs for 5 years, and 8 normal subjects. Flow was measured by venous occlusion plethysmography after 10 minutes of ischemia, using a water-filled plethysmograph at 43 °C. Arterial blood pressure was measured by the arm cuff method. Transmural pressure, calculated as mean arterial minus external pressure, was varied by imposing varying external hydrostatic pressures. Flow at a transmural pressure of 85 mm Hg was calculated for each subject from the least-mean-square plot of transmural pressure vs flow. Mean flow for normal subjects was 41 ml/100 ml/min and differed significantly from that for sustained hypertensive patients (30 ml/100 ml/min), treated hypertensive patients (33 ml/100 ml/min), and intermittent hypertensive patients (32 ml/100 ml/min) (p < 0.05). There was no overlap between sustained hypertensives and normal subjects, but half of the treated hypertensive patients were normal. Intermittent hypertensive patients usually showed evidence of pronounced arterial changes. Prolonged therapy appeared to reverse changes in some sustained hypertensives. This noninvasive method permits comparisons of hypertensive and normotensive subjects at equivalent transmural pressures.

Prevention of structural arteriolar changes in DOCA hypertension with hydrallazine.

Structural changes in resistance vessels were studied by (a) hindquarter perfusion; and (b) planimetry of cross-sections of renal arterioles in uninephrectomized rats treated for 10 weeks with saline and either DOCA (deoxycorticosterone acetate), DOCA plus hydrallazine, vehicle plus hydrallazine or vehicle only. DOCA-treated rats developed hypertension and structural change. Addition of hydrallazine prevented both hypertension and the development of structural change. Structural arteriolar change in DOCA/salt hypertension is related to the high blood pressure or a closely associated factor rather than some other effect of DOCA.

Onset and offset of structural arteriolar changes in DOCA/salt hypertension in the rat.

1. Structural changes in resistance vessels were studied sequentially (a) by hindquarter perfusion and (b) by planimetry of renal arterioles less than or equal to 20 micrometers radius, for 10 weeks during development of DOCA (deoxycorticosterone acetate)/salt hypertension in uninephrectomized rats and 5 weeks after cessation of DOCA treatment. 2. Blood pressure and haemodynamically significant structural change increased progressively during DOCA treatment and both had partially reversed 5 weeks after cessation of DOCA. 3. Arteriolar structural changes contribute progressively to the hypertension during 10 weeks DOCA treatment. Partial reversal of structural changes contributes to the fall in blood pressure after cessation of DOCA. The persisting postDOCA hypertension can be attributed to relatively irreversible structural changes.

Cerebral vasomotor reactivity in normotensive and spontaneously hypertensive rats.

Intravenously injected metaraminol induced a larger blood pressure increase in spontaneously hypertensive rats (SHR) than in normotensive controls (NR) when the pressure was raised from the same starting level. Cerebral blood flow (CBF) response in NR was either perfect autoregulation, partial autoregulation or "break-through." When present, the autoregulatory response was very rapid, i.e. the flow returned to the initial value within 10-15 sec. All SHR showed an initial prompt vasoconstrictor response which was followed after 30-40 sec by a gradual flow increase. The blood pressure elevation was highest in SHR when hypertension was induced by compression of the aorta, which supports the hypothesis that the enhanced response is, at least in part, a consequence of an increased vessel wall to lumen ratio. The characteristic CBF pattern observed in SHR after a metaraminol-induced rise in blood pressure was not seen when the blood pressure was increased by aortic compression, which suggests an effect of the drug separate from its pressor effect. During maximum vasodilatation the cerebrovascular resistance (CVR) was considerably higher in SHR than in NR. Assuming an equivalent vessel density in the 2 groups, our results suggest that structural changes in resistance vessels in SHR encroach on the lumen.