Regression Of Vascular Hypertrophy Research Articles

Eplerenone prevents salt-induced vascular stiffness in Zucker diabetic fatty rats: a preliminary report

BackgroundAldosterone levels are elevated in a rat model of type 2 diabetes mellitus, the Zucker Diabetic fatty rat (ZDF). Moreover blood pressure in ZDF rats is salt-sensitive. The aim of this study was to examine the effect of the aldosterone antagonist eplerenone on structural and mechanical properties of resistance arteries of ZDF-rats on normal and high-salt diet.MethodsAfter the development of diabetes, ZDF animals were fed either a normal salt diet (0.28%) or a high-salt diet (5.5%) starting at an age of 15 weeks. ZDF rats on high-salt diet were randomly assigned to eplerenone (100 mg/kg per day, in food) (ZDF+S+E), hydralazine (25 mg/kg per day) (ZDF+S+H), or no treatment (ZDF+S). Rats on normal salt-diet were assigned to eplerenone (ZDF+E) or no treatment (ZDF). Normoglycemic Zucker lean rats were also divided into two groups receiving normal (ZL) or high-salt diet (ZL+S) serving as controls. Systolic blood pressure was measured by tail cuff method. The experiment was terminated at an age of 25 weeks. Mesenteric resistance arteries were studied on a pressurized myograph. Specifically, vascular hypertrophy (media-to-lumen ratio) and vascular stiffness (strain and stress) were analyzed. After pressurized fixation histological analysis of collagen and elastin content was performed.ResultsBlood pressure was significantly higher in salt-loaded ZDF compared to ZDF. Eplerenone and hydralazine prevented this rise similarily, however, significance niveau was missed. Media-to-lumen ratio of mesenteric resistance arteries was significantly increased in ZDF+S when compared to ZDF and ZL. Both, eplerenone and hydralazine prevented salt-induced vascular hypertrophy. The strain curve of arteries of salt-loaded ZDF rats was significantly lower when compared to ZL and when compared to ZDF+S+E, but was not different compared to ZDF+S+H. Eplerenone, but not hydralazine shifted the strain-stress curve to the right indicating a vascular wall composition with less resistant components. This indicates increased vascular stiffness in salt-loaded ZDF rats, which could be prevented by eplerenone but not by hydralazine. Collagen content was increased in ZL and ZDF rats on high-salt diet. Eplerenone and hydralazine prevented the increase of collagen content. There was no difference in elastin content.ConclusionEplerenone and hydralazine prevented increased media-to-lumen ratio in salt-loaded ZDF-rats, indicating a regression of vascular hypertrophy, which is likely mediated by the blood pressure lowering-effect. Eplerenone has additionally the potential to prevent increased vascular stiffness in salt-loaded ZDF-rats. This suggests an effect of the specific aldosterone antagonist on adverse vascular wall remodelling.

Vascular and metabolic effects of angiotensin II receptor blockers

Angiotensin II receptor blockers (ARBs) are widely used in patients with hypertension, heart failure and type 2 diabetes mellitus (T2DM). Several large clinical trials have demonstrated that these agents are effective in reducing cardiovascular mortality and morbidity. These benefits are partly independent of the degree of blood pressure reduction and most likely related to ARBs' anti-inflammatory, metabolic and vascular effects. Clinical studies showed that the anti-inflammatory effect of ARBs could be related to the dosage and/or the length of the treatment. In large clinical trials, ARBs have inconsistently reduced the risk of new-onset T2DM. Among ARBs, only losartan significantly reduced serum uric acid levels. Moreover, it has been demonstrated that ARBs improve endothelial dysfunction in patients with hypertension and/or coronary artery disease (CAD), while all but one of the studies proved that these agents could usually, after 6 – 12 months of therapy, induce regression of vascular hypertrophy in hypertensive patients. These positive effects could be relevant to vascular protection and, together with the blood pressure reduction, constitute the background of the improved outcome observed in clinical studies on mortality and/or morbidity in hypertensive, high-risk and CAD patients. The clinical significance of the different potency of ARBs needs to be investigated further in specific and adequately powered trials.

Synergistic interaction between enalapril, L-arginine and tetrahydrobiopterin in smooth muscle cell apoptosis and aortic remodeling induction in SHR.

Smooth muscle cell (SMC) apoptosis occurs at the onset of enalapril-induced regression of aortic hypertrophy in SHR. A potential mechanism is the correction of endothelial dysfunction (ED) leading to reduced production of reactive oxygen species and enhanced bioavailability of nitric oxide (NO), a potent apoptosis inducer. Stimulants of NO include the precursor L-arginine and the NO synthase cofactor tetrahydrobiopterin (BH(4)), which correct ED in several models. The objective was to examine the relationships between ED and the cell growth/death balance during vascular remodeling induced by enalapril in SHR. SHR, 10-week-old, received enalapril (ENA: 30 mg x kg(-1) x day(-1) p.o.) for 1 or 2 weeks, or a co-treatment of L-arginine (2.0 g x kg(-1) x day(-1) p.o.) and BH(4) (5.4 mg x kg(-1) x day(-1) i.p. twice daily) administered alone (group: LB) or in combination with enalapril (ENA+LB) for 1 week. Controls received vehicle. After 1 week, ED was completely corrected with LB but not affected significantly by ENA, whereas both treatments failed to induce SMC apoptosis or aortic remodeling. The correction of ED and the induction of SMC apoptosis (3.3-fold increase in TUNEL labeling) required 2 weeks of ENA treatment. The combination of LB with ENA for 1 week, however, was additive for the reduction of SMC proliferation, and synergistic for the induction of apoptosis and regression of vascular hypertrophy. These interactions were independent of blood pressure regulation. Our results suggest that the correction of ED is not sufficient to induce SMC apoptosis and vascular remodeling, although it facilitates these responses during enalapril treatment.

Pharmacodynamic Contribution to the Vasodilator Effect of Chronic AT(1) Receptor Blockade in SHR.

-The present study investigated the pharmacodynamic contribution of AT(1) receptor blockade to the regional hemodynamic effects of long-term treatment with the AT(1) receptor antagonist candesartan cilexetil in adult spontaneously hypertensive rats (SHR). Blood pressure and Doppler flowmetry measurements were made during and after withdrawal of candesartan cilexetil, representing times of maximal and negligible blockade of AT(1) receptor-mediated vasoconstriction. There was marked renal, mesenteric, and hindquarter vasodilation in SHR treated for 4 weeks with candesartan cilexetil (2 mg/kg per day in drinking water, n=8) compared with vehicle (n=8). Blood pressure increased after withdrawal of candesartan cilexetil but was still reduced after 6 days, whereas regional flows and conductances did not reduce significantly compared with the last day of treatment. There was more prolonged inhibition of angiotensin (Ang) I-induced than Ang II-induced pressor responses after withdrawal of candesartan cilexetil, but these returned to control levels before blood pressure reached fully hypertensive levels. The renal and mesenteric vasoconstrictor effects of exogenously administered Ang I and Ang II returned to control levels just 2 days after withdrawal of candesartan cilexetil. Therefore, sustained inhibition of tonic Ang-mediated vasoconstriction caused by blockade of the AT(1) receptor is not the only factor contributing to the hemodynamic profile after long-term administration of candesartan cilexetil. In addition, compared with the vehicle group, blood pressures at maximum vasoconstriction and maximum vasodilation (an indirect measure of vascular hypertrophy) were significantly reduced in candesartan cilexetil-treated SHR on the last day of treatment, as was mesenteric media wall-to-lumen ratio in a separate group of similarly treated SHR. Collectively, these findings indicate that Ang-mediated vasoconstriction rapidly normalizes on withdrawal of AT(1) receptor blockade and that regression of vascular hypertrophy is important in determining blood pressure and hemodynamic status in candesartan cilexetil-treated SHR at this time.

Tempol, Vitamin C and Vitamin E Improve Endothelial Dysfunction, Regress Vascular Hypertrophy and Prevent Progression of Hypertension and Renal Dysfunction in Stroke-Prone Shr

P35 Antioxidant vitamins reduce oxidative stress in vascular injury associated with atherosclerosis and balloon injury. The role of these agents in the pathogenesis of hypertension is unclear. We investigated effects of vitamins C and E and the superoxide dismutase (SOD) mimetic, tempol, on development of blood pressure, vascular structure and endothelial function in salt-loaded stroke-prone SHR (SHRSP). 16 week-old SHRSP (n=26) on a high salt diet (4% NaCl) were randomly divided into 4 groups: control (C), Vit C (1000 mg/d), Vit E (1000 IU/d) and tempol (1 mmol/d). Systolic blood pressure (SBP) and renal function were assessed weekly. 6 weeks after treatment rats were killed. Vascular structure (media:lumen ratio) and endothelial function (acetylcholine (Ach)-induced vasodilation) were assessed in small mesenteric arteries mounted as pressurized preparations. SBP increased from 204± to 265±6 mmHg in C group. Progression of hypertension was prevented in Vit C (234±4 mmHg), Vit E (227±11mmHg) and tempol (208±8 mmHg) groups. Development and severity of proteinuria was delayed in all treated groups compared with C. The media:lumen ratio was reduced (p<0.001) in the Vit E (7.4±0.5%) and tempol (7.2±0.01%) groups compared with C group (12±0.1%). Structure was not significantly altered in the Vit C group. Maximal Ach-induced dilation was significantly improved in all treated groups, particularly in the Vit C group (85±4 % vs C 40±9 %, p<0.01). In conclusion antioxidant vitamins and tempol prevent progression of hypertension and improve renal dysfunction in SHRSP. These processes are associated with improved endothelial function and regression of vascular hypertrophy in small arteries. Our data suggest that oxidative stress plays a role in vascular and renal damage associated with severe hypertension in salt-loaded SHRSP.

Effects of lercanidipine on forearm and calf vascular structural changes in hypertension

It is still undetermined whether pharmacological regression of vascular structural changes associated with hypertension depends on the drug-induced blood pressure reduction “per se” or rather on the antihypertensive effects of the drug coupled with its additional properties (e.g., antioxidative effects, vascular selectivity, etc.). To clarify this aspect in 24 mild to moderate untreated essential hypertensives (age: 47.3 ± 0.5 years; mean arterial pressure, MAP: 115.4 ± 3.6 mmHg, mean ± SEM), with no other major cardiovascular or non-cardiovascular diseases, we measured beat-to-beat MAP (Finapres), heart rate (HR, EKG), forearm and calf blood flows (FBF, CBF, venous occlusion plethysmography) and calculated forearm and calf vascular resistance (FVR:MAP/FBF,CVR:MAP/CBF respectively). We also evaluated forearm and calf minimal vascular resistance (FVRmin and CVRmin) following 12 min of local ischaemia associated with 2 min of isometric exercise. The entire protocol was performed in the no drug condition and repeated following a 6 month treatment with lercanidipine (L, 10 mg/day per os, n = 12) of hydrochlorothiazide (H, 25 mg/day per os, n = 12) accordingly to a double blind design. L caused a significant (p < 0.01) reduction in MAP (−12.9 ± 1.1 mmHg), FVR (−12.6 ± 1.6 U) and CVR (−15.1 ± 1.7 U) without affecting HR values. These effects were coupled with a significant reduction in FVRmin (from 3.1 ± 0.3 to 2.0 ± 0.2 U, p < 0.01) and in CVRmin (from 4.6 ± 0.3 to 3.5 ± 0.3 U, p < 0.05). In contrast, for similar MAP reduction (−10.8 ± 1.4 mmHg, p < 0.01), H caused a slight decrease in FVR and CVR (−6.5 ± 1.3, −7.6 ± 1.5 U respectively) without significantly affecting FVRmin and CVRmin. These data provide evidence that for similar blood pressure reductions only drugs, such as L with additional vasoprotective properties, are capable of favouring a regression of the vascular structural changes associated with hypertension. This implies that the blood pressure reduction “per se” may be not sufficient to cause regression of vascular hypertrophy.

Effect of endothelin antagonism on blood pressure and vascular structure in renovascular hypertensive rats.

To investigate the potential pathogenic role of endothelin in blood pressure elevation and vascular hypertrophy in renovascular hypertensive rats, which present twofold elevations in endothelin-1 mRNA abundance in blood vessels, the response of blood pressure and vascular structure to chronic treatment with the endothelin receptor antagonist bosentan was evaluated. One-kidney, one clip (1K,1C) and two kidney, one clip (2K,1C) Goldblatt hypertensive rats were treated for 2 wk with bosentan (100 mg.kg-1.day-1) in their chow, and systolic blood pressure was measured by the tail-cuff method. Vascular structure was studied in small arteries mounted on a wire myograph. Treatment with bosentan did not result in a significant change in systolic blood pressure or in the structure of small coronary, renal cortical, mesenteric, or femoral arteries in 1K, 1C or in 2K, 1C hypertensive rats. In conclusion, modest (twofold) elevations of endothelin-1 gene expression in blood vessels in renovascular hypertension are not associated with hypotensive responses or regression of vascular hypertrophy during treatment with endothelin antagonists in contrast to what is found in deoxycorticosterone acetate salt hypertensive rats, which exhibit very dramatic increases in endothelin-1 expression (five-to eightfold) and do respond to endothelin antagonism with blood pressure lowering and regression of vascular hypertrophy. These small elevations of vascular endothelin-1 gene expression thus do not appear to indicate the presence of an endothelin component in blood pressure elevation in renovascular hypertension in rats.

Sick Vessel Syndrome

This review describes vascular changes in atherosclerotic and hypertensive vessels as well as effects of treatment. Changes in vascular structure in both atherosclerosis and hypertension are characterized by thickening of the vessel wall and vascular "remodeling." Remodeling tends to preserve the size of the lumen in atherosclerotic vessels and results in a smaller lumen in hypertensive vessels. Changes in vascular function are characterized by preservation of smooth muscle relaxation, with the exception of activity of ATP-sensitive potassium channels, and dysfunction of endothelium. Regression of atherosclerosis, by treatment of hyperlipidemia, results in quite rapid removal of lipid from the vessel wall but with inconsistent improvement in maximal vasodilator capacity. In contrast, endothelial function improves during regression of atherosclerosis, and hyperresponsiveness to serotonin subsides rapidly. Effective treatment of hypertension produces regression of vascular hypertrophy, and some approaches (especially angiotensin-converting enzyme inhibitors) are effective in correcting vascular remodeling. Endothelium-dependent relaxation generally improves during antihypertensive treatment. Reduction in pulse pressure may be more important than reduction in mean arterial pressure in reversing the structural and functional abnormalities of hypertensive vessels.

Effect of SR 47436, a novel angiotensin II AT 1 receptor antagonist, on human vascular smooth muscle cells in vitro

Proliferation of smooth muscle cells within the intima plays a key role in vascular occlusive disorders such as atherosclerosis and restenosis following balloon angioplasty. Among the factors that may be important in the development of vascular lesions, several authors have reported that the local angiotensin system participates in modulating the proliferation of smooth muscle cells after arterial injury. This study was therefore designed to characterize the antagonistic properties and to investigate the antiproliferative effect of a newly developed non-peptide angiotensin II AT 1 receptor antagonist, SR 47436. This compound is a potent and competitive antagonist of the binding of [ 125I]angiotensin II to its receptor on cultured human aortic smooth muscle cells, exhibiting an IC 50 value of 1.7 ± 0.6 nM. SR 47436 was 10-fold more potent than DuP 753 (Losartan) (IC 50 = 20.8 ± 3.7 nM). In these same cells, SR 47436 potently inhibited the angiotensin II-induced [Ca 2+] i increase (IC 50 = 0.53 ± 0.13 vs. 7.4 ± 1.3 nM for DuP 753). Angiotensin II is a potent mitogen for human aortic smooth muscle cells in culture, exhibiting a maximum proliferative response at 1 μM. SR 47436 and Losartan prevented angiotensin II-induced proliferation of these cells in a dose-dependent manner (IC 50 = 0.32 ± 0.09 and 0.71 ± 0.8 μM, respectively). SR 47436 displayed a marked in vitro inhibition of serum-induced smooth muscle cell proliferation (IC 50 = 5.5 ± 0.8 μM). A selective AT 2 receptor antagonist, PD 123177 did not affect angiotensin II-induced responses in these cells. This in vitro study shows that SR 47436 is a potent inhibitor of angiotensin II-induced smooth muscle cell growth and thus may have beneficial effects in the development and regression of vascular hypertrophy, which is associated with the development of atherosclerosis, restenosis and hypertension.

The Effects of ACE Inhibition on Progression of Atherosclerosis

Angiotensin-converting enzyme inhibitors have been extensively studied and established in the treatment of hypertension, heart failure, and ventricular dysfunction. They have various cardiac and vascular protective effects, but the relevant mechanisms of action in these areas remain to be fully understood. Possible effects of converting-enzyme inhibition related to maintenance of normal endothelial function and inhibition of atherosclerosis should be distinguished from effects on myointimal proliferation related to vascular injury and regression of vascular hypertrophy from blood pressure reduction. Experimental animal studies have showed benefit from converting-enzyme inhibition in preventing myointimal proliferation after vascular injury in some species, but no such effect has been shown in clinical studies of restenosis following coronary angioplasty. Laboratory studies have demonstrated a protective effect of converting-enzyme inhibition on endothelial vasomotor function. Further studies have demonstrated prevention of atherosclerosis in hyperlipidemic rabbits and cholesterol-fed cynomolgus monkeys. Possible mechanisms of action apart from blood pressure lowering include inhibition of angiotensin II and other tissue growth factors and accumulation of kinins. These data, among others, provide sufficient rationale for clinical studies to determine whether converting-enzyme inhibitors can reduce atherosclerotic disease and thus widen their application as cardiac and vascular protective agents.

Losartan inhibits the angiotensin II-induced stimulation of the phosphoinositide signalling system in vascular smooth muscle cells

2-n-Butyl-4-chloro-5-hydroxymethyl-1-[(2′-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole, potassium salt (Losartan) (previous name, DuP 753 or MK 954) is a nonpeptide angiotensin II receptor antagonist. This study was performed to investigate the ability of Losartan to inhibit the angiotensin II-induced stimulation of the phospoinositide signalling system and the angiotensin II-induced hypertrophy in aortic vascular smooth muscle cells of normotensive Wistar-Kyoto rats. 10 −7 M Losartan abolished the angiotensin II-induced formation of inositol 1,4,5-trisphosphate in vascular smooth muscle cells. 10 −6 M Losartan completely abolished the angiotensin II-induced elevation of the intracellular free Ca 2+ concentration ([Ca 2+] i). 10 −6 M Losartan lacked effects on the [Arg 8]vasopressin-induced elevation of [Ca 2+] i. In addition, 10 −6 M completely inhibited the angiotensin II-induced stimulation of Na +/H + exchange in the vascular smooth muscle cells. 10 −10 to 10 −6 M Losartan inhibited the angiotensin II-induced cell protein synthesis in a concentration-dependent manner, yielding to an effective concentration (ED 50) of 6.2 ± 1.8 × 10 −8 M (n = 4). Losartan did not affect the platelet-derived growth factor-BB-induced increase in cell protein. These results show that Losartan is a highly specific angiotensin II receptor antagonist which inhibits angiotensin II-induced cell growth and thus may have beneficial effects on the development and regression of vascular hypertrophy.

The development and regression of vascular hypertrophy.

Genetic hypertension [essential hypertension (EH) in humans and spontaneous hypertension in rats (SHRs)] is associated with an altered vascular structure, expressed in resistance vessels (small arteries) as an increased media:lumen ratio. The vascular smooth muscle cells appear normal and there is no cellular hypertrophy. The amount of smooth muscle may be increased in SHR resistance vessels (i.e., there is evidence for hyperplasia). Present evidence in EH indicates that there is no increase in vascular smooth muscle mass, suggesting that the altered structure is due to "remodeling," a rearrangement of a normal amount of normal material. With antihypertensive therapy, reduction in mean blood pressure does not necessarily normalize vascular structure, and there are few grounds for supposing that one drug is better than another in this respect. Preliminary evidence suggests that normalization of the pulse pressure may be more important than normalizing mean blood pressure, if vascular structure is to be corrected. Although vascular structure may not per se be an important determinant of blood pressure, reduction in blood pressure without correcting vascular structure is undesirable. Thus, improvement of the means for correcting vascular structure may be an important way of improving prognosis with antihypertensive treatment.