Beneficial pleiotropic vascular effects of rosuvastatin in two hypertensive models.

OBJECTIVES: The goal of this research was to study the effects of rosuvastatin on systemic and regional hemodynamics in two hypertensive rat models, one genetic, the other induced with inhibition of nitric oxide synthesis. BACKGROUND: Rats naturally have low cholesterol levels that are generally unaffected by statin therapy, thus providing a good model for studying cardiovascular effects unrelated to lipid metabolism. METHODS: Male 20-week-old spontaneously hypertensive rats (SHR) were divided into five groups and given either vehicle or 1, 5, 10, and 20 mg/kg of rosuvastatin daily, by gavage, for 12 weeks. Wistar-Kyoto rats (WKY) were divided into four groups; the first received vehicle and the second rosuvastatin (20 mg/kg). The third and fourth groups were given N(omega)-nitro-L-arginine (L-NAME) (15 mg/kg/day) in drinking water, and the fourth group received rosuvastatin daily, 20 mg/kg for six weeks. At the end of the respective treatments, systemic and organ hemodynamics (radionuclide-labeled microspheres) and cardiovascular mass were determined in all rats. RESULTS: Rosuvastatin reduced arterial pressure in SHR rats, but not in WKY/L-NAME rats. Total peripheral resistance decreased with rosuvastatin in both hypertensive models, whereas cardiac output increased with rosuvastatin in WKY/L-NAME rats. Neither cardiac nor aortic mass was changed. Regional hemodynamics improved with rosuvastatin in both hypertensive models, as evidenced by increased blood flows and decreased vascular resistances. No effect on plasma lipids was observed. CONCLUSIONS: These results showed that rosuvastatin reduced arterial pressure in genetic hypertension and improved systemic and regional hemodynamics in both hypertensive models independently of cholesterol levels. Thus rosuvastatin improved systemic and regional hemodynamics by reducing vascular resistance.

Beneficial cardiovascular actions of eplerenone in the spontaneously hypertensive rat.

BACKGROUND: Aldosterone has been implicated as a potential mediator of cardiac and vascular damage in a variety of disorders. This study examined the role of aldosterone and its interplay with the renin-angiotensin system in the pathogenesis of hypertension. To this end, the effects of the aldosterone antagonist eplerenone and the angiotensin converting enzyme inhibitor lisinopril on cardiovascular mass, myocardial collagen, and coronary circulation were examined in spontaneously hypertensive rats. METHODS: Male, 22-week-old rats were randomly divided into 4 groups (12 in each). The control group received no treatment, the second group was given eplerenone (100 mg/kg/day), the third received lisinopril (3 mg/kg/day), and the fourth was given eplerenone and lisinopril. After 12 weeks of respective treatments, systemic and regional hemodynamics and cardiovascular mass indexes were measured in conscious instrumented rats. RESULTS: Eplerenone decreased arterial pressure but did not affect left ventricular mass or hydroxyproline concentration (an estimate of collagen). It did, however, reduce minimal coronary vascular resistance and increased coronary flow reserve. Lisinopril decreased arterial pressure and ventricular mass but did not affect regional hemodynamics. The combination therapy produced synergistic effects. CONCLUSION: Aldosterone antagonism improved coronary and systemic hemodynamics in adult spontaneously hypertensive rats but did not affect cardiovascular mass indexes. The finding that lisinopril and eplerenone decreased arterial pressure to the same extent but had different cardiovascular effects suggested that these effects might be pressure independent.

Cardiovascular and renal effects of a collagen cross-link breaker (ALT 711) in adult and aged spontaneously hypertensive rats.

BACKGROUND: Increased formation of advanced glycosylation end-products on body proteins is a consequence of aging and leads to exaggerated collagen cross-linking eventually increasing cardiovascular stiffness. This study reports our initial inquires into the cardiovascular and renal effects of a cross-link breaker (ALT-711) in aged spontaneously hypertensive rats (SHR). METHODS AND RESULTS: The first experiment, in 45-week-old SHR, showed that (among four doses) the dose of 1 mg/kg/d of ALT-711 given for 4 months was most effective in reducing left ventricular and aortic mass indexes. ALT-711 also reduced left ventricular hydroxyproline concentration (5.8 +/- 0.2 v 5.1 +/- 0.3 mg/g in controls, P < .05); however, it did not affect systemic or regional hemodynamics. In older SHR, ALT-711 (1 mg/kg/d) reduced (P < .05) systolic pressure (tail-cuff) (from 203 +/- 3 mm Hg at outset to 187 +/- 3 mm Hg at 8 weeks). Systolic pressure remained unchanged in placebo-treated rats. In addition, left ventricular index (3.09 +/- 0.10 v 3.44 +/- 0.05 mg/g) and aortic mass index (1.54 +/- 0.04 v 1.74 +/- 0.05 mg/mm) were reduced by ALT-711. In the third experiment, 1-year-old SHR were given vehicle or ALT-711 (1 mg/kg/d) or placebo until natural death. After 3 months, ALT-711 markedly reduced urinary protein excretion (74.5 +/- 8.6 v 135.4 +/- 11.8 mg/24 h). Echocardiographic studies, performed at the outset and after 3 and 6 months, revealed two changed indexes. Left ventricular end-diastolic diameter increased more in control than in ALT rats, whereas E-wave deceleration time decreased more in control than in ALT rats. CONCLUSIONS: Therapy with ALT-711 exerted beneficial cardiovascular and renal effects in aged SHR, improving systolic pressure, left ventricular mass, geometry, and hydroxyproline content while reducing urinary protein excretion.

Collagen cross-link breakers: a beginning of a new era in the treatment of cardiovascular changes associated with aging, diabetes, and hypertension.

Aging, diabetes, and hypertension are conditions in which arterial and myocardial stiffness is increased. Increased arterial stiffness is manifested by an increased systolic arterial pressure, pulse pressure and pulse wave velocity, whereas increased myocardial stiffness is manifested by impaired left ventricular diastolic filling. Moreover, increased arterial stiffness increases cardiac workload, further aggravating already existing adverse changes in left ventricular structure and function. Indeed, studies in human beings have clearly shown that increased cardiovascular stiffness is a reliable predictor of cardiovascular morbidity and mortality. Increased cardiovascular stiffness is usually attributed to the development of fibrosis (i.e., accumulation of collagen). It has also been recognized that the increased cardiac and vascular stiffness may be due to increased collagen cross-linking due to the formation of advanced glycosylation end-products (AGEs). In agreement with this notion is the finding that an inhibitor of AGEs formation improves vascular stiffness in diabetic rats. More recently, cross-link breakers have been developed, and the beneficial effects of one such agent (ALT-711) have been shown in experimental and clinical settings. This report briefly summarizes age related changes in cardiovascular structure and function and describes results of experimental and clinical studies involving collagen cross-link breakers.

AT1 receptor antagonism attenuates target organ effects of salt excess in SHRs without affecting pressure.

Our recent studies have demonstrated that salt excess in the spontaneously hypertensive rat (SHR) produces a modestly increased arterial pressure while promoting marked myocardial fibrosis and structural damage associated with altered coronary hemodynamics and ventricular function. The present study was designed to determine the efficacy of an angiotensin II type 1 (AT(1)) receptor blocker (ARB) in the prevention of pressure increase and development of target organ damage from high dietary salt intake. Eight-week-old SHRs were given an 8% salt diet for 8 wk; their age- and gender-matched controls received standard chow. Some of the salt-loaded rats were treated concomitantly with ARB (candesartan; 10 mg kg(-1) day(-1)). The ARB failed to reduce the salt-induced rise in pressure, whereas it significantly attenuated left ventricular (LV) remodeling (mass and wall thicknesses), myocardial fibrosis (hydroxyproline concentration and collagen volume fraction), and the development of LV diastolic dysfunction, as shown by longer isovolumic relaxation time, decreased ratio of peak velocity of early to late diastolic waves, and slower LV relaxation (minimum first derivative of pressure over time/maximal LV pressure). Without affecting the increased pulse pressure by high salt intake, the ARB prevented the salt-induced deterioration of coronary and renal hemodynamics but not the arterial stiffening or hypertrophy (pulse wave velocity and aortic mass index). Additionally, candesartan prevented the salt-induced increase in kidney mass index and proteinuria. In conclusion, the ARB given concomitantly with dietary salt excess ameliorated salt-related structural and functional cardiac and renal abnormalities in SHRs without reducing arterial pressure. These data clearly demonstrated that angiotensin II (via AT(1) receptors), at least in part, participated importantly in the pressure-independent effects of salt excess on target organ damage of hypertension.

Long-term mineralocorticoid receptor blockade reduces fibrosis and improves cardiac performance and coronary hemodynamics in elderly SHR.

Aldosterone has been implicated as one of the mediators of cardiovascular injury in various diseases. This study examines whether mineralocorticoid antagonism ameliorates or prevents the adverse cardiac effects of hypertension and aging. Male 22-wk-old spontaneously hypertensive rats (SHR) were divided into two groups, 15 rats in each. One group received no treatment; the other was given eplerenone ( approximately 100 mg.kg(-1).day(-1)). At the age of 54 wk, indexes of cardiovascular mass, systemic and regional hemodynamics, including coronary, left ventricular function, and myocardial collagen content, were determined in all rats. Hemodynamic studies were done in conscious rats. Arterial pressure was lowered only slightly in eplerenone-treated rats, and cardiac output and total peripheral resistance did not differ from control rats. Left and right ventricular and aortic mass indexes were unaffected by eplerenone; however, concentration of hydroxyproline in the right and left ventricle was decreased significantly (P < 0.05) by eplerenone. This was accompanied by an improvement in left ventricular diastolic function and coronary hemodynamics. In conclusion, long-term therapy with the mineralocorticoid receptor antagonist eplerenone ameliorated adverse cardiac effects of both hypertension and aging in SHR. Thus reduction in myocardial fibrosis, paralleled by improvements in left ventricular function and coronary hemodynamics, was observed in eplerenone-treated SHR.

Myocardial fibrosis, impaired coronary hemodynamics, and biventricular dysfunction in salt-loaded SHR.

Arterial pressure in most experimental and clinical hypertensions is exacerbated by salt. The effects of salt excess on right and left ventricular (RV and LV, respectively) functions and their respective coronary vasodilatory responses have been less explored. We therefore examined the effects of 8 wk of NaCl excess (8% in food) on arterial pressure, RV and LV functions (maximal rate of increase and decrease of ventricular pressure; dP/dt(max) and dP/dt(min)), coronary hemodynamics (microspheres), and collagen content (hydroxyproline assay and collagen volume fraction) in young adult normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR), aged 16 wk by the end of the study. Prolonged salt excess in WKY and SHR elevated pressure only modestly, but it markedly increased LV mass, especially in SHR. Moreover, salt excess significantly impaired RV and LV diastolic function in SHR but only LV diastolic function in WKY rats. However, salt loading affected neither RV nor LV contractile function in both strains. Interstitial and perivascular collagen deposition was increased, whereas coronary vasodilatory responses to dipyridamole diminished in both ventricles in the salt-loaded SHR but not in WKY rats. Therefore, accumulation of ventricular collagen as well as altered myocardial perfusion importantly contributed to the development of salt-related RV and LV dysfunctions in this model of naturally occurring hypertension. The unique effects of salt loading on both ventricles in SHR, but not WKY rats, strongly suggest that nonhemodynamic mechanisms in hypertensive disease participate pathophysiologically with salt-loading hypertension. These findings point to the conclusion that the concept of "salt sensitivity" in hypertension is far more complex than simply its effects on arterial pressure or the LV.

Validation of echocardiographic and Doppler indexes of left ventricular relaxation in adult hypertensive and normotensive rats.

This study was performed to validate echocardiographic and Doppler techniques for the assessment of left ventricular (LV) diastolic function in spontaneously hypertensive rats (SHR) and normotensive Wistar rats. In 11 Wistar rats and 20 SHR, we compared 51 sets of invasive and Doppler LV diastolic indexes. Noninvasive indexes of LV relaxation were related to the minimal rate of pressure decline (-dP/dt(min)), particularly isovolumic relaxation time (IVRT), the Tei index, the early velocity of the mitral annulus (E(m)) using Doppler tissue imaging, and early mitral flow propagation velocity using M-mode color (r = 0.28-0.56 and P < 0.05-0.0001). When the role of systolic load was considered, the correlation between Doppler indexes of LV diastolic function and relaxation rate [(-dP/dt(min))/LV systolic pressure] improved (r = 0.48-0.86 and P = 0.004-0.0001, respectively). Similarly, Doppler indexes of LV diastolic function and the time constant of isovolumic LV relaxation (tau) correlated well (r = 0.50-0.84 and P = 0.0002-0.0001, respectively). In addition, eight SHR and eight Wistar rats were compared; their LV end-diastolic diameters were similar, whereas the SHR LV mass was greater. Furthermore, IVRT and Tei index were significantly higher and E(m) was lower in SHR. Moreover, tau was higher in SHR, demonstrating impaired LV relaxation. In conclusion, LV relaxation can be assessed reliably using echocardiographic and Doppler techniques, and, using these indexes, impaired relaxation was demonstrated in SHR.

Crosslink breakers: a new approach to cardiovascular therapy.

PURPOSE OF REVIEW: Advanced glycation end-products accumulate on body proteins with aging, and their formation is greatly enhanced with rising plasma glucose level. Advanced glycation end-products bond together and, consequently, increase protein crosslinking. In the circulatory system, increased collagen crosslinking caused by advanced glycation end-products increases cardiovascular stiffness as well as the risk for cardiovascular morbidity and mortality. A breaker of advanced glycation end-products-related crosslinks, ALT-711, has been recently discovered. This review summarizes the latest evidence that breaking collagen crosslinks may be an efficient new therapeutic approach to the adverse cardiovascular and renal consequences of aging and diabetes. RECENT FINDINGS: The results of recent studies clearly demonstrated that ALT-711, a breaker of advanced glycation end-products-related protein crosslinks, ameliorated the adverse cardiovascular and renal changes associated with aging, diabetes, and hypertension. In diabetic animals, ALT-711 improved left ventricular function, decreased ventricular collagen content and improved its solubility, reduced aortic stiffness, ameliorated diabetic nephrosclerosis, and improved renal function. In older spontaneously hypertensive rats, it reduced left ventricular mass and collagen content, reduced proteinuria, and extended survival. The results of recent studies also indicated that the effects of crosslinks breakers may be mediated in part via reduction in oxidative stress and profibrotic cytokines. SUMMARY: The results of experimental studies and one clinical trial have clearly established the usefulness of ALT-711 in the therapy of the cardiovascular and renal disorders associated with aging, diabetes, and hypertension. Thus, breaking advanced glycation end-products-related collagen crosslinks has emerged as a new approach to cardiovascular therapy.

Long-term left ventricular echocardiographic follow-up of SHR and WKY rats: effects of hypertension and age.

Long-term follow-up of left ventricular (LV) function using echocardiography has not been reported and, in this study, was carried out in normotensive (WKY) rats and spontaneously hypertensive rats (SHR). In 10 WKY rats and SHR, LV diastolic and systolic diameter (LVEDD and LVSD), shortening fraction (SF), and weight (LVW) were determined at 8, 15, 20, 35, and 80 wk of age. The ratio of early to late mitral flow and mitral annulus velocity (VE/VA and Em/Am), isovolumic relaxation time (IVRT), deceleration time of the E wave (DTE), Tei index, and mitral flow propagation velocity (Vp) were measured. No difference in LVEDD was found between SHR and WKY rats; however, LVEDD was increased at 80 wk in both strains. SF decreased slightly in old WKY rats. LVW progressively increased from 20 to 80 wk in both strains and was greater in SHR. VE/VA and Em/Am decreased at 80 wk in WKY rats. LV relaxation (IVRT, Tei index, and Vp) was progressively impaired in SHR compared with WKY rats. LV compliance (DTE) was altered in old SHR. Echocardiography permitted a long follow-up of LV function in SHR and WKY rats. Ventricular relaxation was impaired early in the life of SHR and progressed with aging. Furthermore, LV compliance was altered, but systolic function remained unchanged, in old SHR. In contrast, relaxation and SF were only slightly altered in old WKY rats, suggesting that pressure-related changes in LV function were the dominant features in the SHR.

Echocardiographic measurement of cardiac output in rats.

The systematic evaluation of different transthoracic echocardiographic (TTE) methods to determine cardiac output (CO) and the effect of changes in intravascular volume on echocardiographically determined indexes of cardiovascular structure in the rat has not been documented. With the use of 11 Wistar rats, simultaneous echocardiographic and thermodilution measurements of CO were compared at baseline and after blood withdrawal or transfusion at 43 different levels of intravascular volume and using 10 different echocardiographic approaches. The best correlation (r = 0.93; P < 0.0001), least bias (-3 ml/min), and best precision (16 ml/min) between thermodilution and echocardiographic methods were obtained at the level of aortic annulus using pulsed Doppler. In conclusion, CO could be accurately assessed in rats using TTE and pulsed Doppler at the level of the aortic annulus. This annulus was demonstrated to remain stable, but pulmonary annulus, thoracic aorta, mitral valve, and left ventricular diameters were found to be more modifiable during volumic changes.

Cardiac structural and functional responses to salt loading in SHR.

Increased dietary salt intake induces cardiac fibrosis in the spontaneously hypertensive rat (SHR), yet little information details its effects on left ventricular (LV) function. Additionally, young normotensive rats are more sensitive to the trophic effect of dietary sodium than older rats. Thus cardiac responses to salt loading were evaluated at two ages in the SHR; LV collagen content was also examined. SHR (8 or 20 wk of age) were given an 8% salt diet; their age-matched controls received standard chow. Echocardiographic indexes, arterial pressure, and LV hydroxyproline concentration were measured at 16 and 52 wk in the younger and older SHR groups, respectively. In most SHR, salt excess increased arterial pressure, LV mass, and hydroxyproline concentration and impaired LV relaxation manifested by prolonged isovolumic relaxation time, decreased early and atrial filling velocity ratio (V(E)/V(A)), and slower propagation velocity of E wave (V(P)). LV systolic function remained normal. However, one-quarter of the young salt-loaded SHR developed cardiac failure with systolic and diastolic dysfunction associated with greater LV mass and ventricular fibrosis. They also had lower arterial pressure, decreased fractional shortening, and a restrictive pattern of mitral flow. Moreover, the shorter deceleration time of the E wave and increased V(E)/V(P), an index of LV filling pressure, indicated increased LV stiffness in these rats. These findings demonstrated that sodium sensitivity in SHR is manifested not only by further pressure elevation but also by significant LV functional impairment that most likely is related to enhanced ventricular fibrosis. Moreover, the SHR are more susceptible to cardiac damage when high dietary salt is introduced earlier in life.