Vascular remodeling and improvement of coronary reserve after hydralazine treatment in spontaneously hypertensive rats

The purpose of these studies was to evaluate cardiovascular structural and functional changes in a model of hypertension-induced myocardial hypertrophy in which vasodilator therapy decreased blood pressure to normal levels. Thus, we determined the separate contributions of hypertension and hypertrophy on myocardial and coronary vascular function and structure. Twelve-month-old spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) with and without 12 weeks of vasodilator antihypertensive treatment (hydralazine) were studied using an isolated perfused rat heart model. Hydralazine treatment normalized blood pressure in SHR but did not cause regression of cardiac hypertrophy (heart weight to body weight ratio of SHR + hydralazine 4.33 +/- 0.098 vs. SHR 4.66 +/- 0.091; WKY 3.21 +/- 0.092 and WKY + hydralazine 3.38 +/- 0.152; mean +/- SEM). Coronary flow reserve, elicited by adenosine vasodilation in the perfused heart, was decreased in SHR (29%) compared with WKY (105%) and WKY + hydralazine (100%) and was significantly improved in SHR + hydralazine (75%). Morphometric evaluation of perfusion-fixed coronary arteries and arterioles (30-400 microns diameter) demonstrated a significant increase in the slope of the regression line comparing the square root of medial area versus outer diameter in SHR (0.444) compared with WKY (0.335) and WKY + hydralazine (0.336, p less than 0.05). Blood vessels from SHR + hydralazine were not different from control (0.338). Cardiac oxygen consumption was decreased in SHR (10.9 +/- 0.74 mumols oxygen/min/g/60 mm Hg left ventricular pressure) compared with WKY (22.4 +/- 1.47) and WKY + hydralazine (23.4 +/- 1.90; p less than 0.01), while SHR + hydralazine was intermediate (16.0 +/- 1.60). These studies suggest that significant alterations in myocardial and coronary vascular structure and function occur in hypertension-induced cardiac hypertrophy. The coronary vasculature is responsive to blood pressure, independent of cardiac hypertrophy, although moderate coronary deficits do remain after chronic antihypertensive therapy.     

Effects of omapatrilat on blood pressure and renal injury in L-NAME and L-NAME plus DOCA-treated rats

BACKGROUND: This study investigates the effects of chronic administration of omapatrilat (OMA) on blood pressure (BP), renal injury, and other variables in N(omega)-nitro-L-arginine methyl ester (L-NAME) hypertension and in the low-renin model produced by the simultaneous administration of L-NAME and deoxycorticosterone acetate (DOCA). METHODS: The control, DOCA, L-NAME, L-NAME + DOCA, L-NAME + OMA, and L-NAME + DOCA + OMA groups were used. Tail systolic BP was measured twice a week. After 4 weeks of treatment, mean arterial pressure (MAP), and metabolic, morphologic, and renal variables were measured. RESULTS: The final values of MAP were 109 +/- 5.1 mm Hg for the control group, 113 +/- 3.0 mm Hg for DOCA, 175 +/- 3.7 mm Hg for L-NAME, 193 +/- 3.8 mm Hg for L-NAME + DOCA, 117 +/- 3.9 mm Hg for L-NAME + OMA, and 158 +/- 3.0 mm Hg for L-NAME + DOCA + OMA. The rats treated with L-NAME showed mild and scarce renal lesions, which were prevented by OMA treatment and the L-NAME + DOCA group showed proteinuria and hyaline arteriopathy, which were markedly attenuated in the L-NAME + DOCA + OMA group. Plasma urea and creatinine were significantly increased in the L-NAME + DOCA group, whereas these variables were not significantly greater in the L-NAME + DOCA + OMA group versus controls. The L-NAME + DOCA group showed relative renal and cardiac hypertrophy that was not observed in the L-NAME + DOCA + OMA group. CONCLUSIONS: The simultaneous blockade of neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE) completely prevents L-NAME hypertension. Our results also show that OMA attenuates the increased BP and the renal injury in L-NAME hypertensive rats treated with DOCA. Assuming that this is a low-renin model of hypertension, the protective effect of OMA may be due to an increase in vasodilator peptides produced by both ACE and NEP inhibition.     

Reflex control of coronary vascular tone by cardiopulmonary receptors in humans

To examine whether cardiopulmonary receptors participate in the reflex control of coronary vascular resistance, systemic and coronary hemodynamics were assessed before and during -10 mm Hg lower body negative pressure in eight normal subjects and eight hypertensive patients with left ventricular hypertrophy. In both study groups, lower body negative pressure induced a significant decrease in right atrial pressure, left ventricular filling pressure and cardiac output, an increase in systemic vascular resistance and no change in mean arterial pressure and heart rate. In normal subjects, there was also a significant increase in plasma norepinephrine concentration (from 294 +/- 39 to 421 +/- 47 pg/ml, p less than 0.01). This increase was accompanied by a reduction in coronary blood flow, assessed by the continuous thermodilution method (from 101 +/- 5 to 79 +/- 4 ml/min, p less than 0.05). An increase in coronary vascular resistance (from 0.865 +/- 0.1 to 1.107 +/- 0.1 mm Hg/ml per min, p less than 0.05) and in myocardial oxygen consumption was detected in normal subjects during cardiopulmonary baroreceptor unloading. In contrast, in hypertensive patients, -10 mm Hg lower body negative pressure failed to induce any change in plasma norepinephrine, coronary blood flow or vascular resistance. Intravenous propranolol administration caused no significant change in the systemic hemodynamic response to -10 mm Hg lower body negative pressure in either study group, but it did abolish the decrease in coronary flow and the increase in plasma norepinephrine, coronary vascular resistance and myocardial oxygen consumption observed in normal subjects in control conditions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Improvement of diastolic function after reversal of left ventricular hypertrophy induced by long-term antihypertensive treatment with tertatolol

In 15 previously untreated hypertensive subjects with left ventricular (LV) hypertrophy who responded favorably (supine blood pressure less than or equal to 140/90 mm Hg) to antihypertensive treatment with a nonselective beta-blocking agent, tertatolol, the effects of reversal of LV hypertrophy on systolic and diastolic function were assessed. Patients underwent echocardiographic and radionuclide studies in control conditions (phase 1), after 1 month of blood pressure normalization (phase 2), after reversal of LV hypertrophy or at least a 20% reduction of LV mass compared to basal value (phase 3) and finally, after a 1-month washout (phase 4). In phase 2, blood pressure (130 +/- 2/85 +/- 1 vs 148 +/- 4/104 +/- 1 mm Hg) and heart rate (59 +/- 1 vs 76 +/- 2 beats/min) decreased (both p less than 0.01); LV mass remained unchanged. There were improvements in peak filling rate (end-diastolic volume/s) (2.4 +/- 0.1 vs 2.0 +/- 0.1), ejection fraction (65 +/- 1 vs 61 +/- 1%) and their ratio (stroke counts/s) (3.7 +/- 0.2 vs 3.2 +/- 0.1) (all p less than 0.05). In phase 3, blood pressure and heart rate were unchanged and reversal of LV hypertrophy was accompanied by a further increase in peak filling rate (2.9 +/- 0.1), ejection fraction (69 +/- 1%) and their ratio (4.1 +/- 0.1) compared to phase 2 (all p less than 0.01). Finally, in phase 4 blood pressure and heart rate returned to the basal value, but peak filling rate (2.7 +/- 0.1) and ejection fraction (65 +/- 1%), although reduced compared to phase 3, were still higher than phase 1.(ABSTRACT TRUNCATED AT 250 WORDS)     

Normalization of impaired coronary circulation in hypertrophied rat hearts

We tested the hypothesis that impaired coronary autoregulation, decreased flow reserve, and diminished reactive hyperemic response in hypertrophied hearts with coronary arterial hypertension may be reversible after relief of pressure overload. In 4-week ascending aortic banded rats, in vivo peak systolic left ventricular pressure increased to 178 +/- 8 mm Hg (103 +/- 6 mm Hg in sham-operated control group). This increased pressure produced myocardial hypertrophy, and the left ventricular weight/body weight ratio was 46% above that of the control group. After the rats were killed, the coronary perfusion pressure-flow relations were obtained during resting conditions and maximal vasodilation after a 40-second period of ischemia in beating but nonworking isolated hearts perfused with Tyrode's solution with bovine red blood cells and albumin. In hearts from control rats, coronary autoregulation (i.e., a slight decrease in flow with reduction of pressure) was observed in the range of 50-100 mm Hg of perfusion pressure. A pronounced reactive hyperemic response was observed: a peak flow/resting flow ratio of 2.9 +/- 0.1 and a repayment ratio of 1.7 +/- 0.2 at 100 mm Hg of perfusion pressure. In hearts of banded rats the resting pressure-flow relation was rectilinear in the range of 25-175 mm Hg of perfusion pressure. Flow reserve and the time of reactive hyperemia to one half peak flow decreased at 50, 100, and 150 mm Hg of perfusion pressure compared with values in control rat hearts. Four weeks after debanding, peak systolic left ventricular pressure and cardiac hypertrophy had normalized. The impaired autoregulation, decreased flow reserve, and diminished reactive hyperemic response had completely reversed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of angiotensin-converting enzyme inhibitor and angiotensin type 1 receptor antagonist in deoxycorticosterone acetate-salt hypertensive mice lacking Ren-2 gene

We previously reported that inhibition of angiotensin-converting enzyme (ACE) prevented the hypertension and left ventricular hypertrophy induced by deoxycorticosterone acetate-salt (DOCA-salt) in 129/SvEvTac mice, which have 2 renin genes (Ren-1 and Ren-2). In the present study, we induced hypertension by uninephrectomy and DOCA-salt in mice having only the Ren-1 gene (C57BL/6J) and investigated the effect of an ACE inhibitor (ramipril, 4 mg. kg(-)(1). d(-)(1)) and an angiotensin type 1 (AT(1)) receptor antagonist (L-158809, 4 mg. kg(-)(1). d(-)(1)) on the development of hypertension, cardiac hypertrophy, and renal injury. After 4 weeks of treatment, systolic blood pressure in DOCA-salt mice was significantly increased (128+/-2 mm Hg) compared with controls (109+/-2 mm Hg) (P:<0.001), while plasma renin concentration was decreased by 97% (P:<0.001). DOCA-salt also induced left ventricular and renal hypertrophy and renal damage as manifested by proteinuria. Collagen content in the left ventricle and kidney was significantly higher in DOCA-salt mice (P:<0.001). Urinary albumin (P:<0.05) and proliferating cell nucleic antigen-positive cells in the tubules and interstitium of the renal cortex (P:<0.001) were significantly increased in the DOCA-salt group. Neither the ACE inhibitor nor the AT(1) antagonist had any antihypertensive effect; however, they partially prevented cardiac hypertrophy and completely inhibited left ventricular collagen deposition. In the kidney, both the ACE inhibitor and AT(1) antagonist partially reduced the increase in collagen but had no effect on hypertrophy. They also significantly prevented the effect of DOCA-salt on urinary albumin and proliferating cell nucleic antigen expression in the kidney. Despite the lack of an antihypertensive effect, both ACE inhibitor and AT(1) antagonist prevented cardiac remodeling and renal damage. Our results indicate that ACE inhibitors and AT(1) antagonists exert beneficial effects on the heart and kidney in DOCA-salt hypertensive mice independently of their effects on blood pressure.     

Extrarenal Na+ balance, volume, and blood pressure homeostasis in intact and ovariectomized deoxycorticosterone-acetate salt rats

Water-free Na+ storage may buffer extracellular volume and mean arterial pressure (MAP) in spite of Na+ retention. We studied the relationship among internal Na+, K+, water balance, and MAP in Sprague-Dawley rats, with or without deoxycorticosterone-acetate (DOCA) salt, with or without ovariectomy (OVX). The rats were fed a low-salt (0.1% NaCl) or high-salt (8% NaCl) diet for 5 weeks. DOCA salt increased MAP (161+/-14 versus 123+/-4 mm Hg; P<0.05), and DOCA-OVX salt increased MAP further (181+/-22 mm Hg; P<0.05). DOCA salt increased the total body Na+ by &40% to 45%; however, water-free Na+ retention by osmotically inactive Na+ storage and by osmotically neutral Na+/K+ exchange allowed the rats to maintain the extracellular volume close to normal. DOCA-OVX salt rats showed similar Na+ retention. However, their osmotically inactive Na+ storage capacity was greatly reduced and only partially compensated by neutral Na+/K+ exchange, resulting in greater volume retention despite similar Na+ retention. For every 1% wet weight total body water gain, MAP increased by 2.3+/-0.2 mm Hg in DOCA salt rats and 2.5+/-0.3 mm Hg in DOCA-OVX salt rats. Because water-free Na+ retention buffered total body water content by 8% to 11% wet weight, we conclude that this internal Na+ escape buffered MAP. Extrarenal Na+ and volume balance seem to play an important role in long-term volume and MAP control.     

Reversal of cardiac and large artery structural abnormalities induced by long-term antihypertensive treatment with trandolapril.

In 15 patients with untreated mild to moderate essential hypertension and left ventricular hypertrophy, we assessed blood pressure, echocardiographic left ventricular mass index, brachial artery compliance (pulsed doppler flowmetry), and calculated forearm vascular resistance (strain gauge plethysmography) before, during (6 and 12 months) and after (1 month washout period) 1 year of satisfactory (blood pressure < or = 140/90 mm Hg) antihypertensive therapy with the angiotensin-converting enzyme inhibitor trandolapril (2.0 mg orally once daily). During the antihypertensive effective treatment, we observed a significant reduction of systolic and diastolic blood pressures, left ventricular mass index, and forearm vascular resistance at both 6 and 12 months. In addition, brachial artery compliance was significantly increased. After washout, systolic (156 +/- 3 mm Hg) and diastolic (102 +/- 1 mm Hg) blood pressures returned to levels comparable to baseline. However, left ventricular mass index (132 +/- 4; p < 0.01) and brachial artery compliance (1.53 +/- 0.01; p < 0.01) were still different from baseline. These results demonstrate that chronic antihypertensive treatment with trandolapril is associated with a stable regression of cardiac and vascular abnormalities, which is partially unrelated to the blood pressure lowering effect.     

Paraventricular nucleus lesions attenuate the development of hypertension in DOCA/salt-treated rats

To determine whether paraventricular nucleus (PVN) can play a role in the hypertension in DOCA/salt-treated rats, DOCA/salt hypertension was produced in PVN lesions and sham-operated rats. In lesioned rats, the development of hypertension was significantly attenuated (day 7: 132 +/- 3 v 157 +/- 5 mm Hg, P less than 0.01; day 14: 132 +/- 3 v 157 +/- 5 mm Hg, P less than 0.01; day 21: 189 +/- 2 v 224 +2- 6 mm Hg, P less than 0.01). Lesions lowered systolic blood pressure in even control rats. Mean blood pressure (mBP) from awake free moving rats was also significantly lower in lesioned DOCA/salt-treated rats than those of sham-operated DOCA/salt-treated rats (155 +/- 14 mm Hg v 193 +/- 13, P less than 0.01), while mBP was not different between lesioned and sham-operated control rats. The reduction of mBP by hexamethonium injections was significantly larger in sham-operated DOCA/salt-treated rats than those of lesioned DOCA/salt rats. (-53 +/- 3% v -45 +/- 2, P less than 0.05). Plasma norepinephrine and epinephrine were significantly elevated in DOCA/salt-treated rats, however, PVN lesions inhibited significantly those elevations. 1-Deaminopenicillamine, 4-valine, 8-D-arginine Vasopressin (dPVDAVP) injections did not affect BP and heart rate in all rats. Body weight, water intake, urine volume, urine Na, K, and vasopressin excretion, and urine osmorality were not altered by lesions. These findings suggest that PVN contributes to development of hypertension in DOCA/salt-treated rats with sympathetic nervous activations.     

Sodium-induced cardiac hypertrophy. Cardiac sympathetic activity versus volume load

To investigate the possible contributions of cardiac volume overload and cardiac sympathetic hyperactivity in the effects of sodium on cardiac mass, we evaluated the effects of treatment with saline (1%) and deoxycorticosterone acetate + saline (DOCA/saline) for 10 days and 3 and 6 weeks on ventricular anatomy and intracardiac pressures. Sympathetic activity in the heart and other tissues was assessed at 10 days and 3 weeks by catecholamine turnover rates and tyrosine hydroxylase activity. Both saline and DOCA/saline produced concentric left ventricular (LV) hypertrophy. Right ventricular weight showed only small increases. Saline treatment did not affect LV end-systolic pressure, whereas DOCA/saline caused a moderate increase (to 159 mm Hg). Right atrial pressure was not affected by either treatment, whereas LV end-diastolic pressure increased but only after the development of LV hypertrophy. Both saline and DOCA/saline decreased LV norepinephrine concentration; only DOCA/saline decreased norepinephrine content per LV. However, neither treatment altered the norepinephrine turnover rate constant, the absolute turnover rate, or the tyrosine hydroxylase activity. The results demonstrate that increased saline intake or DOCA/saline produces concentric LV hypertrophy without any increase in blood pressure in the case of saline and with increases in LV filling pressure following rather than preceding the appearance of LV hypertrophy. The lack of an increase in LV norepinephrine turnover and tyrosine hydroxylase activity suggests that the hypertrophy is not mediated through increased cardiac neuronal sympathetic activity.     

Differential structural responses of small resistance vessels to antihypertensive therapy

Regression of left ventricular hypertrophy after control of blood pressure has been documented with some antihypertensive agents but not with others. To determine whether similar differences in regression of wall thickening also occur in resistance vessels during treatment, matched groups of spontaneously hypertensive rats (SHR) were treated for 12 weeks with either hydralazine (H) or captopril and hydrochlorothiazide (C-D) and they were compared with untreated SHR and Wistar-Kyoto rats (WKY). Perfusion pressure was then determined in the hindlimbs of pithed rats under conditions of constant blood flow (4.0 ml/min) and maximal vasodilation (hemodilution to 22% hematocrit combined with continuous nitroprusside and papaverine infusion). This perfusion pressure, which has been validated as an index of thickening (hypertrophy) of resistance vessels walls, averaged 26.8 +/- 0.4(SE) mm Hg in untreated WKY (n = 12) and 37.6 +/- 0.4 mm Hg in untreated SHR (n = 11) (p less than .01). Treatment with H or C-D controlled blood pressure equally in SHR, but the two drugs had significantly different effects on both left ventricular hypertrophy and resistance vessels. Perfusion pressure was reduced from 37.6 +/- 0.4 mm Hg to 34.0 +/- 0.5 mm Hg (p less than .01) with C-D but only to 36.5 +/- 0.5 mm Hg with H (NS). Left ventricular weight was significantly reduced by C-D (2.02 +/- 0.02 vs 2.63 +/- 0.05 mg/g, p less than .01) but only to 2.44 +/- 0.05 mg/g by H.(ABSTRACT TRUNCATED AT 250 WORDS)     

Arterial hypertension difficult to control in the elderly patient. The significance of the "white coat effect"]

OBJECTIVE: Previous studies have revealed a high prevalence of white coat effect among treated hypertensive patients. The difference between clinic and ambulatory blood pressure seems to be more pronounced in older patients. This abnormal rise in blood pressure BP in treated hypertensive patients can lead to a misdiagnosis of refractory hypertension. Clinicians may increase the dosage of antihypertensive drugs or add further medication, increasing costs and producing harmful secondary effects. Our aim was to evaluate the discrepancy between clinic and ambulatory blood pressure in hypertensive patients on adequate antihypertensive treatment and to analyse the magnitude of the white coat effect and its relationship with age, gender, clinic blood pressure and cardiovascular or cerebrovascular events. POPULATION AND METHODS: We included 50 consecutive moderate/severe hypertensive patients, 58% female, mean age 68 +/- 10 years (48-88), clinic blood pressure (3 visits) > 160/90 mm Hg, on antihypertensive adequate treatment > 2 months with good compliance and without pseudohypertension. The patients were submitted to clinical evaluation (risk score), clinic blood pressure and heart rate, electrocardiogram and ambulatory blood pressure monitoring (Spacelabs 90,207). Systolic and diastolic 24 hour, daytime, night-time blood pressure and heart rate were recorded. We considered elderly patients above 60 years of age (80%). We defined white coat effect as the difference between systolic clinic blood pressure and daytime systolic blood pressure BP > 20 mm Hg or the difference between diastolic clinic blood pressure and daytime diastolic blood pressure > 10 mm Hg and severe white coat effect as systolic clinic blood pressure--daytime systolic blood pressure > 40 mm Hg or diastolic clinic blood pressure--daytime diastolic blood pressure > 20 mm Hg. The patients were asked to take blood pressure measurements out of hospital (at home or by a nurse). The majority of them performed an echocardiogram examination. RESULTS: Clinic blood pressure was significantly different from daytime ambulatory blood pressure (189 +/- 19/96 +/- 13 vs 139 +/- 18/78 +/- 10 mm Hg, p < 0.005). The magnitude of white coat effect was 50 +/- 17 (8-84) mm Hg for systolic blood pressure and 18 +/- 11 (-9 +/- 41) mm Hg for diastolic blood pressure. A marked white coat effect (> 40 mm Hg) was observed in 78% of our hypertensive patients. In elderly people (> 60 years), this difference was greater (50 +/- 15 vs 45 +/- 21 mm Hg) though not significantly. We did not find significant differences between sexes (males 54 +/- 16 mm Hg vs 48 +/- 17 mm Hg). In 66% of these patients, ambulatory blood pressure monitoring showed daytime blood pressure values < 140/90 mm Hg, therefore refractory hypertension was excluded. In 8 patients (18%) there was a previous history of ischemic cardiovascular or cerebrovascular disease and all of them had a marked difference between systolic clinic and daytime blood pressure (> 40 mm Hg). Blood pressure measurements performed out of hospital did not help clinicians to identify this phenomena as only 16% were similar (+/- 5 mm Hg) to ambulatory daytime values. CONCLUSIONS: Some hypertensive patients, on adequate antihypertensive treatment, have a significant difference between clinic blood pressure and ambulatory blood pressure measurements. This difference (White Coat Effect) is greater in elderly patients and in men (NS). Although clinic blood pressure values were significantly increased, the majority of these patients have controlled blood pressure on ambulatory monitoring. In this population, ambulatory blood pressure monitoring was of great value to identify a misdiagnosis of refractory hypertension, which could lead to improper decisions in the therapeutic management of elderly patients (increasing treatment) and compromise cerebrovascular or coronary circulation.     

Effects of chronic hypertension and left ventricular hypertrophy on the incidence of sudden cardiac death after coronary artery occlusion in conscious dogs

When acute myocardial infarction occurs in patients with hypertension and left ventricular hypertrophy (LVH), the incidence of sudden cardiac death increases markedly. Possible explanations include increased size of the occluded vascular bed secondary to more extensive atherosclerotic coronary vascular disease in the presence of hypertension, decreased coronary reserve secondary to LVH, and intrinsic electrophysiologic abnormalities in hypertrophied cardiac muscle. To explore these possibilities, we produced acute circumflex coronary occlusion during the resting, conscious state in 32 control dogs and in 28 dogs with hypertensive LVH. Before coronary occlusion, mean arterial pressure was 96 +/- 0.1 mm Hg in control dogs and 125 +/- 5 mm Hg in dogs with hypertensive LVH (p less than 0.01). The control left ventricular/body weight ratio was 4.5 +/- 0.1 g/kg, compared with 6.1 +/- 0.1 g/kg in hypertensive LVH (p less than 0.01). Cumulative mortality at 6, 24 and 48 hours was 9%, 13% and 16% in control dogs and 32%, 43% and 54%, respectively, in dogs with hypertensive LVH (all p less than 0.01 vs control). The perfusion fields of the occluded vessel defined by postmortem coronary angiography were similar in the two groups (31 +/- 2% of left ventricular mass for control vs 29 +/- 2% for hypertensive LVH). Thus, the increased incidence of sudden cardiac death after coronary artery occlusion in hypertensive LVH dogs cannot be explained by increased size of the occluded vascular bed and is probably related to the decreased coronary reserve or intrinsic electrophysiologic abnormalities that characterize pressure-induced hypertrophied cardiac muscle.     

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.     

Coronary microvasculature alteration in hypertensive rats. Effect of treatment with a diuretic and an ACE inhibitor

The development of hypertension is accompanied by rarefaction of arterioles and capillaries in both animal models and humans. Although many studies have examined the effects of antihypertensive therapies on hemodynamics, cardiac hypertrophy, and large vessel structure, the question of whether changes in microvascular density induced by hypertension can be restored by pharmacologic treatment has yet to be answered. We report a series of experiments performed in rats with renovascular hypertension induced by unilateral nephrectomy and renal artery stenosis (Goldblatt one-kidney, one-clip model). Animals were treated for 4 weeks, after renal artery clipping, either with an angiotensin converting enzyme inhibitor (perindopril [PER], 0.76 mg/kg/day), or with an indol derivative diuretic with specific vascular properties (indapamide [IDP], 0.24 mg/kg/day) or with the combination of both drugs at the same doses as during monotherapy. Coronary microvessel densities (arterioles and capillaries) were evaluated by double immunolabeling in nonserial cryostat sections of the left ventricular inner myocardium. After 4 weeks of hypertension (mean arterial pressure, 174+/-11 v 124+/-5 mm Hg in normotensive (NT) controls, P < .01), cardiac hypertrophy (+59%, P < .001) was associated with a significant increase in myocardial arteriolar density (+27%, P < .01), and a decrease in capillary density (-12%, P < .05). Treatment with PER prevented the increase in arterial pressure, heart weight, and arteriolar density, but did not significantly affect the low coronary capillary density in comparison with that measured in untreated hypertensive (HT) rats. Treatment with IDP preserved normal capillary myocardial density but did not significantly lower the blood pressure (BP) (169+/-9 mm Hg) and only slightly reduced the cardiac ventricular hypertrophy: - 14% v untreated HT (P < .05) and +37% v NT (P < .01). In the same way, IDP normalized the left ventricular capillary density in spontaneously HT rats (+18% v untreated rats, P < .01). The combination of both drugs, PER and IDP, at the same low doses as during monotherapy, resulted in normal levels of arterial pressure and complete normalization of cardiac hypertrophy and arteriolar and capillary myocardial densities. In conclusion, the results observed after PER suggest that blockade of the renin-angiotensin system could inhibit large coronary vessel growth but minimally affects the capillary density despite complete normalization of BP. Indapamide could have beneficial effect on myocardial capillary density. The combination of IDP and PER has additional effects and prevents the increase in BP and cardiac weight, and reverses microvascular rarefaction, specifically arteriolar and capillary densities.     

Coronary and systemic hemodynamic effects of nicardipine

Systemic and coronary hemodynamic effects of a new dihydropyridine calcium antagonist, nicardipine, were studied in 15 patients. Nicardipine was administered as a 2-mg bolus intravenously followed by an infusion titrated to maintain a 10 to 20-mm Hg decrease in systolic pressure. Nicardipine increased both heart rate from 69 +/- 3 to 81 +/- 3 beats/min and cardiac output from 7.3 +/- 0.5 to 9.9 +/- 0.5 liters/min (both p less than 0.001) as systemic vascular resistance decreased from 1,183 +/- 70 to 733 +/- 33 dynes s cm-5 (p less than 0.001). Left ventricular end-diastolic pressure remained constant, at 14 +/- 1 vs 14 +/- 1 mm Hg as stroke volume increased from 108 +/- 6 to 123 +/- 6 ml/m2 (p less than 0.001). Coronary blood flow increased from 102 +/- 9 to 147 +/- 13 ml/min, while coronary resistance decreased from 1.17 +/- 0.1 to 0.7 +/- 0.1 mm Hg/ml/min (both p less than 0.001). Heart rate-systolic blood pressure product did not change (104 +/- 5 vs 106 +/- 5 beats/min mm Hg X 10(-2), difference not significant) with drug administration. At the same heart rate before and during nicardipine administration (using atrial pacing in 6 patients), significant augmentation of coronary flow was still observed. Thirteen of 14 patients showed a greater percent decrease in coronary resistance than systemic vascular resistance. Nicardipine differs from other calcium antagonists with respect to consistent augmentation of coronary blood flow. This effect appears to be the result, in part, of increased potency in the coronary bed compared with the systemic vascular bed.     

Regression of hypertensive heart hypertrophy caused by chronic angiotensin-converting enzyme inhibition

We wanted to determine whether an antihypertensive therapy with the angiotensin-converting enzyme inhibitor enalapril can induce regression of hypertensive hypertrophy. 13 patients with hypertensive left ventricular hypertrophy were treated with enalapril (10-40 mg/day) for 9 months. Left ventricular pump function, left ventricular hypertrophy and geometry were studied by echocardiography before and 3, 6 and 9 months after enalapril treatment had been established. Both a decrease in systolic arterial blood pressure as well as a reversal of myocardial hypertrophy was obtained. After 3 months' therapy, systolic arterial blood pressure dropped from 189 +/- 8 to 171 +/- 9 mm Hg and left ventricular muscle mass decreased from 210 +/- 13 to 196 +/- 8 g/m2. After 6 months' therapy, systolic arterial blood pressure decreased further to 154 +/- 7 mm Hg and left ventricular muscle mass to 181 +/- 8 g/m2. After another 3 months' therapy (after 9 months) no further decrease in systolic arterial blood pressure (159 +/- 9 mm Hg), and no further decrease in left ventricular muscle mass (189 +/- 8 g/m2) were obtained. After 9 months' therapy, reversal of myocardial hypertrophy was adequate in relation to the amount of blood pressure lowering. Due to unaltered ventricular loading conditions, as evidenced by identical systolic wall stress values, left ventricular pump function remained unchanged.     

Effects of fenofibrate on cardiac remodeling in aldosterone-induced hypertension

Hypertension and cardiac remodeling are associated with myocardial fibrosis, left ventricular (LV) hypertrophy, and diastolic heart failure. Fenofibrate suppresses aldosterone-mediated increases in myocyte matrix metalloproteinase activity and extracellular signal-regulated kinase phosphorylation. It is unknown whether the peroxisome proliferator-activated receptor-alpha agonist, fenofibrate, improves cardiac remodeling in a model of aldosterone-induced hypertension and LV hypertrophy. Twelve-week-old uninephrectomized FVB mice received 1% NaCl drinking water. Miniosmotic pumps delivered saline or aldosterone for 4 weeks. Mice were either untreated (n=14) or treated with fenofibrate 100 mg/kg per day (n=12) for 1 week before and 4 weeks after surgery. Aldosterone increased systolic blood pressure in untreated mice versus saline-untreated mice (134+/-3 versus 91+/-3 mm Hg; P<0.01). This was unaffected by fenofibrate (131+/-3 mm Hg). Aldosterone increased LV end-diastolic and end-systolic dimensions, which were significantly attenuated by fenofibrate (3.8+/-0.1 versus 3.5+/-0.1 mm, and 1.5+/-0.1 versus 1.15+/-0.1 mm, respectively). Fenofibrate also decreased aldosterone-induced LV hypertrophy (LV weight/body weight, 4.1+/-0.2 versus 4.6+/-0.1 mg/g) and improved percent LV fractional shortening (67+/-7% versus 60+/-2%). Additionally, fenofibrate ameliorated the increased matrix metalloproteinase-2/tissue inhibitors of metalloproteinase-2 ratio and fibrosis seen in aldosterone-untreated hearts (P<0.05 for both). Furthermore, in aldosterone-untreated hearts, fenofibrate decreased transforming growth factor-beta, collagen type III (P<0.05 for both), and collagen type I (P<0.01) protein expression. Conversely fenofibrate increased peroxisome proliferator-activated receptor-alpha, peroxisome proliferator-activated receptor-gamma coactivator-1alpha expression, and acetyl coenzyme A carboxylase phosphorylation (P<0.05 for all) in aldosterone-infused hearts; uncoupling protein-3 and medium-chain acyl coenzyme A dehydrogenase protein expression decreased with fenofibrate (P<0.05 and P<0.01, respectively, versus aldosterone-infused), suggesting that improved myocardial remodeling is independent of fatty acid oxidation. Thus, fenofibrate improved aldosterone-induced LV hypertrophy independently of an effect on blood pressure with decreased fibrosis and altered extracellular matrix.     

Coronary pressure-flow relations in hypertensive left ventricular hypertrophy. Comparison of intact autoregulation with physiological and pharmacological vasodilation in the dog

Coronary pressure-flow relations during autoregulated and vasodilated flow states were compared between eight dogs with renovascular hypertension and left ventricular hypertrophy and 12 normal dogs. Each relation was constructed from serial steady-state measurements of end-diastolic coronary pressure and flow during perfusion of the circumflex artery by an extracorporeal circuit at controlled diastolic pressures of 20-200 mm Hg. Autoregulated pressure-flow relations were compared at three levels of myocardial oxygen demand: resting, high (dobutamine 10 micrograms/kg/min), and low (propranolol 2.5 micrograms/kg/min). Autoregulatory capacity was assessed by calculation of closed-loop flow gain. At each level of myocardial oxygen demand, the lower limit of autoregulation occurred at higher perfusion pressures in the hypertrophy group (rest 65 +/- 3, high 92 +/- 4, low 66 +/- 4 mm Hg) than in the normal group (rest 53 +/- 2, p less than 0.05; high 75 +/- 5, p less than 0.05; low 51 +/- 3 mm Hg) (p less than 0.05). Maximum autoregulatory gain was similar in the normal and hypertrophy groups during resting and low myocardial oxygen demand but was reduced in the hypertrophy group during dobutamine studies. When coronary flow decreased below the lower limit of autoregulation, systolic shortening was reduced in both normal and hypertrophy groups. However, as the autoregulatory limits were at higher pressures in the hypertrophy group, shortening in this group deteriorated at perfusion pressures that did not affect the normal heart. Coronary pressure-flow relations during physiological (peak hyperemia after 15-second flow occlusion) and pharmacologica (intracoronary adenosine 400 micrograms/min) vasodilation was curvilinear and fitted by quadratic regression. During hyperemic vasodilation, maximal conductance per unit mass of myocardium was less in the hypertrophy group over a wide range of perfusion pressures. At a diastolic perfusion pressure of 80 mm Hg, maximum conductance was 4.6 +/- 0.5 ml/min/100 g/mm Hg in the normal group and 3.4 +/- 0.4 ml/min/100 g/mm Hg (p less than 0.05) in the hypertrophy group. Intracoronary adenosine elicited further vasodilation in both groups, but maximum conductance remained less in the hypertrophy group (8.5 +/- 1.7 ml/min/100 g/mm Hg at a perfusion pressure of 80 mm Hg) than in the normal group (13.5 +/- 2.0 ml/min/100 g/mm Hg) (p less than 0.05). Maximal coronary flow reserve is reduced in left ventricular hypertrophy, with a consequent shift of the lower limit of autoregulation to higher perfusion pressures. Thus, as coronary perfusion pressure is decreased, coronary flow and myocardial shortening become impaired at higher     

Structural change in the rat hindlimb during deoxycorticosterone acetate hypertension; its reversibility and prevention

This study measured the time course of the development and reversal of structural change in resistance vessels during deoxycorticosterone acetate (DOCA) hypertension and after cessation of DOCA in Wistar rats by hindquarter perfusion. The relationship of structural change to blood pressure was further assessed by preventing hypertension during DOCA treatment with hydralazine. Blood pressure rose progressively during DOCA treatment reaching 198.6 +/- 2.0 (s.e.) mmHg at 10 weeks. Five weeks after the cessation of DOCA, when it had been given for 2 weeks, hypertension reversed completely but after 4, 8 and 10 weeks of treatment, post-DOCA reversal of hypertension was only partial. Hindquarter perfusion pressure at maximum vasodilatation and maximum vasoconstriction increased with increasing duration of DOCA treatment and reversed 5 weeks post-DOCA to a similar degree to the blood pressure with only partial reversal of both perfusion pressures and hypertension when DOCA had been given for 8 and 10 weeks. Hydralazine did not completely prevent heart hypertrophy in the DOCA rats and caused some cardiac hypertrophy in the control ('vehicle' only) rats, although it both prevented hypertension and evidence of vascular structural change in DOCA rats.