Differential effects of the calcium antagonist, nisoldipine, versus the arterial vasodilator, minoxidil, on ventricular anatomy, intravascular volume, and sympathetic activity in rats

Opposite effects on cardiac volume load or sympathetic activity by calcium-antagonists versus classical arterial vasodilators may be responsible for their different effects on ventricular anatomy, [i.e., left ventricular (LV) and right ventricular (RV) weights and LV internal diameter and wall thickness.] Therefore, we evaluated the time course of changes in intravascular volume and ventricular anatomy in unanesthetized normotensive rats, following treatment for 1, 2, 14, 35, or 70 days with minoxidil (120 mg/L drinking water) or nisoldipine (0.3 and 1.0 mg/g food). Tissue-specific sympathetic activity was assessed by the norepinephrine turnover rate (NE TR) after 14 and 35 days of treatment. Minoxidil produced RV hypertrophy and eccentric LV hypertrophy (i.e., increased LV diameter with unchanged wall thickness) and increased intravascular volume. Nisoldipine did not alter LV anatomy, but the high dose produced a small, significant increase in RV weight, associated with a tendency (p less than 0.1) to increase blood volume. Minoxidil increased NE TR in the LV (after 14 and 35 days), in the RV (after 14 days), as well as in the superior mesenteric artery (after 14 and 35 days), but not in the kidney. Nisoldipine decreased cardiac NE TR, but did not affect NE TR in the other tissues, suggesting a central effect of nisoldipine. We conclude that an increase in blood volume caused by arterial vasodilators may contribute to cardiac volume overload resulting in cardiac hypertrophy. These volume and cardiac changes are largely absent during treatment with calcium-antagonists. Changes in cardiac sympathetic activity possibly modulate (i.e., potentiate or blunt) the extent of cardiac hypertrophy induced by cardiac overload.     

A randomised study of the haemodynamic changes induced by venodilatation and arteriolar dilatation singly and together in left ventricular failure complicating acute myocardial infarction

A randomised between-group study of the immediate haemodynamic effects of venodilatation by intravenous isosorbide dinitrate infusion (50-200 micrograms/kg/h) and arteriolar dilatation by intravenous hydralazine bolus (0.15 mg/kg) given either in random sequence (Groups 1 and 2; n = 12) or simultaneously (Group 3; n = 6) was undertaken in 18 men with radiographic and haemodynamic evidence (left ventricular [LV] filling pressure greater than 20 mm Hg) of LV failure 6-19 h following acute myocardial infarction. Control measurements (1 h) preceded either two consecutive 90-min treatment periods (Groups 1 and 2) or a single 90-min period (Group 3). Given independently, both drugs reduced systemic arterial pressure and vascular resistance, whereas only isosorbide dinitrate reduced LV filling pressure and only hydralazine increased cardiac output and stroke volume. Isosorbide dinitrate/hydralazine in combination significantly reduced LV filling pressure, systolic and diastolic arterial pressure, and total systemic vascular resistance. Cardiac output, stroke volume, and heart rate were increased. In conclusion, combined arteriolar dilatation and venodilatation appears to be of greater haemodynamic benefit than either alone, if the fall in mean systemic pressure does not compromise peripheral perfusion.     

Topical minoxidil: cardiac effects in bald man.

Systemic cardiovascular effects during chronic treatment with topical minoxidil vs placebo were evaluated using a double-blind, randomized design for two parallel groups (n = 20 for minoxidil, n = 15 for placebo). During 6 months of follow-up, blood pressure did not change, whereas minoxidil increased heart rate by 3-5 beats min-1. Compared with placebo, topical minoxidil caused significant increases in LV end-diastolic volume, in cardiac output (by 0.751 min-1) and in LV mass (by 5 g m-2). We conclude that in healthy subjects short-term use of topical minoxidil is likely not to be detrimental. However, safety needs to be established regarding ischaemic symptoms in patients with coronary artery disease as well as for the possible development of LV hypertrophy in healthy subjects during years of therapy.     

Role of cardiac hypertrophy in reducing the sensitivity of cardiopulmonary reflex control of renal sympathetic nerve activity in spontaneously hypertensive rats

The gain of the volume-sensitive cardiopulmonary reflex (VSCR) is impaired in spontaneously hypertensive rats (SHR). Sensitivity of VSCR control of efferent renal sympathetic nerve activity (RSNA) in SHR is restored when cardiac hypertrophy and hypertension are reduced by enalapril treatment. The present study investigated which of these two parameters, cardiac hypertrophy or hypertension, has more influence on the impairment of VSCR control of RSNA in SHR. Rats (SHR or Wistar-Kyoto (WKY) rats) were treated with enalapril (10 mg/kg per day; SHRE and WKYE groups, respectively) or hydralazine (5 mg/kg per day; SHRH and WKYH groups, respectively) mixed in their food for 1 month. Control SHR and WKY rats were fed a normal diet. After the treatment regimen, the VSCR was evaluated by determining the decrease in RSNA elicited by acute isotonic saline volume expansion. Mean arterial pressure (MAP) was assessed via an intrafemural catheter and cardiac hypertrophy was determined by the left ventricular (LV) weight/bodyweight (BW) ratio. Afferent baroceptor nerve activity (BNA) was also evaluated during volume expansion to verify participation of the baroreflex. Volume expansion produced an attenuated renal sympathoinhibitory response in SHR compared with WKY rats. Enalapril treatment restored the volume expansion-induced decrease in RSNA in SHRE (-41 +/- 8%) compared with WKY rats (-44 +/- 3%). Although both enalapril and hydralazine treatment reduced MAP in SHR (P < 0.01; 126 +/- 5, 133 +/- 6 and 160 +/- 6 mmHg in SHRE, SHRH and SHR, respectively), hydralazine did not restore the sensitivity of VSCR control of RSNA in SHRH. Spontaneously hypertensive rats with established hypertension had a higher LV/BW ratio compared with WKY rats (3.22 +/- 0.14 vs 1.98 +/- 0.06 mg/g, respectively; P < 0.01). Enalapril reduced the LV/BW ratio in SHRE (2.30 +/- 0.07 mg/g; P < 0.01). Although hydralazine reduced LV hypertrophy, there was a weaker reduction in SHRH (2.68 +/- 0.04 mg/g; P < 0.05) compared with SHRE. There was no statistically significant difference among the WKY rat, WKYE and WKYH groups (P > 0.05). There was no change in afferent BNA during volume expansion in normal or hypertensive animals. Taken together, these results indicate that the impairment of VSCR control of RSNA in the SHR model of hypertension correlates better with the magnitude of cardiac hypertrophy than the level of arterial pressure.     

The possible role of caspase-3 in pathological and physiological cardiac hypertrophy in rats

The present study has been designed to investigate the effect of Ac-DEVD-CHO, a specific caspase-3 inhibitor in partial abdominal aortic constriction for 4 week-induced pathological and chronic swimming training for 8 week-induced physiological cardiac hypertrophy. Ac-DEVD-CHO (2 mg/kg intraperitoneally, day(-1)) treatment was started three days before partial abdominal aortic constriction and chronic swimming test and it was continued for 4 weeks in partial abdominal aortic constriction and 8 weeks in chronic swimming test experimental model. The left ventricular (LV) function and LV hypertrophy were assessed by measuring LV developed pressure, dp/dt(max), dp/dt(min), ratio of LV weight to body weight, LV wall thickness, LV collagen content, protein content and RNA concentration. Further, venous pressure and mean arterial blood pressure were recorded. The partial abdominal aortic constriction but not chronic swimming test produced LV dysfunction by decreasing LV developed pressure, dp/dt(max), dp/dt(min.)and increasing LV collagen content. Further, partial abdominal aortic constriction and chronic swimming test were noted to produce LV hypertrophy by increasing ratio of LV weight to body weight, LV wall thickness, LV protein content and LV RNA concentration. Moreover, in contrast to chronic swimming test, partial abdominal aortic constriction has significantly increased venous pressure and mean arterial blood pressure. The Ac-DEVD-CHO has markedly attenuated partial abdominal aortic constriction-induced LV dysfunction, LV hypertrophy, increase in venous pressure and mean arterial blood pressure. However it did not modulate chronic swimming test-induced LV hypertrophy. These results have implicated caspase-3 in partial abdominal aortic constriction-induced LV dysfunction and pathological cardiac hypertrophy. However, caspase-3 may not be involved in chronic swimming test-induced physiological cardiac hypertrophy.     

Effects of chronic treatment with captopril (SQ 14,225), an orally active inhibitor of angiotensin I-converting enzyme, in spontaneously hypertensive rats.

The effects of hydralazine (3 mg/kg) and the angiotensin I-converting enzyme (ACE) inhibitor captopril (SQ 14,225) (100 mg/kg) on mean arterial blood pressure, plasma renin activity, urinary volume and urinary Na+,K+, and aldosterone concentrations were examined in spontaneously hypertensive rats of the Okamoto and Aoki strain (SHR) after oral daily dosing for 2 weeks, 3 or 6 months. Captopril caused progressive cumulative reductions in blood pressure resulting in normalization of pressure after 6 months of dosing. Hydralazine also significantly reduced blood pressure but not to the level of normotensive rats of the Wistar-Kyoto strain (WKY). Reductions in heart size paralleled the changes in blood pressure, normalization of cardiac hypertrophy occurring after captopril but not hydralazine. Plasma renin activity increased approximately 2-3 fold after hydralazine and 15-fold after captopril. Neither hydralazine nor captopril had any consistent effects on 24-hr urine volume, urinary Na+,K+ or aldosterone excretion. These results indicate that chronic inhibition of ACE with captopril induces normalization of blood pressure in SHR, a normal-renin model of hypertension.     

Angiotensin type 1 receptor antagonism with irbesartan inhibits ventricular hypertrophy and improves diastolic function in the remodeling post-myocardial infarction ventricle

To evaluate the role of angiotensin II (AII) on diastolic function during post-myocardial infarction (MI) ventricular remodeling, coronary ligation or sham operation was performed in male Sprague-Dawley rats. Experimental animals were maintained on either irbesartan, a selective AT1-receptor antagonist, or no treatment. Measurement of cardiac hypertrophy, diastolic function, and sarcoendoplasmic reticulum adenosine triphosphatase (ATPase; SERCA) and phospholamban (PLB) gene expression was assessed at 6 weeks after MI. Myocardial infarction caused a significant increase in myocardial mass and left ventricular (LV) filling pressure, whereas LV systolic pressure and +dP/dt were reduced. The time constant of isovolumic relaxation (tau) was markedly prolonged after MI. Post-MI hypertrophy was associated with substantial increases in the messenger RNA (mRNA) expression of atrial natriuretic peptide (ANP), but no significant changes in SERCA or PLB levels. Although irbesartan treatment did not significantly alter post-MI LV systolic or filling pressures, it nevertheless effectively decreased ventricular hypertrophy, improved tau, and normalized ANP expression. These results demonstrate that AT1-receptor antagonism has important effects on myocardial hypertrophy and ANP gene expression, which are independent of ventricular loading conditions. In addition, the improvement in diastolic function was not related to changes in SERCA and PLB gene expression, suggesting that enhanced myocardial relaxation was related to the blockade of AII effects on myocyte function or through a reduction of ventricular hypertrophy itself or both.     

Spironolactone prevents cardiac collagen proliferation after myocardial infarction in rats

1. Aldosterone has been considered a key hormone in the regulation of water, sodium and potassium metabolism, thus influencing blood pressure regulation. More recently, several studies have demonstrated that aldosterone is also produced in extra-adrenal tissues (e.g. the heart), suggesting a paracrine effect for aldosterone, such as to increase collagen synthesis in the heart. 2. Because aldosterone production in the heart increases after myocardial infarction (MI), we investigated the effect of chronic administration of spironolactone, an aldosterone receptor antagonist, in rats after MI compared with the effects produced by losartan and hydralazine. 3. Myocardial infarction was produced in male Wistar rats by surgical ligature of the left coronary artery. Sham-operated animals were used as controls. 4. Spironolactone (20 mg/kg per day), losartan (15 mg/kg per day) or hydralazine (20 microg/kg per day) were administered after MI and used for 1 month. 5. At the end of the treatment period, animals underwent haemodynamic recording (arterial and intraventricular pressures). The collagen content of the heart was evaluated by measuring the hydroxyproline (OH-Pro) concentration in right (RV) and left ventricle (LV) muscle fragments. 6. Infarct size was unaffected by drug treatments. The increased LV end-diastolic pressure observed in MI rats was prevented by losartan and remained unchanged following administration of spironolactone or hydralazine. 7. Losartan prevented RV and LV hypertrophy, as well as collagen proliferation in both ventricles, after MI. The postinfarction hypertrophy observed in RV and LV after MI remained unchanged in infarcted groups treated with spironolactone or hydralazine. 8. The OH-Pro concentration was significantly reduced in LV muscle in the MI group treated with spironolactone (682 +/- 40 vs 557 +/- 21 microg/g for MI vs MI + spironolactone, respectively; P < 0.05), an effect not observed in the hydralazine-treated group. 9. These data suggest that spironolactone prevents collagen proliferation in the surviving myocardium by mechanisms independent of the loading conditions of the heart chambers. Control of postinfarction hypertrophy and collagen accumulation produced by losartan seems to depend on the reduction in loading conditions of the heart chambers.     

Effects of angiotensin II type 1 receptor antagonist,YM358, on cardiac hypertrophy and dysfunction after myocardial infarction in rats

This study was undertaken to investigate the effects of an angiotensin II type 1 receptor antagonist, YM358 (2,7-diethyl-5-[[2'(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo [1,5-b] [1,2,4]triazole potassium salt monohydrate), on cardiac hypertrophy and dysfunction in rats with heart failure after myocardial infarction (MI). One day after the coronary ligation, rats were randomized, and administered YM358 or vehicle for 2, 4 or 8 weeks. In MI rats, mean blood pressure, left ventricular (LV) systolic pressure, and the first derivative of LV pressure significantly decreased, and LV end-diastolic pressure (LVEDP) markedly increased after 2 to 8 week treatment of YM358. From 2 weeks after the ligation, ratios of cardiac weight and lung weight to body weight (BW) significantly increased, which indicated the progression of cardiac hypertrophy and lung congestion in MI rats. Two weeks after the ligation, YM358 did not improve LV function, although it decreased the elevated LVEDP and cardiac weights/BW ratios 8 weeks after the ligation. These results indicated that long-term treatment with YM358 improves the reduced cardiac function and reduces cardiac hypertrophy after MI, and may be useful for the treatment of congestive heart failure.     

Differential role of rho-kinase in pathological and physiological cardiac hypertrophy in rats

The present study was undertaken to investigate the effect of fasudil, a specific Rho-kinase inhibitor, in pathological cardiac hypertrophy induced by partial abdominal aortic constriction (PAAC) for 4 weeks in comparison with physiological cardiac hypertrophy caused by chronic swimming training (CST) for 8 weeks in rats. Fasudil (15 and 30 mg/kg day(-1) p.o.) treatment was started 3 days before PAAC and CST, and was continued for 4 weeks in PAAC and 8 weeks in the CST experimental model. Left ventricular (LV) function and LV hypertrophy were assessed by measuring LVDP, +dp/dt(max), -dp/dt(max), ratio of LV weight to body weight (LVW/BW), LV wall thickness (LVWT), LV collagen content, protein content and RNA concentration. Further, venous pressure (VP) and mean arterial blood pressure (MABP) were recorded. Moreover, DNA gel electrophoresis was employed to assess myocardial cell death. PAAC but not CST produced LV dysfunction by decreasing LVDP, +dp/dt(max), -dp/dt(max) and increasing LV collagen content. Further, PAAC and CST were noted to produce LV hypertrophy by increasing LVW/BW, LVWT, LV protein content and LV RNA concentration. Moreover, in contrast to CST, PAAC has significantly increased VP, MABP and LV necrotic cell death. Fasudil, a Rho-kinase inhibitor, markedly attenuated PAAC-induced LV dysfunction, LV hypertrophy, increase in VP, MABP and LV necrotic cell death. However, it did not modulate the CST-induced LV hypertrophy. These results have implicated Rho-kinase in PAAC-induced LV dysfunction and pathological cardiac hypertrophy. However, Rho-kinase may not be involved in CST-induced physiological cardiac hypertrophy.     

Chronic propranolol treatment promotes left ventricular dilation without altering systolic function after large myocardial infarction in rats.

In rats with chronic myocardial infarction (MI), we have examined the effects of prolonged beta-adrenergic blockade with propranolol on left ventricular (LV) performance, weight, and volumes. Sham-operated rats and rats with large MI (greater than 30%) were evaluated. Four groups of rats were studied: control, sham-operated (n = 12); control, MI (n = 12); propranolol (500 mg/L of drinking water)-treated, sham-operated (n = 10); and propranolol treated, MI (n = 10). Treatment was started 3 weeks after coronary ligation. After 5-6 weeks, LV, systemic arterial, and right atrial pressures in addition to aortic blood flow before and during volume loading were measured. LV pressure-volume relations were measured ex vivo. The rats with chronic MI demonstrated expected decreases in LV systolic performance and increased LV end-diastolic and right atrial pressures. Propranolol had no independent effect on LV systolic pressure, LV end-diastolic pressure, resting cardiac index, stressed cardiac index during volume loading, peak developed aortic pressure during aortic occlusion, or ejection fraction index in either sham-operated or infarcted rats; however, heart rate was decreased. LV weight/body weight was 2.17 +/- 0.04 mg/g in control sham-operated rats, which was not different from the propranolol-treated sham-operated rats (2.09 +/- 0.04 mg/g). The LV weight/body weight was increased (p less than 0.01) to 2.21 +/- 0.08 mg/g in the propranolol-treated MI group from 1.94 +/- 0.06 mg/g in the control MI group. The LV pressure-volume relation was not altered by propranolol in the sham-operated rats but was shifted to the right by MI.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lipotab, a polyherbal formulation, attenuates isoprenaline-induced left ventricular remodeling and heart failure in rats

The present study was designed to evaluate the effect of Lipotab, a polyherbal formulation on isoprenaline (ISO)-induced left ventricular (LV) remodeling and heart failure (HF). HF in Wistar albino rats was produced by two consecutive injections of ISO (150 mg/kg, s.c.) at an interval of 24 h. After 15 days of 2nd ISO injection, HF was indicated by rise in left ventricular end-diastolic pressure (LVEDP), lowering of maximal rate of rise of LV pressure divided by LV systolic pressure (LVdP/dtmax/P; cardiac contractility) and maximal rate of fall of LV pressure (LVdP/dtmin), fall in cardiac output (CO), cardiac hypertrophy (heart to body weight ratio) and histopathological changes in heart. HF rats showed a significant increase in serum malondialdehyde (MDA), reduction in serum reduced glutathione (GSH) content and a significant rise in tumor necrosis factor-α (TNF-α) level. Prior treatment with Lipotab (275 mg/kg/day, p.o.) was significantly able to preserve LV functions. Post treatment with Lipotab (275 mg/kg/day, p.o.) also improved LV functions but did not prevent the fall in LVdP/ dtmin, CO and cardiac hypertrophy. Lipotab significantly prevented fall in GSH levels, rise in level of MDA and TNF-α in serum of HF rats. Histopathological examination confirmed hemodynamic and biochemical findings. Results of the present study indicate that Lipotab prevents ISO-induced LV remodeling and consequent HF in rats through its antioxidant and anti-inflammatory activity.     

苯那普利及坎地沙坦对自发性高血压大鼠心肌肥厚过程中SMAD蛋白的影响

目的观察自发性高血压大鼠(SHR)心肌肥厚程度与转化生长因子β1(TGF-β1)、Smad3和Smad7蛋白的表达及苯那普利、坎地沙坦的治疗作用。方法12wk龄SHR连续灌胃给予苯那普利或(和)坎地沙坦,每2wk测定尾动脉压,12wk后检测心脏构型、心脏指数、心肌细胞大小、心肌和血浆AngⅡ含量、心肌中TGF-β1、Smad3和Smad7蛋白的表达。结果SHR血压、心脏指数、心肌细胞大小及心肌组织中TGF-β1、Smad3蛋白明显增加,苯那普利或坎地沙坦治疗均能使上述指标减轻,联合应用具有协同作用,且能降低心肌和血浆AngⅡ含量;苯那普利或坎地沙坦治疗能增加在SHR中表达下降的Smad7蛋白,但两者合用对Smad7表达改善不明显。结论苯那普利和坎地沙坦联合应用对改善自发性高血压大鼠心肌肥厚具有协同作用,可能与调节AngⅡ水平、减少高血压心肌肥厚过程中TGF-β1和Smad3表达有关。     

Venodilating action of nipradilol (K-351) in the pithed rat pretreated with dihydroergotamine

The venodilating action of nipradilol was investigated by monitoring arterial blood pressure (BP), cardiac output (CO), heart rate (HR) and central venous pressure (CVP) in pithed rats treated with dihydroergotamine (DHE). DHE increased CVP and produced a simultaneous rise in BP and CO without appreciable changes in total peripheral resistance (TPR) and HR, indicating that DHE reduces venous capacity through venoconstriction. Nipradilol caused a fall in CVP, BP and CO without changing the TPR in the DHE-pretreated rat. By comparison, hydralazine reduced BP and TPR without changes in CO. Propranolol produced only a transient decrease in BP and TPR. These results indicate that nipradilol dilates venous capacitance vessels and thereby decreases cardiac filling pressure in animals with high venous tone, whereas hydralazine preferentially dilates resistance vessels.     

Pressure-independent enhancement of cardiac hypertrophy in atrial natriuretic peptide-deficient mice

1. Homozygous deletion of the pro-atrial natriuretic peptide (Nppa) gene (ANP-/-) has been associated with both cardiac hypertrophy and salt-sensitive hypertension in mice, suggesting that cardiac hypertrophy in ANP-/- mice may be related, at least in part, to increased afterload. 2. To test the hypothesis that cardiac hypertrophy in ANP-/- mice is independent of blood pressure, male ANP-/- and wild-type ANP+/+ mice were fed a low (0.05%) or basal (0.55%) NaCl diet. Five weeks later, mean arterial pressure (MAP) was measured in conscious mice; the whole heart, atria, left and right ventricles (LV and RV, respectively), brain, lung, kidney, liver and spleen were weighed and fixed for histological analysis. Separate groups of mice were subjected to echocardiographic examination under tribromoethanol anaesthesia. 3. Mean arterial pressure and atrial, LV and RV mass were greater in ANP-/- mice than in ANP+/+ mice fed the basal salt diet. Salt depletion equalized MAP in the two genotypes, but did not alter the relative cardiac hypertrophy in ANP-/- mice. The ANP-/- mice had significant LV cardiomyocyte hypertrophy when fed either basal or low-salt diets. 4. Left ventricle chamber dimensions did not differ between genotypes, but were significantly reduced in mice fed the low-salt diet; LV posterior wall and septal thickness were greater in ANP-/- than ANP+/+ mice and were not altered by diet, indicating a concentric pattern of LV hypertrophy in ANP-/- mice. Left ventricle function (cardiac output, stroke volume, ejection fraction, circumferential wall stress and velocity of circumferential wall shortening) did not differ between strains on either diet; circumferential wall stress was reduced in the low-salt groups; other functional parameters were not altered by diet. 5. These findings indicate that ANP deletion results in cardiomyocyte hypertrophy and biventricular hypertrophy independent of blood pressure, supporting the concept that ANP has direct antihypertrophic effects in the heart.     

Effects of long-term treatment with ketanserin on blood pressure variability and end-organ damage in spontaneously hypertensive rats

It has been proposed that instability of blood pressure may produce organ damage. Ketanserin is an anti-hypertensive drug with an ability to reduce blood pressure variability (BPV) in acute experiments in spontaneously hypertensive rats (SHRs). The present work was designed to observe the effects of long-term treatment with ketanserin on BPV and end-organ damage in SHRs. Ketanserin was mixed in rat chow at an estimated dose of 10 mg/kg/d. After 5 months of drug administration, BP was continuously recorded in conscious, freely moving rats for 24 h. The heart, kidneys, and abdominal aorta were then isolated and examined by using histologic methods and computer image analysis. In another work, the effects of hydralazine (40 mg/kg/d, for 5 months) on BP, BPV, and organ damage were observed in SHRs. Ketanserin significantly decreased BP and BPV, ameliorated impaired arterial baroreflex function, and significantly prevented the target organs of SHRs from being damaged. This preventive effect was characterized by decrease in left ventricular hypertrophy, diminution of glomerulus damage, and amelioration in vascular lesion. Hydralazine decreased BP but did not lower BPV. No organ protection was found in hydralazine-treated rats. In conclusion, long-term treatment with ketanserin reduced hypertensive organ damage. Lowering BP, decreasing BPV, and ameliorating arterial baroreflex function may contribute together to this effect.     

Long-term use of low-dose spironolactone in spontaneously hypertensive rats: effects on left ventricular hypertrophy and stiffness

The aim of the present study was to evaluate the effect of low-dose spironolactone initiated during the early stages of hypertension development and to assess the effects of chronic pressure overload on ventricular remodeling in rats. Male spontaneously hypertensive rats (SHRs) (4 weeks) were randomized to receive daily spironolactone (20 mg/kg) or vehicle (mineral oil) from 4 weeks to 8 months of age. Systolic blood pressure was measured non-invasively by tail-cuff pletysmography at baseline, 4 and 8 months. Hemodynamic assessment was performed at the end of treatment by arterial and ventricular catheterization. An in situ left ventricular pressure-volume curve was created to evaluate dilatation and wall stiffness. Systolic blood pressure at 1 month of age was higher in SHRs than in the Wistar group; it increased throughout the follow-up period and remained elevated with treatment (Wistar: 136 ± 2, SHR: 197 ± 6.8, SHR-Spiro: 207 ± 7.1 mmHg; p < 0.05). Spironolactone reduced cardiac hypertrophy (Wistar: 1.25 ± 0.03 SHR: 1.00 ± 0.03, SHR-Spiro: 0.86 ± 0.02 g; p < 0.05) and left ventricular mass normalized to body weight (Wistar: 2.51 ± 0.06, SHR: 2.70 ± 0.08, 2.53 ± 0.07 mg/g; p < 0.05). Moreover, the left ventricular wall stiffness that was higher in SHRs was partially reduced by spironolactone treatment (Wistar: 0.370 ± 0.032; SHR: 0.825 ± 0.058; SHR-Spiro: 0.650 ± 0.023 mmHg/ml; p < 0.05). Our results show that long-term spironolactone treatment initiated at the early stage of hypertension development reduces left ventricular hypertrophy and wall stiffness in SHRs.     

Influence of nifedipine on ventricular function and myocardial hypertrophy in spontaneously hypertensive rats

We compared left ventricular (LV) hemodynamics, LV muscle mass (LVMM), and LV geometry of 13 spontaneously hypertensive rats (SHRs) treated for 20 weeks with nifedipine (30 mg/kg/day) with those of 11 age-matched untreated SHRs. LVMM, LVMM related to end-diastolic volume (LVMM/EDV), LV pressure (PLV), systolic wall stress (Tsyst), ejection fraction (EF), cardiac index (CI), and isovolumetric contractility indices (dP/dtmax, IP, t-dP/dtmax, and VCE) were determined. Nifedipine treatment lowered PLV from 170 to 136 mm Hg and Tsyst from 222 to 194 10(3) dyn/cm2. LVMM and LVMM/EDV decreased moderately from 800 to 744 mg and from 2.56 to 2.29 mg/microliter, respectively. Left ventricular ejection was markedly increased (EF from 52 to 64%; CI from 154 to 178 ml/min X kg), whereas isovolumic contractility indices remained unchanged. Thus, nifedipine reduced but did not totally prevent myocardial hypertrophy and enhanced LV function. These effects seem to result from reduction in LV afterload and not from altered myocardial contractility.     

Comparison of the angiotensin II type 1-receptor antagonist YM358 and the angiotensin-converting enzyme inhibitor enalapril in rats with cardiac volume overload.

We evaluated the effects of chronic oral administration of an angiotensin II type 1 (AT1)-receptor antagonist YM358 and an angiotensin converting enzyme inhibitor enalapril on hemodynamics and cardiac hypertrophy in rats with volume overload-induced heart failure. We assessed changes of cardiac hemodynamics and cardiac hypertrophy at 2 and 4 weeks after administration of YM358 (3, 30 mg/kg per day) or enalapril (30 mg/kg per day) in abdominal aortocaval shunt rats. YM358 (30 mg/kg) attenuated increases of left ventricle (LV)/body weight (BW), left atrium (LA)/BW, right ventricle (RV)/BW and heart/BW ratios, but did not affect cardiac hemodynamics in shunt rats. Enalapril also reduced the increased LV/BW and heart/BW ratios together with significant reductions of systolic blood pressure, left ventricular systolic pressure and the first derivative of left ventricular pressure. These data suggest that the effects on attenuation of the development of cardiac hypertrophy are not different for YM358 and enalapril, although the effects on cardiac hemodynamics are different for the same dosages. The attenuating action of YM358 on cardiac hypertrophy was independent of the action on hemodynamics and indicated the direct action of the AT1 receptor on the heart.     

Effects of vasodilator drugs on venous tone in conscious rats

The dose-response effects of vasodilator drugs, nitroglycerin, sodium nitroprusside and hydralazine, on mean arterial pressure (MAP) and mean circulatory filling pressure (MCFP), an index of body venous tone, were investigated in conscious, unrestrained, intact rats as well as in rats treated with the ganglionic blocker, hexamethonium. The effects of these drugs were compared with those of the vehicle, normal saline, in control rats. In intact rats, i.v. infusion of nitroglycerin did not alter MAP while i.v. infusions of nitroprusside or hydralazine caused dose-dependent decreases in MAP. After ganglionic blockade, all three drugs decreased MAP. In intact rats, nitroglycerin and sodium nitroprusside did not affect MCFP but hydralazine increased MCFP. After treatment with hexamethonium, all three drugs decreased MCFP. The decreases in MCFP caused by nitroglycerin and nitroprusside, but not that by hydralazine, were significantly greater than the corresponding changes in control rats. Thus, in intact rats, the direct venodilator actions of nitroprusside and nitroglycerin were masked by endogenous sympathetic tone. When sympathetic nerve activity was attenuated, both nitroprusside and nitroglycerin have venodilator effects. Hydralazine, on the other hand, had insignificant venodilator effect both in the presence and absence of sympathetic reflexes.