Salt-induced Cardiac Hypertrophy Research Articles

Sodium-glucose exchanger 2 inhibitor canagliflozin promotes mitochondrial metabolism and alleviates salt-induced cardiac hypertrophy via preserving SIRT3 expression

IntroductionExcess salt intake is not only an independent risk factor for heart failure, but also one of the most important dietary factors associated with cardiovascular disease worldwide. Metabolic reprogramming in cardiomyocytes is an early event provoking cardiac hypertrophy that leads to subsequent cardiovascular events upon high salt loading. Although SGLT2 inhibitors, such as canagliflozin, displayed impressive cardiovascular health benefits, whether SGLT2 inhibitors protect against cardiac hypertrophy-related metabolic reprogramming upon salt loading remain elusive. ObjectivesTo investigate whether canagliflozin can improve salt-induced cardiac hypertrophy and the underlying mechanisms. MethodsDahl salt-sensitive rats developed cardiac hypertrophy by feeding them an 8% high-salt diet, and some rats were treated with canagliflozin. Cardiac function and structure as well as mitochondrial function were examined. Cardiac proteomics, targeted metabolomics and SIRT3 cardiac-specific knockout mice were used to uncover the underlying mechanisms. ResultsIn Dahl salt-sensitive rats, canagliflozin showed a potent therapeutic effect on salt-induced cardiac hypertrophy, accompanied by lowered glucose uptake, reduced accumulation of glycolytic end-products and improved cardiac mitochondrial function, which was associated with the recovery of cardiac expression of SIRT3, a key mitochondrial metabolic regulator. Cardiac-specific knockout of SIRT3 not only exacerbated salt-induced cardiac hypertrophy but also abolished the therapeutic effect of canagliflozin. Mechanistically, high salt intake repressed cardiac SIRT3 expression through a calcium-dependent epigenetic modifications, which could be blocked by canagliflozin by inhibiting SGLT1-mediated calcium uptake. SIRT3 improved myocardial metabolic reprogramming by deacetylating MPC1 in cardiomyocytes exposed to pro-hypertrophic stimuli. Similar to canagliflozin, the SIRT3 activator honokiol also exerted therapeutic effects on cardiac hypertrophy. ConclusionCardiac mitochondrial dysfunction caused by SIRT3 repression is a critical promotional determinant of metabolic pattern switching underlying salt-induced cardiac hypertrophy. Improving SIRT3-mediated mitochondrial function by SGLT2 inhibitors-mediated calcium handling would represent a therapeutic strategy against salt-related cardiovascular events.

TRPC3 deficiency attenuates high salt-induced cardiac hypertrophy by alleviating cardiac mitochondrial dysfunction

Long-term high salt intake leads to cardiac hypertrophy, but the mechanism remains elusive. Transient receptor potential channel, canonical 3(TRPC3), located in mitochondria, regulates mitochondrial calcium and reactive oxygen species(ROS) production. Herein, we investigated whether TRPC3 participates in high salt-induced cardiac hypertrophy by impairing cardiac mitochondrial function. High salt treatment increased the expression of mitochondrial TRPC3 in cardiomyocytes, accompanied by enhanced mitochondrial calcium uptake and elevated ROS production. Inhibition of TRPC3 significantly reduced high salt-induced ROS generation, promoted ATP production by stimulating oxidative phosphorylation, and increased enzyme activity in mitochondria in cardiomyocytes. Additionally, TRPC3 deficiency inhibited high salt-induced cardiac hypertrophy in vivo. A long-term high salt diet increased cardiac mitochondrial TRPC3 expression, elevated expression of cardiac hypertrophic markers atrial natriuretic peptide (ANP),brain natriuretic peptide (BNP) and β-myosin heavy chain (β-MHC) and decreased ATP production and mitochondrial complex I and II enzyme activity in a TRPC3-dependent manner. TRPC3 deficiency antagonises high salt diet-mediated cardiac hypertrophy by ameliorating TRPC3-mediated cardiac mitochondrial dysfunction. TRPC3 may therefore represent a novel target for preventing high salt-induced cardiac damage.

Effects of zamicastat treatment in a genetic model of salt-sensitive hypertension and heart failure

Hyperactivity of sympathetic nervous system plays an important role in the development and progression of cardiovascular diseases. An approach to mitigate the enhanced sympathetic nervous system drive is restricting the biosynthesis of noradrenaline via inhibition of the enzyme dopamine β-hydroxylase (DβH), that catalyzes the hydroxylation of dopamine to noradrenaline in sympathetic nerves. The aim of the present study was to evaluate the effects of zamicastat, a novel DβH inhibitor that decreases noradrenaline and increases dopamine levels in peripheral sympathetically innervated tissues, on the hemodynamic and cardiometabolic parameters in salt-induced hypertension and heart failure in the Dahl salt-sensitive (SS) rat. Zamicastat (10, 30 and 100 mg/kg body weight) was tested acutely against salt-induced hypertension in the Dahl SS rat. Chronic zamicastat treatment (30 mg/kg/day) was evaluated against salt-induced cardiac hypertrophy and biomarkers of cardiometabolic risk and inflammation in Dahl SS rats and upon the survival rate in aged Dahl SS rats fed a high-salt diet.The reduction in the sympathetic tone attained with zamicastat shaped a dose- and time-dependent effect on blood pressure. Prolonged treatment with zamicastat ameliorated end-organ damage, metabolic syndrome and inflammation hallmarks in hypertensive Dahl SS rats. Survival rate of Dahl SS rats fed a high-salt diet demonstrated that zamicastat increased median survival of Dahl SS rats fed a high-salt diet. The use of DβH inhibitors, like zamicastat, is a promising approach to treat hypertension, heart failure and cardiovascular diseases where a reduction in the sympathetic tone has beneficial effects.

A1964 TRPP3 knockout promotes cardiac hypertrophy through modulation of mitochondrial calcium homeostasis in mice

Objectives: High intake of salt is an independent risk factor for cardiac hypertrophy. TRPP3 acts as a “sour” sensor in taste cells, and its potential role in the cardiovascular system is not known. We investigated the role of TRPP3 in high salt-induced cardiac hypertrophy. Methods: Two-month male TRPP3 knockout (TRPP3−/−) mice and their wild-type (WT) littermates were fed a normal diet (0.4% NaCl) or high-salt diet (HSD; 8% NaCl) diet for 24 weeks. Cardiac hypertrophy was examined and cardiomyocyte hypertrophy assayed by wheat germ agglutinin (WGA) staining and detection of protein levels of hypertrophic markers. H9c2 cardiomyocytes were stained with Fura-2AM or Rhod-2AM fluorescence indicators for detection of cytosolic and cardiac mitochondrial calcium ions (Ca2+), respectively. Expression of the mitochondrial Ca2+channelsNCX1, NHE1, MCU and LETM1wasdetected by western blotting. Results: High salt intake increased the HW/BW ratio and HW/TL ratio of WT mice significantly, and this was exacerbated by TRPP3 knockout. Consistently, WGA staining revealed that the cardiomyocyte hypertrophy induced by a HSD was exacerbated markedly in TRPP3−/− mice, and this was accompanied by higher expression of the hypertrophic markers β-MHC, ANP and BNP, compared with WT mice. Cytosolic and mitochondrial Ca2+uptake in H9c2 cardiomyocytes was reduced significantly by TRPP3 knockdown. TRPP3 deficiency resulted in increased expression of NCX1 and NHE1 without affecting expression of MCU and LETM1 in cardiomyocytes. Conclusion: We identified TRPP3 as a novel regulator of pathologic cardiac hypertrophy. The reduced Ca2+influx in cardiomyocytes and upregulation of expression of NCX1 and NHE1 contribute to the pro-hypertrophic effect of TRPP3 knockout.

Repetitive hyperthermia attenuates progression of left ventricular hypertrophy and increases telomerase activity in hypertensive rats

We investigated the hypothesis that repetitive hyperthermia (RHT) attenuates the progression of cardiac hypertrophy and delays the transition from hypertensive cardiomyopathy to heart failure in Dahl salt-sensitive (DS) hypertensive rats. Six-week-old DS rats were divided into the following five groups: a normal-salt diet (0.4% NaCl) (NS group), a normal-salt diet plus RHT by daily immersion for 10 min in 40°C water (NS+RHT group), a high-salt diet (8% NaCl) (HS group), a high-salt diet (8% NaCl) plus RHT (HS+RHT group), and high-salt diet (8% NaCl) plus RHT with 17-DMAG (HSP90 inhibitor) administration (HS+RHT+17-DMAG group). All rats were killed at 10 wk. Cardiac hypertrophy and fibrosis were noted in the HS group, whereas RHT attenuated salt-induced cardiac hypertrophy, myocardial and perivascular fibrosis, and blood pressure elevation. The phosphorylated endothelial nitric oxide synthase (eNOS) and Akt were decreased in the HS group compared with the NS group, but these changes were not observed in the HS+RHT group. The levels of HSP60, 70, and 90 were elevated by RHT. Moreover, the increased levels of iNOS, nitrotyrosine, Toll-like receptor-4, BNP, PTX3, and TBARS in the HS group were inhibited by RHT. Telomeric DNA length, telomerase activity, and telomere reverse transcriptase (TERT) were reduced in the HS group; however, these changes were partially prevented by hyperthermia. In conclusion, RHT attenuates the development of cardiac hypertrophy and fibrosis and preserves telomerase, TERT activity and the length of telomere DNA in salt-induced hypertensive rats through activation of eNOS and induction of HSPs.

Impact of salt on cardiac differential gene expression and coronary lesion in normotensive mineralocorticoid-treated mice

We previously reported that excess of deoxycorticosterone-acetate (DOCA)/salt-induced cardiac hypertrophy in the absence of hypertension in one-renin gene mice. This model allows us to study molecular mechanisms of high-salt intake in the development of cardiovascular remodeling, independently of blood pressure in a high mineralocorticoid state. In this study, we compared the effect of 5-wk low- and high-salt intake on cardiovascular remodeling and cardiac differential gene expression in mice receiving the same amount of DOCA. Differential gene and protein expression was measured by high-density cDNA microarray assays, real-time PCR and Western blot analysis in DOCA-high salt (HS) vs. DOCA-low salt (LS) mice. DOCA-HS mice developed cardiac hypertrophy, coronary perivascular fibrosis, and left ventricular dysfunction. Differential gene and protein expression demonstrated that high-salt intake upregulated a subset of genes encoding for proteins involved in inflammation and extracellular matrix remodeling (e.g., Col3a1, Col1a2, Hmox1, and Lcn2). A major subset of downregulated genes encoded for transcription factors, including myeloid differentiation primary response (MyD) genes. Our data provide some evidence that vascular remodeling, fibrosis, and inflammation are important consequences of a high-salt intake in DOCA mice. Our study suggests that among the different pathogenic factors of cardiac and vascular remodeling, such as hypertension and mineralocorticoid excess and sodium intake, the latter is critical for the development of the profibrotic and proinflammatory phenotype observed in the heart of normotensive DOCA-treated mice.

Salt-Induced Cardiac Hypertrophy and Interstitial Fibrosis Are Due to a Blood Pressure–Independent Mechanism in Wistar Rats1–3

High salt intake is a known cardiovascular risk factor and is associated with cardiac alterations. To better understand this effect, male Wistar rats were fed a normal (NSD: 1.3% NaCl), high 4 (HSD4: 4%), or high 8 (HSD8: 8%) salt diet from weaning until 18 wk of age. The HSD8 group was subdivided into HSD8, HSD8+HZ (15 mg.kg−1.d−1 hydralazine in the drinking water), and HSD8+LOS (20 mg.kg−1.d−1 losartan in the drinking water) groups. The cardiomyocyte diameter was greater in the HSD4 and HSD8 groups than in the HSD8+LOS and NSD groups. Interstitial fibrosis was greater in the HSD4 and HSD8 groups than in the HSD8+HZ and NSD groups. Hydralazine prevented high blood pressure (BP) and fibrosis, but not cardiomyocyte hypertrophy. Losartan prevented high BP and cardiomyocyte hypertrophy, but not fibrosis. Angiotensin II type 1 receptor (AT1) protein expression in both ventricles was greater in the HSD8 group than in the NSD group. Losartan, but not hydralazine, prevented this effect. Compared with the NSD group, the binding of an AT1 conformation-specific antibody that recognizes the activated form of the receptor was lower in both ventricles in all other groups. Losartan further lowered the binding of the anti-AT1 antibody in both ventricles compared with all other experimental groups. Angiotensin II was greater in both ventricles in all groups compared with the NSD group. Myocardial structural alterations in response to HSD are independent of the effect on BP. Salt-induced cardiomyocyte hypertrophy and interstitial fibrosis possibly are due to different mechanisms. Evidence from the present study suggests that salt-induced AT1 receptor internalization is probably due to angiotensin II binding.

Estrogen delays the progression of salt-induced cardiac hypertrophy by influencing the renin-angiotensin system in heterozygous proANP gene-disrupted mice

Left ventricular hypertrophy is considered an independent risk factor for cardiac morbidity and mortality, and many studies have shown that women have a lower incidence of left ventricular hypertrophy even after correcting for numerous risk factors. This cardio-protective effect seen in women has been attributed to estrogen, which likely modulates specific growth-promoting systems such as the renin-angiotensin system, and in turn may lead to the prevention of left ventricular hypertrophy. Furthermore, the underlying mechanisms responsible are poorly understood. The aim of the present study was to examine the effect of estrogen in relation to its impact on the development of left ventricular hypertrophy through its interaction with the renin-angiotensin system by using the proANP heterozygous (ANP +/-) mouse as a model of salt-sensitive cardiac hypertrophy. Male, female ANP +/- mice and also ovariectomized female ANP +/- mice treated with oil or estrogen, were fed either a normal or high-salt diet. All four groups exhibited a general suppression of the renin-angiotensin system under the high salt challenge. However, after the 5-week treatment period, marked left ventricular hypertrophy was noted only in the male and oil-injected ovariectomized female ANP +/- mice treated with high salt. Collectively, we provide direct evidence that the differences in cardiac hypertrophy between genders in ANP +/- mice is attributed to estrogen. Furthermore, estrogen may play a key role in slowing down the progression of salt-induced left ventricular hypertrophy in ANP +/- mice, in part, independent of the classical systemic renin-angiotensin system and possibly through other pathways.

Estrogen protects against the development of salt-induced cardiac hypertrophy in heterozygous proANP gene-disrupted mice

Cardiovascular disease is the leading cause of morbidity and mortality in both men and women, but the incidence for women rises sharply after menopause. This has been mainly attributed in the reduction of the female sex hormone estrogen during menopause, suggesting that estrogen may have cardioprotective effects, although how estrogen exerts its cardioprotective effects is not fully understood. Moreover, the beneficial effect of estrogen on end-organ damage such as cardiac hypertrophy (CH) remains unclear. The aim of the present study was to examine the interaction between estrogen and the natriuretic peptide system (NPS) and their possible roles during the development of CH by using the proANP heterozygous atrial natriuretic peptide (ANP +/-) mouse as a model of salt-sensitive CH. Male, female ANP +/- mice, and also ovariectomized (Ovx) female ANP +/- mice treated with oil or estrogen were fed either a normal or high salt (HS) diet. After a 5-week treatment period, marked CH was noted in the male and oil-injected Ovx female ANP +/- mice treated with HS. The cardiac NPS, i.e. ANP, B-type natriuretic peptide, and natriuretic peptide receptor-A, was activated in these ANP +/- mice. Interestingly, the female and estrogen-injected Ovx female ANP +/- mice did not exhibit CH, and the cardiac NPS remained unchanged. Collectively, we provide direct evidence that estrogen has the ability to resist the induction of salt-induced CH in ANP +/- mice. Furthermore, the development of hypertrophy may be activating the cardiac NPS in an attempt to blunt these structural changes.

Abstract 585: Activated Vitamin D Attenuates Left Ventricular Hypertrophy and Dysfunction in DAHL Salt-Sensitive Rats

Introduction: Cardiovascular disease is the leading cause of death among end-stage renal disease (ESRD) patients. Paricalcitrol (PC), an activated vitamin D analog, is associated with improved survival in patients with ESRD. The mechanism of improved mortality, however, is unclear. We hypothesized that administration of PC would attenuate the development of cardiac dysfunction in Dahl salt sensitive (DSS) rats following a high salt (HS) diet, and improve cardiac structure and function in ESRD patients. Methods: Male DSS rats were fed a HS diet (6% NaCl) for 6 weeks beginning at 6 wk of age. PC was administered IP at 200 ng 3x/wk. Animals were evaluated for cardiac function, hemodynamics, mRNA expression of ANF, and plasma BNP levels. Also, a cohort of 77 ESRD patients treated with PC and followed for one year was examined for cardiac function by echocardiogram. Results: Rats on HS + PC compared with HS + vehicle developed significant decrease in heart weight/body weight (HW/BW) ratio (29%, p<0.05) and lung weight/body weight (LW/BW) ratio (27 %, p<0.05). Echocardiogram analysis revealed that PC treatment lead to significant improvement of fractional shortening compared with HS + vehicle treated animals (52.9±1.0 % vs. 45.7±1.6 %, p<0.05). Furthermore, LV pressure measurement showed that PC treatment resulted in significant improvement of LV end diastolic pressure (46%, p<0.05). In addition, significant increase in plasma BNP level was attenuated by PC treatment (67% reduction, p<0.05). PC treatment also significantly attenuated HS diet induced ANF mRNA increase. PC, however, did not have significant change in mean arterial pressure suggesting that beneficial effect seen by PC is not due to lowering of hypertension. In humans, twelve month echo changes in ESRD patients demonstrated that an improvement in E/A ratio and ejection fraction was associated with increasing dose of PC (p<0.05). Conclusion: Administration of PC 3x/week attenuated the development of LVH and LV dysfunction in high salt-induced cardiac hypertrophy and cardiac dysfunction in DSS rats. This finding may also be present in ESRD patients, but these findings remain observational and require confirmation.

Effect of AT2 blockade on cardiac hypertrophy as induced by high dietary salt in the proatrial natriuretic peptide (ANP) gene-disrupted mouse

The role of the angiotensin II type 2 receptor (AT2) during alterations in cardiac size remains largely unclear. Through employment of an AT2 antagonist, the present study explored a possible involvement of the AT2 receptor during salt-induced cardiac hypertrophy in the proatrial natriuretic peptide gene-disrupted mouse (ANP-/-). ANP-/- mice received either saline solution or the AT2 antagonist, PD123319, and were then placed on a high salt diet (8.0% NaCl) for 3 weeks. Cardiac and pulmonary size, expression of the renin-angiotensin system (RAS), and the behaviour of various hypertrophy marker genes were assessed. PD123319 caused enhanced expression of the systemic RAS, yet the cardiac RAS was largely unaffected. Although AT2 blockade did not alter whole cardiac mass, right ventricle mass, as well as pulmonary mass-to-body mass ratios were significantly decreased. Collagen type I was decreased in the latter tissues, likely contributing to the regression in mass. Several players essential in the maintenance of myocardial extracellular matrix homeostasis including B-type natriuretic peptide, matrix metalloproteinase-2, tumour necrosis factor, and transforming growth factor were also significantly altered by PD123319. These data suggest that AT2 blockade is involved in significant changes in myocardial extracellular matrix components translating into decreases in tissue mass in the salt-sensitive ANP-/- animal.

Interactions between atrial natriuretic peptide and the renin–angiotensin system during salt-sensitivity exhibited by the proANP gene-disrupted mouse

To understand the involvement of the systemic and cardiac components of the renin-angiotensin system (RAS) in the development of cardiac hypertrophy induced by salt intake, the present study analyzed the effect of high dietary salt (8.0% NaCl) in mice possessing a full complement (+/+) or ablation (-/-) of atrial natriuretic peptide (ANP). A 3 week treatment of 8.0% NaCl was able to induce cardiac hypertrophy in both genotypes, though exaggerated hypertrophy was noted in the ANP -/- mouse. Although a marked decrease in angiotensin II (Ang II) plasma levels in both genotypes fed a high salt diet was observed, systemic RAS mRNA components were altered only in the ANP-/- animals and remained unchanged in ANP+/+ mice. Decreased Ang II plasma levels were better correlated with decreases in angiotensinogen protein expression observed in both genotypes. High salt had no effect on cardiac RAS mRNA components in the ANP-/- animals, but did cause a significant decrease in some cardiac RAS mRNA components in ANP+/+ mice. As expected, high salt was able to increase plasma ANP levels and ventricular mRNA expression of ANP (ANP+/+ mice only) and B-type NP in both genotypes. The latter peptides are key cardiac markers of hypertrophy whose increased expression correlate well with the physical salt-induced cardiac alterations observed in this study. These findings suggest that although the RAS does not play a key role in salt-induced cardiac hypertrophy, ANP is an important determinant of the degree of salt-sensitivity observed in the proANP gene-disrupted animal.

Adenovirus-mediated kallikrein gene delivery reverses salt-induced renal injury in Dahl salt-sensitive rats

The tissue kallikrein-kinin system has been shown to play a role in cardiac and renal functions. In this study, we investigated the ability of kallikrein gene delivery to reverse salt-induced cardiac hypertrophy and renal injury in Dahl salt-sensitive rats. Adenovirus harboring the human tissue kallikrein gene, Ad.CMV-cHK, was delivered intravenously into Dahl salt-sensitive rats suffering from hypertension, cardiac hypertrophy and renal damage induced by a high salt diet (4% NaCl) for four weeks. Expression of human kallikrein mRNA was detected in rat kidney, heart, aorta and liver, and immunoreactive human kallikrein levels were measured in the serum and urine of rats receiving gene delivery. A single injection of Ad.CMV-cHK caused a significant reduction of blood pressure for more than two weeks. Kallikrein gene transfer caused left ventricular mass reduction and elevated glomerular filtration rate, renal blood flow, urinary excretion, urinary kinin, nitrite/nitrate content, cGMP and cAMP levels. Morphological investigations showed that kallikrein gene transfer caused a significant reversal in salt-induced tissue and organ damage. In the heart, cardiac hypertrophy and fibrosis were reduced, and in the kidney, both glomerular sclerotic lesions and tubular damage were reversed. Adenovirus-mediated kallikrein gene delivery is effective in reversing salt-induced cardiac hypertrophy and renal injury in Dahl-salt sensitive rats.

Action of the calcium channel blocker lacidipine on cardiac hypertrophy and endothelin-1 gene expression in stroke-prone hypertensive rats.

1. The tissue-protective effects of calcium channel blockers in hypertension are not well dissociated from their effect on systolic blood pressure (SBP). We have previously shown that lacidipine, a dihydropyridine-type calcium antagonist, reduced the cardiac hypertrophy and the cardiac endothelin-1 (ET-1) gene overexpression occurring in salt-loaded stroke-prone spontaneously hypertensive rats (SL-SHRSP), an effect occurring without systolic blood pressure (SBP) change. In the present study, we have examined whether this action was dose-related and if it could be associated with ET receptor changes. The action of lacidipine was also examined in control SHRSP and in Wistar Kyoto rats (WKY). 2. The daily dose of 0.3 mg kg-1 lacidipine which did not lower SBP but significantly prevented ventricle hypertrophy and cardiac preproET-1-mRNA expression in SL-SHRSP was inactive in control SHRSP. With the higher dose of lacidipine (1 mg kg-1 day-1), we observed a further reduction of cardiac hypertrophy and of ET-1 gene expression in SL-SHRSP and a significant effect on those parameters in control SHRSP but only a small reduction of SBP in both groups. 3. In WKY, salt loading did not induce change in SBP or increase of cardiac ET-1 gene expression and ventricle mass. In these normotensive rats, lacidipine (1 mg kg-1 day-1) did not modulate the basal preproET-1-mRNA expression and did not affect SBP or heart weight. 4. The maximum binding capacity (Bmax) and the dissociation constant (KD) of [125I]-ET-1 binding and the relative proportion of low- and high-affinity binding sites for ET-3 were not significantly affected by salt loading or lacidipine treatment in SHRSP. 5. These results show that lacidipine exerted a dose-related inhibition of ventricle hypertrophy and preproET-1-mRNA expression in SHRSP and indicate that this effect was unrelated to SBP changes. The dose-dependency of this inhibition suggests that salt-induced cardiac hypertrophy could be related to ET-1 gene overexpression. The results further show that ET receptor changes are not involved in the pathophysiological process studied here.

Inhibition by Lacidipine of Salt-Dependent Cardiac Hypertrophy and Endothelin Gene Expression in Stroke-Prone Spontaneously Hypertensive Rats

Stroke-prone spontaneously hypertensive rats receiving a high salt diet were orally treated by the calcium antagonist lacidipine, at a dose which did not reduce systolic blood pressure. We observed that lacidipine inhibited the salt-induced cardiac hypertrophy and the concomitant increase of mRNA transcripts for preproendothelin-1 in ventricles. These data show that elevated blood pressure cannot necessarily account for cardiac hypertrophy and indicate that the therapeutic action of lacidipine is not only related to its haemodynamic properties, but also to the inhibition of the gene expression of growth factors such as endothelin.

Biochemical aspects of salt-induced, pressure-independent left ventricular hypertrophy in rats.

In an attempt to investigate the effect of chronic salt loading on heart size and biochemical composition, sixty 3-month-old male Wistar-Kyoto rats (WKY) were equally divided into two groups: One group was given 1% NaCl in drinking water, and the other group was given tap water as the control. After 7 months, five randomly selected rats from each group were examined for body weight (BW), indirect blood pressure (BP), hematocrit (Hct), and organ weights. Ventricles of the heart, aorta, and mesenteric arteries were biochemically analyzed for collagen (C) and noncollagenous protein NC) and deoxyribonucleic acid (DNA). Although here was no difference between the salt and control groups in BP (129 +/- 3 mmHg vs. 125 +/- 4 mmHg, mean +/- SE), BW (376 +/- 8 g vs. 372 +/- 5 g) and Hct (42.8% +/- 1.0% vs. 44.3% +/- 0.8%), left ventricular weight (857 +/- 19 mg vs. 788 +/- 8 mg) and kidney weight (2.59 +/- 00.9 g vs 2.31 +/- 0.05 g) were both significantly (P less than 0.01) greater in the salt group, whereas the weights of the right ventricle, aorta, and adrenal glands were equal. Biochemical analysis showed significant increase in NC/DNA ratio and total collagen content as well as decreased DNA concentration in the left ventricle of the salt group compared with the control, suggesting hypertrophy rather than hyperplasia of myocardial cells with concomitant activation of collagen synthesis. Since the manner of reactive collagen production appeared different from that reported for spontaneously hypertrophic rats (SHR) or in hypoxia- or aortic constriction-induced cardiac hypertrophy, some unique mechanism may be involved in salt-induced cardiac hypertrophy.