Age-matched Dahl Salt-resistant Rats Research Articles

AT1 receptor blockade reduces cardiac calcineurin activity in hypertensive rats.

The possible role of calcineurin in the attenuation of cardiac hypertrophy and fibrosis by blockade of the angiotensin II type 1 (AT1) receptor was investigated in Dahl salt-sensitive (DS) rats. The effect of the calcineurin inhibitor FK506 was also studied. DS rats progressively developed severe hypertension when fed a diet containing 8% NaCl from 7 weeks of age. In addition, marked cardiac hypertrophy and fibrosis were apparent and the activity of calcineurin and its mRNA expression in the myocardium was increased in these animals at 12 weeks in comparison with age-matched Dahl salt-resistant rats. The abundance of angiotensin-converting enzyme (ACE) and transforming growth factor (TGF)-beta1 mRNAs was also increased in the hearts of DS rats at 12 weeks. Treatment of DS rats with a non-antihypertensive dose of the selective AT1 receptor blocker candesartan (1 mg/kg per day) or FK506 (0.1 mg/kg per day) from 7 to 12 weeks attenuated both calcineurin activity and its mRNA expression in the heart, as well as the development of cardiac hypertrophy and fibrosis, without affecting cardiac function. Treatment with candesartan, but not FK506, prevented the upregulation of ACE and TGF-beta1 gene expression. Both candesartan and FK506 prevented the load-induced induction of fetal-type cardiac genes. These results demonstrate that AT1 receptor blockade attenuates the development of cardiac hypertrophy and fibrosis as well as the activation of calcineurin, without an antihypertensive effect, in rats with salt-sensitive hypertension. Calcineurin may be downstream from TGF-beta1 in AT1 receptor-mediated angiotensin II signaling in vivo.

Increased expression of cardiotrophin-1 during ventricular remodeling in hypertensive rats.

Cardiotrophin-1 (CT-1) stimulates longitudinal myocardial cell hypertrophy. We examined the expression of CT-1, leukemia inhibitory factor (LIF), and gp130 by competitive RT-PCR and Western blotting in Dahl salt-sensitive (DS) rats with a high-salt diet, which showed a distinct transition from left ventricular hypertrophy (LVH) to congestive heart failure (CHF). The expression levels of CT-1 mRNA and protein were significantly increased at the CHF stage compared with the LVH stage and age-matched Dahl salt-resistant (DR) rats (n = 6 for each group). mRNA expression of LIF was not changed in the left ventricle at any stage by RT-PCR. gp130 mRNA and protein levels of DS rats at 11 and 17 wk were significantly increased compared with age-matched DR rats. The isolated myocyte length of DS rats at 17 wk was the longest among the four groups of rats. The LV end-diastolic dimension (LVDd) of DS rats, determined by echocardiography, was significantly increased at the CHF stage. There was a significant correlation between the CT-1 protein level and LVDd. CT-1 may play a role in ventricular remodeling during transition from LVH to CHF in the rat hypertensive model.

Neurohumoral Factors during Transition from Left Ventricular Hypertrophy to Failure in Dahl Salt-Sensitive Rats

The relationship between the reduction in the positive inotropic effects (PIE) of β-adrenergic stimulation and the level of systemic and tissue neurohumoral factors during the course from left ventricular (LV) hypertrophy to congestive heart failure (CHF) was studied in Dahl salt-sensitive rat (DS) CHF model. Control studies were performed in age-matched Dahl salt-resistant (DR) rats. In DS rats at CHF stage, plasma atrial natriuretic peptide (ANP) and norepinephrine (NE) levels were elevated markedly and myocardial NE level was decreased compared with those in the age-matched DR rats. On the other hand, at the hypertrophy stage, we observed no significant differences in plasma ANP or NE level between the two strains in spite of decrease in myocardial NE concentration. The PIE induced by isoproterenol was reduced at the stage of compensatory LV hypertrophy, which was followed by further reduction of PIE at CHF stage. The results distinctively indicate that β-adrenergic desensitization in the myocardium which was accompanied with the abnormalities in local sympathoneuronal regulation begins during mechanically compensated LV hypertrophy and precedes systemic augmentation of sympathomimetic hormones.

Transition from compensatory hypertrophy to dilated, failing left ventricles in Dahl salt-sensitive rats

To establish an experimental model for studying a specific transitional stage for compensatory hypertrophy to heart failure, we studied the pathophysiology of the left ventricle (LV) in Dahl salt-sensitive (DS) rats fed a high-salt diet. DS rats fed an 8% NaCl diet after the age of 6 wk developed concentric LV hypertrophy at 11 wk, followed by marked LV dilatation at 15-20 wk. During the latter stage, the DS rats showed labored respiration with LV global hypokinesis. All the DS rats died within 1 wk by massive pulmonary congestion. The dissected left ventricles revealed chamber dilatation and a marked increase in mass without myocardial necrosis. In contrast, corresponding Dahl salt-resistant (DR) rats fed the same diet showed neither mortality nor any of these pathological changes. The in vivo LV end-systolic pressure-volume relationship shifted to the right with a less steep slope in the failing DS rats compared with that in age-matched DR rats. Isometric contractions of LV papillary muscles isolated from these DS rats showed reduced tension development in the failing stage, but normal tension development in the hypertrophied stage. In conclusion, the DS rat fed a high-salt diet is a useful model showing rapidly developing congestive heart failure, in which the transition from compensatory hypertrophy to decompensatory dilatation of LV is easily and consistently manifested.

Effect of dietary salt on the skeletal muscle microvasculature in Dahl rats.

The purpose of this study was to identify microvascular alterations that could contribute to increased peripheral vascular resistance in the Dahl salt-sensitive rat with salt-induced hypertension. Intravital microscopy was used to study the spinotrapezius muscle arteriolar network in anesthetized salt-sensitive rats fed either a high salt (7% sodium chloride) or low-normal salt (0.45% sodium chloride) diet for 4 weeks. Age-matched Dahl salt-resistant rats on high and low-normal salt diets served as controls. The high salt diet had no effect on arterial pressure in salt-resistant rats but increased arterial pressure in salt-sensitive rats. Mean resting diameter of arcade arterioles in salt-sensitive rats on high salt diet was reduced by 25% compared with salt-sensitive rats on low salt or salt-resistant rats on either diet. After abolition of vascular tone with 10(-3) M adenosine, arcade diameters were comparable in all groups. No difference among groups was found in either resting or passive diameter of the more distal transverse arterioles. Measurement of vessel lengths and numbers in cleared muscle specimens revealed no differences among groups in the anatomic density of either arcade or transverse arterioles. These data suggest that a reduction in the resting diameter of arcade, but not transverse, arterioles may increase spinotrapezius muscle vascular resistance in hypertensive salt-sensitive rats. The similarity in vascular densities among groups indicates that structural rarefaction of arterioles does not contribute to any increase in spinotrapezius muscle resistance at this stage of salt-induced hypertension.

Up-regulation of renal prostaglandin receptors in genetic salt-dependent hypertension.

Development of hypertension in Dahl salt-sensitive rats (DS) is accompanied by reduced renomedullary prostaglandin synthesis, which may be responsible for their lower natriuretic capacity. To examine the changes in renomedullary prostaglandin E2 synthesis, the effects of high (8.0%) and normal (0.6%) NaCl diets were examined in DS and in Dahl salt-resistant rats (DR). In response to an 8.0% NaCl diet, the number of prostaglandin E2 receptors in the renal outer medulla of DR increased (2.97 +/- 0.2 vs 2.18 +/- 0.2 pmol/mg on 0.6% NaCl diet) while no change was noted in their affinities (Kd, 9.5 +/- 0.2 vs 9.4 +/- 0.3 nM). Receptor number and affinity in the renal cortex, inner medulla, and liver of DR were not affected. In contrast, renomedullary receptors of DS had a lower affinity than those of age-matched DR (Kd, 13.9 +/- 0.2 nM on 0.6% NaCl diet and 14.0 +/- 0.3 nM on 8.0% NaCl diet) and did not increase in number after a high salt diet. This apparent inability of DS to modulate prostaglandin receptors may contribute to their susceptibility to salt-induced hypertension.