Pressure overload causes cardiac hypertrophy in beta1-adrenergic and beta2-adrenergic receptor double knockout mice.

OBJECTIVE: Cardiac hypertrophy arises as an adaptive response to increased afterload. Studies in knockout mice have shown that catecholamines, but not alpha1-adrenergic receptors, are necessary for such an adaptation to occur. However, whether beta-adrenergic receptors are critical for the development of cardiac hypertrophy in response to pressure overload is not known at this time. METHODS AND RESULTS: Pressure overload was induced by transverse aortic banding in beta1-adrenergic and beta2-adrenergic receptor double knockout (DbetaKO) mice, in which the predominant cardiac beta-adrenergic receptor subtypes are lacking. Chronic pressure overload for 4 weeks induced cardiac hypertrophy in both DbetaKO and wild-type mice. There were no significant differences between banded mice in left ventricular weight to body weight ratio, in the left ventricular wall thickness, in the cardiomyocyte size or in the expression levels of the load-sensitive cardiac genes such as ANF and beta-MHC. Additionally, the left ventricular systolic pressure, an index of afterload, and cardiac contractility, evaluated as dp/dtmax, the maximal slope of systolic pressure increment, and Ees, end-systolic elastance, were increased at a similar level in both wild-type and DbetaKO banded mice, and were significantly greater than in sham controls. CONCLUSION: Despite chronic activation of the cardiac beta-adrenergic system being sufficient to induce a pathological hypertrophy, we show that beta1-adrenergic and beta2-adrenergic receptors are not an obligatory component of the signaling pathway that links the increased afterload to the development of cardiac hypertrophy.

Attenuation of aortic banding-induced cardiac hypertrophy by propranolol is independent of beta-adrenoceptor blockade.

OBJECTIVE: Racemic propranolol attenuates cardiac hypertrophy secondary to abdominal aortic banding-induced pressure overload by a mechanism independent of its effect on cardiac work load. This was only observed, however, using doses of propranolol that were much higher than those needed to induce beta-adrenoceptor blockade. Thus, the question remains as to whether the antihypertrophic effect of propranolol depends on its ability to antagonize cardiac beta-adrenoceptor-mediated action (positive chronotropic effect, trophic effect) or on beta-adrenoceptor-independent action. METHODS: In a rat model of chronic pressure overload induced by abdominal aortic banding, we evaluated the effects on left ventricular hypertrophy (LVH) of the propranolol isomers, L-propranolol and D-propranolol, which compared to L-isomer is approximately 50-fold less potent as a beta-adrenoceptor antagonist, but is similarly potent as a membrane-stabilizer, as well as of timolol, a non-selective beta-adrenergic antagonist devoid of membrane stabilizing activity, and disopyramide, which is a membrane stabilizer, but not a beta-adrenoceptor blocker. RESULTS: Compared to sham-operated rats, banded rats had 30% greater left ventricular to body weight (LVW/BW) ratio (P < 0.01). The increase in LVW/BW ratio was significantly attenuated by treatment with 40 and 80 (but not 10) mg/kg per day of L-propranolol. Left ventricular hypertrophy was also prevented by D-propranolol, 40 and 80 mg/kg per day, and disopyramide, 50 mg/kg per day, whereas timolol, 30 and 60 mg/kg per day, showed no antihypertrophic effect. In separate groups of banded rats in which the reduction in heart rate induced by propranolol (80 mg/kg per day) was prevented by chronic cardiac pacing at 375 b.p.m., hypertrophy was again prevented, indicating that the effects of L-propranolol on LVH are not related to a reduction in cardiac work load. CONCLUSIONS: In the aortic banding-induced model of LVH: (i) the antihypertrophic effect of propranolol is independent of its beta-adrenergic blocking activity; and Iii) since disopyramide and D-propranolol also proved to be able to antagonize banding-induced LVH, the hypothesis is proposed that membrane-stabilizing activity, among the ancillary properties of propranolol, most likely accounts for the antihypertrophic effect of this drug.

Na+/H+ exchange inhibition attenuates left ventricular remodeling and preserves systolic function in pressure-overloaded hearts.

Cardiac hypertrophy is a homeostatic response to elevated afterload. Na+/H+ exchanger (NHE) inhibition reduces the hypertrophic response in animal models of left ventricular hypertrophy (LVH) and myocardial infarction. We examined the effect of chronic treatment with cariporide, a selective inhibitor of Na+/H+ exchanger isoform 1 (NHE-1), on left ventricular (LV) systolic and diastolic function under pressure overload conditions. Male CD-1 mice were randomized to receive either a control diet or an identical diet supplemented with 6000 p.p.m. of cariporide. Cardiac pressure overload was induced by thoracic aortic banding. LV dimension and systolic and diastolic function were assessed in sham and banded mice by echocardiography and cardiac catheterization 2 and 5 weeks after surgery. Histological analysis was also performed. After 2 weeks of pressure overload, the vehicle-treated banded mice (Veh-Bd) had enhanced normalized LV weight (about +50%) and normal chamber size and function, whereas cariporide-treated banded mice (Car-Bd) showed a preserved contractility and systolic function despite a marked attenuation of LVH. Diastolic function did not differ significantly among groups. After 5 weeks, the Veh-Bd developed LV chamber enlargement and systolic dysfunction as evidenced by a 16% increase in LV end-diastolic diameter, a 36% decrease in myocardial contractility, and a 26% reduction in percent fractional shortening. In contrast, Car-Bd showed an attenuated increase in LV mass, normal chamber size, and a maintained systolic function. A distinct histological feature was that in banded mice, cariporide attenuated the development of cardiomyocyte hypertrophy but not the attendant myocardial fibrosis. In conclusion, the results of the present study indicate that (i) the hypertrophic response to pressure overload is dependent on NHE-1 activity, and (ii) at the 5-week stage, banding-induced deterioration of LV performance is prevented by NHE-1 inhibition.British Journal of Pharmacology (2004) 141, 526-532. doi:10.1038/sj.bjp.0705631

Video-assisted orotracheal intubation in mice.

Orotracheal intubation in mice is a complicated technique because of the peculiar oropharyngeal anatomy and the difficulty in visualizing the laryngis aditus. Here we report a new and simple method for rapid endotracheal intubation by using a small bore, straight fibre-optic arthroscope. Under endoscope-assisted visualization of the laryngis aditus, a polyethylene cannula, inserted on a guide-wire in order to facilitate the introduction of the tip across the vocal cords, was advanced in the trachea. The success rate of intubation was 100%. We were also able to re-intubate the mice 4 and 8 weeks later without any major complications. We conclude that this method can be easily and safely used for studies where controlled pulmonary ventilation is necessary.

Inhibition of left ventricular remodelling preserves chamber systolic function in pressure-overloaded mice.

Controversy exists whether the development of left-ventricular hypertrophy (LVH) is a mechanism able to prevent cardiac dysfunction under conditions of pressure overload. In the present study we re-assessed the long-term effects of attenuating LVH by using L- and D-propranolol, which are equally able to inhibit the development of LVH induced by aortic banding. The aortic arch was banded proximal to the left common carotid artery in 71 CD-1 mice that were then assigned randomly to receive L-propranolol, D-propranolol (both 80 mg/kg per day) or vehicle. Concurrently, sham-operated mice were given L-propranolol, D-propranolol or vehicle. LV dimension and performance were evaluated under isoflurane anaesthesia by cine-magnetic resonance imaging, echocardiography and cardiac catheterization up to 8 weeks after surgery. After 2 weeks of pressure overload, the vehicle-treated banded mice had enhanced LV weight, normal chamber size and increased relative wall thickness (concentric hypertrophy), whereas L-propranolol- or D-propranolol-banded mice showed a markedly blunted hypertrophic response, i.e. normal chamber size and normal relative wall thickness, as well as preserved systolic LV chamber function. After 4 weeks, the vehicle-treated banded mice showed LV enlargement with a reduced relative wall thickness (eccentric remodelling) and a clear-cut deterioration in LV systolic function. In contrast, L-propranolol- or D-propranolol-treated banded mice showed normal chamber size with a normal relative wall thickness and preserved systolic function. A distinct histological feature was that in banded mice, L-or D-propranolol attenuated the development of cardiomyocyte hypertrophy but not the attendant myocardial fibrosis. At the 8-week stage, LV dysfunction was present in propranolol-treated banded mice although it was much less severe than in vehicle-treated banded mice. It is concluded that (i) deterioration of LV systolic performance is delayed if LV hypertrophy is inhibited, (ii) banding-induced deterioration of LV systolic function is associated with LV eccentric remodelling and (iii) the antihypertrophic effect of propranolol is due to a selective action on cardiomyocytes rather than on collagen accumulation