Spironolactone differently influences remodeling of the left ventricle and aorta in L-NAME-induced hypertension.

Aldosterone receptor antagonist, spironolactone, has been shown to prevent remodeling of the heart in several models of left ventricular hypertrophy. The aim of the present study was to determine whether the treatment with spironolactone can prevent hypertension, reduction of tissue nitric oxide synthase activity and left ventricular (LV) and aortic remodeling in N(G)-nitro-L-arginine methyl ester (L-NAME)-induced hypertension. Four groups of rats were investigated: control, spironolactone (200 mg/kg), L-NAME (40 mg/kg) and L-NAME + spironolactone (in corresponding dosage). Animals were studied after 5 weeks of treatment. The decrease of NO-synthase activity in the LV and kidney was associated with the development of hypertension and LV hypertrophy, with increased DNA concentration in the LV, and remodeling of the aorta in the L-NAME group. Spironolactone prevented the inhibition of NO-synthase activity in the LV and kidney and partially attenuated hypertension and LVH development and the increase in DNA concentration. However, remodeling of the aorta was not prevented by spironolactone treatment. We conclude that the aldosterone receptor antagonist spironolactone improved nitric oxide production and partially prevented hypertension and LVH development without preventing hypertrophy of the aorta in NO-deficient hypertension. The reactive growth of the heart and aorta seems to be controlled by different mechanisms in L-NAME-induced hypertension.

L-arginine fails to protect against myocardial remodelling in L-NAME-induced hypertension.

BACKGROUND: We investigated whether the substrate for nitric oxide synthesis L-arginine is able to modify hypertension and left ventricular hypertrophy development induced by chronic blockade of nitric oxide synthase activity by NG-nitro-L-arginine-methyl ester (L-NAME). MATERIAL AND METHODS: Four groups of rats were investigated: control, L-arginine 1.5 g kg-1, L-NAME 40 mg kg-1, and L-NAME +L-arginine in corresponding doses. Systolic blood pressure was measured by non-invasive tail-cuff plethysmography each week. After 4 weeks, the animals were sacrificed and hydroxyproline and coenzyme Q9 and Q10 concentrations in the left ventricle, and nitric oxide synthase activity in the left ventricle, kidney and brain were investigated. RESULTS: In the L-NAME group, nitric oxide synthase activity was decreased in the left ventricle, kidney and brain, and hypertension, left ventricular hypertrophy and fibrosis developed. Heart remodelling was associated with the decrease of coenzyme Q9 and Q10 concentrations in the left ventricle. Simultaneous treatment with L-NAME and L-arginine prevented nitric oxide synthase activity diminution in the left ventricle but not in the kidney and brain, and completely failed to prevent hypertension, left ventricular hypertrophy and fibrosis. Nevertheless, l-arginine prevented the diminution of coenzyme Q9 and Q10 concentrations in the left ventricle. CONCLUSIONS: We conclude that L-arginine failed to prevent hypertension, left ventricular hypertrophy and fibrosis development despite restoration of nitric oxide synthase activity in the left ventricle. However, L-arginine prevented the diminution of coenzyme Q levels in the left ventricle.

Adenosine and cardioprotection: what can we learn from nature's genetic polymorphism?

Adenosine is an endogenous nucleoside that has been shown to be beneficial for the myocardium in different settings by a large number of experimental studies. In this article, we 1) outline adenosine's metabolic pathways, 2) address cardioprotective properties of adenosine, and 3) discuss possible implications of the two recently published clinical studies disclosing a positive effect of adenosine monophosphate deaminase 1 (AMPD1) gene mutation on cardiovascular survival in heart failure and ischemic heart disease. (Fig. 2, Ref. 84.)

Heart remodeling in the hereditary hypertriglyceridemic rat: effect of captopril and nitric oxide deficiency.

AIM: The hereditary hypertriglyceridemic (hHTg) rat is characterized by insulin resistance, hypertension, and hypertriglyceridemia. Thus, we investigated whether (a) remodeling of the heart left ventricle (LV) is present under the given hypertensive situation and (b) whether this potential alteration could be influenced by an inhibition of the angiotensin converting enzyme (ACE) and/or by a blockade of nitric oxide production. METHODS: Five groups of rats were investigated: control Wistar (C) rats, hHTg rats, hHTg rats given captopril (100 mg/kg/day) (hHTg + CAP) or NG-nitro-l-arginine methyl ester (L-NAME, 40 mg/kg/day) (hHTg + L-NAME), and hHTg rats given the combination of both drugs (hHTg + CAP + L-NAME) for 28 days. Systolic blood pressure (SBP) was measured by tail-cuff plethysmography each week. After cervical dislocation, the relative weights of the left and right ventricles (LV/BW, RV/BW) were obtained, the LV nucleic acid concentrations were analyzed, and the fibrosis amount was quantified with aid of a semiquantitative histological technique. RESULTS: In the hHTg group, the increased SBP (141.7 +/- 4.4 vs. 117.2 +/- 3.1 mmHg in controls) was linked to hypertrophy of the LV (1.63 +/- 0.05 vs. 1.30 +/- 0.03 g/kg in controls) with only a minimum of fibrosis. DNA concentration in the LV was decreased (0.45 +/- 0.03 vs. 0.69 +/- 0.04 mg/g w.w. in controls) in the hHTg group. Captopril normalized SBP and decreased the LV/BW (1.44 +/- 0.04 g/kg). Chronic administration of L-NAME to the hHTg rats additionally enhanced (189.3 +/- 5.9 mmHg) the already raised SBP, stimulated fibrosis development, and increased DNA concentration (0.54 +/- 0.02 mg/g w.w.) in the LV compared to hHTg group, yet without additional weight increase of the LV. The combined treatment of the hHTg rats with CAP and L-NAME resulted in normal SBP and the development of LV hypertrophy, and fibrosis was substantially reduced. CONCLUSIONS: (a) The heart of hHTg rats carries signs of LV hypertrophy with minimal fibrosis. (b) Nevertheless, LV fibrosis was increased in the hHTg + L-NAME group. (c) Captopril normalized SBP and decreased the extent of LV hypertrophy in both the nontreated hHTg and the hHTg + L-NAME groups and (d) substantially reduced the development of LV fibrosis in the hHTg + L-NAME group. LVH in hHTg rats may be induced by sympathoadrenal system activation, circulating volume enlargement, and impairment of nitric oxide (NO) production rather than by activation of the renin-angiotensin-aldosterone system.

Impaired endothelial function of thoracic aorta in hereditary hypertriglyceridemic rats.

OBJECTIVE: Hereditary hypertriglyceridemia (hHTG) in rats was found to be associated with metabolic abnormalities and elevation of blood pressure. There is controversy regarding the relation between hHTG and vascular function. The aim of this study was to determine the reactivity and accompanying structural changes in thoracic aorta from hereditary hypertriglyceridemic rats and hHTG rats that were given, for a long time, N(G)-nitro-l-arginine methyl ester (L-NAME) with and without simultaneous captopril treatment. METHODS: Isolated rings of thoracic aorta were mounted in organ chambers for isometric tension recording or for measurement of endothelium-dependent relaxation. Morphological changes of thoracic aorta (wall thickness, diameter) were measured using light microscopy. RESULTS: Endothelium-dependent relaxation (EDR) to acetylcholine (ACh, 10(-5) M) was significantly attenuated in the hHTG group compared to control Wistar rats (59.3 +/- 8.5% vs. 95.8 +/- 6.5%, p < 0.001), but normalized after pretreatment with captopril. EDR to ACh was further inhibited in hHTG rats treated with L-NAME (36.0 +/- 2.3%, p < 0.001). Maximum residual relaxation was only partly restored with captopril treatment (72.4 +/- 5.8%, p < 0.001). Hypertriglyceridemia did not significantly alter the sensitivity of the thoracic aorta to exogenous noradrenaline. The diameter/wall thickness (D/W) ratio in aortas of control Wistar rats averaged 16.25 +/- 0.57. This ratio was significantly lower in hHTG rats (12.52 +/- 0.38, p < 0.01) and was not altered after treatment with captopril. In the hHTG rats treated with L-NAME, the D/W ratio was further significantly decreased (8.25 +/- 0.30, p < 0.001). Simultaneous captopril treatment attenuated the decrement of this ratio (9.80 +/- 0.75, p < 0.05). CONCLUSIONS: Results showed that hHTG is accompanied by functional and morphological alterations in the rat thoracic aorta. These changes in hHTG and in hHTG rats treated with L-NAME could be, at least in part, protected by captopril treatment.

Frequency-domain analysis of the QRS complex after treatment of childhood cancer with anthracycline cytostatics.

Long-term cardiac complications, occurring several years after completion of anticancer treatment, may develop from subclinical myocardial damage induced during cardiotoxic therapy. The aim of this study was to evaluate the usefulness of frequency-domain signal-averaged ECG analysis of the QRS complex for assessing the cardiotoxicity of anthracycline cytostatics. Altogether, 172 signal-averaged electrocardiography (SAECG) registrations were performed in 50 repeatedly evaluated oncologic patients. These registrations were performed 0.2-15 years after completion of anthracycline therapy for childhood cancer. The control group consisted of 120 healthy children and young volunteers; in 20 of these controls, SAECGs were performed repeatedly. Using gliding window fast Fourier transformation within the QRS complex, values area ratio (AR) 60-120 Hz/0-120 Hz were calculated in X, Y, and Z lead. Area ratio of patients after anthracycline therapy was significantly higher than those in control group in X lead. Differences in frequency content in the QRS complex between patients and controls might signal an initial stage of anthracycline-induced myocardial damage.