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BACKGROUND: Left ventricular hypertrophy (LVH) secondary to hypertension has been accepted to prevent heart failure (HF) while paradoxically increasing cardiovascular morbi-mortality. OBJECTIVES: To evaluate whether antihypertensive treatment inhibits LVH, restores beta-adrenergic response and affects myocardial oxidative metabolism. METHODS: Ninety spontaneously hypertensive rats (SHR) were distributed into groups and treated (mg/kg, p.o.) with: losartan 30 (L), hydralazine 11 (H), rosuvastatin 10 (R), carvedilol 20 (C). Hypertension control group comprised 18 normotensive rats (Wistar-Kyoto, WKY). Following euthanasia at 16months, contractility was measured in 50% of rats (Langendorff system) before and after isoproterenol (Iso) 10-9M, 10-7M and 10-5M stimulation. Left ventricular weight (LVW) was measured in the remaining hearts, and normalized by BW. Expression of thioredoxin 1 (Trx-1), peroxyredoxin 2 (Prx-2), glutaredoxin 3 (Grx-3), caspase-3 and brain natriuretic peptide (BNP) was determined. RESULTS: Systolic blood pressure (mmHg): 154±3 (L), 137±1 (H), 190±3 (R)*, 206±3 (SHR)*, 183±1 (C)**, and 141±1 (WKY) (*p<0.05 vs. L, H, WKY, **p<0.05 vs. L, H, WKY, SHR). LVW/BW was higher in SHR and R (p<0.05). Groups SHR, R and C evidenced baseline contractile depression. Response to Iso 10-5M was similar in WKY and L. Expression of Trx-1, Prx-2 and Grx-3 increased in C, H, R and L (p<0.01). CONCLUSIONS: Present findings argue against the traditional idea and support that LVH might not be required to prevent HF. Increased expression of thioredoxins by antihypertensive treatment might be involved in protection from HF.

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Previous experiments showed that enalapril (EN) treatment as well as enalaprilic acid, when added to the perfusion bath, diminish the inotropic response of the papillary muscles to isoproterenol (ISO). The main objective of this study was to evaluate, in normal rats, the effect of EN on basal contractility and inotropic response to ISO on the whole perfused ventricles (Langendorff preparation). Blood pressure (BP), increase in body weight (IBW), ventricular weight/body weight ratio (R) and concentration of ventricular proteins and DNA were also analyzed. Five groups were studied: EN10: 5 mg/kg/day, 10 days; EN21(L): 5mg/kg/day, 21 days; EN21(H): 15 mg/kg/day, 21 days. C10 and C21 were untreated controls. Cardiac contractility was evaluated by the maximal developed pressure, maximal rate of rise of pressure and maximal velocity of relaxation; no changes were found due to EN treatments either on basal conditions or on ISO stimulation. Significant differences (p<0.05 vs C21) were: lower BP and R in EN21(L) and EN21(H), slower IBW in EN21(H), decreased ventricular DNA in EN21(H). In conclusion, daily treatment for ten or twenty one days with enalapril does not change either basal cardiac contractile performance or inotropic response to ISO in the Langendorff preparation. Longterm treatment with EN seems to modify nuclear processes involved in cardiomyocite DNA content.

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We hypothesized that in cardiac muscles, angiotensin II partially inhibits the contractile response to beta-agonists. We studied the contractile response of isolated rat left ventricular papillary muscles to isoproterenol and the effect of angiotensin II on this response. We also investigated whether the effect of angiotensin II is mediated by bradykinin, prostaglandins, nitric oxide, and/or cGMP. Contractility of isolated papillary muscles was recorded with a force transducer, and rest tension, maximal developed tension (DT), maximal rate of rise in developed tension [T(+)], and maximal velocity of relaxation [T(-)] were measured (1) under basal conditions, (2) after pretreatment with various drugs, and (3) after cumulative doses of isoproterenol. Pretreatment groups included (1) vehicle (controls); (2) angiotensin II; (3) angiotensin II and N(omega)-nitro-L-arginine, an inhibitor of nitric oxide release; (4) L-arginine, the substrate for nitric oxide synthase; (5) L-arginine and N(omega)-nitro-L-arginine; (6) 8-bromo-cGMP, analogous to the second messenger of nitric oxide; (7) angiotensin II and icatibant (Hoe 140), a bradykinin B2 antagonist; and (8) angiotensin II and indomethacin, a cyclooxygenase inhibitor. There were no differences in contractile parameters before and after any of the pretreatments. Isoproterenol increased DT, T(+), and T(-), and these effects were attenuated by angiotensin II, L-arginine, and 8-bromo-cGMP. The effects of angiotensin II and L-arginine were blocked by inhibition of nitric oxide release with N(omega)-nitro-L-arginine. Neither the bradykinin B2 antagonist nor the cyclooxygenase inhibitor altered the effects of angiotensin II. We concluded that angiotensin II partially inhibits the contractile response of cardiac papillary muscles to isoproterenol This effect is likely mediated by nitric oxide release, perhaps acting via cGMP. Kinins and prostaglandins do not appear to participate in the inhibitory effect of angiotensin II. Attenuation of the contractile effect of isoproterenol by angiotensin II may help explain why cardiac function improves in heart failure after blockade of the renin-angiotensin system.

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It is not clear whether regression of cardiac hypertrophy normalizes cardiac contractility. We studied the effect of enalapril treatment on the contractile response to beta-adrenergic stimulation with isoproterenol in renal hypertension. Male Wistar rats (n = 28) were divided into a clipped group (n = 14) and control group (n = 14). Three weeks after surgery, half of the animals from each group received for 21 days either enalapril (2.5 mg/kg) twice a day or vehicle by gastric intubation. Arterial pressure and body weight were measured twice a week. At the end of the experimental period, the hearts were excised, the ventricles were weighed, and the left ventricular papillary muscle was mounted in a bath. Myocardial contractility was characterized by the maximal developed tension, the maximal rate of rise of tension (+T), and the maximal velocity of relaxation (-T), which were measured at basal conditions and after cumulative doses of isoproterenol (10(-11) to 10(-4) M). The ratio of ventricular weight to body weight increased in hypertensive rats. Enalapril induced a decrease in arterial pressure and in the cardiac mass in both treated groups (p less than 0.05). The basal values of maximal developed tension, +T, and -T were similar in the four groups. The increment in +T and -T in response to isoproterenol (10(-4) M) was depressed in the hypertensive animals and in both treated groups (p less than 0.05). There was no significant difference in the +T/-T ratio or in the ED50 among the groups.(ABSTRACT TRUNCATED AT 250 WORDS)

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To evaluate the effect of nitrendipine on cardiac hypertrophy and inotropic response to isoproterenol in two-kidney, one-clip (2K,1C) renovascular hypertension, male Wistar rats (n = 56) were divided into a clipped group (K) (n = 28) and a sham group (S) (n = 28). Twenty-one days after surgery, the rats were placed in metabolic cages where they received either a normal diet (S and K rats) or a similar one containing N (18 mg/day) (SN and KN rats) during 3 weeks. Arterial pressure and body weight were measured twice a week. At the end of the experimental period, the hearts were excised, the ventricles were weighed, and cardiac proteins were measured by the Lowry method in seven hearts of each group. In the remaining hearts, the left ventricular papillary muscle was excised and mounted in a bath where the developed tension (dt) and the maximal rate of rise of developed tension (+T) were recorded in basal conditions, and after cumulative doses of isoproterenol (10(-11) to 10(-4) M). The arterial pressure, ventricular weight, and cardiac proteins were similar in S, SN, and KN groups and were significantly higher in the K group (p less than 0.05). No difference in the basal values of +T and dt were observed among the four groups. The increment in +T after isoproterenol was higher in treated (KN and SN) than in nontreated (K and S) groups (p less than 0.05). In conclusion, nitrendipine enhances the contractile response to isoproterenol and reverses the cardiac hypertrophy in the 2K, 1C model.

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Studies in two-kidney--one clip hypertensive rats have demonstrated that long-term treatment with enalapril induced regression of cardiac hypertrophy, but the cardiac contractile response to beta-adrenergic stimulation remained depressed. In the present study, we evaluate the contractile response to beta-adrenergic stimulation of isolated papillary muscle in normal rats with isoproterenol (10(-11) M to 10(-4) M) in the presence of enalaprilic acid (10(-6) M or 10(-4) M) or enalaprilic acid (10(-4) M) and angiotensin II (10(-6) M). Myocardial contractility was characterized by maximal developed tension and maximal rate of rise of tension (+T), and the relaxant effect of isoproterenol by the ratio of (+T), and the maximal velocity of relaxation (-T)(+T/-T ratio). The rest tension (g/mm2) and the cross-sectional area (mm2) were similar in all the muscles studied. Enalaprilic acid (either 10(-6) M or 10(-4) M) in the bath did not induce any change in contractile and relaxation parameters. The increment in +T and -T (expressed as percentage) in response to cumulative doses of isoproterenol (10(-11) M to 10(-4) M) was significantly depressed in the presence of enalaprilic acid (10(-4) M) when compared with control hearts in which only vehicle was added before isoproterenol (p less than 0.05). The addition of angiotensin II after enalaprilic acid (10(-4) M) did not normalize the response in +T and -T. Enalaprilic acid diminishes the contractile response of the papillary muscle to beta-adrenergic stimulation. The inhibition of the local angiotensin II does not seem to be involved in this result.

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Sodium homeostasis exerts a powerful influence on the cardiovascular system in normotensive and hypertensive animals. Previous studies indicate that factors other than blood pressure can influence cardiac hypertrophy. In the present experiments, we evaluated the effects of different sodium diets in the two-kidney, one clip hypertension model in the rat. After the renal artery had been clipped, the rats received a normal sodium (177 meq/kg), high sodium (517 meq/kg), and low sodium (7 meq/kg) diet during 4 weeks. The final blood pressure was almost the same in the three groups (normal sodium 170 +/- 12 mm Hg; low sodium 168 +/- 4 mm Hg; and high sodium 162 +/- 7 mm Hg). Sodium restriction significantly reduced the development of cardiac hypertrophy as compared with rats on normal or high sodium diets. Thus, ventricular weight and ventricular weight/body weight ratio were significantly higher in rats subjected to a normal or high sodium diet (p less than 0.01). The hypertrophied hearts of rats on normal and high sodium diets showed a larger increase in the number of cardiac beta-adrenergic receptors than those observed in hearts from low sodium diet, clipped rats. These results show that sodium modulates the development of cardiac hypertrophy in two-kidney, one clip hypertensive rats. Similarly, the cardiac beta-adrenergic receptors appear to be influenced by dietary sodium intake. A possible role of the sympathetic nervous system is suggested.

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Previous studies from our laboratory, have demonstrated that 21 days after unclipping the decrease in arterial pressure (AP) was followed by a regression of cardiac hypertrophy (CH) and a normalization of contractile response to Isoproterenol (I) stimulation in two kidney one clip (2K1C) hypertension. The purpose in this study was to reexamine the effects of Alpha Methyl Dopa (AMD) treatment on AP, CH and cardiac response to I stimulation in this model. A total of 43 male rats, ten weeks old, were used. In 19 rats a silver clip was placed under ether anaesthesia in the left renal artery (clip group) (K). The remaining 24 animals constituted the control group (C). Twenty one days later, in 9 and in 17 animals from K and C groups, treatment with AMD 100 mg/kg/day per os was started and maintained during the three week-follow-up period (K alpha and C alpha groups). AP was measured twice a week by the tail cuff method and body weight was registered once a week. We defined hypertension when the systolic pressure was 150 mmHg or more. Three weeks after clipping and 21 days after treatment, in the clipped animals, simultaneously with matched controls (C alpha and K alpha) the cardiac response to Isoproterenol stimulation was studied. For this purpose, under pentobarbital anesthesia the carotid artery and the femoral artery and vein were cannulated in order to measure mean arterial pressure (MAP), left ventricular systolic pressure, heart rate (HR) and DP/DT+ Max in basal conditions and after I (0.001, 0.02, 0.04, 0.12 and 0.24 microgram/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

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Resultados previos mostraron que la hipertrofia cardíaca (HC) y la respuesta contráctil al Isoproterenol (I) en el modelo 2R Ic, se normalizagba tres semanas sdespués del descenso de la presión arterial (PA) por el declipado de la arteria renal. En el presente trabajo se estudió el efecto de la Alfa Metidopa (aMD) sobre la PA, HC y la respuesta al I. Con ese propósito, a 43 ratas macho Wistar, de 280 gramos, se las dividió en: a) Grupo Control (C) (n = 24). Luego de tres semanas de control de PA, a 17 de ellas se les administró aMD per os a la dosis de 100 mg/kg/día durante 21 días (C alta). b) Grupo clip (K) (n = 19), a los que se les colocó un clip de plata en la arteria renal izquierda. Luego de tres semanas de hipertensión a (n = 9) (K alfa) se les administró aMD en forma similar a C Alfa. La respuesta al I se evaluó a los 21 a C y K y a los 42 días a C alfa y K alfa. A tal fin, previa anestesia se canularon la carótida, la arteria y vena femorales y se registró la frecuencia cardíaca (FC), la presión arterial media (PAM), la presión sistólica y diastólica de ventrículo izquierdo y la DP/DT + MAX en condiciones basales, y luego de dosis unicas crecientes de I. Al finalizar la experiencia se determinó el peso biventricular (PC) y se normalizó por el peso corporal (pc). La PA aumentó en K (p < 0,05): 179 ñ 2,3 vs C 125 ñ 2,9 y con aMD descendió: C alfa 111 + 2,5 y K alfa 151,7 ñ 6 (p < 0,05). EIPC (g) con aMD fue menor en C alfa (p < 0,05) 0,69 ñ 0,04 vs 0,78 ñ 0,05 y en K alfa...

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Previous studies from our laboratory, have demonstrated that 21 days after unclipping the decrease in arterial pressure (AP) was followed by a regression of cardiac hypertrophy (CH) and a normalization of contractile response to Isoproterenol (I) stimulation in two kidney one clip (2K1C) hypertension. The purpose in this study was to reexamine the effects of Alpha Methyl Dopa (AMD) treatment on AP, CH and cardiac response to I stimulation in this model. A total of 43 male rats, ten weeks old, were used. In 19 rats a silver clip was placed under ether anaesthesia in the left renal artery (clip group) (K). The remaining 24 animals constituted the control group (C). Twenty one days later, in 9 and in 17 animals from K and C groups, treatment with AMD 100 mg/kg/day per os was started and maintained during the three week-follow-up period (K alpha and C alpha groups). AP was measured twice a week by the tail cuff method and body weight was registered once a week. We defined hypertension when the systolic pressure was 150 mmHg or more. Three weeks after clipping and 21 days after treatment, in the clipped animals, simultaneously with matched controls (C alpha and K alpha) the cardiac response to Isoproterenol stimulation was studied. For this purpose, under pentobarbital anesthesia the carotid artery and the femoral artery and vein were cannulated in order to measure mean arterial pressure (MAP), left ventricular systolic pressure, heart rate (HR) and DP/DT+ Max in basal conditions and after I (0.001, 0.02, 0.04, 0.12 and 0.24 microgram/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

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Resultados previos mostraron que la hipertrofia cardíaca (HC) y la respuesta contráctil al Isoproterenol (I) en el modelo 2R Ic, se normalizagba tres semanas sdespués del descenso de la presión arterial (PA) por el declipado de la arteria renal. En el presente trabajo se estudió el efecto de la Alfa Metidopa (aMD) sobre la PA, HC y la respuesta al I. Con ese propósito, a 43 ratas macho Wistar, de 280 gramos, se las dividió en: a) Grupo Control (C) (n = 24). Luego de tres semanas de control de PA, a 17 de ellas se les administró aMD per os a la dosis de 100 mg/kg/día durante 21 días (C alta). b) Grupo clip (K) (n = 19), a los que se les colocó un clip de plata en la arteria renal izquierda. Luego de tres semanas de hipertensión a (n = 9) (K alfa) se les administró aMD en forma similar a C Alfa. La respuesta al I se evaluó a los 21 a C y K y a los 42 días a C alfa y K alfa. A tal fin, previa anestesia se canularon la carótida, la arteria y vena femorales y se registró la frecuencia cardíaca (FC), la presión arterial media (PAM), la presión sistólica y diastólica de ventrículo izquierdo y la DP/DT + MAX en condiciones basales, y luego de dosis unicas crecientes de I. Al finalizar la experiencia se determinó el peso biventricular (PC) y se normalizó por el peso corporal (pc). La PA aumentó en K (p < 0,05): 179 ñ 2,3 vs C 125 ñ 2,9 y con aMD descendió: C alfa 111 + 2,5 y K alfa 151,7 ñ 6 (p < 0,05). EIPC (g) con aMD fue menor en C alfa (p < 0,05) 0,69 ñ 0,04 vs 0,78 ñ 0,05 y en K alfa...(AU)

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Properties of cardiac beta-adrenergic receptors from two kidney-one clip hypertension and control rats were studied to determine whether or not alterations in the receptor contribute to the decreased responsiveness of two kidney-one clip rat hearts to adrenergic stimulation. The number and affinity of the beta-receptors were assessed by the binding of [3H]DHA in an enriched ventricular membrane fraction obtained from the rat hearts 3 and 4 weeks after the application of the clip. In the rats with 3 weeks of development of hypertension no significant difference was found neither in the number nor in the affinity of receptors (30.9 +/- 5.3 fmol/mg protein, KD: 1.62 +/- 0.43 nM) compared to the control rats (33.3 +/- 6.3 fmol/mg protein, KD: 2.21 +/- 0.59 nM). In rats with 4 weeks of development of hypertension, there was an increased number of receptors (54.7 +/- 3.7 fmol/mg protein, KD: 1.41 +/- 0.17 nM) compared with control rats studied in paralleled conditions (40.0 +/- 2.3 fmol/mg protein, KD: 1.13 +/- 0.12 nM). These results suggest that the reported beta-adrenergic subsensitivity in this model of hypertensive rats could be mediated by a biochemical mechanism other than a direct alteration of the beta adrenergic receptors, and that there is a compensatory increase in the density of receptors during the development of the hypertension.

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Properties of cardiac beta-adrenergic receptors from two kidney-one clip hypertension and control rats were studied to determine whether or not alterations in the receptor contribute to the decreased responsiveness of two kidney-one clip rat hearts to adrenergic stimulation. The number and affinity of the beta-receptors were assessed by the binding of [3H]DHA in an enriched ventricular membrane fraction obtained from the rat hearts 3 and 4 weeks after the application of the clip. In the rats with 3 weeks of development of hypertension no significant difference was found neither in the number nor in the affinity of receptors (30.9 +/- 5.3 fmol/mg protein, KD: 1.62 +/- 0.43 nM) compared to the control rats (33.3 +/- 6.3 fmol/mg protein, KD: 2.21 +/- 0.59 nM). In rats with 4 weeks of development of hypertension, there was an increased number of receptors (54.7 +/- 3.7 fmol/mg protein, KD: 1.41 +/- 0.17 nM) compared with control rats studied in paralleled conditions (40.0 +/- 2.3 fmol/mg protein, KD: 1.13 +/- 0.12 nM). These results suggest that the reported beta-adrenergic subsensitivity in this model of hypertensive rats could be mediated by a biochemical mechanism other than a direct alteration of the beta adrenergic receptors, and that there is a compensatory increase in the density of receptors during the development of the hypertension.

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