ABSTRACT
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.
Subject(s)
Angiotensin II/pharmacology , Heart/physiology , Myocardial Contraction/drug effects , Nitric Oxide/metabolism , Animals , Kinins/antagonists & inhibitors , Kinins/metabolism , Male , Rats , Rats, WistarSubject(s)
Hypertension/complications , Pregnancy Complications, Cardiovascular/physiopathology , Sodium, Dietary/administration & dosage , Animals , Aorta/metabolism , Blood Pressure/physiology , DNA/metabolism , Female , Hypertension/etiology , Hypertension/physiopathology , Pregnancy , Pregnancy Complications, Cardiovascular/etiology , Proteins/metabolism , Rats , Rats, Inbred SHR , Renin-Angiotensin System/physiologyABSTRACT
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)
Subject(s)
Enalapril/therapeutic use , Hypertension, Renovascular/drug therapy , Animals , Body Weight/drug effects , Cardiomegaly/drug therapy , Isoproterenol/pharmacology , Male , Muscle Relaxation/drug effects , Myocardial Contraction/drug effects , Papillary Muscles/physiology , Rats , Rats, Inbred StrainsABSTRACT
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.
Subject(s)
Hypertension, Renal/drug therapy , Isoproterenol/therapeutic use , Myocardial Contraction/drug effects , Nitrendipine/therapeutic use , Animals , Blood Pressure/drug effects , Body Weight/drug effects , Cardiomegaly/drug therapy , Heart/drug effects , Male , Organ Size/drug effects , Rats , Rats, Inbred StrainsABSTRACT
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.
Subject(s)
Cardiomegaly/etiology , Diet , Hypertension, Renovascular/complications , Sodium/administration & dosage , Animals , Blood Pressure , Body Weight , Cardiomegaly/pathology , Cardiomegaly/physiopathology , Hypertension, Renovascular/physiopathology , Male , Myocardium/metabolism , Myocardium/pathology , Natriuresis , Organ Size , Proteins/metabolism , Rats , Rats, Inbred Strains , Receptors, Adrenergic, beta/metabolism , SystoleABSTRACT
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.
Subject(s)
Adrenergic beta-Agonists/pharmacology , Enalaprilat/pharmacology , Myocardial Contraction/drug effects , Angiotensin II/pharmacology , Animals , Dose-Response Relationship, Drug , In Vitro Techniques , Isoproterenol/pharmacology , Male , Papillary Muscles/drug effects , Rats , Rats, Inbred StrainsABSTRACT
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)
Subject(s)
Blood Pressure/drug effects , Cardiomegaly/drug therapy , Hypertension, Renovascular/drug therapy , Isoproterenol/pharmacology , Methyldopa/pharmacology , Animals , Heart Rate/drug effects , Male , Myocardial Contraction/drug effects , Organ Size/drug effects , Rats , Rats, Inbred StrainsABSTRACT
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...
Subject(s)
Rats , Animals , Male , Blood Pressure/drug effects , Cardiomegaly/drug therapy , Hypertension, Renovascular/physiopathology , Isoproterenol/pharmacology , Methyldopa/pharmacology , Heart Rate , Organ Size/drug effects , Rats, WistarABSTRACT
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)
ABSTRACT
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)
Subject(s)
Rats , Animals , Male , Comparative Study , Hypertension, Renovascular/physiopathology , Methyldopa/pharmacology , Isoproterenol/pharmacology , Blood Pressure/drug effects , Cardiomegaly/drug therapy , Organ Size/drug effects , Heart Rate/drug effects , Rats, WistarABSTRACT
Experiments were performed in male Wistar rats with renovascular hypertension (167 +/- 4.2 mmHg) produced by clipping the renal artery for a 3-wk period (2-kidney, 1-clip Goldblatt). The results were compared with those obtained in age-matched normotensive controls. Hypertension of 3-wk duration elicited a significant increase in ventricular weight (1.01 +/- 0.02 g) with respect to the controls (0.82 +/- 0.01 g) but had no significant effect on body weight. The inotropic responsiveness to beta-adrenergic stimulation was diminished in papillary muscles from renal hypertensive rats: the maximum increase in the maximal rate of rise of tension produced by isoproterenol was 27.39 +/- 5.4 and 11.77 +/- 2.91 g X mm-2 X s-1 (P less than 0.05) in control and hypertensive animals, respectively. Similar results were obtained when the estimated maximal velocity of shortening of the contractile element (Vmax) was used to assess myocardial contractility. The inotropic response to CaCl2 was also significantly depressed in the 2-kidney, 1-clip rats. However, the relaxant and the chronotropic responses to isoproterenol were not significantly modified in the Goldblatt rats. Assays of beta-adrenergic receptors to l-[3H]dihydroalprenolol binding, showed no significant changes in the number (expressed per mg of membrane protein) or in the affinity of the beta-receptors. These results suggest that at an early stage of the renal hypertensive model the impaired inotropic response to isoproterenol is not mediated by an alteration of the beta-receptors and should be searched at a postreceptor adenyl cyclase level.
Subject(s)
Hypertension, Renovascular/physiopathology , Isoproterenol/pharmacology , Myocardial Contraction/drug effects , Papillary Muscles/physiopathology , Receptors, Adrenergic, beta/physiology , Animals , Calcium Chloride/pharmacology , Cardiomegaly/etiology , Hypertension, Renovascular/complications , Male , Papillary Muscles/drug effects , Rats , Rats, Inbred Strains , Receptors, Adrenergic, beta/drug effects , Time FactorsABSTRACT
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.
Subject(s)
Adrenergic beta-Antagonists/metabolism , Hypertension, Renovascular/physiopathology , Myocardium/metabolism , Animals , Blood Pressure/drug effects , Dihydroalprenolol/metabolism , Male , Myocardium/analysis , Propranolol/pharmacology , Rats , Rats, Inbred Strains , Receptors, Adrenergic, beta/analysisABSTRACT
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.
ABSTRACT
The chronic effect of propranolol on induced water intake and on the subfornical organ was studied. Propranolol reduced water intake postdehydration. It did not inhibit the increase in plasma renin activity due to dehydration or the dipsogenic response to angiotensin II. Propranolol decreased the subfornical organ large protrusion cells. This result suggests that propranolol impairs the thirst not related to angiotensin II. The subfornical organ changes may indicate that propranolol blocks a beta-adrenergic system originating in ependymal cells.
Subject(s)
Drinking/drug effects , Neurosecretory Systems/drug effects , Propranolol/pharmacology , Subfornical Organ/drug effects , Angiotensin II/pharmacology , Animals , Isoproterenol/pharmacology , Male , Microscopy, Electron, Scanning , Rats , Rats, Inbred Strains , Renin/blood , Subfornical Organ/ultrastructure , Water Deprivation/physiologyABSTRACT
1. Rats on normal sodium diet (group 1) and on chronically maintained low sodium diet (group 2) were studied during a control period, after clipping the renal artery (two-kidney, one-clip hypertension) and after nephrectomy (one-kidney, one-clip hypertension). 2. The low sodium diet neither prevented the development nor changed the severity of two-kidney, one-clip hypertension, and the latter was not accompanied by an increase in plasma renin activity. 3. After nephrectomy arterial pressure further increased and plasma renin activity decreased in group 1, and both remained unchanged in group 2. 4. Blood volume was the same in both groups 10 days before and 10 days after nephrectomy. 5. Sodium does not seem to be 'necessary' in the two-kidney, one-clip hypertension although it may play an enhancing role in the one-kidney model.
