Local stretching increases the electrophysiological heterogeneity of myocardium and accelerates and increases the complexity of VF in the stretched area, without significantly modifying the occurrences of the types of VF activation patterns in the nonstretched zone.

The objective of this study was to determine in conscious dogs the role of endothelium-derived nitric oxide in mediating the arterial pressure and renal response to a prolonged increment of sodium intake. After a control period of 3 days, an inhibitor of nitric oxide synthesis, A rG -nitro-L-arginine-methyl ester, was infused intravenously during 5 consecutive days (0.1 /tg/kg per minute). Sodium intake (80 mmol/d) did not change throughout the experiment in one group (n=4). In another group (rt=6), 1 day after infusion of this inhibitor was started, sodium intake increased from 80 to 300 mmol/d during 4 consecutive days. Inhibition of nitric oxide synthesis in dogs with normal sodium intake induced a significant decrease in natriuresis and diuresis (P<.05) without changes in arterial pressure. However, in dogs treated with the nitric oxide synthesis inhibitor, mean arterial pressure increased from 95.2±3.3 to 106.2±4.0 mm Hg (P<.01) the first day that sodium intake was elevated and remained increased the following 3 days. In a different group of dogs (n=5), the increment of sodium intake during 4 days did not induce changes in arterial pressure when nitric oxide synthesis was not inhibited. Cumulative sodium balance was higher (P<.01) in dogs treated simultaneously with the nitric oxide synthesis inhibitor and high sodium intake (158±21 mmol sodium) than in those treated only with the nitric oxide synthesis inhibitor (82±19 mmol sodium) or with high sodium intake (36±13 mmol sodium). Our results demonstrated that dogs fail to handle appropriately a prolonged increase in sodium intake when nitric oxide synthesis is inhibited, and as a consequence, arterial pressure increases significantly. This elevation in arterial pressure seems to be secondary, at least partly, to an increase in extracellular fluid volume. It is strongly suggested that hypertension is a necessary compensation for maintaining sodium balance when nitric oxide synthesis is chronically diminished. (Hypertension 1993;22:49-55) KEY WORDS • hypertension, sodium-dependent • nitric oxide • endothelium-derived relaxing factor • sodium I t is well known that the increase in renal sodium excretion that occurs in response to an elevation in sodium intake is important for the maintenance of normal body fluid volumes and arterial pressure. A correlation has been found between renal excretory function and arterial pressure in several genetic models of hypertension, and, in some strains, a critical relation exists between sodium intake and the magnitude of hypertension.1 ' 2 Different mechanisms have been proposed to be responsible for the altered renal response to elevations in sodium intake that occurs in several models of hypertension. 35 One factor that may limit the ability of the kidney to respond normally to prolonged increments in sodium intake is a decrease in endothelium-derived nitric oxide (EDNO) synthesis. synthesis during 3 consecutive days induces a significant and sustained decrease in sodium and water excretion. In another study by our gr...

Metabolic syndrome (MetS) has become one of the main concerns for public health because of its link to cardiovascular disease. Murine models have been used to study the effect of MetS on the cardiovascular system, but they have limitations for studying cardiac electrophysiology. In contrast, the rabbit cardiac electrophysiology is similar to human, but a detailed characterization of the different components of MetS in this animal is still needed. Our objective was to develop and characterize a diet-induced experimental model of MetS that allows the study of cardiovascular remodeling and arrhythmogenesis. Male NZW rabbits were assigned to control (n = 15) or MetS group (n = 16), fed during 28 weeks with high-fat, high-sucrose diet. We measured weight, morphological characteristics, blood pressure, glycaemia, standard plasma biochemistry and the metabolomic profile at weeks 14 and 28. Liver histological changes were evaluated using hematoxylin-eosin staining. A mixed model ANOVA or unpaired t-test were used for statistical analysis (P<0.05). Weight, abdominal contour, body mass index, systolic, diastolic and mean arterial pressure increased in the MetS group at weeks 14 and 28. Glucose, triglycerides, LDL, GOT-AST, GOT/GPT, bilirubin and bile acid increased, whereas HDL decreased in the MetS group at weeks 14 and 28. We found a 40% increase in hepatocyte area and lipid vacuoles infiltration in the liver from MetS rabbits. Metabolomic analysis revealed differences in metabolites related to fatty acids, energetic metabolism and microbiota, compounds linked with cardiovascular disease. Administration of high-fat and high-sucrose diet during 28 weeks induced obesity, glucose intolerance, hypertension, non-alcoholic hepatic steatosis and metabolic alterations, thus reproducing the main clinical manifestations of the metabolic syndrome in humans. This experimental model should provide a valuable tool for studies into the mechanisms of cardiovascular problems related to MetS, with special relevance in the study of cardiovascular remodeling, arrhythmias and SCD.

Stretch induces modifications in myocardial electrical and mechanical activity. Besides the effects of substances that block the stretch-activated channels, other substances could modulate the effects of stretch through different mechanisms that affect Ca 2ϩ handling by myocytes. Thirty-six Langendorff-perfused rabbit hearts were used to analyze the effects of the Na ϩ /Ca 2ϩ exchanger blocker KB-R7943, propranolol, and the adenosine A 2 receptor antagonist SCH-58261 on the acceleration of ventricular fibrillation (VF) produced by acute myocardial stretching. VF recordings were obtained with two epicardial multiple electrodes before, during, and after local stretching in four experimental series: control (n ϭ 9), KB-R7943 (1 M, n ϭ 9), propranolol (1 M, n ϭ 9), and SCH-58261 (1 M, n ϭ 9). Both the Na ϩ /Ca 2ϩ exchanger blocker KB-R7943 and propranolol induced a significant reduction (P Ͻ 0.001 and P Ͻ 0.05, respectively) in the dominant frequency increments produced by stretching with respect to the control and SCH-58261 series (control ϭ 49.9%, SCH-58261 ϭ 52.1%, KB-R7943 ϭ 9.5%, and propranolol ϭ 12.5%). The median of the activation intervals, the functional refractory period, and the wavelength of the activation process during VF decreased significantly under stretch in the control and SCH-58261 series, whereas no significant variations were observed in the propranolol and KB-R7943 series, with the exception of a slight but significant decrease in the median of the fibrillation intervals in the KB-R7943 series. KB-R7943 and propranolol induced a significant reduction in the activation maps complexity increment produced by stretch with respect to the control and SCH-58261 series. In conclusion, the electrophysiological effects responsible for stretch-induced VF acceleration in the rabbit heart are reduced by the Na ϩ /Ca 2ϩ exchanger blocker KB-R7943 and by propranolol but not by the adenosine A2 receptor antagonist SCH-58261. cardiac electrophysiology; mechanical stretch; Fourier analysis STRETCH induces the modulation of electrical and mechanical activity in myocytes. The modulation of electrical activity, also referred to as mechanoelectrical feedback (14,35), includes the depolarization of the resting potential (2,17,21,27,28,31,70), alterations of the shape and duration of action potentials (3,11,21,27,28,31,47,57,70), changes in refractoriness (4,7,9,11,27,36,47,48), and the induction of afterdepolarizations (16,18,34). These electrophysiological changes have been related to the generation of different types of cardiac arrhythmias (7, 9, 13-15, 24, 26, 35, 40, 47). The mechanical effects of stretch consist of an immediate and slow increase in force (45, 64), involving changes in myofilament Ca 2ϩ sensitivity, in the concentrations of intracellular Ca 2ϩ , and in the magnitude of Ca 2ϩ transients (1,3,29,33,58,69). These changes have been related to several mechanisms, including the actions of 1) endogenous angiotensin II (1, 46); 2) the Na ϩ /H ϩ exchanger (1, 3, 46, 66); 3) the Na ϩ /Ca 2ϩ exchanger (3,...

The objective of the present study was to determine the role of endothelium-derived nitric oxide in mediating the renal response to extracellular volume expansion with isotonic saline (5% body weight). In anesthetized dogs (n=7) and before volume expansion, nitric oxide synthesis was inhibited in the right kidney by continuous intrarenal infusion of JV G -nitro-L-arginine-methyl ester (1 /tg/kg/min). Arterial pressure and renal hemodynamics of both kidneys did not change significantly either during nitric oxide synthesis inhibition or during 5% volume expansion. However, in response to extracellular volume expansion, increases in natriuresis, diuresis, and fractional excretion of lithium (an index of proximal sodium reabsorption) were inhibited in the right kidney by 27%, 28%, and 41%, respectively, when compared with the contralateral kidney. Increases of renal interstitial hydrostatic pressure during 5% volume expansion were not statistically different between both kidneys. In another group of dogs (n=4), the administration of L-arginine (0.5 mg/kg/min) into the right renal artery prevented the renal effects induced by the nitric oxide synthesis inhibitor during volume expansion. The findings in this study suggest that nitric oxide production plays an important role in regulating the renal response to extracellular volume expansion. The proximal tubule seems to be involved in the reduced renal excretory response to volume expansion during nitric oxide synthesis inhibition. (Hypertension 1992;19:780-784) KEY WORDS • natriuresis • diuresis • sodium loading • endothelium-derived relaxing factor • nitric oxide • lithium R ecent studies have provided evidence that the renal response to vasodilators that induce an increase of medullary blood flow seems to be mediated by an increase of endothelium-derived nitric oxide (EDNO).1 -2 It also has been suggested that the endothelial cells of the vasa recta are able to produce nitric oxide 3 and that increases in flow stimulate endothelial cells of rabbit thoracic aorta to release nitric oxide.4 Finally, it has been shown that EDNO plays an important role in the regulation of sodium excretion. 5These studies suggest that EDNO may play an important role in the regulation of renal function when medullary blood flow increases. One such condition is during extracellular volume expansion (ECVE). However, the role of EDNO in the regulation of the renal excretory response to saline loading has not been assessed.The hypothesis of the present study is that endogenous EDNO may serve as a mediator in the renal response to volume expansion, because an increase in medullary blood flow seems to play an important role in determining the renal response to ECVE. 6 -8 To test this hypothesis, we inhibited nitric oxide synthesis in the right kidney by the intrarenal infusion of N G -nitro-Larginine-methyl ester (L-NAME) at a dose that does not produce changes in renal function. The natriuretic and diuretic responses of both kidneys to 5% saline loading were compared using the contralateral...