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Myocardial infarction leads to compensatory ventricular remodeling. Disturbances in myocardial contractility depend on the active transport of Ca2+ and Na+, which are regulated by Na+-K+ ATPase. Inappropriate regulation of Na+-K+ ATPase activity leads to excessive loss of K+ and gain of Na+ by the cell. We determined the participation of Na+-K+ ATPase in ventricular performance early and late after myocardial infarction. Wistar rats (8-10 per group) underwent left coronary artery ligation (infarcted, Inf) or sham-operation (Sham). Ventricular performance was measured at 3 and 30 days after surgery using the Langendorff technique. Left ventricular systolic pressure was obtained under different ventricular diastolic pressures and increased extracellular Ca2+ concentrations (Ca2+e) and after low and high ouabain concentrations. The baseline coronary perfusion pressure increased 3 days after myocardial infarction and normalized by 30 days (Sham 3 = 88 ± 6; Inf 3 = 130 ± 9; Inf 30 = 92 ± 7 mmHg; P < 0.05). The inotropic response to Ca2+e and ouabain was reduced at 3 and 30 days after myocardial infarction (Ca2+ = 1.25 mM; Sham 3 = 70 ± 3; Inf 3 = 45 ± 2; Inf 30 = 29 ± 3 mmHg; P < 0.05), while the Frank-Starling mechanism was preserved. At 3 and 30 days after myocardial infarction, ventricular Na+-K+ ATPase activity and contractility were reduced. This Na+-K+ ATPase hypoactivity may modify the Na+, K+ and Ca2+ transport across the sarcolemma resulting in ventricular dysfunction.

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Myocardial infarction leads to compensatory ventricular remodeling. Disturbances in myocardial contractility depend on the active transport of Ca2+ and Na+, which are regulated by Na+-K+ ATPase. Inappropriate regulation of Na+-K+ ATPase activity leads to excessive loss of K+ and gain of Na+ by the cell. We determined the participation of Na+-K+ ATPase in ventricular performance early and late after myocardial infarction. Wistar rats (8-10 per group) underwent left coronary artery ligation (infarcted, Inf) or sham-operation (Sham). Ventricular performance was measured at 3 and 30 days after surgery using the Langendorff technique. Left ventricular systolic pressure was obtained under different ventricular diastolic pressures and increased extracellular Ca2+ concentrations (Ca2+e) and after low and high ouabain concentrations. The baseline coronary perfusion pressure increased 3 days after myocardial infarction and normalized by 30 days (Sham 3 = 88 +/- 6; Inf 3 = 130 +/- 9; Inf 30 = 92 +/- 7 mmHg; P < 0.05). The inotropic response to Ca2+e and ouabain was reduced at 3 and 30 days after myocardial infarction (Ca2+ = 1.25 mM; Sham 3 = 70 +/- 3; Inf 3 = 45 +/- 2; Inf 30 = 29 +/- 3 mmHg; P < 0.05), while the Frank-Starling mechanism was preserved. At 3 and 30 days after myocardial infarction, ventricular Na+-K+ ATPase activity and contractility were reduced. This Na+-K+ ATPase hypoactivity may modify the Na+, K+ and Ca2+ transport across the sarcolemma resulting in ventricular dysfunction.

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Pyruvate is an energy substrate that has both inotropic and antioxidant properties. In this study, we tested the hypothesis that survivorship would be better after resuscitation with 1.7% sodium pyruvate than 0.9% sodium chloride in a profound hemorrhagic shock model. The study was performed in a blinded manner. Rats were randomly assigned into two groups (ten in each group), a sodium chloride resuscitation group and a sodium pyruvate resuscitation group. After a 60-min shock period, we infused 80 ml/kg of a resuscitation solution. We continuously monitored mean arterial pressure and heart rate for 50 min after resuscitation. We recognized death by the disappearance of blood pressure pulsation and precordial movement. We performed a comparison of survivorship at 50 min post resuscitation using a Z-test of proportions. Nine (90%) of the animals that received sodium pyruvate were living 50 min after resuscitation, whereas only three (30%) of the animals that received sodium chloride survived to the same time point. We conclude that sodium pyruvate is better than sodium chloride as a resuscitation solution in a model of profound hemorrhagic shock.

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The purpose of this study was to determine whether beta-adrenergic receptors are involved in the elevation of blood pressure, tachycardia, and cardiac hypertrophy in rats chronically exposed to cold (5 degrees C). Four groups of rats were used. Two groups of rats were exposed to 5 degrees C and the other 2 groups were kept at 25 degrees C. In each temperature condition, one group received regular food while the other received food to which a nonspecific beta-adrenoceptor antagonist, d,l-propranolol, was added. The blood pressure of the untreated, cold-exposed group increased significantly within 3 weeks of exposure to cold and remained elevated until the end of the experiment. Chronic treatment with d,l-propranolol decreased the rate of cold-induced elevation of blood pressure at doses of 1.0 and 1.2 g/kg of food, and produced a complete reversal of hypertension at a higher dose ( 1.5 g/kg of food). Propranolol also prevented tachycardia in cold-exposed rats. The fact that propranolol decreased the elevation of blood pressure and prevented tachycardia suggests that both beta1- and beta2-adrenoceptors are blocked in cold-exposed rats. Propranolol, however, did not affect cold-induced cardiac hypertrophy.

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Hypertension, tachycardia and cardiac hypertrophy develop in rats exposed to mild cold (5 degrees C, 41 degrees F) for 1 to 3 weeks. Elevation of blood pressure (BP) during cold exposure is sodium dependent, although the rats still have an elevation of BP with a minimum of NaCl in their diet. Drugs that interfere with the renin-angiotensin-aldosterone (RAA) system at various levels (propranolol, clonidine, captopril, losartan and spironolactone) are able to prevent the development of cold-induced hypertension (CIH). Plasma renin activity (PRA) increases during the first 3 weeks of exposure to cold and then gradually decreases toward control level. Increased blood pressure and dipsogenic sensitivity to administration of angiotensin II (Ang II) have been demonstrated during the first 3 weeks of exposure to cold suggesting an upregulation of Ang II receptors when PRA is elevated. Additional studies have shown greater Fos-like immunoreactivity in the diencephalon of cold-exposed compared to warm-acclimated rats after 1 hr i.v. infusion of Ang II (333 ng/kg/min). Thus, most characteristics of cold-induced hypertension mimic those of hypertension induced experimentally by chronic administration of large doses of deoxycorticosterone acetate (DOCA) and salt. The results suggest that CIH is a mineralocorticoid-induced hypertension and that various levels of the RAA system contribute.

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In most forms of experimentally induced hypertension in rats, females develop a less severe form of the disease than males. The objective of the present study was to compare the two genders with respect to the development of cold-induced hypertension. The results of the study indicate that both males and females develop comparable elevations of blood pressure and at approximately the same rate. Thus, the blood pressures of both groups increased significantly within 2 weeks of exposure to cold and reached similar maximal levels by the seventh week. The dipsogenic responsiveness of both groups of cold-exposed rats to acute administration of the peptide hormone, angiotensin II (AngII), was increased to approximately the same extent above that of warm-adapted counterparts, suggesting an increase in the responsiveness to AngII in the brain. To assess this possibility, the induction of the oncogene, cFos, was studied in brain following IV infusion of AngII (333 ng/kg/min). Fos-like immunoreactivity (FLI) was greater (p < 0.01) in subfornical organ, supraoptic and paraventricular hypothalamic nuclei of both cold-exposed groups compared to warm-adapted controls. Thus, both male and female rats have similar elevations of blood pressure as well as increased dipsogenic and FLI responsiveness to administration of AngII during chronic exposure to cold.

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Administration of L-5-hydroxytryptophan (25 micrograms/kg, s.c.), the immediate precursor of serotonin, to rats induces drinking and increases tail skin temperature. Decreases in both the metabolic rate (rate of oxygen consumption) and colonic temperature also occur. These responses are similar to those observed following acute administration of angiotensin II. However, both drinking and the increase in tail skin temperature are unaffected by prior administration of the non-peptide angiotensin II, AT-1 receptor antagonist, losartan potassium, but are partially attenuated by the beta-adrenoceptor antagonist, propranolol. This suggests that the responses are independent of the angiotensin AT-1 receptor but may be mediated, in part at least, by the beta-adrenoceptor. The hypothesis is presented that when either L-5-hydroxytryptophan or angiotensin II is administered to rats, they act centrally to reduce the set-point for body temperature regulation, thus resulting in the reflex activation of mechanisms that reduce body temperature, including an increase in tail skin temperature and a decrease in metabolic rate.

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Chronic dietary administration of pyridoxine HCl (300 mg/kg/day), L-tryptophan (1.26 g/kg/day), or a combination of the two can attenuate the elevation of systolic blood pressure in DOCA-salt-treated rats. With these treatments, the characteristic increase in the weight of the heart accompanying chronic administration of DOCA (786 micrograms/kg/day) was also attenuated. Thus, both tryptophan and pyridoxine possess antihypertensive properties, and the combination of the two appeared to provide greater protection than either alone. The results are consistent with the possibility that pyridoxine, an important cofactor in the metabolic pathways for tryptophan, may facilitate the conversion of tryptophan to antihypertensive compounds. Additional studies will be required to determine which of the metabolites of tryptophan possess antihypertensive properties. Pyridoxal phosphate, one of the metabolites of pyridoxine, was also administered chronically in the diet (1.0 and 2.0% by weight) to rats whose blood pressures were elevated by administration of DOCA. The results of this study suggest that pyridoxal phosphate can also lower the blood pressure of rats with established hypertension. Thus, these studies reveal that pyridoxine, pyridoxal phosphate and tryptophan are potential antihypertensive agents.

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The objective of this experiment was to determine whether bilateral renal denervation (RD) prevents the elevation of blood pressure and cardiac hypertrophy characteristically induced by chronic exposure to cold. Four groups (nine male rats each) were used. The kidneys of two groups were bilaterally denervated, while the remaining two groups were sham operated. Systolic blood pressures of the four groups, measured indirectly from the tail, did not differ significantly during the control period and following RD. At this time, 1 RD and 1 sham-operated group was exposed to cold (5 degrees C, 41 degrees F). The remaining RD and sham-operated groups were kept at 25 degrees C. Blood pressure of the cold-exposed, sham-operated group increased significantly during the 1st week of cold exposure (125 +/- 2 mmHg; 1 mmHg = 133.3 Pa), and rose to 139 +/- 4 mmHg by the 5th week, whereas the blood pressure of the RD group exposed to cold remained at the control level (116 +/- 2 mmHg). Both RD and sham-operated cold-exposed groups developed cardiac hypertrophy with significantly increased resting heart rates compared with controls kept at 25 degrees C. Plasma renin activities and renal norepinephrine content of kidneys of both RD groups at 7 weeks after RD were significantly less than those of sham-operated controls, confirming that renal nerves had been severed. Thus, RD prevented the elevation of blood pressure induced by chronic exposure to cold but had no significant effect on cardiac hypertrophy.

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Chronic exposure to cold (5 degrees C) is well known to increase both tyrosine hydroxylase (TH) activity in brown adipose tissue and systemic blood pressure. The effect of chronic dietary administration of the alpha-adrenergic antagonist, prazosin, and the amino acid, L-arginine, on both the elevation of blood pressure during exposure to cold and on TH activity and expression of TH mRNA in the adrenal glands of rats was studied. As observed previously, chronic exposure to cold increased systolic blood pressure significantly and induced cardiac hypertrophy. Chronic dietary treatment with prazosin (8 mg/kg food) and arginine (20 g/kg food) returned blood pressure to control levels, did not affect body weight significantly, but failed to prevent cardiac hypertrophy. Both prazosin and L-arginine reduced the drinking response to administration of angiotensin II. Treatment with arginine and prazosin was accompanied by a significant increase in the urinary outputs of dopamine and L-DOPA. The 3 cold-treated groups (control, L-arginine and prazosin) had increases in plasma T3 and decreases in plasma T4 and plasma renin activity. Plasma concentrations of epinephrine and norepinephrine were increased significantly in the L-arginine-treated group. TH mRNA and TH activity in the adrenal glands were increased in the 3 cold-treated groups and these measures were correlated directly and significantly with plasma norepinephrine and epinephrine concentrations. Although both prazosin and arginine prevented the cold-induced elevation of blood pressure, they did not prevent the increase in TH mRNA, TH activity or epinephrine in plasma. The protective effect of arginine and prazosin in cold-induced hypertension may be related both to their reduction in plasma renin activity and to a reduced responsiveness to angiotensin II, as well as to their abilities to increase the secretion of dopamine.

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The systolic blood pressures of two groups of rats that were exposed to cold (5 degrees C) for 4 weeks were elevated significantly above that of warm-acclimated controls maintained at 24 degrees C. At this time these groups were given the antithyroid drug aminotriazole in their food at 0.3 g/kg. At the same time, one group was given 15.8 micrograms thyroxine (T4)/kg body mass per day, while the second received 31.6. The doses were chosen as replacement (15.8 micrograms/kg) and twice replacement (31.8 micrograms/kg) for the rats. The results of the study revealed that both groups receiving aminotriazole and T4 had reductions in blood pressure within 1 week of initiation of treatment. Blood pressures reached control level after 5 weeks. Cardiac hypertrophy accompanying cold-induced hypertension was reduced with the lower dose of T4 and prevented with the higher dose. Serum concentrations of T4 and triiodothyronine (T3) in the two treated groups were reduced, while serum thyroid-stimulating hormone concentration and thyroid mass were increased above that of the warm-acclimated control group. This suggests that the rats were hypothyroid relative to the warm-acclimated control group. However, the treated rats grew at the same rate as nontreated, cold-exposed controls and had similar food and water intakes, a similar dipsogenic response to acute administration of isoproterenol, and similar colonic temperatures.(ABSTRACT TRUNCATED AT 250 WORDS)

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IP loads of NaCl solution (1% of body weight) varying in concentration from 0.15-1.0 M were used to assess their ability to induce hyperhydration in rats that were allowed access to water for 6 h after loading. The hypertonic concentrations (0.25, 0.50, and 1.0 M) increased water intake in a concentration-related fashion. Only loads of 0.50 and 1.0 M NaCl solution increased urine output above that of water-loaded controls. All hypertonic concentrations increased fluid exchange (i.e., water intake less urine output) significantly. There was a direct concentration-related increase in accumulative mean fluid exchange (delta FE, fluid exchange of NaCl-loaded group less that of control group). There was also a direct concentration-related increase in the time of hyperhydration. When related to each other, delta FE was a direct linear function of time of hyperhydration. The slope and intercept of this relationship were compared with those found in an earlier study for angiotensin II (AngII) and isoproterenol (ISO), both potent dipsogens. Comparison revealed that slopes, but not intercepts, of the relationship between delta FE and time of hyperhydration for any two of the three treatments differed significantly. These data suggest that a given time of hyperhydration can be achieved at a lower delta FE with NaCl loads than with administration of either AngII or ISO. This suggests, in turn, that loading with NaCl solutions produces a more effective hyperhydration than is achieved with administration of either AngII or ISO.

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Elevation of diastolic, systolic, and mean blood pressures and cardiac hypertrophy occur in rats exposed to cold (5 degrees C) for 1-3 weeks. The renin-angiotensin-aldosterone system is believed to play a role in the development of cold-induced hypertension since plasma renin activity increases within the first 2 weeks, presumably initiating the hypertensive process, and then returns to control level. The present study was designed to assess the role of angiotension II (Ang II) in the hypertensive process by chronic administration of losartan potassium, an Ang II1 receptor antagonist. Twenty-four rats were divided into four equal groups. After a 1-week control period, one group was kept at 25 degrees C while the remaining three groups were exposed to cold (5 degrees C). One of the cold-treated groups was untreated while the remaining two were given losartan in drinking water at a concentration calculated to provide 56 and 112 mg/kg/day. The untreated cold-exposed group had a significant elevation of systolic blood pressure within 1 week of exposure to cold. Losartan at both doses prevented the elevation of blood pressure and blocked both the dipsogenic and vascular responses to administration of Ang II. Exposure to cold increased food intake, urine output and water intake significantly above that of warm-adapted controls. Treatment with losartan tended to decrease each of these toward the level of controls. At the conclusion of the seventh week of exposure to cold, the rats were sacrificed and heart, kidneys, and brown fat removed and weighed.(ABSTRACT TRUNCATED AT 250 WORDS)

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Administration of a single dose of angiotensin II (AII) has been shown to induce a state of hyperhydration in rats that can last from 6-10 h depending upon the route of administration and the dose. The objective of the present study was to determine whether another dipsogenic agent, isoproterenol (ISO), a beta-adrenoceptor agonist, could also induce a state of hyperhydration. The results indicate that a single SC dose of ISO can induce a hyperhydration that lasts from 4-6 h depending upon the dose administered. Administration of graded doses of either AII or ISO induced graded increases both in the time of hyperhydration and change in accumulative mean fluid exchange, (delta FE, fluid exchange of treated less fluid exchange of control). These two parameters were related linearly and directly for each drug, although the slopes, but not the intercepts, of the relationship for each drug differed significantly. Because the objective of optimal hyperhydration should be to achieve the longest duration of positive fluid balance with the least amount of ingested fluid (i.e., delta FE), the slopes of the two lines provide a convenient way to compare the hyperhydration induced by AII and ISO. By this criterion, it would appear that AII provides a more optimal hyperhydration than ISO.

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Water intake, urine output, and fluid exchange (water intake less urine output) were measured in rats at hourly intervals for 7 hours and at 24 hours following acute administration of angiotensin II (AII, 200 micrograms/kg SC). AII induced the expected abrupt increase in water intake and a more gradual increase in urine output. The change in fluid exchange (fluid exchange of the AII-treated group less fluid exchange of controls) became positive within the first hour after treatment with AII, decreased linearly with time, and reached 0 at approximately 10 to 12 hours after treatment with AII. When AII was administered intracerebroventricularly (50 ng), similar results were observed. In this case, the change in fluid exchange (delta F) reached 0 in about 6 hours. Imposition of a water load (1% of body weight, IP) on the group receiving AII SC failed to affect the time required for delta F to reach 0 if the water load was disregarded. However, inclusion of the load as a part of intake extended the time the rats remained in positive fluid balance beyond that of the nonloaded, AII-treated control group. In the case of the larger water load (3% of body weight, IP), delta F returned to that of controls in about 4 to 5 hours if the water load was disregarded. However, inclusion of the load as part of intake extended the period of hyperhydration well beyond that of both the nonloaded, AII-treated group and the AII-treated group given the 1% load.(ABSTRACT TRUNCATED AT 250 WORDS)

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Chronic treatment with L-tryptophan (4 g/day) reduced mean blood pressure in 8 of 9 patients with mild to moderate essential hypertension. No significant side effects of treatment were observed. An additional group of 8 patients was treated chronically with L-5-hydroxytryptophan (800 mg/day), the immediate precursor of serotonin. Five of the 8 patients had a significant reduction in mean arterial pressure. No significant side effects of treatment were observed. The reduction of blood pressure accompanying treatment with L-5-hydroxytryptophan suggests that at least a portion of the antihypertensive effect of L-tryptophan is mediated via serotonin.

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This study was designed to assess the effect of chronic dietary administration (2.5 and 5.0% by weight) of the neutral amino acid, L-tryptophan, on the development of hypertension during chronic exposure to cold. In addition, a warm-adapted and cold-treated control group receiving unsupplemented food were used. Chronic administration of the lower dose of L-tryptophan (850 mg/day) prevented the elevation of blood pressure attenuated cardiac hypertrophy, and had no effect on body weight during exposure to cold. The higher dose of L-tryptophan (1,690 mg/day) attenuated the rate of blood pressure increase, did not affect cardiac hypertrophy, attenuated the gain in body weight, and increased the urinary output of epinephrine. Thus, this dose may be associated with some toxicity. Both doses of tryptophan failed to prevent certain other responses characteristically occurring during exposure to cold: i.e. increased weight of the kidneys, adrenal glands and brown adipose tissue; increased food and water consumption; increased dipsogenic responsiveness to angiotensin II, and increased plasma aldosterone concentration. The results indicate that chronic dietary administration of L-tryptophan (850 mg/day) can prevent the development of cold-induced hypertension, as it can in all other models of hypertension tested thus far in rats.

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To ascertain if muscle damage occurred in swimmers as a result of high-intensity training and to find if fluid and dietary manipulation could affect muscle damage, we studied 40 members of the University of Florida swimming team using creatine kinase (CK) and lactic dehydrogenase (LDH) as markers of muscle damage during a 6-month period of intensive training. During this time, training intensity, fluid intake during exercise and dietary supplementation were all modified one by one to examine their individual effects. During a control period of 4 weeks, all swimmers drank water before and during (120 min) workouts. CK in men at the end of this period averaged 315, SD 122 (normal less than 170 IU.l-1). Half of the swimmers were then given 500 ml of a glucose-electrolyte solution (GES) (Na 21 mmol.l-1, Cl 13 mmol.l-1, K 2.5 mmol.l-1, PO4 5 mmol.l-1 and glucose 6%) before workouts and twice at intervals during the workout, while half continued to drink the same volume of water. One week after division into fluid groups, the workout intensity was increased by about 10%. Another week later CK had increased to 500, SD 180 IU.l-1 in swimmers drinking water, but fell to 280, SD 105 IU.l-1 in those drinking GES (P less than 0.05). The second phase of the study began after a 4-week control period during which all athletes drank water before and during workouts. The swimmers were divided into four matched groups.(ABSTRACT TRUNCATED AT 250 WORDS)

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Chronic dietary administration of L-tryptophan at 2.5 and 5.0% by weight reduced the elevated systolic blood pressure of spontaneously hypertensive (SH) rats. Blood pressure was reduced significantly by 3 weeks after initiation of treatment and continued to fall during the course of the 15 weeks of treatment. Body weights of the treated rats were not affected significantly by treatment, nor were daily food and fluid intakes and urine outputs. SH rats, treated with the higher dose of tryptophan, also significantly reduced their urinary outputs of epinephrine and norepinephrine compared with SH controls, while both doses of tryptophan increased urinary outputs of dopamine significantly above that of SH controls. Treatment with tryptophan increased significantly the specific binding of [125I]angiotensin II (Ang II) to membranes from the diencephalon in a dose-dependent manner. Measurement of catecholamine concentration of the supernatant from homogenates used for the Ang II binding assay revealed a significant correlation between the specific binding of Ang II to brain membranes of the two tryptophan-treated groups and the concentration of norepinephrine in the supernatant. There was also a significant correlation between the specific binding of Ang II and the concentration of dopamine in the supernatant of the control group and the group treated with the higher dose of tryptophan. These results show that chronic dietary administration of tryptophan can reduce the elevated blood pressure of SH rats and support the possibility that this neutral amino acid may act via its effect on the concentration of the neurohormones, norepinephrine and dopamine, in the diencephalon to regulate the binding of Ang II to its receptors.

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Chronic dietary administration of either l-tryptophan (5.0%) or nicotinic acid (5.0%) reduced the elevated blood pressure of rats with established, deoxycorticosterone-acetate (DOCA)-salt-induced hypertension without affecting either body weight or cardiac hypertrophy. In a second study, chronic dietary administration of nicotinic acid (2.5 and 5.0%) provided significant protection against the development of an elevated blood pressure in rats treated with DOCA salt. A modest (approximately 10%) reduction in cardiac hypertrophy was also observed in the two nicotinic-acid-treated groups. Treatment with either dose of nicotinic acid did not, however, prevent either the renal hypertrophy characteristic of DOCA-salt-induced hypertension in rats or their reduced renal concentrating ability during a 24-hour dehydration; nor did treatment with nicotinic acid reduce the excessive ingestion of saline characteristic of chronic treatment with DOCA. In contrast, treatment with the higher dose of nicotinic acid prevented the excessive loss of sodium into urine characteristic of DOCA-salt-induced hypertension when the rats were loaded (3% of body weight, i.p.) with a hypotonic (0.075 M) saline solution. These results suggest that increased production of nicotinic acid resulting from dietary administration of tryptophan may play a role in the protective effect of tryptophan against the development of DOCA-salt-induced hypertension. These studies do not, however, provide a mechanism by which nicotinic acid may manifest its beneficial effects.

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