Biomedical subjects

M J Fregly

Publications and source records attributed to M J Fregly.

At least 19 recordsLinked to original sources

PubMed1995

Bradykinin-induced water intake and brain fos-like immunoreactivity in rats.

We have previously shown that peripheral injection of bradykinin in combination with the kininase II inhibitor, captopril, to rats produces a robust water intake. We now extend this observation to another kininase II inhibitor, enalapril. Water intake increases with dose of dose of bradykinin, but has an inverted U-shaped relationship with dose of kininase II inhibitor. The induced water intake is completely blocked by peripheral administration of the bradykinin antagonist, Hoe 140, and is partly attenuated by peripheral injection of an angiotensin (Ang) II receptor antagonist, losartan. Relative to captopril alone, the combination of captopril and bradykinin greatly elevated plasma renin activity, but did not reduce blood pressure. We further show that, while either bradykinin or enalapril alone induce little or no Fos-like immunoreactivity in areas of the brain related to fluid balance, their combination induces staining in many cells in the supraoptic and paraventricular magnocellular nuclei, as well as along the lamina terminalis. These data suggest that bradykinin may have a role in regulation of fluid balance, partly mediated through Ang II.

Angiotensin I↗

PubMed1995

Effect of administration of angiotensin II and isoproterenol, alone and in combination, on drinking and tail skin temperature of the rat.

Both angiotensin II (AII) and the beta-adrenergic agonist isoproterenol are well known to induce drinking and increase tail skin temperature (TSK) in rats. Previous studies have shown that these two compounds have an additive, rather than interactive, dipsogenic effect when administered together. The present studies confirmed the additivity of the dipsogenic effect of the two compounds and attempted to extend these results to TSK. The results reveal that at a series of dosage combinations of AII [100 and 125 micrograms/kg, subcutaneously (SC)] and isoproterenol (ISOP) (10, 12.5, and 25 micrograms/kg, SC) administered together, the increase in TSK usually induced by each compound was canceled. This occurred at the lower doses of ISOP in combination with AII. Thus, the differences between dipsogenic and thermoregulatory effects of combined doses of AII and ISOP suggest a difference in central integration. Important differences between the thermoregulatory responses to administration of the two compounds include increases in metabolic rate and colonic temperature when ISOP is administered and decreases in both when AII is administered. It is suggested that the effect of the two compounds to cancel each other with respect to TSK is related to their opposite effects on metabolic rate.

Angiotensin II↗

PubMed1995

Effect of renal denervation on elevation of blood pressure in cold-exposed rats.

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.

Animals↗

PubMed1995

Effect of pyridoxine and tryptophan, alone and combined, on the development of deoxycorticosterone acetate-induced hypertension in rats.

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.

Analysis of Variance↗

PubMed1995

Increased dipsogenic responsiveness to angiotensin II in rats exposed to cold: rate of loss after return to thermoneutral ambient temperature.

Subcutaneous administration of angiotensin II (Ang II) to rats exposed chronically to 5 degrees C induced an increased drinking response compared with that of warm-acclimated controls. The exaggerated drinking response was also observed when graded doses of Ang II were administered into the lateral cerebroventricle (icv) of chronically cold-exposed rats. A maximal drinking response occurred in cold-treated, but not in control, rats when the lowest dose of Ang II (1.6 ng/rat) was administered icv. Thus, it is clear that the dipsogenic responsiveness to either centrally or peripherally administered Ang II is increased by chronic exposure to cold. To assess whether the increased responsiveness was retained after removal from cold, graded doses of Ang II were administered to rats removed from cold to a thermoneutral environment. The results again showed a maximal responsiveness to the lowest dose of Ang II administered (25 micrograms/kg, sc) to cold-treated rats that had either just been removed from cold or removed from cold 2 hr prior to treatment. Cold-exposed rats had an ED50 for Ang II-induced drinking that was about half that of their warm-acclimated controls. To assess how long the cold-induced increase in dipsogenic responsiveness to Ang II lasted after return to a thermoneutral temperature, rats were removed from cold for 24, 48, or 60 hr and then administered graded doses of Ang II (25, 50, or 100 micrograms/kg, sc). The results suggest that between 46 and 52 hr after removal from cold, the cold-induced increase in dipsogenic responsiveness to Ang II returned to the level of the controls. Hence, the physiological changes in the dipsogenic mechanism induced by exposure to cold are not immediately reversible when the rats are returned to a thermoneutral ambient temperature.

Angiotensin II↗

PubMed1992

Marathon running: physiological and chemical changes accompanying late-race functional deterioration.

Twenty-one experienced runners were studied before, during and immediately after a marathon race to ascertain whether either depletion of energy substrate or rise in body temperature, or both, contribute to late-race slowing of running pace. Seven runners drank a glucose/electrolyte (GE) solution ad libitum (Na+ 21 mmol l-1, K+ 2.5 mmol l-1, Cl- 17 mmol l-1, PO4(2-) 6 mmol l-1, glucose 28 mmol l-1) throughout the race; 6 drank water and 8 drank the GE solution diluted 1:1 with water. Although average running speeds for the three groups were not significantly different during the first two-thirds (29 km) of the race, rectal temperature was significantly higher (P < 0.05) and reduction of plasma volume was greater (P < 0.05) in runners who replaced sweat losses with water. During the last one-third of the race, the average running pace of the water-replacement group slowed by 37.2%; the pace slowed by 27.9% in the 8 runners who replaced their sweat loss with GE diluted 1:1 with water (1/2 GE) and 18.2% in runners who replaced fluid loss with full-strength solution (GE). Eleven runners (5 in the water group, 4 in the 1/2 GE group and 2 in the GE group) lapsed into a walk/run/walk pace during the last 6 miles of the race. Ten of these had a rectal temperature of 39 degrees C or greater after 29 km of running, and plasma volume in these runners was reduced by more than 10%.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1992

Effect of chronic administration of dexfenfluramine on blood pressure in salt-sensitive rats.

Chronic administration of dexfenfluramine, at a relatively low daily dose, slowed the development of salt-induced elevation of blood pressure in salt-sensitive (Dahl DS and Rapp SS) rats. This effect could not be accounted for by drug-related anorexia alone. Elevated serotonin activity, possibly in the brain, may underlie this antihypertensive action of dexfenfluramine.

Animals↗

PubMed1992

Comparison of preference thresholds for NaCl solution in rats of the Sprague-Dawley and Long-Evans strains.

Rats of the Sprague-Dawley and Long-Evans strains were compared with respect to their preference threshold and preference maximum concentrations for NaCl solution in a two-bottle choice paradigm. The preference threshold for NaCl in rats of the Sprague-Dawley strain occurred when the concentration of NaCl presented was 0.030 M. The preference maximum concentration was 0.10 M. In the case of rats of the Long-Evans strain, a preference threshold concentration was not clearly manifested although the preference maximum concentration was also 0.10 M. Thus, the previously reported lack of an appetite for isotonic NaCl solution in rats of the Long-Evans strain compared to those of the Sprague-Dawley strain is most likely related to the failure of rats of the former strain to discriminate between water and NaCl solution until the concentration of NaCl exceeds 0.15 M. However, at this concentration, both strains rejected NaCl solution in favor of water. In contrast to the results with NaCl solution, rats of the Long-Evans strain appear to have a greater appetite for 5% glucose solution than do those of the Sprague-Dawley strain. Whether this is related to a reduced preference threshold concentration for glucose remains to be tested.

Animals↗

PubMed1992

Hyperhydrating effect of acute administration of angiotensin II in rats.

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)

Angiotensin II↗

PubMed1992

Comparison of the hyperhydrating effects of angiotensin II and isoproterenol.

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.

Adrenergic beta-Antagonists↗

PubMed1992

Effect of losartan potassium and deoxycorticosterone acetate on tail skin temperature response to acute administration of angiotensin II.

The potent vasoconstrictor peptide, angiotensin II (AII) (200 micrograms/kg, SC), increases tail skin temperature (TST) and tail blood flow when acutely administered either peripherally (SC) or centrally (ICV) to rats. Colonic temperature declines with the increase in TST. These responses are apparently mediated by way of AII subtype receptor AT1 because they are blocked by acute administration of the nonpeptide AT1 receptor antagonist, losartan potassium (DuP 753) (10 mg/kg, SC). The responses were also blocked by the peptide AII receptor antagonist, saralasin, at 100 micrograms/kg SC. Chronic administration of the steroid deoxycorticosterone acetate (DOCA, 250-300 micrograms/day for 45 days) sensitized the response of TST to acute administration of AII. The increase in responsiveness resulting from chronic treatment with DOCA is consistent with the increase in dipsogenic responsiveness to AII under similar conditions. The latter was shown to be correlated with the upregulation of AII receptors in the diencephalon. While the location of the AII receptors mediating the increase in TST is not known with certainty, it is reasonable to suggest that they are also upregulated by chronic treatment with DOCA.

Angiotensin II↗

PubMed1992

The effect of intermittent exposure to cold on the development of hypertension in the rat.

Continuous exposure to a cold (5 degrees C) environment has been shown to induce hypertension in rats. The total time required for the first significant elevation of blood pressure is dependent on a number of factors, including the ambient temperature and the weight of the rat at the time of exposure to cold. The present study was also concerned with the minimal time of daily exposure to cold that would result in a significant elevation of blood pressure. To achieve this, we used four groups of rats. One was exposed to cold for 4 h daily (09:00 to 13:00), a second group was exposed to cold for 8 h daily (09:00 to 17:00), and a third was exposed for 24 h daily. The fourth group remained at 25 degrees C. Systolic blood pressures of the group exposed to continuous cold became elevated significantly above pre-cold exposure level within 2 weeks of cold exposure. Blood pressures of the groups exposed to cold for 4 and 8 h daily became elevated significantly above the level of the warm-adapted control group by day 27 of exposure to cold, but failed to reach the level of the chronically cold-exposed group even after 42 days of exposure to cold. There was a sigmoid-type relationship between the hours per day exposed to cold and systolic blood pressure at the end of the experiment. Thus, graded elevations of systolic blood pressure occur with increasing daily duration of exposure to cold.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Hypertension during chronic exposure to cold: comparison between Sprague-Dawley and Long-Evans strains.

It is now well established that chronic exposure of rats to cold (5-6 degrees C) induces an elevation of systolic, diastolic, and mean blood pressures and cardiac hypertrophy within 3 weeks. Since rats of the Long-Evans (LE) strain are known to be resistant to the induction of deoxycorticosterone salt induced hypertension, their cardiovascular responses to chronic exposure to cold were compared with those of rats of the Sprague-Dawley (SD) strain. The results of these studies revealed clear differences between the LE and SD strains of rats. Thus, rats of the SD strain had a significant elevation in their blood pressure; a significantly increased urinary output of norepinephrine and epinephrine; a significantly greater dipsogenic responsiveness to acute administration of angiotensin II, and significant increases in weights of the heart, kidneys, adrenals, and brown adipose tissue compared with their warm-adapted controls. All of these changes are characteristic of rats acclimated to cold. In contrast, rats of the LE strain appear to be less responsive to cold in that blood pressure failed to rise as sharply and to attain as high a level. Furthermore, urinary outputs of norepinephrine and epinephrine were significantly lower in cold-treated rats of the LE strain compared with cold-treated rats of the SD strain, but dipsogenic responsiveness to angiotensin II was unchanged. Although increases in the weight of the previously mentioned organs were also observed in cold-treated rats of the LE strain compared with their warm-adapted controls, weights of the heart and interscapular brown adipose tissue of both groups were significantly less than those of counterparts of the SD strain.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗

PubMed1992

Angiotensin-related intakes of water and NaCl in Fischer 344 and Sprague-Dawley rats.

Rats of the Fischer 344 (F344) strain drank less water after either peripheral or central acute administration of angiotensin III (ANG III) than rats of the Sprague-Dawley (SD) strain. In contrast, water intakes following acute administration of ANG II were comparable in the two strains. Chronic peripheral administration of ANG II produced a salt appetite in SD but not in F344 rats; ANG III was ineffective in both strains. These data suggest that some aspects of responsiveness to ANG peptides are reduced in F344 rats. In two of three studies, water intake after acute peripheral administration of either ANG I or the beta-adrenergic agonist isoproterenol did not differ between strains; in one study, the response to both dipsogens was lower in F344 rats. Plasma renin activity was elevated to the same level by isoproterenol in both strains of rats. These results suggest that the ability of isoproterenol to release renin, the subsequent generation of ANG I, and the conversion to ANG II are similar in the two strains. However, this similarity did not extend to cardiovascular responses. Rats of the F344 strain showed a smaller decrease in blood pressure following administration of isoproterenol than did those of the SD strain. Whether this is related to differences in either the regulation of beta-adrenoreceptors or postreceptor effects in vascular smooth muscle between strains will require additional investigation.

Analysis of Variance↗

PubMed1992

Repletion of acute sodium deficit in rats drinking either low or high concentrations of sodium chloride solution.

These studies investigate the relationship between expression of sodium appetite and restoration of physiological normalcy after acute sodium depletion in Sprague-Dawley rats. After depletion (treatment with diuretic and 24 h without NaCl), separate groups of rats were allowed to drink either a low (0.03 M) or a high (0.3 M) concentration of NaCl. Intake and urinary output of sodium and selected plasma measures were made at various times up to 48 h. Depleted rats with access to 0.3 M NaCl consumed more Na+ than their deficit in the first hour and were volume expanded as a result of this excessive intake, but they continued to consume NaCl for 6-12 h. Depleted rats given 0.03 M NaCl drank a comparable volume to the 0.3 M group in the first hour and thus only approximately 10% of the solute. The intake of 0.03 M NaCl slowed after 6-12 h, at which time the cumulative intake matched the deficit and the plasma parameters had returned to nondepleted levels. Under these conditions of slow intake, it appears that sodium appetite is more closely matched to need than is the case when highly concentrated sources of sodium are available. Satiation of sodium appetite seems to require the passage of time as well as repletion of body sodium.

Animals↗

PubMed1992

Role of gonadal hormones in hypertension in the Dahl salt-sensitive rat.

The present studies examine the effect of gonadal hormones on the development of hypertension in Dahl salt-sensitive rats fed a high salt diet. In the first study, administration of estradiol benzoate did not prevent hypertension in either adult ovariectomized females or intact males. In a second study, neonatal castration of males slowed the onset of salt-induced hypertension, and females that were treated neonatally with testosterone developed somewhat higher pressures that did untreated females. These data extend to Dahl S rats the findings observed originally in spontaneously hypertensive rats that blood pressure is modulated by gonadal hormones. These results are consistent with the conclusion that gonadal hormones may exert organizational effects on cardiovascular control regions of the brain during early postnatal development in rats.

Animals↗

PubMed1992

Effect of DuP 753, a nonpeptide angiotensin II receptor antagonist, on the drinking responses to acutely administered dipsogenic agents in rats.

The present studies examine the effect of the nonpeptide angiotensin II (AII) type 1 receptor antagonist, DuP 753, on water intake in rats treated with dipsogenic stimuli, which are thought to induce drinking via release of renin and subsequent formation of AII. Subcutaneous administration of DuP 753 in doses that are known to inhibit drinking induced by AII failed to inhibit the water intake of rats following subcutaneous administration of the beta-adrenoceptor agonist isoproterenol. The peptide antagonist1 Sar, 8Ileu-AII, which blocks both AII type 1 and AII type 2 receptors, also failed to inhibit isoproterenol-induced drinking, suggesting that neither subtype is involved in this drinking response. Additional studies verified previous reports that acute subcutaneous administration of both the beta-adrenoceptor antagonist propranolol and the angiotensin I-converting enzyme inhibitor captopril could block the drinking response to subcutaneous administration of isoproterenol. Subcutaneous administration of DuP 753 also failed to inhibit the drinking responses to subcutaneous administration of serotonin, 5-hydroxytryptophan, hypertonic saline, and polyethylene glycol. However, central intraventricular administration of DuP 753 inhibited the drinking response to subcutaneous administration of isoproterenol. The results are discussed in terms of the importance of AII in mediating isoproterenol-, serotonin-, and 5-hydroxytryptophan-induced water intake and suggest a need to readdress this mechanism.

5-Hydroxytryptophan↗

PubMed1992

Effect of a reduction in sodium intake on cold-induced elevation of blood pressure in the rat.

Chronic exposure of rats to cold (5 degrees C) induces hypertension within 3 weeks. The objective of this study was to determine the effect of treatment with graded levels of dietary NaCl on the induction of hypertension during chronic exposure to cold. Four groups of male rats were used. The first, given a commercial sodium-deficient diet containing 0.30% NaCl, served as the warm-adapted control group. The second, third, and fourth groups were given the same diet containing 0.075%, 0.15%, and 0.30% NaCl, respectively. Because cold-exposed rats ingest approximately twice as much food as warm-adapted controls, this represented half, the same, and twice the amount of NaCl ingested by the control group. The latter three groups were placed in cold air (5 degrees C). All cold-treated groups had an elevation of systolic blood pressure that was proportional to the concentration of NaCl in the diet by the seventeenth week of exposure to cold. Cardiac hypertrophy occurred to the same extent in all cold-exposed groups and was thus unaffected by the NaCl content of the diet or by the extent of elevation of blood pressure. Hence, cardiac hypertrophy during chronic exposure to cold is supported by other factors, possibly by the increased concentration of either norepinephrine or triiodothyronine, or both, which occurs characteristically in rats under these conditions. The results of this experiment suggest that the amount of NaCl ingested daily plays a role in the cold-induced elevation of blood pressure observed in rats.

Acclimatization↗