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N E Rowland

Publications and source records attributed to N E Rowland.

At least 91 records · Page 5Linked to original sources

Angiotensin-converting enzyme inhibition and Na appetite: microbehavioral analysis and nycthemeral physiology.

The present experiments describe a marked nycthemeral rhythm in both the appetite for 0.3 M NaCl solution and components of the renin-angiotensin-aldosterone axis stimulated in Sprague-Dawley rats by chronic administration of enalapril, an angiotensin I-converting enzyme inhibitor. Continuous recording of water, NaCl, and food intakes shows that the sodium appetite is manifest as discrete bouts of salt ingestion in temporal proximity to meals and is partially independent of water bouts. In particular, salt bouts occur without water bouts in the late afternoon of a 12:12-h light-dark cycle and continue periprandially with water bouts during the night. Intake of all three commodities is minimal in the morning. In a second experiment, it was determined that plasma renin activity (PRA) was maximally elevated by chronic enalapril in the daytime and that plasma aldosterone was reduced by enalapril but continued to show nycthemeral rhythm peaking in the afternoon. The concurrent maxima in PRA and aldosterone in the afternoon in enalapril-treated rats thus coincides with NaCl intake in the absence of water intake.

Aldosterone↗

Role of angiotensin II receptors in tail skin temperature response to isoproterenol.

The objective of these experiments was to assess the possibility that the increase in tail skin temperature (TSK) accompanying administration of the beta-adrenergic agonist isoproterenol (ISO) was mediated by angiotensin II (AngII) as a result of stimulation of renin release by ISO. Although AngII is known to be a potent vasoconstrictor in mammals, acute administration of this peptide to rats induces a vasodilation of blood vessels in the tail and an increase in TSK. The objective was approached in several (DuP 753); ways: (i) use of the nonpeptide AngII receptor antagonist losartan potassium (DuP 753); (ii) use of the peptide AngII receptor antagonist saralasin; (iii) use of the AngI-converting enzyme inhibitor captopril, and (iv) chronic administration of AngII. The rationale for these experiments was that blockade of AngII receptors (Experiments 1 and 2), inhibition of the enzyme that converts AngI to AngII (Experiment 3), or down-regulation of the AngII receptors (Experiment 4) would be expected to prevent any contribution to the ISO-induced increase in TSK by AngII. The results of these experiments are consistent in revealing that the response of TSK to ISO administration is due in part (approximately 55%) to a direct effect of ISO and in part (approximately 45%) to an indirect effect resulting from the ISO-stimulated release of renin from the kidneys and the formation of AngII in the blood.

Angiotensin II↗

Effects of glucose and fat antimetabolites on norepinephrine turnover in rat hypothalamus and brainstem.

Rats were injected acutely with antimetabolites of either glucose (2 deoxy-D-glucose, 2DG), fat (methylpalmoxirate, MP or mercaptoacetate, MAC), or the combination of these agents, in dosages known to stimulate food intake. Norepinephrine (NE) turnover in hypothalamus and brainstem was determined after these treatments by the method of synthesis inhibition. Glucoprivation (2DG) increased NE turnover in hypothalamus, confirming previous studies. Fat antimetabolites alone had no effect on NE turnover, nor did a peripherally-acting fructose antimetabolite. Combination of MP and 2DG, but not MAC and 2DG, produced a greater NE turnover than 2DG alone. These data suggest that peripheral signals of metabolic emergency do not activate brain NE systems, except when these systems are already activated by an ongoing cerebral metabolic emergency. The role of hypothalamic NE in metabolic integration of feeding is discussed, and possible hemispheric differences.

Animals↗

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↗

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↗

Administration of dexfenfluramine in pregnant rats: effect on brain serotonin parameters in offspring.

Dexfenfluramine (DFEN) was infused SC at doses of either 6 or 12 mg/kg/day during the last week of pregnancy in rats. Compared with untreated controls, weight gain of dams was attenuated by DFEN without effect on the number or birth weight of offspring. Brain serotonin (5-HT) concentration and/or paroxetine binding to the 5-HT uptake carrier was reduced by 20% on the day after birth in one study but not in two other studies. No decreases in brain 5-HT parameters were observed on or after the sixth postnatal day. In contrast, mothers sustained large depletions of brain 5-HT when measured at least 3 weeks after giving birth. These data indicate that fetal brains either are protected from or recover rapidly from the 5-HT-depleting actions of high-dosage regimens of DFEN in rats.

Animals↗

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↗

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↗

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↗

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↗

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↗

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↗

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↗

Ontogeny of preference and aversion to salt in Fischer 344 rats and Syrian hamsters.

Fischer 344 (F344) rats and Syrian hamsters, unlike rats of the Sprague-Dawley or Wistar strains, exhibit an aversion to dilute NaCl solutions as adults. In the present studies, using the anterior intraoral infusion method, it is shown that both F344 rats and hamsters accept more dilute NaCl than either water or concentrated NaCl (i.e., show a "single bottle" preference/aversion function identical to Sprague-Dawley rats) at both 6 and 18 days of age. At 18 days of age, they also show a preference for dilute NaCl over water in a simultaneous choice paradigm. In contrast, only 1-3 days later when these animals are weaned, they strongly reject NaCl solutions from sipper tubes in favor of water. It is unlikely that an abrupt discontinuity in neurosensory development can fully explain this dramatic reversal in salt acceptance.

Aging↗

Effects of exercise and anion on intake of sodium solutions in Syrian hamsters.

Previous studies have shown that hamsters have low spontaneous intakes of NaCl solutions and are refractory to induction of salt appetite. In order to examine the generality of these results, the intakes of NaCl and NaHCO3 solutions are reported for hamsters housed either in normal laboratory conditions (sedentary) or with free access to exercise wheels. Spontaneous salt intakes, as well as those induced by acute sodium depletion and treatment with either the angiotensin converting enzyme inhibitor, enalapril, or deoxycorticosterone acetate (DOCA), were measured. The intakes of NaCl and NaHCO3 were similar. Salt intakes tended to be lower in exercising than in sedentary groups. Neither acute sodium depletion nor administration of enalapril increased salt intake systematically, but treatment with DOCA increased intakes of both salt and water. These results are contrasted with the efficacy of all three treatments to induce salt appetite in rats.

Aldosterone↗

Bradykinin-induced dipsogenesis in captopril-treated rats.

The dipsogenic responsiveness to acute administration of the peptide, bradykinin, was studied in 4 groups of male Sprague-Dawley rats. All groups received captopril (35 mg/kg, IP) 15 minutes prior to the study. The first group then received saline (1 ml/kg, IP) while the remaining three groups received bradykinin at 50, 100 and 200 micrograms/kg, SC, respectively. The rats were placed alone into metabolic cages without food and given a preweighed bottle of tap water. Water intakes and urine outputs were then measured at 0.5, 1.0 and 2.0 hours thereafter. Bradykinin induced a dose-related increase in water intake but had no significant effect on urine output. To assess whether bradykinin might induce drinking by way of angiotensin II (AII) receptors, the AII receptor antagonist. Sar1, Ile8-AII (Sar, 300 and 600 micrograms/kg, SC) was administered to both bradykinin- (200 micrograms/kg, SC) and bradykinin plus captopril-treated (35 mg/kg, IP) groups of rats in a two-way ANOVA statistical design. Bradykinin again stimulated drinking in captopril-treated rats, but the drinking was not blocked significantly by administration of Sar. The results of this study indicate that blockade of the angiotensin I converting enzyme increases the half-life of bradykinin and unmasks its dipsogenic properties. The results suggest further that bradykinin does not appear to induce drinking via interaction with receptors for AII.

1-Sarcosine-8-Isoleucine Angiotensin II↗

Effect of a nonpeptide angiotensin II receptor antagonist, DuP 753, on angiotensin-related water intake in rats.

The effect of peripheral administration of the nonpeptide angiotensin II-1 (AII) receptor blocker, DuP 753, on the dipsogenic responses to peripherally administered angiotensins I, II, and III was tested. In all cases, DuP 753 significantly inhibited the drinking response, whether administered 15 or 45 minutes prior to administration of the dipsogen. These results suggest that the drinking responses to angiotensins I, II, and III are mediated by AII-1 receptors. They also suggest that either AIII acts via the AII-1 receptor or that DuP 753 competes at an AIII-sensitive receptor. These studies also showed that when both AII and DuP 753 were given cerebroventricularly (ICV), potent inhibition of the drinking response occurred. Further, when DuP 753 was administered peripherally and AII ICV, drinking was also inhibited. Hence, DuP 753 must penetrate the brain, at least at the circumventricular sites implicated in angiotensin-related drinking. However, centrally administered DuP 753 failed to inhibit the drinking response to peripherally administered AII. This observation is presently unexplained, but may be related to the possibility that centrally administered DuP 753 is inactivated more quickly than when it is administered peripherally. Additional studies will be required to assess this.

Angiotensin I↗

Sham drinking in rats: osmotic and volumetric manipulations.

Male rats, fitted with indwelling gastric fistulas, were tested with either a closed fistula (normal drinking) or an open fistula (sham drinking) following either intracellular dehydration (with NaCl), extracellular dehydration (with PEG), or the combination of the two stimuli. In normal drinking tests, the combined stimulus induced an intake of water that was the sum of the individual effects. In sham-drinking tests, both NaCl- and PEG-treated rats drank up to twice that of their normal drinking counterparts, but those given NaCl + PEG showed no such increase. Various body fluid measurements confirmed the persistence of the respective dehydration states at the end of sham-drinking sessions. The relatively poor or absent sham drinks after these stimuli are contrasted with vigorous sham drinking following fluid deprivation. In a second experiment, sham drinking following NaCl injections did not improve with repeated testing, but intake after intravenous infusion of NaCl did show some increase but was still modest and slow compared with that after fluid deprivation.

Animals↗