Biomedical subjects

M J Fregly

Publications and source records attributed to M J Fregly.

At least 91 records · Page 5Linked to original sources

PubMed1988

Augmentation of isoproterenol-induced drinking by acute treatment with certain dopaminergic agonists.

Bromocriptine (1 mg/kg, IP), a dopaminergic agonist that crosses the blood-brain barrier, augmented the dipsogenic responsiveness of rats to acute administration of the beta-adrenergic agonist, isoproterenol (15 micrograms/kg, SC), when administered at the same time. When administered alone, it had no effect on either water intake or urine output. Dopamine (20 mg/kg IP), which does not cross the blood-brain barrier, also augmented the dipsogenic responsiveness to acute administration of isoproterenol. However, a major difference between the responses to bromocriptine and dopamine was that the latter augmented drinking only when administered 15 to 30 min prior to isoproterenol. During the 30 min between injection of dopamine and the injection of isoproterenol, output of urine and sodium increased approximately 6-fold above the level of controls such that the concentration of the urine excreted by the treated group was approximately isotonic. However, in spite of a 6-fold increase in output of urine by the treated, compared to the control group, dopamine-treated rats ingested water only to the same extent as untreated controls when access to water was allowed. This suggests that an isotonic contraction of extracellular fluid may not induce a dipsogenesis. It also suggests that the augmentation of isoproterenol-induced drinking by dopamine was not the result of a dehydration-induced drink superimposed on the isoproterenol-induced drink. The centrally and peripherally acting dopaminergic antagonist, spiroperidol (spiperone), inhibited the isoproterenol-induced drinking response in a dose-related fashion. However, the peripherally acting dopaminergic antagonist, domperidone,was without effect on isoproterenol induced drinking.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

Effects of increased circulating angiotensin II (AII) on fluid exchange and binding of AII in the brain.

Previous studies have shown that elevated levels of circulating angiotensin II (AII) can influence the binding capacity of this peptide for its receptors in peripheral tissues, but the effect of increased circulating levels of AII on its receptors in the brain has not been well-defined. In the present study, the effect of chronic subcutaneous infusions of AII on: (1) the binding of AII to neuronal membranes from the diencephalon (hypothalamus, thalamus and septum) (HTS) of the brain; (b) water intake and urine output, (c) blood pressure, and (d) their interrelationships was evaluated in rats. Significant increases in daily water intake and urine output accompanied chronic infusions of AII at a rate of 125 ng/kg/min. Both blood pressure and the concentration of aldosterone in plasma were also elevated in these rats. The acute dipsogenic response to either central (10 ng) or peripheral (100 micrograms/kg, SC) administration of AII was also tested both in controls and in rats receiving chronic infusions of AII at a rate of either 40 or 125 ng/kg/min, and no differences were observed. Analysis of the HTS region of the brain revealed a significant increase in the specific binding of AII in AII-infused rats compared to controls. Scatchard analysis of the specific binding of AII to its receptors in the HTS of rats treated with 40 ng AII/kg/min for 6 days revealed a significant increase in the number of binding sites for AII compared to controls (Bmax 12.13 vs. 8.79 fmol/mg protein), but no change in binding affinity (Kd).(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗

PubMed1988

Sodium appetite: species and strain differences and role of renin-angiotensin-aldosterone system.

The characteristics of the appetite for NaCl in humans differ in some aspects from those in other species. The mechanisms of appetite for NaCl have been studied in detail in two species, rats and sheep. We review the treatments known to induce an appetite for NaCl in rats, with special reference to differences among strains in their spontaneous preference for NaCl solution. The current view of the mechanism is critically appraised, with particular emphasis on the role of angiotensin II, mineralocorticoids, cerebroventricular sodium transport, and the relation between preference for NaCl and the concentration of sodium in saliva. The appetite for NaCl in rodents other than rats is considered next, and reveals that mice, hamsters and gerbils are reluctant to ingest NaCl either spontaneously or after treatment with several of the natriorexigenic stimuli that are effective in rats. The characteristics of the appetite for NaCl in non-rodent species, including sheep, rabbit, dog, and non-human primates, are then described. We discuss some of the possible differences in mechanism that might account for this behavioral diversity among species.

Animals↗

PubMed1988

Comparison of the effects of the dipeptidyl peptidase inhibitors captopril, ramipril, and enalapril on water intake and sodium appetite of Sprague-Dawley rats.

Two experiments were performed with Sprague-Dawley rats to study the effects of different inhibitors of angiotensin I converting enzyme (ACE) on water intake and sodium appetite. Subcutaneous administration of low doses of either enalapril (MK421) or ramipril (Hoe498), like captopril, was dipsogenic. Acute administration of ramipril also enhanced the drinking response to peripherally administered angiotensin I (Ang I). Higher doses inhibited the drinking response to Ang I, administered acutely either peripherally or centrally. These data provide behavioral evidence that the nonsulfhydryl inhibitors enalapril and ramipril inhibit brain converting enzyme activity and that they are considerably more potent than captopril. All three of these compounds, administered chronically in food, induced an appetite for sodium chloride (NaCl) solution. Enalapril and ramipril were more potent than captopril. Plasma renin activity was increased by each of these inhibitors, but the magnitude of the increase was not clearly related to the amount of NaCl consumed. The water intake in response to acute administration of either Ang I or isoproterenol was not reliably increased in rats treated chronically with these inhibitors.

Angiotensin I↗

PubMed1988

Induction of an appetite for sodium in rats that show no spontaneous preference for sodium chloride solution--the Fischer 344 strain.

Fischer 344 rats show no spontaneous preference for isotonic sodium chloride (NaCl) solution. These experiments indicate, however, that a strong appetite for this solution may be induced by various methods, including adrenalectomy, administration of a mineralocorticoid hormone, acute depletion of sodium, and treatment with inhibitors of the angiotensin I converting enzyme (ACE). These treatments were also shown to produce the expected changes in the renin-angiotensin-aldosterone system, which thus appears to be involved in the induction of an appetite for NaCl solution in this strain of rat. The intakes of NaCl induced in the Fischer 344 rats by these experimental paradigms are less than those that have been reported in either Sprague-Dawley or Wistar strains in similar paradigms. In the case of sodium depletion, the intake of NaCl solution by Fischer 344 rats appears to be more closely related to the deficit than in the other two strains. Thus, the Fischer 344 strain of rats may be a particularly good model for studies of need-related sodium appetite.

Adrenalectomy↗

PubMed1988

Characteristics of thirst and sodium appetite in mice (Mus musculus).

The intakes of water and sodium chloride (NaCl) solution were examined in mice following treatment with agents that either stimulate or mimic various components of the renin-angiotensin-aldosterone system. Injections of either angiotensin II (Ang II) or isoproterenol produced very little water intake compared with the robust responses to either intracellular dehydration or to extracellular dehydration induced by treatment with polyethylene glycol (PEG). In studies on appetite for NaCl solution, mice exhibited no spontaneous preference for 0.15 M NaCl solution over water and did not change this preference during treatment with deoxycorticosterone acetate (DOCA), a sodium-deficient diet, or after adrenalectomy. Plasma concentrations of aldosterone were increased in intact mice fed a sodium-deficient diet but were not eliminated by adrenalectomy. However, acute treatment with furosemide in combination with a sodium-deficient diet stimulated an appetite for NaCl solution. Chronic oral administration of an angiotensin I (Ang I) converting enzyme inhibitor failed to induce a NaCl appetite. These findings show that mice are refractory to the induction of either water or NaCl intake by stimuli of the renin-angiotensin-aldosterone system, stimulation that is highly effective in rats; this suggests that there may be major differences among rodents in the hormonal determinants of behaviors related to hydromineral homeostasis.

Angiotensin II↗

PubMed1988

Effect of chronic dietary treatment with L-tryptophan on the development of renal hypertension in rats.

Chronic dietary administration of L-tryptophan (2.5 and 5.0 g/100 g food) to rats provided significant protection against the development of hypertension induced by bilateral encapsulation of the kidneys with latex envelopes. Lower doses of tryptophan (0.5 and 1.0 g/100 g food) attenuated the rate of elevation of blood pressure, but failed to maintain systolic blood pressures at levels significantly below that of untreated renal hypertensive controls. The body weight of the rats was not affected significantly by treatment with any dose of tryptophan used. Chronic treatment with tryptophan also protected against the reduced urinary concentrating ability during a 24-hour dehydration that characteristically accompanies renal encapsulation. A modest (5-8%) effect of treatment to reduce cardiac hypertrophy was also observed. The mechanism of the antihypertensive effect of tryptophan is not revealed by these studies although they rule out the possibilities that reduction in sodium intake and/or reduction in body weight may be important factors.

Aldosterone↗

PubMed1988

Effect of chronic dietary treatment with nicotinic acid on the development and maintenance of deoxycorticosterone-acetate-salt-induced hypertension.

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.

Animals↗

PubMed1987

Postingestional modulation of drinking induced in rats by angiotensin II: intragastric infusion and sham drinking studies.

The dipsogenic potency of angiotensin II (ANGII, 200 micrograms/kg, SC) was examined after the removal of various postingestional factors. In the first experiment, rats with intragastric catheters were injected SC with ANGII and allowed water to drink. During the induced drinking, either NaCl (1.5 M) or water was injected into the stomach via the catheter at a rate of 0.1 ml for each ml water ingested orally. The water intake was identical in the two conditions. In a second experiment, rats, fitted with gastric fistulas, were administered ANGII and subsequent water intake with fistulas open was compared to that occurring with the fistulas closed. Rats drank more water during the first trial with fistulas open than with fistulas closed. Water intake during subsequent trials with an open fistula rose above that observed on the first trial. In a third experiment, rats with gastric fistulas were offered 0.15 M NaCl to drink. Intake was greater when the fistula was open than when it was closed. Intake of 0.15 M NaCl increased during the second trial with fistula open. Rats drank more 0.15 M NaCl during the first trial with an open fistula in Experiment 3 than those rats given water to drink on their first trial with fistula open in Experiment 2. These data suggest both oropharyngeal and postingestional factors interact in the control of ANGII-induced fluid intake.

Angiotensin II↗

PubMed1987

Effect of acute administration of bromocriptine on isoproterenol- and angiotensin II-induced water intake in estrogen-treated rats.

Chronic administration of an estrogenic agent is well known to attenuate the drinking response of rats to treatment with a variety of dipsogenic agents, and to increase plasma concentration of prolactin. Treatment with prolactin is also known to reduce the drinking response to administration of the dipsogenic agent, isoproterenol. Hence, a possibility existed that the antidipsogenic effect of chronic treatment with estrogen was mediated by an increased plasma prolactin concentration. Since bromocriptine, a dopaminergic agonist, is known to reduce plasma prolactin concentration in estrogen-treated rats, it was administered (1.0 mg/kg, IP) 15 min prior to treatment with either isoproterenol (25 micrograms/kg, SC) or angiotensin II (200 micrograms/kg, SC). The results suggest that the antidipsogenic effect of chronic treatment of rats with estradiol benzoate (30.4 and 45.7 micrograms/kg/day) can be reversed, at least partially, by acute administration of bromocriptine.

Angiotensin II↗

PubMed1987

Water intake induced in rats by serotonin and 5-hydroxytryptophan: different mechanisms?

The present studies were designed to investigate further the mechanism by which water intake is induced in rats by peripheral administration of either serotonin (5HT) or its precursor 5-hydroxytryptophan (5HTP). Consistent with previous studies that have implicated mediation by the renal renin-angiotensin system (RAS), we now report that bilateral nephrectomy completely abolishes the drinking response to various doses of 5HT. In contrast, nephrectomy had little effect on the drinking induced by 5HTP. Thus, 5HTP may induce drinking by mechanisms other than its peripheral conversion to 5HT and subsequent activation of the RAS. The drinking responses to both 5HT and 5HTP were blocked by peripheral administration of the 5HT receptor antagonist, metergoline, but the drug was at least ten-fold more potent against 5HTP than 5HT. Intracerebroventricular (ICV) administration of metergoline also prevented the drinking response to peripherally-administered 5HTP. The drinking responses to both 5HT and 5HTP were enhanced by peripheral administration of low doses of an angiotensin I converting enzyme inhibitor, captopril. Collectively, these findings support previous conclusions that 5HT-induced intake of water is mediated exclusively by the renal RAS. However, 5HTP-induced drinking may additionally involve a renin-independent, serotonin-mediated mechanism, possibly in the brain.

5-Hydroxytryptophan↗

PubMed1987

Re-examination of the effect of either a lateral or third ventricular cannula on captopril-induced salt appetite in rats.

In Study A, rats were implanted with a cannula aimed at either the lateral (LV) or ventral third (V3V) brain ventricles 1 week prior to starting a chronic oral regimen of captopril. The presence of neither cannula significantly impaired the emergence of captopril-induced appetite for NaCl solution. In Study B, V3V cannulae were implanted in rats after a captopril-induced appetite for NaCl was established. The surgery produced a 1-2 day attenuation of NaCl intake, but this was no greater than that observed in a sham-operated group that received no cannula. These results do not support those of others who suggest that captopril (and, by inference, other agents) can leak across a damaged blood-brain barrier for at least 2 weeks after placement of a cannula. Possible reasons for the differences in results are addressed.

Administration, Oral↗

PubMed1987

Water versus NaCl intake by rats administered certain dipsogens acutely.

Isotonic saline was ingested in a greater volume than water when any one of three dipsogenic agents [L-5-hydroxytryptophan (25 mg/kg, SC), isoproterenol (25 micrograms/kg, SC), and angiotensin II (100 micrograms/kg, SC)] was administered acutely to rats given either isotonic saline or water to drink. These results are consistent with, but not exclusive to, the hypothesis that feedback inhibition of ingested isotonic saline on further fluid intake is less than that of water. Additional studies showed that the dipsogenic response to angiotensin II (200 micrograms/kg, SC) decreased as the concentration of NaCl solution offered to drink increased beyond 0.15 M in rats given either water or NaCl solution to drink. This suggests the possibility that the intensity of taste of the NaCl solutions may be a factor in their intake under these conditions, although the intake of these salt solutions by untreated controls did not reflect this. When the rats were allowed to choose between either 0.15 or 0.25 M NaCl solution and water, administration of angiotensin II (either 100 or 200 micrograms/kg, SC) increased water intake in preference to the NaCl solution. These results suggest that the rat, under these conditions, has a preference for water over NaCl solution.

5-Hydroxytryptophan↗

PubMed1987

Chronic treatment with L-5-hydroxytryptophan prevents the development of DOCA-salt-induced hypertension in rats.

Chronic subcutaneous (s.c.) infusion (osmotic minipump) of L-5-hydroxytryptophan (L-5-HTP, 4.2 to 12.6 mg/day) to uninephrectomized, deoxycorticosterone acetate-salt-treated (DOCA) rats (1.36 mg/kg per day via s.c. silastic implants) reduced their exaggerated intake of isotonic saline significantly (12.6 mg/day), prevented the elevation of blood pressure (4.2 to 12.6 mg/day), prevented cardiac hypertrophy (12.6 mg/day), and provided modest protection against reduction of urinary concentrating ability, characteristic of DOCA-treated rats during a 24-h dehydration. The exaggerated dipsogenic response of DOCA-treated rats to administration of angiotensin II (AII, 50 and 100 micrograms/kg, s.c.) was also reduced by treatment with L-5-HTP (4.2 and 8.4 mg/day). The specific binding of AII to its receptors in membranes from the diencephalon of the brain was increased significantly above control level by chronic treatment with DOCA, but was returned to control level by concomitant treatment with L-5-HTP. Daily urinary excretion of dopamine, increased by treatment with DOCA, was unaffected by treatment with L-5-HTP (6.3 mg/day). Daily urinary excretion of epinephrine was increased by treatment with L-5-HTP (6.3 and 12.6 mg/day). These results suggest that chronic administration of L-5-HTP provides significant protection against the development of DOCA-induced hypertension, polydipsia, polyuria, and cardiac hypertrophy in rats. The mechanism by which L-5-HTP protects is unclear and remains to be established.

5-Hydroxytryptophan↗

PubMed1987

Chronic dietary administration of tryptophan prevents the development of deoxycorticosterone acetate salt induced hypertension in rats.

Hypertension developed within 3 to 5 weeks in uninephrectomized rats administered deoxycorticosterone acetate (DOCA) at a dose of 850 micrograms X kg-1 X day-1 via Silastic tubes and given isotonic saline to drink. Chronic dietary administration of tryptophan (25 and 50 g/kg of food) to DOCA-treated rats reduced their exaggerated intake of NaCl solution and attenuated the elevation of blood pressure induced by treatment with DOCA alone. Treatment with tryptophan also protected against the reduction in urinary concentrating ability during a 24-h dehydration that is characteristic of DOCA-treated rats. Other tests assessed the responsiveness to the beta-adrenergic agonist, isoproterenol. These included measurement of drinking and heart rate following acute administration of isoproterenol. The characteristically depressed drinking and chronotropic responses of DOCA-treated rats to acute administration of isoproterenol were unaffected by tryptophan. Responsiveness to angiotensin II (AII) was also tested by assessment of dipsogenic and metabolic responses to acute administration of AII. The increased drinking and tail skin temperature responses to administration of AII, characteristic of DOCA-treated rats, were reduced in a graded fashion by treatment with graded doses of tryptophan. The specific binding of AII to its receptors in membranes form the diencephalon of the brain was increased by treatment with DOCA but was returned to control level by concomitant treatment with tryptophan. The content of serotonin in the mesencephalon of the brain was not changed significantly by treatment with tryptophan, but the content of 5-hydroxyindole acetic acid in the same region increased significantly, suggesting that turnover of serotonin was increased by chronic treatment with tryptophan. The cardiac hypertrophy characteristic of treatment with DOCA was attenuated significantly by chronic treatment with tryptophan, while the low, resting plasma renin activity of the DOCA-treated group was unchanged. These results suggest that tryptophan provides significant protection against the development of DOCA-induced hypertension, polydipsia, polyuria, and cardiac hypertrophy in rats. It also reduces the hyperresponsiveness to treatment with AII, possibly by decreasing the specific binding of AII to its receptors. It also appears to increase the turnover of serotonin in the brain. Whether either one or all of these is responsible for the antihypertensive effect of tryptophan remains for further study.

Angiotensin II↗

PubMed1987

Diminished metabolic responsiveness to beta-adrenergic stimulation in estradiol benzoate-treated rats.

Earlier studies have shown that chronic treatment with estradiol benzoate reduced the responsiveness of heart rate, drinking, and tail-skin temperature to administration of the beta-adrenergic agonist, isoproterenol. The objective of the present study was to assess the relationship between the isoproterenol-induced elevations in rate of oxygen consumption and tail-skin temperature in adult ovariectomized rats treated chronically with estradiol benzoate (28 micrograms/day) and untreated, ovariectomized controls. Isoproterenol (0, 10, 25, and 50 micrograms/kg, s.c.) elevated both rate of oxygen consumption and tail-skin temperature in ovariectomized and ovariectomized plus estradiol benzoate-treated rats in a dose-related fashion. However, in both cases the response of the estradiol-treated group was less than that of controls. A comparison of the regressions of rate of oxygen consumption versus dose of isoproterenol administered to each group revealed significant differences between the intercepts, but not the slopes. A similar comparison with respect to the regression of tail-skin temperature versus dose of isoproterenol administered to each group revealed significant differences between both the slopes and intercepts of the relationships. A comparison of the regressions of rate of oxygen consumption versus tail-skin temperature for control and estrogen-treated rats revealed significant differences between both slopes and intercepts of the relationships. The latter comparison suggests a reduced change in tail-skin temperature for a given change in rate of oxygen consumption in the estrogen-treated group. It is concluded from these results that the reduction in metabolic response to beta-adrenergic stimulation in estrogen-treated rats explains, in part at least, the attenuated response of tail-skin temperature. The tail of the rat is important in short-term temperature regulation. When threatened acutely with overheating, the rat uses its tail as a heat radiator, increasing its skin blood flow, temperature, and heat loss. Administration of isoproterenol to rats at doses of 50-100 micrograms/kg, subcutaneously can increase tail-skin temperature as much as 6 degrees C. This response is mediated by beta-adrenoceptors since it can be either attenuated or prevented by prior administration of propranolol. It serves as a simple and reliable test of beta-adrenergic responsiveness in rats. Chronic treatment with the oral contraceptive, Enovid (7.5 mg/kg food) attenuated this response. Chronic administration of the estrogenic component (ethinyl estradiol, 48-50 micrograms/kg/day) of Enovid also attenuated the response.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1986

Mineralocorticoids modulate central angiotensin II receptors in rats.

The effect of chronic administration of deoxycorticosterone acetate (DOCA) on the regulation of angiotensin II (AII) receptors in the brains of adult rats was compared with their drinking and pressor responsiveness to both peripheral and central administration of AII. Analysis of AII receptor binding in a block of tissue containing the hypothalamus, thalamus and septum (HTS) after treatment for 8 weeks with DOCA-salt (240 micrograms/kg/day) revealed a significant increase in the number of AII-binding sites compared to salt-loaded controls (Bmax 9.65 vs 6.80 fmol/mg protein) and no change in binding affinity (Kd). Significant increases in the drinking responses to peripheral (200 micrograms/kg) and central (10 ng) administration of AII were observed in these rats. Additional studies indicated that the pressor responses to either centrally (25 ng) or peripherally (20 micrograms/kg, s.c.) administered AII were augmented in DOCA-treated rats. The effect of mineralocorticoids on AII-binding sites was also investigated in primary neuronal cultures from the brains of one-day-old rats. Pretreatment of these cultures with either DOCA or aldosterone (ALDO) induced a time- and concentration-dependent increase in the specific binding of [125I]AII. Maximal increases in AII binding of 53 and 62% above control values were observed when cultures were treated with 500 pg of either ALDO or DOCA per milliliter of culture medium. Scatchard analysis of specific binding of [125I]AII in neuronal cultures treated with DOCA revealed a significant increase in Bmax but no change in Kd. Thus, mineralocorticoid hormones induce an increase in the number of AII-receptor binding sites in the HTS of rats which parallels physiological responses to both central and peripheral administration of AII. This relationship may be independent of the concentration of AII in the blood, since an increase in the number of AII binding sites was also observed in neurons cultured from the brains of one-day-old rats which had been treated with mineralocorticoid hormones.

Aldosterone↗

PubMed1986

Effect of the presynaptic dopaminergic agonist, quinpirole, on the drinking responses of rats to angiotensin II, isoproterenol, and hypertonic saline.

The dopamine (DA2) agonist, quinpirole hydrochloride (LY 171555), has been reported to inhibit central presynaptic release of norepinephrine, an effect similar to that of clonidine, an alpha 2-adrenoceptor agonist. Since clonidine exerts an antidipsogenic effect on all types of laboratory-induced drinking, the objective of these experiments was to determine whether administration of quinpirole hydrochloride produced a similar effect. The drinking responses of rats to administration of angiotensin II (200 micrograms/kg, SC), isoproterenol (25 micrograms/kg, SC), and hypertonic saline (1 M NaCl, 1% of body weight, IP) were blocked by administration of quinpirole hydrochloride (7.5 mg/kg, IP). When administered alone, quinpirole had no effect on water intake. Thus, the antidipsogenic effect of quinpirole hydrochloride resembles that of clonidine and suggests that release of norepinephrine occurs centrally at some point along the final common pathway for drinking in rats.

Angiotensin II↗