Drinking to intracerebroventricularly infused angiotensin II, III, and IV in the SHR

Spontaneously hypertensive rats (SHR) revealed exaggerated water consumption to the intracerebroventricular (ICV) infusion of angiotensin II (AII), and angiotensin III (AIII), as compared with Wistar-Kyoto (WKY) and Sprague-Dawley (SD) normotensive rat strains, in agreement with an earlier report (30) that employed ICV bolus injections of AII and AIII. However, the ICV infusion of AII(3-8) (AIV) did not yield reliable drinking. A second hypothesis that the infusion of AII and AIII would yield equivalent drinking within members of each strain, as previously observed with bolus ICV injections in SD rats, was not confirmed. In contrast, ICV infusion of AII yielded greater water intake than AIII in members of each strain tested. These results suggest that the slow infusion of these ligands allowed endogenous aminopeptidases to adequately keep pace with the degradation of these peptides in contrast with bolus injections that could temporarily saturate the available aminopeptidases thus extending the half-life of the ligand.     

Effect of atrial natriuretic factor on central angiotensin II-induced responses in rats

The effect of intracerebroventricular (ICV) injection of atrial natriuretic factor (ANF) on drinking and pressor responses induced by centrally administered angiotensin II (AII) was examined in the rat. The ICV injection of ANF attenuated water intake induced by AII or 48-hr water deprivation. In contrast, ANF did not affect AII-induced pressor responses. The ICV injection of ANF did not cause recognizable change in blood pressure in spontaneously hypertensive rats or Wistar-Kyoto rats. These results suggested that ANF in the brain is involved in the central control of water intake. Brain ANF may be considered as a selective antagonist of the dipsogenic effect of AII but not its pressor effect.     

Pressor responsiveness to angiotensin in soy-fed spontaneously hypertensive rats

Dietary soy may attenuate the development of arterial hypertension. In addition, some soy-containing foods exhibit angiotensin-converting enzyme (ACE) inhibitory properties. Accordingly, we tested the hypothesis that ACE inhibition contributes to the antihypertensive effect of dietary soy. Mean arterial blood pressure (MAP) was recorded from conscious spontaneously hypertensive rats (SHR) at least 24 h after the implantation of catheters. Cumulative dose-response curves to intravenous angiotensin I (AI) (5-100 ng x kg(-1) x min(-1)) and angiotensin II (AII) (1-20 ng x kg(-1) x min(-1)) were constructed for male, sham-operated female, and ovariectomized female (OVX) SHR that were maintained on either casein or soy diets. The soy diet was associated with a significant reduction in baseline MAP in the OVX SHR (approximately 20 mmHg, 1 mmHg = 133.322 Pa). AI and AII infusions caused graded increases in MAP in all groups. However, there was no significant attenuation of the pressor responses to AI in the soy-fed SHR. Conversely, we observed a significant rightward displacement of the AII dose-response curves in the soy-fed sham-operated and OVX SHR. We conclude that ACE inhibition does not account for the antihypertensive effect of dietary soy in mature SHR.     

Potentiation of pressor response to angiotensin II at the preoptic area in spontaneously hypertensive rat

Cardiovascular responses to angiotensin II(AII) at the preoptic area (POA) were compared between normotensive Wistar Kyoto rat (WKY) and spontaneously hypertensive rat(SHR) by measuring blood pressure and heart rate under unrestrained, conscious state via a catheter implanted chronically into the abdominal aorta and by injection of drugs into POA through a chronic guide cannula. AII injected into POA at doses of 0.3 ng and 1 ng produced a dose-dependent pressor response, accompanied with a slight decrease of heart rate, in both WKY and SHR. However, in SHR, the pressor response to AII was more than 2 times greater than that in WKY and was quick in onset and lasted about 30 min. When AII in combination with [Sar1, Ile8]-angiotensin II (0.5 microgram), an AII receptor antagonist, were simultaneously administered to POA, the pressor response to AII was strongly inhibited in both WKY and SHR. The results suggest that the pressor response to AII due to its receptor stimulation at POA is markedly potentiated in SHR.     

Acute abdominal vagotomy reduces drinking to peripheral but not central angiotensin II

Rats were tested two or three days after bilateral abdominal vagotomy or a laparotomy control procedure for their drinking responses to subcutaneous (1 mg-kg-1) or intracerebroventricular (100 ng) injections of angiotensin II. Vagotomy delayed the initiation of drinking and decreased 60-min water intake after subcutaneous, but not after intracerebroventricular, angiotensin II. This is the shortest postoperative interval in which the decrease in drinking after systemic injection of angiotensin II by abdominal vagotomy has been observed. The failure of vagotomy to decrease the response to intracerebroventricular angiotensin II demonstrates that the deficit after subcutaneous injection was not a nonspecific effect of recent vagotomy. These results, therefore, suggest that the abdominal vagus is necessary for normal drinking in response to circulating angiotensin II. Furthermore, the selective and acute onset of the deficit is consistent with the loss of a specific, rather than tonic facilitatory, vagal mechanism for drinking after elevation of circulating angiotensin II levels. Finally, the results imply that the physiological mechanisms which mediate the drinking responses to central and peripheral angiotensin are not identical.     

Sensitivity of spontaneously hypertensive and of Wistar Kyoto rats to the antidipsogenic action of eledoisin

This study investigated the sensitivity of spontaneously hypertensive rats (SHR) and of Wistar Kyoto rats (WKR) to the antidipsogenic action of the tachykinin eledoisin (ELE). Drinking was evoked by: (a) intracerebroventricular (i.c.v.) injection of angiotensin II, (b) subcutaneous (s.c.) administration of hypertonic NaCl (1.5 M; 1 ml/100 g b.wt.) or (c) 18 h of water deprivation with free access to food. In accordance with previous studies, the dipsogenic effect of all three treatments was exaggerated in the SHR. And when treated with i.c.v. ELE (12.5-25 ng/rat) they were far less sensitive than WKR to its antidipsogenic action on angiotensin-induced drinking. Smaller differences in strain sensitivity were also observed for the effect of ELE on cell dehydration- and on water deprivation-induced drinking, but only at the dose of 200 and 50 ng/rat, respectively. The different sensitivity of the SHR to the antidipsogenic effect of ELE supports the idea that tachykininergic mechanisms for control of water intake are differently regulated in the SHR than they are in the normotensive WKR.     

The effect of the central iso-renin angiotensin system on pressor responsiveness to angiotensin II

The effect of intraventricular (IVT) infusion of a subpressor dose (6.25 or 12.5 ng/kg/min) of angiotensin II (AII) on the pressor responses to intravenous (IV) infusion of AII were studied in pentobarbital anesthetized rats. This study was undertaken to determine whether the central iso-renin angiotensin system alters pressor responsiveness to IV infused AII. Pressor responses to IV infusion of AII were potentiated by concurrent IVT infusion of a subpressor dose of AII. IVT pressor doses of AII decreased plasma renin activity, however, IVT subpressor doses of AII did not. These results suggest that the central iso-renin angiotensin system plays an important role in pressor responsiveness to IV AII and that the potentiation of IV AII is not related to decreases in endogenous AII as a result of IVT administered AII.     

Heart rate reflex responses during gestation in normotensive and spontaneously hypertensive rats following angiotensin II and vasopressin

Gestation in the human and in rats is accompanied by a decrease in blood pressure and a reduction of the pressor response to vasoconstrictor agents. In humans, the decreased vascular reactivity to angiotensin II (AII) may occur simultaneously with a state of increased baroreceptor sensitivity. We have consequently evaluated the heart rate response to elevation of blood pressure following administration of either AII or arginine8-vasopressin (AVP) in conscious unrestrained, nonpregnant, or term-pregnant normotensive rats (Sprague-Dawley, SDR; Wistar-Kyoto, WKR) and in spontaneously hypertensive rats (SHR). The decrease in heart rate in response to increase in blood pressure by AII in nonpregnant animals was similar in SDR and SHR, but much greater in WKR. The heart rate response to increase in blood pressure by AVP was similar in all three strains of cycling rats. Gestation (20th day) did not change the heart rate response to increase in blood pressure by AII in normotensive animals, but increased slightly the reflex responses in SHR, as shown by a significant increase of the slope of the relationship of the decrement in heart rate versus the increment of blood pressure. The heart rate response to increase in blood pressure by AVP was greater during gestation in normotensive SDR and WKR, but not in SHR. These results show that the heart rate responses to an increase in blood pressure by vasoconstrictor peptides is dependent on the strain of animals used and suggest that the baroreceptor reflexes play a minor role in the blunted effect of vasconstrictor agens at the end of gestation in normotensive and spontaneously hypertensive rats.     

Hsp70 regulation on Nox4/p22phox and cytoskeletal integrity as an effect of losartan in vascular smooth muscle cells

A series of signaling cascades are activated after angiotensin II binds to angiotensin II type I receptor (AT₁R), a peptide that is an important mediator of oxidative stress. Hsp70 regulates a diverse set of signaling pathways through interactions with proteins. Here, we tested the hypothesis of angiotensin II AT₁R inhibition effect on Hsp70 interaction with Nox4/p22phox complex and Hsp70 leading to actin cytoskeleton modulation in spontaneously hypertensive rats (SHR) vascular smooth muscle cells (VSMCs). SHR and Wistar–Kyotto rats (VSMCs from 8 to 10 weeks) were stimulated with angiotensin II (100 nmol/L) for 15 min (AII), treated with losartan (100 nmol/L) for 90 min (L), and with losartan for 90 min plus angiotensin in the last 15 min (L + AII). Whereas SHR VSMCs exposure to angiotensin II overexpressed AT₁R and Nox4 nicotinamide–adenine dinucleotide phosphate (NADPH) oxidase and slightly downregulated caveolin-1 expression, losartan decreased AT₁R protein levels and increased caveolin-1 and Hsp70 expression in SHR VSMC membranes. Immunoprecipitation and immunofluorescence confocal microscopy proved interaction and colocalization of membrane translocated Hsp70 and Nox4/p22phox. Increased levels of Hsp70 contrast with the decreased immunoprecipitation of Nox4/p22phox and RhoA in membranes from SHR VSMCs (L) vs SHR VSMCs (AII). Hsp72 depletion resulted in higher Nox4 expression and increased NADPH oxidase activity in VSMCs (L + AII) from SHR when contrasted with nontransfected VSMCs (L + AII). After Hsp72 knockdown in SHR VSMCs, losartan could not impair angiotensin II-enhanced stress fiber formation and focal adhesion assembly. In conclusion, our data showing a negative regulation of Hsp70 on Nox4/p22phox demonstrates a possible mechanism in explaining the antioxidative function joined to cytoskeletal integrity modulation within the effects of losartan in VSMCs from SHR.     

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.     

Angiotensin and thirst: studies with a converting enzyme inhibitor and a receptor antagonist

Although exogenous angiotensin is recognized as a potent dipsogen, the participation of endogenous angiotensin in thirst has not been well established. To investigate this question, we produced thirst in rats by relative cellular dehydration (hypertonic NaCl injection), or hypovolemia (hyperoncotic polyethylene glycol injection). An angiotensin receptor antagonists (sar(1)-ala(8)- angiotensin II, P-113), or a converting enzyme inhibitor (SQ, 20, 881, SQ) given to thirsty rats by intracerebroventricular (IVT) or peripheral routes. P-113 infused i.v. (10 μg/kg/min) or injected IVT (10 μg) did not alter the drinking response to either thirst stimulus. The latter treatment reduced the drinking response to 50 ng of IVT angiotensin II (p < 0.005). SQ given i.m. (2 mg/kg), IVT (2 × 50 μg), or both routes did not alter relative cellular dehydration thirst. Injection of SQ IVT did not alter hypovolemic thirst, whereas a significantly (p < 0.005) enhanced response occured after i.m. SQ. The enhanced response was not observed when animals were given both IVT and i.m. SQ. The IVT treatment with SQ markedly reduced (P < 0.005) drinking after 50 ng IVT angiotensin I. The data demonstrate that inhibition of angiotensin receptors or converting enzyme does not prevent appropriate drinking responses to primary thirst stimuli. Thus, if angiotensin participates in these endogenous thirst drives, its role is not an absolute requirement.     

A possible explanation of genetic hypertension in the spontaneously hypertensive rat

Converting enzyme inhibitors prevent the development of hypertension and normalize arterial blood pressure in spontaneously hypertensive rats (SHR), suggesting a critical role for angiotensin II in genetic hypertension. We hypothesized that the SHR is hyperresponsive to the slow-pressor effect of angiotensin II. To test this hypothesis, 14 SHR and 14 normotensive Wistar Kyoto rats (WKY) were treated chronically with captopril (100 mg X kg-1 X day-1 in drinking water) beginning at 5 weeks of age. At 9 weeks of age, either angiotensin II (125 ng/min; 7 SHR and 7 WKY) or vehicle (7 SHR and 7 WKY) was infused for 2 weeks via an osmotic minipump implanted into the peritoneal cavity. Captopril treatment was maintained and systolic blood pressure was monitored 3 times weekly. Although systolic blood pressure was similar in SHR and WKY infused with vehicle (101 +/- 2 versus 103 +/- 5 mmHg, respectively during the second week), systolic blood pressure in SHR treated with angiotensin II was much greater than systolic blood pressure in WKY treated with angiotensin II (193 +/- 9 versus 132 +/- 11 mmHg, respectively during the second week, p less than 0.001). These results indicate that compared to WKY, SHR are remarkably more sensitive to the slow-pressor effect of chronic, low-dose infusions of angiotensin II. Our results support the hypothesis that the critical genetic defect in SHR is a change in the sensitivity to the slow-pressor effect of angiotensin II.     

Angiotensin II receptors are reduced in the CNS of the young Brattleboro rat

In the rat, angiotensin II (AII), following specific interaction with sensitive central nervous system (CNS) receptors promotes release of vasopressin (ADH). We have examined the integrity of this chain of events by comparing the concentration, Bmax, and dissociation constant, Kd, in the CNS of Brattleboro rats (BB), a strain incapable of synthesizing ADH, with Long Evans (LE) control rats that can synthesize ADH. AII binding properties in the hypothalamic-thalamic-septal-midbrain (HTSM) area from young and old BB and LE, as well as systolic blood pressure, were determined. There was a reduction in the HTSM-AII receptor concentration of young BB when compared with young LE rats. Young BB had lower pressure than age and sex matched LE controls. Neither Bmax nor pressure was significantly different between older BB and LE. A decline in HTSM-AII receptor concentration with age observed with LE is consistent with observations in SHR and WKY rats. Parallel Scatchard plots obtained indicated the presence of a single class of CNS AII receptors. These data suggest that ADH synthesis and AII receptor concentration are partially interdependent and that the CNS AII-ADH system is redundant in the maintenance of blood pressure.     

The role of the subfornical organ in drinking induced by angiotensin in the Japanese quail,Coturnix coturnix japonica

Summary Synthetic 5-valine angiotensin II (AII) induced copious drinking when applied directly to the subfornical organ (SFO) in the Japanese quail. Reliable response was obtained with as little as 1 ng of AII. The amount of water intake increased dose-dependently from 5 ng to 1 ng. A latent period of 73.0 ± 11.0 seconds at 100 ng was noted. The electrical destruction of the SFO significantly reduced the amount of water intake induced by both intravenous and intracranial AII injections. The decrease was proportional to the extent of the SFO lesion. It is conceivable, therefore, that the SFO plays an important role in elicitation of drinking by AII in birds as suggested in mammals.     

Hypothalamic alpha-adrenergic blockade modifies drinking and blood pressure responses to central angiotensin II in conscious rats

These experiments investigated in the awake rat the involvement of noradrenergic projections to the rostral hypothalamus in the drinking and pressor responses elicited by intracerebroventricular (i.c.v.) injections of 25 ng of angiotensin II. Phentolamine mesylate in doses of 2.5-125 micrograms injected into the rostral hypothalamus produced a dose-dependent depression of both the drinking and pressor responses elicited by i.c.v. administration of angiotensin II. A paradoxical increase in heart rate was associated with a decrease in pressor responses with increasing doses of phentolamine. This response was due to tissue injections, since pretreatment by injecting 12.5 micrograms of phentolamine into the ventricle did not block either the cardiovascular or drinking responses to i.c.v. injections of angiotensin II. Yohimbine (0.33-3.3 micrograms), DL-propranolol (25 micrograms), and atenolol (25 micrograms) did not, but prazosin (0.7 microgram) did significantly alter the pressor responses. Although yohimbine also was without effect on drinking, prazosin reduced the drinking responses. These results suggest that alpha 1-adrenergic receptors in the rostral hypothalamus are involved in the control of both the drinking and pressor responses elicited by i.c.v. injections of angiotensin II. In the case of propranolol and atenolol, beta-adrenergic receptors altered only the drinking response in a nonspecific manner by eliciting competing behaviors. Whether they are involved in modifying the drinking response only remains to be demonstrated.     

The effect of prolonged infusion and withdrawal of angiotensin II in the spontaneously hypertensive rat

In spontaneously hypertensive rats (SHR) and their normotensive Wistar-Kyoto controls (WKY), prolonged intravenous administration of angiotensin II (AII, 0.2 microgram X kg-1 X min-1 for 3h) resulted in similar increases in arterial blood pressure. Heart rate decreased in WKY and increased in SHR. At the end of the infusion, blood pressure dropped substantially in SHR, but not in WKY: at 5 h after AII withdrawal, blood pressure in SHR had fallen from a control value of 172 +/- 3.3 to 146 +/- 3.9 mmHg (p less than 0.01), whereas pressure in WKY had fallen from 116 +/- 3.0 to 107 +/- 4.2 mmHg (statistically non significant). Thus, pressure at 5 h after AII withdrawal was still substantially higher (p less than 0.01) in the SHR than in the WKY. The results demonstrate that the fall in blood pressure following withdrawal of a prolonged infusion of AII in SHR is much less than that reported to occur following withdrawal of a prolonged infusion of vasopressin (AVP) in SHR.     

Chronic losartan treatment decreases angiotensin II-mediated facilitation of noradrenaline release in the caudal artery of spontaneously hypertensive rats

Sympathetic activity is modulated by angiotensin II (AII), both at pre- and postsynaptic level in the rat caudal artery. In the spontaneously hypertensive rat (SHR), this artery receives more dense sympathetic innervation than blood vessels of normotensive strains. This fact seems to be linked to the enhanced pressor responses elicited by noradrenaline in SHR. In this work we describe, in the SHR, the effect of a chronic treatment with the angiotensin II AT1-receptor antagonist, losartan, in modulating noradrenergic mechanisms involved in caudal artery contraction. The effect of losartan is compared to that of captopril, given at doses leading to a similar decrease of both arterial blood pressure and left ventricular hypertrophy. The contractile response of caudal artery rings induced by endogenous noradrenaline released by low frequency transmural nerve stimulation (TNS) has been studied. Under our conditions, TNS (0.5-1 Hz) induced higher contractile responses in SHR treated with losartan than in the control and captopril-treated groups. This difference seems to be due to an increase of the postsynaptic effect of noradrenaline (NA) rather than to an increase of noradrenaline release from sympathetic endings, since i) DE50 value for NA was lower in losartan-treated SHR than in the other groups, and ii) AII induced a dose-dependent increase of TNS-evoked release of radioactivity from caudal artery segments loaded with [3H]-NA, in both control and captopril-treated groups but had no effect in the losartan-treated group. These results show that chronic treatment with losartan, although slightly enhancing the pressor effect of NA at postsynaptic level, fully supresses the facilitatory role of AII on NA release.     

Abnormal renal medullary response to angiotensin II in SHR is corrected by long-term enalapril treatment

This study tested the hypotheses that renal medullary blood flow (MBF) in spontaneously hypertensive rats (SHR) has enhanced responsiveness to angiotensin (ANG) II and that long-term treatment with enalapril can correct this. MBF, measured by laser Doppler flowmetry in anesthetized rats, was not altered significantly by ANG II in Wistar-Kyoto (WKY) rats, but was reduced dose dependently (25% at 50 ng. kg(-1). min(-1)) in SHR. Infusion of N(G)-nitro-L-arginine methyl ester (L-NAME) into the renal medulla unmasked ANG II sensitivity in WKY rats while L-arginine given into the renal medulla abolished the responses to ANG II in SHR. In 18- to 19-wk-old SHR treated with enalapril (25 mg. kg(-1). day(-1) when 4 to 14 wk old), ANG II did not alter MBF significantly, but sensitivity to ANG II was unmasked after L-NAME was infused into the renal medulla. Endothelium-dependent vasodilation (assessed with aortic rings) was significantly greater in treated SHR when compared with that in control SHR. These results indicate that MBF in SHR is sensitive to low-dose ANG II and suggest that this effect may be due to an impaired counterregulatory effect of nitric oxide. Long-term treatment with enalapril improves endothelium-dependent vascular relaxation and decreases the sensitivity of MBF to ANG II. These effects may be causally related to the persistent antihypertensive action of enalapril in SHR.     

Sexual dimorphism in the renin-angiotensin system in aging spontaneously hypertensive rats

In young adult spontaneously hypertensive rats (SHR), mean arterial pressure (MAP) is higher in males than in females and inhibition of the renin-angiotensin system (RAS) eliminates this sex difference. After cessation of estrous cycling in female SHR, MAP is similar to that in male SHR. The purpose of this study was to determine the role of the RAS in maintenance of hypertension in aging male and female SHR. At 16 mo of age, MAP was similar in male and female SHR (183+/-5 vs. 193+/-8 mmHg), and chronic losartan (40 mg.kg-1.day-1 po for 3 wk) reduced MAP by 52% (to 90+/-8 mmHg, P<0.05 vs. control) in males and 37% (to 123+/-11 mmHg, P<0.05 vs. control) in females (P<0.05, females vs. males). The effect of losartan on angiotensin type 1 (AT1) receptor blockade was similar: MAP responses to acute doses of ANG II (62.5-250 ng/kg) were blocked to a similar extent in losartan-treated males and females. F2-isoprostane excretion was reduced with losartan more in males than in females. There were no sex differences in plasma renin activity, plasma angiotensinogen or ANG II, or renal expression of AT1 receptors, angiotensin-converting enzyme, or renin. However, renal angiotensinogen mRNA and protein expression was higher in old males than females, whereas renal ANG II was higher in old females than males. The data show that, in aging SHR, when blood pressures are similar, there remains a sexual dimorphism in the response to AT1 receptor antagonism, and the differences may involve sex differences in mechanisms responsible for oxidative stress with aging.     

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.