Administration Of Angiotensin II Research Articles

The effect of angiotensin II on myosin heavy chain expression in cultured myocardial cells.

Angiotensin II (AII), the principal mediator of the renin-angiotensin system, is an important regulator of vascular and cardiac homeostasis. AII has also been shown to be a regulator of cardiac hypertrophy and of the corresponding changes in amount and composition of certain tissue proteins. We examined the trophic effects of AII on cultured myocytes derived from neonatal rat ventricles and followed, by Northern blot analysis and polyacrylamide gel electrophoresis, the expression of alpha- and beta-myosin heavy chain iso-mRNAs and isoproteins. Our findings show that a single administration of AII is sufficient to induce a trophic response in cultured beating myocytes and to enhance the expression of beta-myosin heavy chain iso-mRNA and isoprotein, having no effect on alpha-myosin heavy chain. Induction of alpha-myosin heavy chain expression by thyroid hormone before AII was administered showed that AII could not potentiate a shift from alpha- to beta-myosin heavy chain predominance. We suggest that the potency of AII to regulate the expression of myosin heavy chain isogenes is restricted to the beta isoform and is overridden by thyroid hormone.

Centrally mediated vasodilation of the rat's tail by angiotensin II

Acute peripheral administration of angiotensin II (AngII) to rats vasodilates the tail and reduces both metabolic rate and body temperature. To assess the role of the brain in these responses to AngII, a discrete lesion was aimed at the subfornical organ (SFO). Such lesions are known to abolish drinking and other responses to circulating AngII. A control group was sham-operated. Following recovery from surgery, dipsogenic responses to administration of Angll (150 μ/kg, SC) were tested. All lesioned rats failed to drink. One week later, the changes in colonic (Tc) and tail skin (TSK) temperatures were measured following an identical injection of AngII. As reported before, control rats showed a substantial rise in in TSK (maximum rise 2.5°C after 12 min). In contrast, the lesioned rats showed very little rise (0.3°C) in TSK, significantly less than controls. The maximal drop in Tc of the control group was slightly more (0.3°C) than that of the lesioned group (0.2°C), but the difference was not significant. The rats were, next, acutely exposed to cold (5°C). Control rats showed a significantly larger decrease in TSK than lesioned rats. Lesions were verified both anatomically and using the functional metric of AngII-induced Fos-like immunoreactivity (Fos-IR). AngII induced strong Fos-IR in the SFO, median preoptic nucleus (MnPO), and in the magnocellular hypothalamic regions of control rats. The lesions ablated the anterior part of the SFO and dorsal MnPO, and greatly attenuated AngIIinduced Fos-IR in the magnocellular hypothalamic regions. Thus, there appears to be central (SFO/MnPO) mediation of both the increase in T SK following administration of AngII and the decrease in T SK in the cold.

Centrally Mediated Vasodilation of The Rat's Tail By Angiotensin II

Acute peripheral administration of angiotensin II (AngII) to rats vasodilates the tail and reduces both metabolic rate and body temperature. To assess the role of the brain in these responses to AngII, a discrete lesion was aimed at the subfornical organ (SFO). Such lesions are known to abolish drinking and other responses to circulating AngII. A control group was sham-operated. Following recovery from surgery, dipsogenic responses to administration of Angll (150 μ/kg, SC) were tested. All lesioned rats failed to drink. One week later, the changes in colonic (Tc) and tail skin (TSK) temperatures were measured following an identical injection of AngII. As reported before, control rats showed a substantial rise in in TSK (maximum rise 2.5°C after 12 min). In contrast, the lesioned rats showed very little rise (0.3°C) in TSK, significantly less than controls. The maximal drop in Tc of the control group was slightly more (0.3°C) than that of the lesioned group (0.2°C), but the difference was not significant. The rats were, next, acutely exposed to cold (5°C). Control rats showed a significantly larger decrease in TSK than lesioned rats. Lesions were verified both anatomically and using the functional metric of AngII-induced Fos-like immunoreactivity (Fos-IR). AngII induced strong Fos-IR in the SFO, median preoptic nucleus (MnPO), and in the magnocellular hypothalamic regions of control rats. The lesions ablated the anterior part of the SFO and dorsal MnPO, and greatly attenuated AngIIinduced Fos-IR in the magnocellular hypothalamic regions. Thus, there appears to be central (SFO/MnPO) mediation of both the increase in T SK following administration of AngII and the decrease in T SK in the cold.

Angiotensin II-induced myocardial fibrosis in rats: role of nitric oxide, prostaglandins and bradykinin

Chronic elevations in plasma angiotensin II (AngII) are associated with an efflux of plasma macromolecules into the perivascular and contiguous interstitial space. This is followed by the appearance of macrophages and type I collagen-producing, fibroblast-like cells that precede the accumulation of fibrous tissue at these sites. Whether this perivascular and interstitial fibrosis is a direct effect of AngII on collagen turnover of these cells or an indirect response mediated by nitric oxide, prostaglandins and/or bradykinin released in response to AngII, is uncertain. We measured perivascular and interstitial fibrosis (picrosirius-stained tissue) in response to 14-day infusion of AngII (150 ng/kg/min, s.c.) in male Sprague-Dawley rats. Treated animals were compared to untreated controls and to groups receiving AngII together with either an NO-synthase inhibitor [NG-nitro-L-arginine methyl ester (L-NAME) 10 mg/kg/day in drinking water], a cyclo-oxygenase inhibitor (indomethacin, 2 mg/kg/day in drinking water), or a bradykinin B2 receptor antagonist (Hoe140, 115 ng/kg/min, s.c.). When left and right ventricles of treated rats were compared to untreated controls, AngII led to a respective 68 and 48% increase in perivascular collagen volume fraction (PCVF) and a 54 and 22% increase in interstitial collagen volume fraction (ICVF). Co-administration of AngII + L-NAME did not attenuate either PCVF or ICVF while indomethacin significantly attenuated PCVF by 37 and 33% of left and right ventricle, respectively, but did not alter ICVF in either ventricle when compared to AngII-treated animals. Co-administration of AngII + Hoe140 completely prevented perivascular and interstitial collagen accumulation with the extent of perivascular fibrosis comparable to untreated controls. The perivascular and interstitial fibrosis of the rat right and left ventricles seen in association with the exogenous administration of AngII is mediated by the release of bradykinin and prostaglandins, and therefore is an indirect response to elevated circulating AngII.

Uterine circulatory dysfunction induced by whole-body vibration and its endocrine pathogenesis in the pregnant rat.

Effects of whole-body vibration on normal pregnancy were studied in the rat. Uterine blood flow and five endocrine functions corticosterone (CS), estradiol (E2), progesterone (P), prostaglandin E2 (PGE2) and prostaglandin F2 alpha (PGF2 alpha) concentration were measured in rats exposed to whole-body vibration with an acceleration of 10 m.s-2 at a frequency of 8 Hz. While no change in uterine blood flow was observed in control rats, uterine blood flow was significantly decreased 75 and 90 min after exposure to vibration. The uterine blood flow at 15 and 30 min was increased by pretreatment with intraperitoneal injections of angiotensin II (AII). In contrast, in AII pretreated rats exposed to the vibration, uterine blood flow was significantly reduced 90 min after exposure. The CS concentration was increased by vibration independently of the pretreatment with AII. Neither E2 nor PGF2 alpha concentration were changed by the vibration with or without AII administration. The P and PGE2 concentrations were both decreased by vibration in the absence of AII, while the decrease in PGE2 induced by the vibration was also found in AII-treated rats. The present results indicated that the pregnant rats subjected to whole-body vibration responded with changes in uterine and ovarian function. The observed decrease in uterine blood flow may have been the result of reduced PGE2 concentration resulting from an indirect effect of vibration.

Effect of neuropeptide Y on endotoxin-induced suppression of the response to various agonists in conscious rats

Hypotension during endotoxic shock is related to reduced vascular responsiveness to vasoconstrictors. Neuropeptide Y (NPY) is known to potentiate the pressor response to some agonists, and NPY infusion has been shown to improve hemodynamics and survival in endotoxemic rats. We therefore studied the effect of NPY infusion on the suppressed pressor effect of norepinephrine (NE), angiotensin II (AII), vasopressin (VP), and endothelin (ET) in conscious endotoxemic rats. Chronically cannulated conscious rats were infused with a non-hypotensive dose of endotoxin (LPS, 10 μg/10μl/min) throughout the experiment. Infusion of NPY, 40 pmol/10μl/min was started 15 minutes before the LPS infusion, and continued for 65 minutes. Five minutes after the termination of NPY infusion, increasing agonist doses were administered i.v. to construct dose-response curves. Each experiment included one control group where saline replaced LPS, and one control group where saline replaced NPY. LPS infusion caused suppression of the pressor responses to all four agonists, as expressed by ED 50 and by decreased pressor response to the individual agonist doses. In addition, LPS infusion altered the bradycardic response to AII and ET. NPY infusion prior to the administration of NE, AII and VP resulted in partial reversal of the LPS-induced suppressed responsiveness to these agonists. NPY infusion had no effect on the response to ET in either control or endotoxemic rats. Partial reversal of the suppressed responsiveness to the three agonists by NPY infusion may contribute to the observed NPY-induced improvement of blood pressure and survival rate during endotoxic shock.

Intrapericardial basic fibroblast growth factor induces myocardial angiogenesis in a rabbit model of chronic ischemia

The objective of this study was to determine whether basic fibroblast growth factor (bFGF), a known angiogenic factor, can promote new vessel growth when infused within the pericardial space in a model of chronic myocardial ischemia. Intravenous angiotensin II (AII) was infused to induce left ventricular hypertrophy and concomitant ischemia in New Zealand white rabbits. Basic FGF was infused into the intrapericardial space with an osmotic pump. Animals were assigned to one of four groups: group 1 received intrapericardial bFGF and intravenous AII, group 2 received intrapericardial bFGF and intravenous saline solution, group 3 received intrapericardial albumin and intravenous AII, and group 4 received intravenous AII only. Epicardial angiogenesis was graded histologically on a scale of 0 to 2. Animals receiving intravenous administration of AII displayed left ventricular hypertrophy that disproportionately affected the interventricular septum with a wall thickness of 5.62 ± 1.00 mm versus 3.98 ± 0.61 mm in the AII group and the saline solution control group, respectively ( p < 0.005). A highly localized angiogenic effect of bFGF was observed. The mean angiogenesis scores were 1.9, 1.4, 1.3, and 0.2 ( p < 0.001) with an angiogenesis score of 2 (marked increase in vascularity) noted in 86%, 40%, 43%, and 0% of hearts in groups 1 through 4, respectively. We conclude that intrapericardial bFGF enhances new epicardial small-vessel growth in a rabbit model; furthermore this effect is enhanced in the presence of left ventricular hypertrophy.

The Role of Angiotensin II in the Regulation of Blood Flow to Choroid Plexuses and Cerebrospinal Fluid Formation in the Rat

The effect of peripherally administered angiotensin II (AII) on blood flow to choroid plexuses was examined in pentobarbital-anesthetized rats. The indicator fractionation method with 123I- or 125I-N-isopropyl-p-iodoamphetamine as the marker was employed to measure blood flow. Basal blood flow to choroid plexus of the lateral cerebral ventricle (LVCP) (3.19 +/- 0.23 ml g-1 min-1) was lower than that to choroid plexuses of the third (3VCP) and fourth (4VCP) ventricles (3.90 +/- 0.38 and 3.95 +/- 0.36 ml g-1 min-1, respectively). The effect of AII on choroidal blood flow varied depending on peptide dose and anatomical location of the choroidal tissue. AII infused intravenously at rates of 30 and 50 ng kg-1 min-1 decreased blood flow to both LVCP and 4VCP by 12-20%. Both lower (10 ng kg-1 min-1) and higher (100 and 300 ng kg-1 min-1) AII doses did not alter blood flow to LVCP and 4VCP. Blood flow to the 3VCP was not affected by any dose of the peptide used. In comparison, blood flow to cerebral cortex increased by 33% during intravenous AII infusion at a rate of 300 ng kg-1 min-1. The choroidal blood flow-lowering effect of moderate AII doses was abolished by both AT1 (losartan) and AT2 (PD 123319) receptor subtype antagonists (3 mg kg-1 i.v.). To determine whether the hemodynamic changes observed in choroid plexuses with moderate AII doses influence CSF formation, the ventriculocisternal perfusion was performed in rats (under the experimental conditions described) with Blue Dextran 2000 as the indicator.(ABSTRACT TRUNCATED AT 250 WORDS)

Fibronectin accumulation within cardiac myocytes in rats with elevated plasma angiotensin II

Elevation in plasma angiotensin II (AngII) is associated with cardiac myocyte necrosis. Myocyte necrosis followed by wound healing and fibrosis represents a structural remodeling of the myocardium thought to contribute to abnormal myocardial function. Fibronectin (FN) is generally considered an early component of the healing process that precedes collagen accumulation. To better understand the time course of this remodeling process involving both cardiac myocytes and extracellular matrix, (i.e., FN and collagen), we used two animal models: (1) endogenous activation of the renin-angiotensin system by surgical induction of renovascular hypertension and (2) exogenous AngII administration (150 ng/min/kg). Animals were killed at different time points within the first two weeks. Both “cellular” (cFN) and “plasma” (pFN) FN immunolabeling were compared with collagen distribution (picrosirius red stain), together with histopathologic (hematoxylin-eosin stain) and ultrastructural examination of cardiac myocytes. In each experimental group, the pattern and time course of FN immunolabeling was coincident with histopathologic evidence of myocyte injury and/or remodeling. We found different patterns of FN labeling of cardiac myocytes: (a) homogenous intracellular distribution in necrotic myocytes, most obvious on days 1 and 2; (b) patchy intracellular distribution in nonnecrotic myocytes starting on day 4; and (c) marking internalized capillaries. Both FNs were codistributed throughout the myocardium of each ventricle; however, cFN was less pronounced and not seen in mature scars. Ultrastructural examination revealed different kinds of intramyocytic inclusions, characterized by vacuoles containing fibrillar/flocculent material, remnants of unknown origin, or internalized capillaries. We conclude that FNs are markers of cardiac myocyte necrosis and early interstitial remodeling and that renovascular hypertension and AngII administration exhibit the same time course and pattern of FN and collagen expression.

Peptide Hormones Influence in Vitro Interrenal Secretion of Cortisol in the Trout, Oncorhynchus mykiss

Adrenocorticotrophic hormone (ACTH), angiotensin II (AII), and the urophysial peptides, urotensins I and II (UI and UII), stimulate cortisol secretion by interrenal preparations of seawater (SW) and freshwater (FW) adapted trout. Steroid secretion was not disturbed in sham-treated control groups. The increased cortisol secretion following perifusion of tissue with 10-7M ACTH in combination with 10-7M AII, 10-7M UI, or 10-7M UII was greater than after separate administration of ACTH, AII, UI, or UII. These responses were no greater than the summation of the separate effects of ACTH, AII, or UII in SW and FW derived tissue or of ACTH and UI in FW derived tissue. However, the increased cortisol secretion (600-700%) after UI and ACTH in combination in SW adapted fish was significantly higher than the summated responses (100-200%) to UI and ACTH when administered separately. These results suggest that in SW fish interrenal UI enhances the steroidogenic action of ACTH, a potentially important response in SW teleost fish.

Bicarbonate transport along the loop of Henle. II. Effects of acid-base, dietary, and neurohumoral determinants.

The loop of Henle contributes to renal acidification by reabsorbing about 15% of filtered bicarbonate. To study the effects on loop of Henle bicarbonate transport (JHCO3) of acid-base disturbances and of several factors known to modulate sodium transport, these in vivo microperfusion studies were carried out in rats during: (a) acute and chronic metabolic acidosis, (b) acute and chronic (hypokalemic) metabolic alkalosis, (c) a control sodium diet, (d) a high-sodium diet, (e) angiotensin II (AII) intravenous infusion, (f) simultaneously intravenous infusion of both AII and the AT1 receptor antagonist DuP 753, (g) acute ipsilateral mechanicochemical renal denervation. Acute and chronic metabolic acidosis increased JHCO3; acute metabolic alkalosis significantly reduced JHCO3, whereas chronic hypokalemic alkalosis did not alter JHCO3. Bicarbonate transport increased in animals on a high-sodium intake and following AII administration, and the latter was inhibited by the AII (AT1) receptor antagonist DuP 753; acute renal denervation lowered bicarbonate transport. These data indicate that bicarbonate reabsorption along the loop of Henle in vivo is closely linked to systemic acid-base status and to several factors known to modulate sodium transport.

Proliferogenic effect of neurotensin (NT) and neuromedin-N (NMN) on the rat adrenal cortex: Evidence that angiotensin-II mediates the effect of NMN, but not of NT

NT and NMN, two biologically active peptides acting via the same specific receptor, are both able to stimulate in vivo the proliferative activity of rat adrenocortical cells. The present study aimed to investigate whether the mechanism underlying this effect of NT and NMN may involve an enhanced production of angiotensin-II (ANG-II), a potent adrenocortical proliferogenic factor. Metaphases per adrenal section were counted 120 min after vincristin injection. A bolus administration of ANG-II resulted in a marked increase in the number of metaphase-arrested cells 12, 24 and 48 h after the beginning of the experiment; the concomitant administration of saralasin (SAR), a competitive antagonist of ANG-II, completely blocked the proliferogenic efect of ANG-II. NT-evoked rise in the number of metaphases occurred 48 h after administration and was not influenced by the simultaneous SAR injection. On the contrary, NMN injection induced a burst of adrenocortical cell proliferation within 12 h, and this effect was prevented by SAR. These data suggest that ANG-II mediates the proliferogenic effect of NMN, but not that of NT.

Synergist interaction between angiotensin II and DOCA on sodium and water balance in rats

Blockade of central angiotensin receptors with the specific antagonist [Leu 8]-ANG II abolished water ingestion and water and sodium excretion induced by infusion of angiotensin II (ANGII) into the lateral ventricle (LV) of rats. The antagonist reduced but did not suppress the salt appetite induced by ANGII infusion. Subcutaneous injection of deoxycorticosterone acetate (DOCA) caused increases in water and 3% NaCl ingestion and decreases in sodium excretion. When central ANGII infusion was combined with peripheral DOCA, the water intake was similar to that induced by ANGII alone and the ingestion of 3% NaCl was increased, whereas sodium excretion was inhibited. When ANGII was infused alone, a detailed temporal analysis of fluid and sodium balance showed a negative balance similar those saline controls that persisted throughout the experiment. Combined administration of ANGII and DOCA induce significant changes in water and sodium balance. Sodium and water maintained a positive balance through out the 8-h experiment. The data support an interaction of central ANGII and DOCA on sodium intake and water and sodium balance.

Renal Proliferative and Phenotypic Changes in Rats With Two-Kidney, One-Clip Goldblatt Hypertension

Angiotensin II (AII) is a vasoconstrictive peptide with hypertrophic and mitogenic effects on many cell types. Previous studies have shown that in vivo administration of AII in rats results in proliferation of, and phenotypic changes in, many renal cell populations, but in doses also causing hypertension. Thus, it was not possible to differentiate nonhemodynamic from hypertensive effects of AII. Therefore, we studied rats with renin-dependent, AII-mediated hypertension (the two-kidney, one-clip Goldblatt model; mean systolic blood pressure 238 +/- 48 v 140 +/- 6 mm Hg in sham-operated controls). The unclipped kidneys, which were exposed to high blood pressure, developed significant glomerular and tubulointerstitial injury, tubulointerstitial cell proliferation, dense focal interstitial monocyte-macrophage influx, increased deposition of types I and IV collagen, as well as increased cellular expression of desmin and actin, in tubulointerstitial areas when examined at 11 weeks. In contrast, clipped kidneys, protected from hypertension but with high local renin expression, had minimal abnormalities. These studies suggest that in this model increased renin, and presumably AII, does not mediate significant proliferative or phenotypic changes in the kidney in the absence of hypertension at 11 weeks.

Angiotensin II increases glucose utilization during acute hyperinsulinemia via a hemodynamic mechanism.

To determine whether hemodynamic changes can modulate insulin action in vivo, we administered angiotensin II (AII) to normal men under three separate, euglycemic conditions. First, in the presence of physiological hyperinsulinemia (approximately 115 microU/ml), infusion of AII at rates of 2, 10, and 20 ng/min per kg caused significant elevations of blood pressure, whole-body glucose clearance, and plasma insulin concentrations in an AII dose-dependent manner. Second, in the presence of plasma insulin concentrations that stimulate glucose transport maximally (approximately 5,000 microU/ml), AII infusions increased whole-body glucose clearance without enhancing glucose extraction across the leg. Third, in the presence of basal insulin concentrations (approximately 13 microU/ml), AII infusions had no effect on whole-body glucose turnover or leg glucose extraction. Thus, AII enhanced whole-body glucose utilization without directly stimulating glucose transport in a major skeletal muscle bed. To evaluate a possible hemodynamic mechanism for the effects of AII on glucose utilization, we measured blood flow to two areas that differ in their sensitivity to insulin: the kidneys and the leg. We found that AII redistributed blood flow away from the predominantly insulin-independent tissues of the kidney and toward the insulin-sensitive tissues of the leg during both sham and hyperinsulinemic glucose clamps. The redistribution of flow had no effect on whole-body glucose turnover when leg glucose uptake was unstimulated (sham clamps). However, when leg glucose uptake was activated by insulin, the redistribution of flow caused a net increase in whole-body glucose utilization. Our findings indicate that hemodynamic factors can modulate insulin action in vivo. Furthermore, our results suggest that variable activity of the renin-angiotensin system may contribute to inconsistencies in the association between insulin resistance and hypertension.

Induction of hyperhydration in rats by IP loading with graded concentrations of NaCl solution

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

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.

Role of angiotensin II and AT 1 receptors in hippocampal LTP

Results of a previous study showed that angiotensin II (AII) inhibited the induction of long-term potentiation (LTP) in hippocampal granule cells in response to dorsomedial perforant path stimulation in urethane-anesthetized rats. The results of present experiments demonstrate a dose-dependent inhibition of LTP induction under the same conditions due to ethanol (EtOH) administered by stomach tube and diazepam (DZ) injected IP. The inhibition of LTP induction by EtOH and DZ can be blocked by saralasin (SAR) applied directly to the dorsal hippocampus and by lorsartan (DuP 753) administered IP. Lorsartan or a metabolite crosses the blood-brain barrier because it also blocks the inhibition of LTP induction due to AII administration directly into the dorsal hippocampus. Lorsartan is a competitive antagonist of the AT 1 subtype AII receptor. Therefore, the AII and the EtOH and DZ inhibition of LTP induction are mediated by the AII subtype receptor AT 1. AIII and the AT 2 antagonist PD123319 did not produce any significant effects. These in vivo effects can be reproduced in brain slices and therefore cannot be attributed to other factors, such as the urethane. In addition, electrical stimulation of the lateral hypothalamus (LH) inhibits LTP induction, and the inhibition can be blocked by SAR. These data on LH stimulation indicate that LH AII-containing neurons send axons into the hippocampus that inhibit the induction of LTP. These results not only provide new information on a neurotransmitter involved in the amnesic effects of benzodiazepines and ethanol-induced memory blackouts, but also testable hypotheses concerning recent observations that angiotensin converting enzyme (ACE) inhibitors elevate mood and improve certain cognitive processes in the elderly.

Effect of chronic exposure to cold on vascular responsiveness to phenylephrine and angiotensin II.

Chronic exposure of rats to cold (5 degrees C, 3-4 weeks) results in the development of hypertension. To assess potential mechanisms by which this may occur, the vascular responsiveness to administration of phenylephrine (an alpha-adrenergic agonist) and angiotensin II (AII) was studied in unanesthetized rats at 1, 3 and 5 weeks of exposure to cold (5 degrees C). Vascular responsiveness to intravenous administration of graded doses of phenylephrine was reduced in cold-treated rats, the earliest effect being observed within 1 week of exposure. With respect to AII, vascular responsiveness to graded intravenous doses increased maximally within 1 week of exposure to cold and returned toward the level of the control group at 3 weeks. After 5 weeks of exposure to cold, it had returned to the level of the control group. These results suggest that vascular responsiveness to alpha-adrenergic stimulation appears to be directed toward prevention of an elevation of blood pressure in cold-treated rats. In contrast, vascular responsiveness to administration of AII is increased during the first 3 weeks of exposure to cold, at a time when plasma renin activity is also increased, and may thus play an important role in the initiation of cold-induced elevation of blood pressure.

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 μg/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 AT 1 because they are blocked by acute administration of the nonpeptide AT 1 receptor antagonist, losartan potassium (DuP 753) (10 mg/kg, SC). The responses were also blocked by the peptide AII receptor antagonist, saralasin, at 100 μg/kg SC. Chronic administration of the steroid deoxycorticosterone acetate (DOCA, 250–300 μg/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.