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.     

心房钠尿肽的中枢性心血管和肾效应

在麻醉大鼠观察了颈动脉、脊髓蛛网膜下腔和侧脑室内注射心房钠尿肽(Atrial natri-uretic peptide,ANP)后,血压,心率或/和尿量、尿钠和尿钾的变化,并观察了 ANP 对血管紧张素Ⅱ(AGⅡ)中枢效应的影响。结果如下:(1)在大鼠头部交叉循环条件下,经受血鼠颈总动脉内注射α-人心房钠尿多肽(α-human atrial natriurctic polypeptide,α-hANP)(15μg/kg)后,受血鼠平均动脉压(MAP)无改变,而供血鼠的 MAP 降低,⊿MAP为-2.4±0.84kPa(-18±6.3mmHg,P<0.05),(2)脊髓蛛网膜下腔注射心房肽,Ⅱ(AtriopeptinⅡ,APⅡ)(5μg/kg)对血压、心率和尿量无明显影响;(3)侧脑室注射 APⅡ(20μg/kg)后血压和心率无显著改变,尿量仅在注射后第30至50min 时显著增加,而尿钠无改变;(4)侧脑室注射 AGⅡ(1μg/kg),血压升高,⊿MAP 为1.3±0.17kPa(10±1.3mmHg,n=10,P<0.001)。注射1h 后,尿量增加106%(P<0.01),尿钠增加642%(P<0.01);(5)事先侧脑室注射 APⅡ(20μg/kg),2min 后再注入 AGⅡ(1μg/kg),AGⅡ的中枢升压效应不受影响,⊿MAP为1.5±0.25kPa(11±1.9mmHg,n=7,P<0.01),而尿量和尿钠的增值明显减小。以上结果表明,ANP 难于透过血脑脑脊血屏障,可能与其分子量较大有关。在静脉注射 ANP 所致降压效应中,似无中枢机制的参与。ANP 对 AGⅡ     

Central angiotensin II stimulates cutaneous water intake behavior via an angiotensin II type-1 receptor pathway in the Japanese tree frog Hyla japonica

Angiotensin II (Ang II) stimulates oral water intake by causing thirst in all terrestrial vertebrates except anurans. Anuran amphibians do not drink orally but absorb water osmotically through ventral skin. In this study, we examined the role of Ang II on the regulation of water-absorption behavior in the Japanese tree frog (Hyla japonica). In fully hydrated frogs, intracerebroventricular (ICV) and intralymphatic sac (ILS) injection of Ang II significantly extended the residence time of water in a dose-dependent manner. Ang II-dependent water uptake was inhibited by ICV pretreatment with an angiotensin II type-1 (AT₁) receptor antagonist but not a type-2 (AT₂) receptor antagonist. These results suggest that Ang II stimulates water-absorption behavior in the tree frog via an AT₁-like but not AT₂-like receptor. We then cloned and characterized cDNA of the tree frog AT₁ receptor from the brain. The tree frog AT₁ receptor cDNA encodes a 361 amino acid residue protein, which is 87% identical to the toad (Bufo marinus) AT₁ receptor and exhibits the functional characteristics of an Ang II receptor. AT₁ receptor mRNAs were found to be present in a number of tissues including brain (especially in the diencephalon), lung, large intestine, kidney and ventral pelvic skin. When tree frogs were exposed to dehydrating conditions, AT₁ receptor mRNA significantly increased in the diencephalon and the rhombencephalon. These data suggest that central Ang II may control water intake behavior via an AT₁ receptor on the diencephalon and rhombencephalon in anuran amphibians and may have implications for water consumption in vertebrates.     

Role of brain angiotensin AT1 receptor in the carbachol-induced natriuresis and expression of nNOS in the locus coeruleus and proximal convoluted tubule

Central administration of losartan effectively blocked the increase of blood pressure and drinking response induced by angiotensin II (Ang II) or carbachol. However, the relationship between angiotensin AT(1) receptors and the natriuresis induced by brain cholinergic stimuli is still not clear. The purpose of the study is to reveal the role of brain angiotensin AT(1) receptor in the carbachol-induced natriuresis and expression of neuronal nitric oxide synthase (nNOS) in the locus coeruleus (LC) and proximal convoluted tubule (PCT). Our results indicated that 40 min after intracerebroventricular (ICV) injection of carbachol (0.5 microg), urinary sodium excretion was significantly increased to 0.548+/-0.049 micromol x min(-1) x 100 g(-1). Immunohistochemistry showed that carbachol induced an increase of neuronal nitric oxide synthase immunoreactivity (nNOS-IR) in the LC and renal proximal tubular cells. After pretreatment with losartan (20 microg), carbachol-induced urinary sodium excretion was reduced to 0.249+/-0.067 micromol x min(-1) x 100 g(-1). The same was true for carbachol-induced increase of nNOS-IR in the LC and PCT. The present data suggest that ICV cholinergic stimulation could induce a natriuresis and upregulate the activity of nNOS in the LC and PCT. The blockade of AT(1) receptors might downregulate the effects induced by carbachol in the LC and PCT. Consequently, we provide a new evidence that brain angiotensinergic pathway and NO-dependent neural pathway contribute to the natriuresis following brain cholinergic stimulation and thus play an important role in the regulation of fluid homeostasis. Furthermore, the final effect of nitric oxide on proximal tubular sodium reabsorption participated in the natriuresis induced by brain cholinergic stimulation.     

Involvement of endogenous ouabain-like compound in the cardiac hypertrophic process in vivo

The Na(+)/K(+)-ATPase inhibitor ouabain has been shown to trigger hypertrophic growth of cultured cardiomyocytes; however, the significance of endogenous ouabain-like compound (OLC) in the hypertrophic process in vivo is unknown. Here we characterized the involvement of OLC in left ventricular (LV) hypertrophy induced by norepinephrine (NE) and angiotensin II (Ang II) infusions in rats. Administration of NE (300 microg/kg/h) via subcutanously implanted osmotic minipumps for 72 h resulted in a significant increase in left ventricular weight to body weight (LVW/BW) ratio (P<0.001) and a substantial up-regulation of atrial natriuretic peptide (ANP) gene expression (13.2-fold, P<0.001). NE infusion induced a transient increase in plasma OLC levels at 12 h (P<0.05), which returned to control levels by 72 h. Adrenalectomy markedly reduced both basal and NE-induced increase in plasma OLC levels. LVW/BW ratio was not modulated by adrenalectomy; however, ANP gene expression was blunted by 44% (P<0.01) and 47% (P<0.05) at 12 and 72 h, respectively. In agreement, adrenalectomy reduced up-regulation of ANP without affecting LV mass in rats infused with Ang II (33 microg/kg/h). Administration of exogenous ouabain (1 nM to 100 microM) for 24 h had no effect on ANP gene expression in cultured neonatal rat ventricular myocytes. However, the up-regulation of ANP mRNA levels induced by the alpha-adrenergic agonist phenylephrine (1 microM) was markedly enhanced by ouabain (100 microM) (5.6-fold vs. 9.6-fold, P<0.01). These data show that OLC as an adrenal-derived factor may be required for the induction LV ANP gene expression during the hypertrophic process.     

Chronic treatment with trans resveratrol prevents intracerebroventricular streptozotocin induced cognitive impairment and oxidative stress in rats

We have recently shown free radical generation is associated with cognitive impairment in intracerebroventricular (ICV) streptozotocin (STZ) model of sporadic dementia of Alzheimer's type in rats. Trans resveratrol is a polyphenolic compound and is known to have antioxidant activity. In the present study, the effect of trans resveratrol was investigated on ICV STZ induced cognitive impairment and oxidative stress in rats. Adult male Wistar rats were injected with ICV STZ bilaterally, on day 1 and day 3. The learning and memory behavior was assessed using passive avoidance paradigms, elevated plus maze and the closed field activity test while the parameters of oxidative stress assessed were malondialdehyde [MDA] and glutathione. The rats were treated with trans resveratrol chronically at doses of 10 and 20 mg/kg,i.p. for 21 days starting from day 1 of STZ injection. Trans resveratrol treatment significantly prevented ICV STZ induced cognitive impairment. There was a rise in brain glutathione and an insignificant increase in brain MDA in trans resveratrol treated ICV STZ rats as compared to significantly elevated brain MDA levels in the vehicle treated ICV STZ animals. The study demonstrates the effectiveness of trans resveratrol in preventing the cognitive deficits as well as the oxidative stress caused by ICV STZ in rats and it's potential in the treatment of neurodegenerative diseases such as Alzheimer's disease.     

Endogenous angiotensin II suppresses stretch-induced ANP secretion via AT1 receptor pathway

Angiotensin II (Ang II) is released by stretch of cardiac myocytes and has paracrine and autocrine effects on cardiac myocytes and fibroblasts. However, the direct effect of Ang II on the secretion of atrial natriuretic peptide (ANP) is unclear. The aim of the present study is to test whether Ang II affects stretch-induced ANP secretion. The isolated perfused beating atria were used from control and two-kidney one-clip hypertensive (2K1C) rats. The volume load was achieved by elevating the height of outflow catheter connected with isolated atria from 5 cmH₂O to 7.5 cmH₂O. Atrial stretch by volume load caused increases in atrial contractility by 60% and in ANP secretion by 100%. Ang II suppressed stretch-induced ANP secretion and tended to increase atrial contractility whereas losartan stimulated stretch-induced ANP secretion. Neither PD123319 nor A779 had direct effect on stretch-induced ANP secretion. The suppressive effect of Ang II on stretch-induced ANP secretion was blocked by the pretreatment of losartan but not by the pretreatment of PD123319 or A779. In hypertrophied atria from 2K1C rats, stretch-induced ANP concentration attenuated and atrial contractility augmented. The response of stretch-induced ANP secretion to Ang II and losartan augmented. The expression of AT1 receptor protein and mRNA increased but AT2 and Mas receptor mRNA did not change in 2K1C rat atria. Therefore, we suggest that Ang II generated endogenously by atrial stretch suppresses stretch-induced ANP secretion through the AT1 receptor and alteration of Ang II effect in 2K1C rat may be due to upregulation of AT1 receptor.     

Interaction of atrial natriuretic polypeptide and angiotensin II on protooncogene expression and vascular cell growth.

Recent evidence suggests that vasoconstrictive substances, including angiotensin II (Ang II), may function as a vascular smooth muscle growth promoting substance and may contribute to vascular hypertrophy in hypertension. Atrial natriuretic polypeptide (ANP) is known to be a physiological antagonist to Ang II in blood pressure and fluid homeostasis. Moreover, we have demonstrated that ANP can attenuate Ang II's action on vascular hypertrophy. In this study, we investigated the potential molecular mechanisms for the interaction of ANP and Ang II on vascular cell growth. Ang II dose-dependently induced RNA synthesis in post confluent cultured rat aortic smooth muscle (RASM) cells. ANP (10(-7) M) inhibited the hypertrophic effect of Ang II at the concentration of 10(-10) - 10(-8) M) but exerted no effect on the action of higher doses (10(-7) - 10(-6) M) of Ang II. Ang II (10(9) - 10(-8) M) and a protein kinase C activator, phorbol 12-myristate 13-acetate (PMA, 10(-8) M) rapidly induced c-fos as well as c-Jun and Jun-B mRNA expression in RASM cells. ANP (10(-7) M) itself had no apparent effect on the expression of these protooncogenes. Furthermore, ANP did not inhibit the induction of these protooncogenes by Ang II or PMA. Paradoxically, ANP (10(-7) M) significantly enhanced c-fos mRNA expression induced by Ang II and PMA. However, the chloramphenicol acetyl transferase (CAT) assay using a CAT expression vector containing the AP-1 binding element showed that ANP had no effect on the basal and PMA-stimulated AP-1 activity in transfected RASM cells. We conclude, therefore, that the inhibitory effect of ANP on the growth of vascular smooth muscle cells in vitro does not occur through the regulation of these protooncogene expressions.     

Role of nitric oxide on atrial natriuretic peptide release induced by angiotensin II in superfused rat atrial tissue

The present study investigated the role of nitric oxide (NO) on atrial natriuretic peptide (ANP) release stimulated by angiotensin II (Ang II) (10(-7) M) in superfused sliced rat atrial tissue. The use of N(G)-nitro-L-arginine methyl ester (L-NAME) at 10(-4) M, an inhibitor of nitric oxide synthase did not modify basal ANP release. In presence of Ang II (10(-7) M), we observed that L-NAME enhanced ANP secretion induced by Ang II. Furthermore, cGMP levels increased significantly in the presence of Ang II and was attenuated by L-NAME. On the other hand, the perfusion of 8 bromo-cGMP (10(-5) M) with Ang II reduced the effect of this octapeptide on ANP secretion. Secondly, we evaluated the effect of authentic NO on ANP release and observed that perfusion of NO reduced significantly the effect of Ang II on ANP release. We propose that the effect of Ang II on ANP secretion was modulated by NO likely via cGMP pathway.     

Central interaction of the brain atrial natriuretic polypeptide (ANP) system and the brain renin-angiotensin system in ANP secretion from heart--evidence for possible brain-heart axis

To elucidate the involvement of the brain renin-angiotensin system and the brain atrial natriuretic polypeptide (ANP) system in the regulation of ANP secretion from the heart, the effects of intracerebroventricular administration of angiotensin II and ANP on the plasma ANP level were examined in conscious unrestrained rats. The intracerebroventricular administration of angiotensin II at doses of 100 ng and 1 microgram significantly enhanced ANP secretion induced by volume-loading with 3-mL saline infusion (peak values of the plasma ANP level: control, 220 +/- 57 pg/mL; 100 ng angiotensin II, 1110 +/- 320 pg/mL, p less than 0.01; 1 microgram angiotensin II, 1055 +/- 60 pg/mL, p less than 0.01). The intracerebroventricular injection of angiotensin II at the same doses alone had no significant effect on the basal plasma ANP level. The enhancing effect of central angiotensin II on ANP secretion induced by volume-loading was significantly attenuated by pretreatment with the intravenous administration of the V1-receptor antagonist of vasopressin or with the intracerebroventricular administration of phentolamine. The intracerebroventricular administration of alpha-rANP(4-28) (5 micrograms) had no significant influence on the basal plasma ANP level; however, it significantly attenuated central angiotensin II potentiating effect of volume-loading induced ANP secretion. These results indicate that the brain renin-angiotensin system regulates ANP secretion via the stimulation of vasopressin secretion and (or) via the activation of the central alpha-adrenergic neural pathway, and that the brain ANP system interacts with the brain renin-angiotensin system in the central modulation of ANP secretion from the heart.(ABSTRACT TRUNCATED AT 250 WORDS)