The dipsogenic potency of peripheral angiotensin II

The effective intravenous dose of angiotensin II for the induction of drinking in the rat has been reduced to a physiologically reasonable level of approximately 10 ng/min/rat or 25 ng/min/kg. It can be as low as 4 ng/min/rat when the natural state of thirst is more closely simulated with concurrent cellular dehydration. These doses are not different from those employed intravenously in the intact mammal to produce the hormone's pressor response. In addition: (i) the drinking produced by the hormone occurs sooner and more reliably and is greater in volume when the hormone is combined with mild cellular dehydration, and (ii) the drinking is blocked by a specific competitive inhibitor of angiotensin II, but (iii) is not affected by diurnal cycle. The evidence supports the suggestion that angiotensin II is a normal participant in drinking provoked by hypovolemia.     

Pertussis toxin blocks the dipsogenic actions of carbachol, but does not block the dipsogenic and pressor actions of angiotensin II

Rats were tested for dipsogenic and pressor responses to intracerebroventricularly (icv) administered Ang II and for dipsogenic responses to icv administered carbachol in the absence and presence of pertussis toxin, also administered icv. Pertussis toxin did not inhibit the pressor or dipsogenic responses to Ang II, but did inhibit the dipsogenic responses to carbachol. This suggests that the pressor and dipsogenic responses to Ang II in the brain are not mediated by a pertussis toxin-sensitive G protein, but that the muscarinic cholinergic dipsogenic response is mediated by a pertussis toxin-sensitive G protein.     

Role of thromboxane receptors in the dipsogenic response to central angiotensin II

Central angiotensin II (ANG II) regulates thirst. Because thromboxane A2-prostaglandin H2 (TP) receptors are expressed in the brain and mediate some of the effects of ANG II in the vasculature, we investigated the hypothesis that TP receptors mediate the drinking response to intracerebroventricular (icv) injections of ANG II. Pretreatment with the specific TP-receptor antagonist ifetroban (Ifet) decreased water intake with 50 ng/kg icv ANG II (ANG II + Veh, 7.2 +/- 0.7 ml vs. ANG II + Ifet, 2.8 +/- 0.8 ml; n = 5 rats; P < 0.001) but had no effect on water intake induced by hypertonic saline (NaCl + Veh, 8.4 +/- 1.1 ml vs. NaCl + Ifet, 8.9 +/- 1.8 ml; n = 5 rats; P = not significant). Administration of 0.6 microg/kg icv of the TP-receptor agonist U-46,619 did not induce drinking when given alone but did increase the dipsogenic response to a near-threshold dose of 15 ng/kg icv ANG II (ANG II + Veh, 1.1 +/- 0.7 vs. ANG II + U-46,619, 4.5 +/- 0.9 ml; n = 5 rats; P < 0.01). We conclude that central TP receptors contribute to the dipsogenic response to ANG II.     

Participation of noradrenergic neurotransmission in angiotensin III-induced dipsogenic behavior in the rat.

Conscious, adult, male Sprague-Dawley rats, instrumented with in-dwelling cannula for drug application into the lateral cerebral ventricle, were used to evaluate the participation of noradrenergic neurotransmission in angiotensin III (AIII)-induced dipsogenic behavior. Intracerebroventricular (i.c.v.) administration of AIII (20, 40 or 80 pmol) elicited a robust and dose-related drinking response. Chemical lesion produced by i.c.v. injection of the catecholaminergic neurotoxin, 6-hydroxydopamine (25 micrograms x 3), or the selective noradrenergic neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (250 micrograms), promoted significant antagonization of the dipsogenic behavior produced by AIII (40 or 80 pmol, i.c.v.). Under equimolar doses (3.25 or 6.50 nmol), the specific alpha 1-adrenoceptor blocker, prazosin, antagonized; the specific alpha 2-adrenoceptor antagonist, yohimbine, enhanced; and the nonselective alpha-adrenoceptor blocker, phentolamine, elicited minimal action, on AIII (40 pmol)-induced drinking response. These results suggest that central noradrenergic neurotransmission may participate actively in AIII-induced dipsogenesis, in a process that may involve both alpha 1- and alpha 2-adrenoceptors.     

Central angiotensin receptor blockade impairs thermolytic and dipsogenic responses to heat exposure in rats

The effect of central angiotensin AT(1) receptor blockade on thermoregulation and water intake after heat exposure was investigated. Rats were placed in a chamber heated to 39 +/- 1 degrees C for 60 min and then returned to their normal cage (at 22 degrees C), and water intake was measured for 120 min. Artificial cerebrospinal fluid (5 microl) was injected intracerebroventricularly 60 min before heat exposure in five control rats. Colonic temperature increased from 37.22 +/- 0.21 to 40.68 +/- 0.31 degrees C after 60 min. In six rats injected intracerebroventricularly with 10 microg of the AT(1) antagonist losartan, colonic temperature increased from 37.41 +/- 0.27 to 41.72 +/- 0.28 degrees C after 60 min. This increase was significantly greater than controls (P < 0.03). Losartan-treated rats drank 1.1 +/- 0.4 ml of water compared with 5.9 +/- 0.77 ml (P < 0.002) drank by control animals, despite a similar body weight loss in the two groups. Central losartan did not inhibit the drinking response to intracerebroventricular carbachol in heated rats, suggesting that losartan treatment did not nonspecifically depress behavior. We conclude that central angiotensinergic mechanisms have a role in both thermoregulatory cooling in response to heat exposure and also the ensuing water intake.     

Altered dipsogenic responses and expression of angiotensin receptors in the offspring exposed to prenatal high sucrose

The present study determined water and salt intake as well as expression of AT₁ and AT₂ receptors in the brain and kidney in the adult offspring rats prenatally exposed to high sucrose. Following the exposure during pregnancy, water intake and salt intake at baseline levels were not changed in the adult offspring. However, after 24 h water deprivation, consumption of water and salt was significantly increased compared to that of the control. Plasma sodium and osmolality levels remained the same between the offspring in the control and the exposed groups, while hematocrit was higher in the offspring exposed to prenatal high sucrose immediately following water deprivation. Density of renal AT₁ receptor protein was the same between the control and the exposed group, while AT₂ receptor protein in the kidney was significantly increased in the offspring exposed to prenatal high sucrose in association of thicker basal membrane of glomerular. In the forebrain, both AT₁ and AT₂ receptor levels were significantly increased in the offspring with history of prenatal high sucrose. In addition, water deprivation induced more c-fos expression in the central dipsogenic areas, including the paraventricular and supraoptic nuclei in the offspring exposed to prenatal high sucrose. The results suggested that prenatal high intake of sucrose may affect development of pathways in regulation of dipsogenic behavior in face of dehydration, which was associated with altered expression of AT₁ or/and AT₂ receptors in the kidney and brain.     

The action of angiotensin on the isolated perfused cat heart

The effects of angiotensin I (AI) and angiotensin (AII) on myocardial contractility, heart rate and coronary perfusion were observed in the isolated perfused cat heart. AII (10^?11 mol) and AI (10^?10 mol) both caused slowly developing sustained increases in systolic pressure of approximately 55%. There were inconsistent small increases in heart rate. Coronary perfusion was initially diminished, but later increased to above control values during the positive inotropic effect. The actions of both AI and AII were blocked by 1 sar 8 ile AII (10^?9 mol). The converting enzyme inhibitors SQ 20881 (10^?8 mol) and SQ 14225 (10^?8 mol) blocked the effect of AI. The actions of AII or AI were not blocked by α or β adrenergic blockade or by prior treatment with reserpine.     

An angiotensin II antagonist with strongly prolonged action

A highly hydrophobic analogue of angiotensin II (AT), [Sar1,(2',3',4',5',6'-Br5)Phe8]AT exhibited strong and persistent specific antagonism against AT, both in vitro and in vivo. This peptide exhibited 32% of the binding affinity of [Sar1]AT towards membranes of bovine adrenal cortex, it was a specific AT antagonist of irreversible character on smooth muscle assays, and it also suppressed for over 120 min at 7.10(-8) M/kg the blood pressure response towards AT in the rat blood pressure assay. This compound harbours therefore the potential of a new class of AT-specific antihypotensive drugs.     

Direct action of angiotensin II on the central neurons]

Reactions of the nervous cells in the somatosensory and visual regions of the brain cortex and the frontal hypothalamus in rabbits, as well as of the isolated nervous peripharyngeal ring of the Helix pomatia to the microionophoretic application of angiotensin II (A-II) was studied. Reactions of the neurons in the rabbit brain to A-II displayed an increase in the spike frequency depending on the quantity of the agent applied. Reactions of the frontal hypothalamus neurons showed a lower threshold than those of the brain cortex. A-II application to the some of the recorded cells of the mollusc evoked a marked reversible decrease in the membrane potential; as to the membrane resistance--it diminished 2--4 fold. These experimental data pointed to the direct A-II effect on the central neurons.     

Acute sympathoexcitatory action of angiotensin II in conscious baroreceptor-denervated rats

Angiotensin II (ANG II) has complex actions on the cardiovascular system. ANG II may act to increase sympathetic vasomotor outflow, but acutely the sympathoexcitatory actions of exogenous ANG II may be opposed by ANG II-induced increases in arterial pressure (AP), evoking baroreceptor-mediated decreases in sympathetic nerve activity (SNA). To examine this hypothesis, the effect of ANG II infusion on lumbar SNA was measured in unanesthetized chronic sinoaortic-denervated rats. Chronic sinoaortic-denervated rats had no reflex heart rate (HR) responses to pharmacologically evoked increases or decreases in AP. Similarly, in these denervated rats, nitroprusside-induced hypotension had no effect on lumbar SNA; however, phenylephrine-induced increases in AP were still associated with transient decreases in SNA. In control rats, infusion of ANG II (100 ng x kg(-1) x min(-1) iv) increased AP and decreased HR and SNA. In contrast, ANG II infusion increased lumbar SNA and HR in sinoaortic-denervated rats. In rats that underwent sinoaortic denervation surgery but still had residual baroreceptor reflex-evoked changes in HR, the effect of ANG II on HR and SNA was variable and correlated to the extent of baroreceptor reflex impairment. The present data suggest that pressor concentrations of ANG II in rats act rapidly to increase lumbar SNA and HR, although baroreceptor reflexes normally mask these effects of ANG II. Furthermore, these studies highlight the importance of fully characterizing sinoaortic-denervated rats used in experiments examining the role of baroreceptor reflexes.     

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.     

Mode of action of angiotensin II and vasopressin on their target cells

In this short review, the cellular mode of action of angiotensin II and arginine-vasopressin is described with emphasis on the transmembrane signalling system. Two target cells are considered: the zona glomerulosa cell of the adrenal gland and the vascular smooth muscle cell. The information provided should help practitioners in endocrinology and hypertension to understand the physiological concepts which are expected to form the basis for future therapeutic developments.