Previous studies have shown that preconditioning rats with a non-pressor dose of angiotensin II (AngII) sensitizes the pressor response produced by later treatment with a higher dose of AngII and that AngII and aldosterone (Aldo) can modulate each other’s pressor effects through actions involving the central nervous system (CNS). The current studies tested whether Aldo can cross-sensitize the pressor actions of AngII to enhance hypertension by employing an Induction-Delay-Expression (I-D-E) experimental design. Male rats were implanted for telemetered BP recording. During I, sub-pressor doses of either sc or icv Aldo were delivered for 1 week. Rats were then rested for 1 week (D) to assure that any exogenous Aldo was metabolized. After this, AngII was given sc for 2 weeks (E). During I and D Aldo had no sustained effect on BP. However, during E AngII-induced hypertension was greater in the groups receiving sc or icv Aldo during I in comparison to those groups receiving vehicle. Central administration of mineralocorticoid receptor antagonist blocked sensitization. Brain tissue collected at the end of D and E showed increased mRNA expression of several renin-angiotensin-aldosterone system components in cardiovascular-related forebrain regions of cross-sensitized rats. Cultured subfornical organ neurons preincubated with Aldo displayed greater increases in [Ca2+]i after AngII, and there was greater Fra-like immunoreactivity present at the end of E in cardiovascular-related forebrain structures. Taken together, these results indicate that Aldo pretreatment cross-sensitizes the development of AngII-induced hypertension probably by mechanisms that involve the CNS.

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Bilateral injections of the GABA(A) agonist muscimol into the lateral parabrachial nucleus (LPBN) disrupt satiety and induce strong ingestion of water and 0.3M NaCl in fluid-replete rats by mechanisms not completely clear. In the present study, we investigated the effects of the blockade of central muscarinic cholinergic receptors with atropine injected intracerebroventricularly (i.c.v.) on 0.3M NaCl and water intake induced by muscimol injections into the LPBN in fluid-replete rats. Male Holtzman rats with stainless steel cannulas implanted bilaterally into the LPBN and unilaterally into the lateral ventricle (LV) were used. Bilateral injections of muscimol (0.5nmol/0.2μL) into the LPBN induced 0.3M NaCl (32.2±9.9mL/4h, vs. saline: 0.4±0.2mL/4h) and water intake (11.4±4.4mL/4h, vs. saline: 0.8±0.4mL/4h) in fluid-replete rats previously treated with i.c.v. injection of saline. The previous i.c.v. injection of atropine (20nmol/1μL) reduced the effects of LPBN-muscimol on 0.3M NaCl (13.5±5.0mL/4h) and water intake (2.9±1.6mL/4h). The i.c.v. injection of atropine did not affect 0.3M NaCl (26.8±6.2mL/2h, vs. saline i.c.v.: 36.5±9.8mL/2h) or water intake (14.4±2.5mL/2h, vs. saline i.c.v.: 15.6±4.8mL/2h) in rats treated with furosemide+captopril subcutaneously combined with bilateral injections of moxonidine (α(2)-adrenoceptor/imidazoline agonist, 0.5nmol/0.2μL) into the LPBN, suggesting that the effect of atropine was not due to non-specific inhibition of ingestive behaviors. The results show that active central cholinergic mechanisms are necessary for the hypertonic NaCl and water intake induced by the blockade of the inhibitory mechanisms with injections of muscimol into the LPBN in fluid-replete rats. The suggestion is that in fluid-replete rats the action of LPBN mechanisms inhibits facilitatory signals produced by the activity of central cholinergic mechanisms to maintain satiety.

Renovascular hypertensive 2-kidney, 1-clip (2K1C) rats have an increased activity of the renin-angiotensin system and an initial transitory increase in daily water and NaCl intake. However, the dipsogenic and natriorexigenic responses to angiotensin II (ANG II) have not been tested yet in 2K1C rats. Therefore, in the present study, we evaluated water and 0.3 M NaCl intake induced by water deprivation (WD)-partial rehydration (PR) or intracerebroventricular (icv) ANG II in 2K1C rats. In addition, the cardiovascular changes to these treatments were also evaluated. Male Holtzman rats received a silver clip around the left renal artery to induce 2K1C renovascular hypertension. In the 5th week, a group of animals received a guide cannula in the lateral ventricle for icv injections. Daily water intake increased from the 3rd week after surgery and remained elevated until the 6th week (last recording week), whereas daily 0.3 M NaCl intake transiently increased from the 2nd to the 5th week after surgery. On the 6th week, in spite of comparable daily 0.3 M NaCl intake between 2K1C and sham rats, WD-PR and icv ANG II induced an increased 0.3 M NaCl intake in 2K1C rats. Water intake induced by WD-PR, not by icv ANG II, also increased in 2K1C rats. The increase in arterial pressure to WD-PR or icv ANG II was similar in sham and 2K1C rats. Therefore, these results suggest that 2K1C rats are more responsive to the natriorexigenic effects of ANG II, whereas other responses to ANG II are not modified.

Bilateral injections of the GABAA agonist muscimol into the lateral parabrachial nucleus (LPBN) induce 0.3 M NaCl and water intake in satiated and normovolemic rats, a response reduced by intracerebroventricular (icv) administration of losartan or atropine (angiotensinergic type 1 (AT1) and cholinergic muscarinic receptor antagonists, respectively). In the present study, we investigated the effects of the injections of losartan or atropine into the subfornical organ (SFO) on 0.3 M NaCl and water intake induced by injections of muscimol into the LPBN. In addition, using intracellular calcium measurement, we also tested the sensitivity of SFO-cultured cells to angiotensin II (ANG II) and carbachol (cholinergic agonist). In male Holtzman rats with cannulas implanted bilaterally into the LPBN and into the SFO, injections of losartan (1 μg/0.1 μl) or atropine (2 nmol/0.1 μl) into the SFO almost abolished 0.3 M NaCl and water intake induced by muscimol (0.5 nmol/0.2 μl) injected into the LPBN. In about 30% of the cultured cells of the SFO, carbachol and ANG II increased intracellular calcium concentration ([Ca2+]i). Three distinct cell populations were found in the SFO, i.e., cells activated by either ANG II (25%) or carbachol (2.6%) or by both stimuli (2.3%). The results suggest that the activation of angiotensinergic and cholinergic mechanisms in the SFO is important for NaCl and water intake induced by the deactivation of LPBN inhibitory mechanisms with muscimol injections. They also show that there are cells in the SFO activated by both angiotensinergic and cholinergic stimuli, perhaps those involved in the responses to muscimol into the LPBN.