APX Rats Research Articles

Forced-choice discrimination of equimolar NaCl and LiCl solutions in rats: effects of ablating the chemosensitive area postrema on acquisition and retention

The area postrema (AP), a chemosensitive organ located in the fourth ventricle, has been shown to mediate the formation of a lithium-induced conditioned taste avoidance (CTA) in rats. The present experiments examined the role of the AP in the discrimination between two equimolar solutions of sodium chloride (NaCl) and lithium chloride (LiCl). In the first experiment adult male rats were trained to discriminate between equimolar (0.12 M) solutions of NaCl and LiCl in a forced-choice procedure over a 10-day acquisition phase. Subsequently half of the rats ( n=7) received AP lesions (APX) and the other half ( n=7) were given sham lesions (SHAM). In the retention phase all animals were again exposed to the same salt solutions over a 10-day period. Good discrimination ( P<0.001) between the two salt solutions was demonstrated by the end of the acquisition phase and both the APX and SHAM groups exhibited robust retention ( P<0.01) of this discrimination in the second phase. However, when only a LiCl solution was available the APX group ingested significantly more ( P<0.01) than the SHAM rats. No significant group difference emerged when only NaCl was available. In the second experiment rats received ablations of AP or sham lesions and were then trained to discriminate between 0.12 M NaCl and LiCl solutions in a forced-choice procedure over a 10-day period. Both groups exhibited a clear discrimination ( P<0.01) between the two solutions by the end of the acquisition phase. APX rats ingested significantly more LiCl ( P<0.01) than did the SHAM group when this was the only type of fluid available. Again, no such difference was evident when only NaCl was available. These experiments demonstrate that the AP is not necessary for either the acquisition or retention of a discrimination between equimolar solutions of NaCl and LiCl in a forced-choice procedure and that this discrimination is not mediated by a conditioned taste aversion to the LiCl solution.

Hypotensive Response to Losartan in Normal Rats

We have reported that the angiotensin II (Ang II) AT1 receptor antagonist losartan markedly lowers arterial pressure in sodium-replete, normotensive rats. We hypothesized that this action of losartan was mediated by its blocking the effects of endogenous Ang II. To test this hypothesis, rats were instrumented with arterial and venous catheters for measurement of arterial pressure and infusion of losartan, respectively. After 3 days of control measurements, losartan was infused for 10 days (10 mg/kg/d) in rats on a normal daily sodium intake (NNa; approximately 2 mmol/d, n=6) and rats on a high daily sodium intake (HNa; approximately 15 mmol/d, n=7) to suppress endogenous Ang II. Although basal plasma renin activity was markedly suppressed in HNa rats (0.9 +/- 0.4 ng Ang I/ mL/h) compared with NNa rats (4.0 +/- 0.3 ng Ang I/mL/h), control arterial pressure was not different between NNa (113 +/- 4 mm Hg) and HNa (113 +/- 2 mm Hg) rats. Losartan decreased arterial pressure from control levels in NNa rats on the first day of infusion (-12 +/- 2 mm Hg) but had no effect on arterial pressure in HNa rats (+4 +/- 4 mm Hg). Furthermore, by day 10 of losartan infusion, arterial pressure had decreased further from control levels in NNa rats (-32 +/- 2 mm Hg) but remained unchanged compared with control in HNa rats (+5 +/- 6 mm Hg). A second study was conducted to test the hypothesis that the area postrema, a circumventricular organ proposed to mediate the long-term neurogenic pressor activity of Ang II is a site of action for losartan. After 3 control days, losartan was administered for 10 days to area postrema-lesioned rats (APx; n=11) or sham-lesioned rats (n=10) consuming an NNa diet. Control arterial pressure was similar in sham (95 +/- 3 mm Hg) and APx (96 +/- 2 mm Hg) rats. Basal plasma renin activity was not different between groups (sham, 4.1 +/- 1.5 versus APx, 5.3 +/- 1.6 mm Hg Ang I/mL/h). On day 1 of losartan treatment, arterial pressure decreased to a significantly lower level in sham (80 +/- 2 mm Hg) compared with APx (90 +/- 3 mm Hg) rats. This trend continued through day 4 of losartan infusion, in which arterial pressure in sham rats (72.2 +/- 2 mm Hg) was significantly lower than in APx rats (83 +/- 4 mm Hg). However, during the remainder of the losartan infusion, there were no significant differences between groups with the exception of day 8 (sham, 72 +/- 2 mm Hg; APx, 84 +/- 2 mm Hg). Taken together, these results support the hypothesis that the hypotensive actions of losartan in sodium-replete, normotensive rats are due to blockade of the physiological effects of endogenous Ang II. Furthermore, an intact area postrema is essential for full expression of the hypotensive actions of losartan in normal rats.

Enhanced bradycardia but not renal sympathoinhibition during hemorrhage in rats with area postrema lesions

Hypotensive hemorrhage inhibits renal sympathetic nerve activity (SNA) and heart rate (HR) in rats. The area postrema (AP) is reported to modulate autonomic responses to arginine vasopressin (AVP) and may be a site where circulating AVP influences SNA and HR during hypotensive hemorrhage. We found a similar renal sympathoinhibition in AP-lesioned (APX) and sham-lesioned (Sham) rats during hypotensive hemorrhage and a greater bradycardia in APX compared with Sham rats. Further inhibition of renal SNA with AVP infusion was not observed in APX rats, although the bradycardic action of AVP infusion was comparable to that in Sham rats. Thus the AP attenuates bradycardia but not renal sympathoinhibition during hypotensive hemorrhage in normal rats. Nonetheless, an intact AP permits further reduction in renal SNA during infusion of AVP. If AVP contributes to hypotensive hemorrhage-induced renal sympathoinhibition, its action may occur at sites other than the AP or at the AP where such action is counterbalanced by sympathoexcitatory factor(s) also activated during hypotensive hemorrhage. Finally, enhanced bradycardia during hypotensive hemorrhage in APX rats suggests it may not be the site of action for AVP-induced bradycardia in intact rats.

Food Aversion Induced by Area Postrema Ablation

Rats with lesions of the area postrema (APX rats) avoid foods ingested on a regular basis during the period of severe hypophagia immediately following surgery (Tomoyasu & Kenney, 1989). The present work determined whether APX rats would also avoid foods to which they are exposed only after they have recovered from the lesion-induced hypophagia. APX and SHAM-lesion rats were fed a novel food for 8 days beginning at least 1 month after surgery when food intakes (adjusted for body weight) and weight gains of the APX rats had returned to control levels. During 24 h, two-food choice tests, APX rats avoided the food ingested a month after the ablation while avidly ingesting an alternative food, but SHAM rats showed no preference between the foods. There was no indication that this aversion developed by APX rats to foods ingested after recovery from hypophagia is weaker than that developed to foods ingested immediately after the lesion. We conclude that area postrema ablation results in the development of an unconditioned stimulus capable of supporting food-aversion conditioning which remains effective more than 1 month after the ablation. Hence, the relationship between APX-induced food aversion and hypophagia must be indirect and complex. Also, conditioning of food aversions induced by area postrema ablation alone may confound studies of the role of this structure in mediating the development of food aversions after other physiological and/or pharmacological manipulations.

Area postrema and differential reflex effects of vasopressin and phenylephrine in rats

In normal rats, baroreflex inhibitions of heart rate (HR) and splanchnic but not lumbar sympathetic neural activity (SNA) are greater when mean arterial pressure (MAP) is increased by intravenous infusion of arginine vasopressin (AVP) compared with phenylephrine (PE) or methoxamine. In normal rabbits, baroreflex inhibitions of HR and lumbar and renal SNA are all greater when MAP is increased by AVP vs. PE. The differential reflex bradycardic and renal sympathoinhibitory effects of AVP vs. PE in rabbits require an intact area postrema. To determine whether differential reflex effects of AVP vs. PE in rats is selective for HR or inclusive of renal SNA and to examine the role of the rat area postrema in such action, we monitored HR and renal SNA in normal (sham operated, n = 8) and area postrema-lesioned (APX, n = 8) rats under chloralose anesthesia during slow increases in MAP (less than 0.3 mmHg/s; 3 min) induced intravenously by AVP (0-16 mU.kg-1.min-1) and by PE (0-8 micrograms.kg-1.min-1). Reflex inhibition of HR (-delta betas.min-1.delta mmHg-1) was greater when MAP was increased by AVP vs. PE in normal rats (-2.7 +/- 0.5 vs. -1.7 +/- 0.1, P less than 0.05), and this difference was absent in APX rats (-2.5 +/- 0.5 vs. +/- -2.2 +/- 0.4). Similarly, maximum bradycardia (-delta beats/min) by AVP vs. PE was greater in normal rats (-64 +/- 8 vs. -48 +/- 7, P less than 0.05) but not in APX rats (-53 +/- 5 vs. -52 +/- 6).(ABSTRACT TRUNCATED AT 250 WORDS)

Role of atrial peptide in the acute natriuretic response to uninephrectomy

Unilateral nephrectomy (UNX) is associated with an immediate natriuretic response of the remaining kidney. The role of atrial natriuretic peptide (ANP), as assessed by right atrial appendectomy (APX), was investigated in euvolemic anaesthetized rats. In sham APX rats, UNX resulted in a twofold increase in urinary sodium and potassium excretion (1.03 +/- 0.11 to 2.08 +/- 0.17 and 1.39 +/- 0.05 to 2.26 +/- 0.08 mueq/min, respectively) and a doubling of urinary excretion of guanosine 3',5'-cyclic monophosphate (cGMP). No significant change in glomerular filtration rate, renal plasma flow, and lithium clearance occurred in response to UNX. APX totally prevented the UNX-induced natriuresis and diuresis as well as the rise in urinary cGMP. Post-UNX plasma concentration of ANP was higher in sham-operated compared with APX rats (45 +/- 9 vs. 20 +/- 2 fmol/ml). In sham APX rats, UNX was associated with a transient (less than 15 min) rise in arterial pressure; in APX rats, this immediate increase in arterial pressure was of similar magnitude but of longer (greater than 30 min) duration. The observed stimulation of ANP release after UNX and the blunting of the natriuretic response to UNX by APX suggest that ANP may be an important mediator of the renal response to contralateral renal ablation.

Response to chronic insulin administration: Effect of area postrema ablation

The effects of daily administration of protamine zinc insulin (PZI) on plasma insulin and glucose levels and on food intake and body weight of rats with lesions of the area postrema and adjacent caudal-medial portions of the nucleus of the solitary tract (APX rats) were examined. Prior to insulin treatment, APX rats weighed less and had lower plasma immunoreactive insulin (IRI) levels than nonlesioned controls but did not differ from controls in plasma glucose levels. Five daily injections of 5 U/kg PZI raised plasma IRI and lowered plasma glucose levels similarly for both lesioned and nonlesioned rats. When injected with increasing doses of PZI over a 30-day period, both lesioned and nonlesioned rats showed increases of food intake and rate of weight gain in response to 8 U/kg PZI. These data indicate that APX does not affect either physiological or behavioral responses to chronic peripheral insulin administration.

Effect of circulating vasopressin on arterial pressure regulation in rats

It has been hypothesized that moderately increased blood levels of arginine vasopressin (AVP) contribute to the development and/or maintenance of hypertension. In this study, male Sprague-Dawley rats on a fixed 1 meq daily sodium intake received 10-day intravenous infusions of 0.2 and 2.0 ng.kg-1.min-1 AVP. The higher infusion rate was above the acute vasoconstrictor threshold for AVP administration and also produced a maximal antidiuretic effect. During chronic AVP administration, however, daily mean arterial pressure, heart rate, and body fluid composition were not changed, despite a maintained antidiuresis. To test the hypothesis that circulating AVP failed to cause hypertension as a result of sensitization of the baroreflex or a direct sympathoinhibitory effect of the peptide, additional experiments were performed in rats subjected to sinoaortic denervation (SAD) or ablation of the area postrema (APX). Infusion of AVP for 10 days into SAD or APX rats caused a sustained antidiuresis but did not change arterial pressure, heart rate, or body fluid composition. In all groups of rats, the depressor response to ganglionic blockade (20 mg/kg hexamethonium) was used to estimate the autonomic component of resting arterial pressure; no change in autonomic cardiovascular control was found using this method in any of the groups during AVP infusion. Long-term elevation of plasma AVP in rats, therefore, does not cause hypertension or significantly affect autonomic regulation of arterial pressure.

Effects of Testosterone and Dihydrotestosterone on Spermatogenesis, Rete Testis Fluid, and Peripheral Androgen Levels in Hypophysectomized Rats

To compare the effects of testosterone (T) and dihydrotestosterone (DHT) on the maintenance and the restoration of spermatogenesis, hypophysectomized (APX) rats were treated daily for 35 days with 0.5 mg of T propionate (TP) or DHT propionate (DHTP) beginning 5 or 33 days after hypophysectomy. In the maintenance experiment, the weights of the testes and the number of early spermatids were significantly lower in DHTP-than in TP-treated animals, while late spermatids were present only in rats treated with TP. In the restoration experiment, TP increased testicular weight and the number of germinal cells, whereas DHTP had very little effect on the testis. In an attempt to explain these findings, we measured androgen levels in the rete testis fluid (RTF) and peripheral plasma of APX rats treated with TP or DHTP. The concentration of T in the RTF of TP-treated rats was nearly 3-fold higher than the level of DHT in the RTF of animals given DHTP. Plasma T levels measured 1/2, 2, 4, and 24 hours after the last of three daily injections of TP were considerably higher than were the corresponding plasma DHT levels in animals given DHTP. In animals treated with free steroids, peripheral androgen levels between 1/2 and 4 hours after the last injection were much higher in rats given T than in those given DHT, but thereafter this difference disappeared. We conclude that the difference in the ability of subcutaneously injected TP and DHTP to maintain and to restore spermatogenesis in APX rats was due to a difference in androgen levels in the testes of these animals.

Regulation of ovarian cholesterol esters: evidence for the enzymatic sites of prostaglandin-induced loss of corpus luteum function.

AbstractThe regulation of cholesterol ester synthetase and cholesterol esterase by prostaglandins and gonadotrophins in luteinized ovaries of the rat was studied. Prostaglandin F2α (PGF2α) depressed ovarian cholesterol esters by 75% (p&lt;.025) within 48 hr. Hypophysectomy (APX) produced a similar effect; prolactin administration to this group maintained cholesterol esters at a higher level than in the APX group but the trophic effect of prolactin was abolished by simultaneous PGF2α treatment. Progesterone output in incubated ovarian slices was reduced 50% by PGF2α treatment in vivo (p&lt;.005), an effect similar to that produced by APX. Prolactin administration in vivo maintained the ability of the incubated tissue to synthesize progesterone at an elevated rate in APX rats but simultaneous PGF2α treatment abolished this action of prolactin. Cholesterol ester synthetase activity was severely depressed (p&lt;.005) by PGF2α treatment to animals with intact pituitaries, a decrease similar to that produced by APX alone. The effect of APX on synthetase activity was reversed by prolactin treatment but not when PGF2α was administered with prolactin. Esterase activity, also maintained by prolactin in APX animals (p&lt;.005), was not affected to the same extent by PGF2α although a decrease in activity was produced in both the intact and the APX+ prolactin group by PGF2α (p&lt;.10). However simultaneous administration of luteinizing hormone (LH) reversed the effect of PGF2α in the APX+ prolactin +PGF2α group on esterase activity. These data indicate that the luteolytic action of PGF2α is directly on the corpus luteum and this action appears to be mediated by a neutralization of prolactin activity. The loss in synthetase activity and to some extent in esterase activity, induced by PGF2α depressed ovarian cholesterol ester turnover and the availability of cholesterol for conversion to progesterone.