Porter, James P., and Kristen R. Potratz. Effect of intracerebroventricular angiotensin II on body weight and food intake in adult rats. Am J Physiol Regul Integr Comp Physiol 287: R422-R428, 2004. First published April 29, 2004; 10.1152/ajpregu.00537.2003.-We recently reported that intracerebroventricular infusions of ANG II decreased food intake and increased energy expenditure in young rats. The aim of the present study was to determine if intracerebroventricular ANG II has similar effects in adult rats. The time course of the effect was also investigated with the idea that at earlier time points, a potential role for increased hypothalamic expression of corticotropinreleasing hormone (CRH) in the anorexia could be established. Finally, the contribution of ANG II-induced water drinking to the decrease in food intake was directly investigated. Rats received intracerebroventricular saline or ANG II using osmotic minipumps. Food intake, water intake, and body weight were measured daily. Experiments were terminated 2, 5, or 11 days after the beginning of the infusions. ANG II (ϳ 32 ng ⅐ kg Ϫ1 ⅐ min Ϫ1 ) produced a transient decrease in food intake that lasted for 4 -5 days although body weight continued to be decreased for the entire experiment most likely due to increased energy expenditure as evidenced by increased uncoupling protein-1 mRNA expression in brown adipose tissue. At 11 and 5 days, the expression of CRH mRNA was decreased. At 2 days, CRH expression was not suppressed even though body weight was decreased. The decrease in food intake and body weight was identical whether or not rats were allowed to increase water consumption. These data suggest that in adult rats ANG II acts within the brain to affect food intake and energy expenditure in a manner that is not related to water intake. corticotropin-releasing hormone; uncoupling protein-1; paraventricular nucleus; brown adipose tissue; blood pressure IT IS NOW WELL KNOWN that ANG II has effects on food intake and energy expenditure (4 -7). We recently showed in young 3-wk-old rats that chronic intracerebroventricular infusion of ANG II decreased the rate of weight gain, in part by decreasing food intake, and in part by increasing energy expenditure (14). Systemic infusion of identical doses of ANG II had no effect, suggesting that the response was mediated by an action of the peptide within the brain. However, it was not known if the observed effects of ANG II were somehow associated with the fact that the rats were young and in a rapid growing phase. For example, a potential effect of intracerebroventricular ANG II to inhibit growth hormone release could have contributed to the decrease in weight gain (9,17). A primary aim of the present study, therefore, was to determine if intracerebroventricular infusion of ANG II had similar effects on body weight and energy expenditure in adult rats that were beyond the rapid growing phase.A possible connection between brain ANG II and food intake involves corticotropin-releasing hormone (CRH) in the paraventricu...

To investigate mechanisms underlying the agonist-induced desensitization of the type 1A angiotensin II receptor (AT1A-R), we have stably expressed in Chinese hamster ovary (CHO) cells the wild-type receptor and truncated mutants lacking varying lengths of the cytoplasmic tail. Assay of inositol 1,4,5-trisphosphate (IP3) formation in response to agonist demonstrated that the truncated mutants T318, T328, and T348 lacking the last 42, 32, or 12 amino acid residues, respectively, couple with Gq protein with an efficiency similar to that of full-length receptors, whereas coupling of Gq protein was abolished in the T310 truncated mutant devoid of the carboxyl-terminal 50 amino acids. Exposure of CHO/AT1A-R cells expressing the wild-type AT1A-R to angiotensin II resulted in rapid and dose-dependent homologous desensitization of receptor-mediated IP3 formation, which was independent of the receptor internalization. Mastoparan, an activator of G protein-coupled receptor kinase (GRK), induced desensitization of the AT1A-R. The agonist-induced desensitization of the receptor was largely prevented by heparin, a potent inhibitor of GRK, whereas it was only partially attenuated by a protein kinase C (PKC)-specific inhibitor. The homologous or heterologous desensitization of the receptor was greatly impaired in the truncated mutants T318 and T328, lacking the Ser/Thr-rich (13 or 12 Ser/Thr residues) cytoplasmic tail of the AT1A-R. Deletion of the last two Ser residues, including one PKC consensus site in the receptor tail, prevented only phorbol 12-myristate 13-acetate-induced desensitization by 30%. Moreover, we found an agonist-induced translocation of a heparin-sensitive kinase activity. The angiotensin II-stimulated heparin-sensitive kinase could phosphorylate a thioredoxin fusion protein containing the entire AT1A-R cytoplasmic tail (N295 to E359), which lacks consensus phosphorylation sites for GRK1, GRK2, and GRK3. The heparin-sensitive kinase may not be GRK2, GRK3, or GRK6 expressed in CHO/AT1A-R cells, since angiotensin II did not induce translocation of these receptor kinases. Potential Ser/Thr phosphorylation sites located between S328 and S347 in the cytoplasmic tail of AT1A-R seem to play a critical role in the heterologous and homologous desensitization of the receptor. A heparin-sensitive kinase other than GRK2, GRK3, or GRK6 may be involved in the agonist-induced homologous desensitization of the AT1A-R.

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Porter JP, King SH, Honeycutt AD. Prenatal high-salt diet in the Sprague-Dawley rat programs blood pressure and heart rate hyperresponsiveness to stress in adult female offspring. Am J Physiol Regul Integr Comp Physiol 293: R334-R342, 2007. First published May 9, 2007; doi:10.1152/ajpregu.00887.2006.-Several animal models have been developed to study fetal programming of hypertension. One model involves feeding high-salt (HS) diet to rats before and during pregnancy, during lactation, and after weaning for 10 days. In the present investigation, we limited HS diet to the prenatal period in an attempt to find a narrower critical window for fetal programming. The HS diet did not result in low-birth weight offspring. In the adult offspring, radiotelemetry was used to assess blood pressure and heart rate in the conscious unstressed state. As adults, the HS offspring were not hypertensive compared with normal-salt (NS) control animals. However, the pressor and tachycardic responses to 1-h of restraint were significantly enhanced in HS female offspring, and recovery after restraint was delayed. This was accompanied by an increase in relative expression of corticotropin-releasing hormone (CRH) mRNA in the paraventricular nucleus of the hypothalamus during basal and stressed conditions. There was no augmented stress response or relative increase in CRH mRNA in adult HS male offspring. When challenged with 1 wk of 8% NaCl diet as adults, neither HS male nor female offspring exhibited salt sensitivity compared with NS groups. These data show that a high-salt diet limited to the prenatal period is not sufficient to program hypertension in adult offspring. However, this narrower critical period is sufficient to imprint a lasting hyperresponsiveness to stress, at least in adult female offspring. These data indicate that excessive maternal salt intake during pregnancy can adversely affect the cardiovascular health of adult offspring. corticotropin-releasing hormone; paraventricular nucleus; hypertension; radiotelemetry; sodium chloride; pregnancy; prenatal nutrition physiology IN RECENT YEARS, SEVERAL ANIMAL models have been developed to study developmental origins (also known as fetal programming) of adult diseases, including hypertension. Most of these have been models of low birth weight in an attempt to better understand clinical data in humans that suggest low birth weight is associated with hypertension in later life. Of these, the protein undernutrition model has received the most attention. Limiting maternal protein intake during pregnancy produces small offspring in rats. These offspring are hypertensive as adults (24,31,45). Another model has used ligation of the uterine arteries to produce underperfusion of the placenta. Offspring are small and develop hypertension as adults (1, 36). A third model involves injection of dexamethasone into pregnant animals near parturition. Once again, offspring are small and develop hypertension later in life (11, 44). All of these models provide evidence that the fetal environment...