Weight loss and hypophagia after high-dose AT1-blockade is only observed after high dosing and depends on regular leptin signalling but not blood pressure.

AT(1)-blockade has been shown to induce weight loss in animals or patients. The aim of this study was to investigate whether weight reduction after AT(1)-blockade is dependent on dose, blood pressure reduction and leptin signalling. Spontaneously hypertensive rats (SHR) and lean and obese Zucker rats were treated for 4 weeks with candesartan (0, 2, 6 or 16 mg/kg/day). Body weight, food intake and hypothalamic mRNA levels of (an)orexigenic peptides were determined. Obese Zucker rats served as a model of primary leptin resistance. In SHR, body mass index and food intake were decreased selectively by 16 mg/kg/day candesartan but not after using normal (2 mg/kg/day) or supranormal (6 mg/kg/day) doses. Correlation analysis between blood pressure and body weight indicated no relationship of hypotensive potency on weight loss. The hypothalamic mRNA levels of the orexigenic peptide MCH (melanin-concentrating hormone) were diminished in parallel. Consistent to the results in SHRs, 16 mg/kg/day candesartan revealed a decrease of body weight, food intake and hypothalamic MCH mRNA levels in lean Zucker rats. In obese Zucker rats, none of these parameters were reduced by candesartan. Loss of body weight and hypophagia are not general features of AT(1)-blockers, since neither was seen after normal or moderately supranormal doses, but they were, after the highest doses. These actions of AT(1)-blockers occur independently of their ability to lower blood pressure. They do depend on an intact leptin signalling, since they were absent in obese Zucker rats that feature a genetic mutation of the leptin receptor.

Angiotensin II inhibition reduces stress sensitivity of hypothalamo-pituitary-adrenal axis in spontaneously hypertensive rats.

Angiotensin II type 1 (AT(1)) receptors are expressed within organs of the hypothalamo-pituitary-adrenal (HPA) axis and seem to be important for its stress responsiveness. Secretion of CRH, ACTH, and corticosterone (CORT) is increased by stimulation of AT(1) receptors. In the present study, we tested whether a blockade of the angiotensin II system attenuates the HPA axis reactivity in spontaneously hypertensive rats. Spontaneously hypertensive rats were treated with candesartan (2 mg/kg), ramipril (1 mg/kg), or mibefradil (12 mg/kg) for 5 wk. In addition to baseline levels, CORT and ACTH responses to injection of CRH (100 microg/kg) were monitored over 4 h. mRNA of CRH, proopiomelanocortin, AT(1A), AT(1B), and AT(2) receptors was quantified by real-time PCR. All treatments induced equivalent reductions of blood pressure and had no effect on baseline levels of CORT and ACTH. However, both candesartan and ramipril significantly reduced CRH-stimulated plasma levels of ACTH (-26 and -15%) and CORT (-36 and -18%) and lowered hypothalamic CRH mRNA (-25 and -29%). Mibefradil did not affect any of these parameters. Gene expression of AT(1A), AT(1B), and AT(2) receptors within the HPA axis was not altered by any drug. We show for the first time that antihypertensive treatment by inhibition of AT(1) receptors or angiotensin-converting enzyme attenuates HPA axis reactivity independently of blood pressure reduction. This action is solely evident after CRH stimulation but not under baseline conditions. Both a reduced pituitary sensitivity to CRH and a down-regulation of hypothalamic CRH expression have the potential to reduce HPA axis activity during chronic AT(1) blockade or angiotensin-converting enzyme inhibition.