An activated renin–angiotensin system maintains normal blood pressure in aryl hydrocarbon receptor heterozygous mice but not in null mice

Abstract

It has been postulated that fetal vascular abnormalities in aryl hydrocarbon receptor null (ahr −/− ) mice may alter cardiovascular homeostasis in adulthood. We tested the hypothesis that blood pressure regulation in adult heterozygous mice (ahr +/− ) would be normal, compared to ahr −/− mice, since no vascular abnormalities have been reported in the heterozygote animals. Mean arterial blood pressure (MAP) was measured using radiotelemetry prior to and during treatment with inhibitors of the autonomic nervous system, nitric oxide synthase (NOS), angiotensin converting enzyme (ACE), or endothelin-1 A receptor (ET A ). Also, indices of renin-angiotensin system (RAS) activation were measured. ahr +/− and ahr −/− mice were normotensive and hypotensive, respectively, compared to wild-type (ahr +/+ ) littermates. Responses of all genotypes to autonomic nervous system inhibition were normal. ahr +/− mice responded normally to NOS inhibition, while the responses of ahr −/− mice were significantly blunted. In contrast, ahr +/− mice were significantly more responsive to inhibition of ACE, an ET A antagonist, or both, while ahr −/− mice were significantly less response to ACE inhibition and more response to an ET A antagonist. ahr +/− mice also exhibited significant increases in plasma renin and ACE activity, plasma sodium, and urine osmolality, indicative of RAS activation. Thus, normotension in ahr +/− mice appears to be maintained by increased RAS and ET-1 signaling, while hypotension in ahr −/− mice may result from decreased RAS signaling. In conclusion, despite the lack of overt fetal vascular abnormalities in ahr +/− mice, the loss of a single ahr allele has a significant effect on blood pressure regulation.

Role of CYP1A1 in Modulating the Vascular and Blood Pressure Benefits of Omega-3 Polyunsaturated Fatty Acids

“…Studies demonstrate that sustained activation of the AHR by xenobiotics promotes the development of cardiovascular disease, including increasing blood pressure and increasing the progression of atherosclerosis (Dalton et al, 2001;Korashy and El-Kadi, 2006;Kopf et al, 2010). In contrast, genetic deletion of AHR results in low blood pressure (Zhang et al, 2010;Agbor et al, 2011Agbor et al, , 2012. Thus, it has been proposed that constitutive (i.e., physiologic) AHR signaling via an endogenous ligand is cardiovascular protective, whereas sustained (i.e., toxicologic) AHR signaling via xenobiotic ligands promotes cardiovascular disease pathogenesis.…”

A less stressful alternative to oral gavage for pharmacological and toxicological studies in mice

“…We have applied this pill formulation method successfully to incorporate both therapeutic drugs and xenobiotics into pills, including the angiotensin converting enzyme inhibitor, captopril (Zhang et al , 2010); the endothelin A receptor antagonist, PD155080 (de Frutos et al , 2010; Zhang et al , 2010), and the environmental pollutant, 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) (Kopf et al , 2010). We have used various solvents to dissolve the drugs or xenobiotics, including water, dimethly sulfoxide, p -dioxane, and corn oil, and no problems were observed when incorporating any of these solvents into the transgenic dough.…”

Endothelin-1 contributes to increased NFATc3 activation by chronic hypoxia in pulmonary arteries

“…All treatments were started 1 day before CH exposure, followed by 2 days during CH. NFAT-luc mice were treated as follows: 1) bosentan (dual ET receptor antagonist; 30 mg·kg Ϫ1 ·day Ϫ1 ; gift from Actelion Pharmaceuticals, Switzerland) was administered in the drinking water; 2) cyclosporine A (CsA, calcineurin inhibitor; 25 mg·kg Ϫ1 ·day Ϫ1 ; Calbiochem) or Cremophor EL (vehicle, Sigma) was injected subcutaneously; 3) PD155080 (selective ETAR antagonist; 50 g·kg Ϫ1 ·day Ϫ1 ; College of Pharmacy, University of New Mexico) or placebo was administered in oral dough pellets (17,84); 4) diltiazem (L-type Ca 2ϩ channel inhibitor; 100 mg·kg Ϫ1 ·day Ϫ1 ; Sigma) or saline (vehicle) was administered subcutaneously via osmotic pumps (Alzet); or 5) the ROK inhibitors fasudil (30 mg·kg Ϫ1 ·day Ϫ1 ), HA 1152 (1 mg·kg Ϫ1 ·day Ϫ1 ) (both from LC Laboratories), or saline (vehicle) was administered subcutaneously via osmotic pumps.…”