Abstract
Polymorphisms in the genes encoding adducin, a membrane-skeletal protein, are associated with hypertension in humans and rats (Milan hypertensive strain, MHS). MHS rats, with their control normotensive strain (MNS), are a model for a subgroup of patients with essential hypertension. The relationship between adducin gene polymorphisms and renal dysfunction has been well-studied, but the mechanisms that underlie vascular functional abnormalities are unclear. Ca2+ homeostasis plays a crucial role in the genesis of vascular myogenic tone, and increases in cytosolic Ca2+ concentration ([Ca2+]cyt) appear to underlie at least part of the increased peripheral vascular resistance in hypertension. We hypothesize that Ca2+ signaling mediated by Na/Ca exchanger (NCX) and TRPC-encoded receptor-operated Ca2+ channels is up-regulated in MHS mesenteric artery myocytes compared with that in MNS. The [Ca2+]cyt was determined with digital imaging of Fura-2-loaded freshly dissociated mesenteric artery smooth muscle cells (ASMCs). On average, the MNS rats had a mean systolic BP (SBP) of 113 ± 1 mmHg; the SBP of the MHS rats was significantly higher (144 ± 2 mmHg, P < 0.05). Freshly dissociated MHS ASMCs had significantly higher resting [Ca2+]cyt than did MNS ASMCs (97 ± 2 nM vs. 78 ± 3 nM, P < 0.05). Receptor-operated entry was activated by the diacylglycerol analogue, 1-oleoyl-2-acetyl-sn-glycerol (OAG). In the presence of extracellular Ba2+, OAG (100 μM)-induced elevations of cytosolic Ba2+ (Fura-2 340/380 nm ratio) were significantly larger in MHS ASMCs. The ATP (5 μM)-induced Ca2+ responses were also augmented in MHS ASMCs (729 ± 70 nM vs. 533 ± 44 nM, P < 0.05). These changes in MHS ASMCs correlate with ∼3-fold up-regulation of TRPC6, while expression of other TRPCs was not changed. Recently we showed that expression of TRPC6 and NCX1 in ASMCs is inter-related and TRPC6 and NCX1 are both up-regulated in ouabain hypertensive rats (Pulina et al., Amer. J. Physiol. 298(1):H263-H274, 2010). Here, we show that NCX1 is also robustly (∼13-fold) up-regulated in MHS ASMCs. The findings suggest that up-regulation of NCX1 and TRPC6 can represent a general downstream phenomenon intrinsic to various forms of hypertension.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
