Regulation of Vascular Tone from Spontaneously Hypertensive Rats by the HMG-CoA Reductase Inhibitor, Simvastatin

Abstract

The acute effect of simvastatin on aortic rings from spontaneously hypertensive rats (SHRs) was identified. Simvastatin-evoked relaxations of both depolarized and phenylephrine-precontracted arteries were independent of the presence of endothelium. This effect was inhibited by diltiazem and mevalonate, but not by the Rho-kinase inhibitor, Y-27632. Simvastatin prevented contraction induced by phenylephrine, calcium ionophore A-23187 and CaCl₂ in Ca²⁺-free medium. Y-27632 decreased the effect of simvastatin. On the contrary, contraction induced by noradrenaline in Ca²⁺-free medium was not affected. These results suggest that simvastatin elicited an effect on vascular smooth muscle cells from SHRs that may involve blockade of extracellular calcium entry and decrease vascular contraction by affecting Rho-kinase.

Endothelium-dependent vasorelaxation to the AMPK activator AICAR is enhanced in aorta from hypertensive rats and is NO and EDCF dependent

“…Although we did not investigate intracellular signaling mechanisms within the vascular smooth muscle that could contribute to AICAR-mediated endothelium-independent relaxation in the present study, previous in vitro biochemical experiments demonstrate that AMPK is able to phosphorylate and desensitize MLCK and thus could presumably induce relaxation in the context of an intact vascular system (31). Endothelium-independent relaxation to AICAR may also occur due to effects of AMPK on HMG-CoA reductase (10,16,33,44), which could involve modulation of Rho-kinase and L-type channel extracellular calcium entry (45), thus potentially exerting influence over vascular smooth muscle mechanisms of calcium sensitization and calcium-mediated contraction. As indicated, however, we did not undertake to study these mechanisms in the current study, and additional cellular and physiological studies will be required to elucidate mechanisms of AMPK-mediated relaxation in vascular smooth muscle.…”

Pharmacological Actions of Statins: A Critical Appraisal in the Management of Cancer

“…Moreover, statins, promoting the dedifferentiation of SMC, could up-regulate the expression of calcium channels, thereby reverting the loose of efficacy of calcium channel blockers that occurs with disease progression (Clunn et al, 2010). Simvastatin per se has been reported to block calcium entry through the inhibition of Rho/Rho kinase (Pérez-Guerrero et al, 2005). Statins have been also reported to protect from pulmonary arterial hypertension, reducing neointimal thickening and improving endothelial dysfunction and inflammation, in hypoxic, high pulmonary blood flow and embolism conditions (Nishimura et al, 2003;Girgis et al, 2007).…”

Repurposing simvastatin as a therapy for preterm labor: evidence from preclinical models

“…In addition, they are reported to have immunomodulation, anti-inflammatory, and antioxidative stress properties (13, 14). Of relevance to PTL, studies have also suggested that statins can exert anticontractile effects on vascular smooth muscle cells and endometriotic stromal cells, as well as on mouse and human myometrial tissue (15–19). These properties make statins potential candidates to repurpose for the prevention of PTB and the morbidity associated with it.…”