Changes in the regulation of cerebral vasoactive reactions and aging: the contribution of H₂S to cGMP-induced dilation

Signal cascade NO → soluble guanylate cyclase (sGC) → сyclic guanosine monophosphate (cGMP) → protein kinase G (PKG) plays a significant role in vascular dilation. Its disorders can cause the development of cerebrovascular diseases. The key unit in the NO → PKG signaling system is cGMP. Intracellular cGMP levels are largely regulated by cGMP-hydrolyzing phosphodiesterase (PDE) enzymes that break down cGMP. Aging is accompanied by a decrease in NO synthesis and cGMP levels and an increase in PDE activity. Under these conditions, it is possible to increase the contribution of compensatory mechanisms of activation of individual sections of the NO → PKG signaling pathway, in particular with the participation of intermediaries that change the cGMP level. Hydrogen sulfide (H₂S) is currently considered as one of the activators of the NO → PKG pathway, which can increase cGMP levels in cells by inhibiting PDE or its direct interaction with cGMP to form biologically active compounds that are less susceptible to enzymatic break down. H₂S-mediated cGMP activation has been shown in cardiomyocytes and smooth muscle cells of mesenteric and aortic vessels, but this mechanism has not been studied in cerebral vessels. The aim of the work was to study the contribution of H₂S to the regulation of cGMP-induced vasodilation of cerebral vessels and changes in this mechanism of regulation of vasoactive reactions during aging. In Sprague-Dawley 4 (young) and 18-month-old (aging) rats, a comparative study of the pial arteries dilatation to the effect of the penetrating into cells analog cGMP – 8-Br-cGMP was performed using intravital microphotography, and an assessment of the effect of exogenous (donor – NaHS) and endogenous H₂S on the cGMP-induced vasodilation. Propargylglycine was used as a blocker of endogenous H₂S. It was shown that in 4-month-old rats, the H₂S-mediated regulation of cGMP-induced dilation of the pial arteries was expressed only at the level of large arteries with a diameter of more than 40 microns. Aging leads to an increased contribution of endogenous H₂S to cGMP-induced dilation of the pial arteries of all calibers and an increased sensitivity of cGMP-mediated reactions of small pial arteries to exogenous H₂S.

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