Rationale Nitric oxide, the classic endothelial derived relaxing factor (EDRF), acts via cyclic GMP and calcium without notably affecting membrane potential. A major component of EDRF activity derives from hyperpolarization and is termed endothelial derived hyperpolarizing factor (EDHF). Hydrogen sulfide (H2S) is a prominent EDRF, since mice lacking its biosynthetic enzyme, cystathionine γ-lyase (CSE), display pronounced hypertension with deficient vasorelaxant responses to acetylcholine. Objective The purpose of this study is to determine if H2S is a major physiologic EDHF. Methods and Results We now show that H2S is a major EDHF, as in blood vessels of CSE deleted mice hyperpolarization is virtually abolished. H2S acts by covalently modifying (sulfhydrating) the ATP-sensitive potassium channel, as mutating the site of sulfhydration prevents H2S-elicited hyperpolarization. The endothelial intermediate conductance (IKCa) and small conductance (SKCa) potassium channels mediate in part the effects of H2S, as selective IKCa and SKCa channel inhibitors, charybdotoxin and apamin, inhibit glibenclamide insensitive H2S induced vasorelaxation. Conclusions H2S is a major EDHF that causes vascular endothelial and smooth muscle cell hyperpolarization and vasorelaxation by activating the ATP-sensitive, intermediate conductance and small conductance potassium channels through cysteine S-sulfhydration. As EDHF activity is a principal determinant of vasorelaxation in numerous vascular beds, drugs influencing H2S biosynthesis offer therapeutic potential.
Aging leads to a multitude of changes in the cardiovascular system, including systolic hypertension, increased central vascular stiffness, and increased pulse pressure. In this paper we will review the effects of age-associated increased vascular stiffness on systolic blood pressure, pulse pressure, augmentation index, and cardiac workload. Additionally we will describe pulse wave velocity as a method to measure vascular stiffness and review the impact of increased vascular stiffness as an index of vascular health and as a predictor of adverse cardiovascular outcomes. Furthermore, we will discuss the underlying mechanisms and how these may be modified in order to change the outcomes. A thorough understanding of these concepts is of paramount importance and has therapeutic implications for the increasingly elderly population.
Background Erythrocyte cell membranes undergo morphologic changes during storage, but it is unclear whether these changes are reversible. We assessed erythrocyte cell membrane deformability in patients before and after transfusion to determine the effects of storage duration and whether changes in deformability are reversible after transfusion. Methods Sixteen patients undergoing posterior spinal fusion surgery were studied. Erythrocyte deformability was compared between those who required moderate transfusion (≥5 units erythrocytes) and those who received minimal transfusion (0–4 units erythrocytes). Deformability was measured in samples drawn directly from the blood storage bags before transfusion, and in samples drawn from patients before and after transfusion (over 3 postoperative days). In samples taken from the blood storage bags, we compared deformability of erythrocytes stored for a long duration (≥21 days), those stored for a shorter duration (<21 days), and cell-salvaged erythrocytes. Deformability was assessed quantitatively using the elongation index (EI) measured by ektacytometry, a method which determines the ability for the cell to elongate when exposed to shear stress. Results Erythrocyte deformability was significantly decreased from the preoperative baseline in patients after moderate transfusion (EI decreased by 12±4 to 20±6 %) (P = 0.03) but not after minimal transfusion (EI decreased by 3±1 to 4±1 %) (P = 0.68). These changes did not reverse over 3 postoperative days. Deformability was significantly less in erythrocytes stored for ≥21 days (EI = 0.28±0.02) than in those stored for <21 days (EI = 0.33±0.02) (P = 0.001) or those drawn from patients preoperatively (EI = 0.33±0.02) (P = 0.001). Cell-salvaged erythrocytes had intermediate deformability (EI = 0.30±0.03) that was greater than that of erythrocytes stored ≥21 days (P = 0.047), but less than that of erythrocytes stored <21 days (P = 0.03). Conclusions The findings demonstrate that increased duration of erythrocyte storage is associated with decreased cell membrane deformability and that these changes are not readily reversible after transfusion.
Melanopsin (opsin4; Opn4), a non-image-forming opsin, has been linked to a number of behavioral responses to light, including circadian photo-entrainment, light suppression of activity in nocturnal animals, and alertness in diurnal animals. We report a physiological role for Opn4 in regulating blood vessel function, particularly in the context of photorelaxation. Using PCR, we demonstrate that Opn4 (a classic G protein-coupled receptor) is expressed in blood vessels. Force-tension myography demonstrates that vessels from Opn4 −/− mice fail to display photorelaxation, which is also inhibited by an Opn4-specific small-molecule inhibitor. The vasorelaxation is wavelength-specific, with a maximal response at ∼430-460 nm. Photorelaxation does not involve endothelial-, nitric oxide-, carbon monoxide-, or cytochrome p450-derived vasoactive prostanoid signaling but is associated with vascular hyperpolarization, as shown by intracellular membrane potential measurements. Signaling is both soluble guanylyl cyclase-and phosphodiesterase 6-dependent but protein kinase G-independent. β-Adrenergic receptor kinase 1 (βARK 1 or GRK2) mediates desensitization of photorelaxation, which is greatly reduced by GRK2 inhibitors. Blue light (455 nM) regulates tail artery vasoreactivity ex vivo and tail blood blood flow in vivo, supporting a potential physiological role for this signaling system. This endogenous opsin-mediated, lightactivated molecular switch for vasorelaxation might be harnessed for therapy in diseases in which altered vasoreactivity is a significant pathophysiologic contributor.hotorelaxation, the reversible relaxation of blood vessels to cold light, was initially described by Furchgott et al. in 1955 (1). Subsequent studies have attempted to define the signal transduction mechanisms responsible for this phenomenon. The process seems to be cGMP-dependent but endothelialindependent. The role of nitric oxide (NO) in photorelaxation has been controversial (2-7), with some studies showing that NOS inhibition with L-NAME not only fails to inhibit the response (2) but in some cases enhances and prolongs it (3). Moreover, several published reports examining photorelaxation demonstrate an attenuation of the response with each subsequent light stimulation. A number of investigators have proposed that NO dependence results from the photo-release of NO stores from nitrosothiols and that the endothelium and NOS are important for the repriming of these stores (stores that become depleted with each photo-stimulation); however, the source of those nitrosothiols has not as yet been clearly identified (6). Importantly, photo-release of NO occurs in the UV-A spectrum at 366 nm (4-6), a wavelength at which intravascular nitrosospecies and nitrite have the potential to release substantial quantities of NO (7). However, this wavelength is very different from that at which others have observed vascular responses. Given the controversy surrounding the photorelaxation mechanism, we postulated an entirely new mechanism: that photorelaxation i...
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