The main etiology for mortality and a great percent of morbidity in patients with diabetes mellitus is atherosclerosis. A hypothesis for the initial lesion of atherosclerosis is endothelial dysfunction, defined pragmatically as changes in the concentration of the chemical messengers produced by the endothelial cell and/or by blunting of the nitric oxide-dependent vasodilatory response to acetylcholine or hyperemia. Endothelial dysfunction has been documented in patients with diabetes and in individuals with insulin resistance or at high risk for developing type 2 diabetes. Factors associated with endothelial dysfunction in diabetes include activation of protein kinase C, overexpression of growth factors and/or cytokines, and oxidative stress. Several therapeutic interventions have been tested in clinical trials aimed at improving endothelial function in patients with diabetes. Insulin sensitizers may have a beneficial effect in the short term, but the virtual absence of trials with cardiovascular end-points preclude any definitive conclusion. Two trials offer optimism that treatment with ACE inhibitors may have a positive impact on the progression of atherosclerosis. Although widely used, the effect of hypolipidemic agents on endothelial function in diabetes is not clear. The role of antioxidant therapy is controversial. No data have been published regarding the effects of hormonal replacement therapy on endothelial dysfunction in postmenopausal women with type 2 diabetes.

The mechanism of action of acupuncture remains largely unknown. The reaction to acupuncture needling known as 'de qi', widely viewed as essential to the therapeutic effect of acupuncture, may be a key to understanding its mechanism of action. De qi includes a characteristic needling sensation, perceived by the patient, and 'needle grasp' perceived by the acupuncturist. During needle grasp, the acupuncturist feels pulling and increased resistance to further movement of the inserted needle. We hypothesize that 1) needle grasp is due to mechanical coupling between the needle and connective tissue with winding of tissue around the needle during needle rotation and 2) needle manipulation transmits a mechanical signal to connective tissue cells via mechanotransduction. Such a mechanism may explain local and remote, as well as long-term effects of acupuncture.

We hypothesize that actin polymerization within vascular smooth muscle (VSM) in response to increased intravascular pressure is a novel and previously unrecognized mechanism underlying arterial myogenic behavior. This hypothesis is based on the following observations. 1) Unlike skeletal or cardiac muscle, VSM contains a substantial pool of unpolymerized globular (G) actin whose function is not known. 2) The cytosolic concentration of G-actin is significantly reduced by an elevation in intravascular pressure, demonstrating the dynamic nature of actin within VSM and implying a shift in the F:G equilibrium in favor of F-actin. 3) Agents that inhibit actin polymerization and stabilize the cytoskeleton (cytochalasins and latrunculin) inhibit the development of myogenic tone and decrease the effectiveness of myogenic reactivity. 4) Depolymerization of F-actin with cytochalasin D causes VSM relaxation and increased G-actin content, whereas polymerization of F-actin with jasplakinolide causes VSM contraction and decreased G-actin content. These results are consistent with observations in other cell types in which actin dynamics have been implicated in contractility and/or motility. Actin filament formation in VSM may therefore underlie mechanotransduction and, by providing additional sites for interaction with myosin, enhance force production in response to pressure. Although the mechanism by which actin polymerization is stimulated by pressure is not known, it likely occurs via integrin-mediated activation of signal transduction pathways previously associated with VSM contraction (e.g., PKC activation, Rho A, and tyrosine phosphorylation).

Background and Purpose-Magnesium sulfate is used extensively for prevention of eclamptic seizures. Empirical and clinical evidence supports the effectiveness of magnesium sulfate; however, questions remain as to its safety and mechanism. This review summarizes current evidence supporting the possible mechanisms of action and several controversies for magnesium sulfate treatment. Summary of Review-Several mechanisms are presented, including the effects of magnesium sulfate on peripheral and cerebral vasodilation, blood-brain barrier protection, and as an anticonvulsant. Conclusions-Though the specific mechanisms of action remain unclear, the effect of magnesium sulfate in the prevention of eclampsia is likely multi-factorial. Magnesium sulfate may act as a vasodilator, with actions in the peripheral vasculature or the cerebrovasculature, to decrease peripheral vascular resistance or relieve vasoconstriction. Additionally, magnesium sulfate may also protect the blood-brain barrier and limit cerebral edema formation, or it may act through a central anticonvulsant action.

Background and Purpose-The role of SK Ca and IK Ca channels in myogenic tone and endothelium-derived hyperpolarizing factor (EDHF) responsiveness was investigated under control conditions and after ischemia and reperfusion in parenchymal arterioles (PA) versus middle cerebral arteries (MCA). Methods-MCA and PA were dissected from male Wistar rats that were ischemic for 1 hour with 24 hours of reperfusion (nϭ12) or sham controls (nϭ12). Basal tone and reactivity to apamin (300 nmol/L), TRAM-34 (1.0 mol/L), and nitro-L-arginine (0.1 mmol/L) were compared in PA and MCA pressurized to 40 mm Hg and 75 mm Hg, respectively. SK Ca and IK Ca channel mRNA expression was measured using real-time PCR. Results-PA developed greater basal tone than MCA (42Ϯ4% versus 19Ϯ3%; PϽ0.01). Addition of apamin and TRAM-34 increased tone of PA by 25Ϯ3% and 16Ϯ2%, respectively, whereas MCA had no response to either inhibitor. After ischemia and reperfusion, the response to nitric oxide synthase inhibition (NOS) was diminished in PA, whereas EDHF responsiveness was preserved. In addition, stimulated EDHF dilation was partially reversed by apamin and completely reversed by TRAM-34 in both control and ischemic PA. SK Ca and IK Ca channel mRNA expression was similar in PA and MCA and not altered by ischemia and reperfusion. However, IK Ca channel mRNA expression was 4-to 5-fold greater than SK Ca channels. Conclusions-It appears that SK Ca and IK Ca channel activity diminishes basal tone of PA, but not MCA. The preservation of EDHF responsiveness of PA after ischemia and reperfusion suggests an important role for this vasodilator under conditions when NOS is inhibited.

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These data suggest that vit D3 alters AMH signaling and steroidogenesis in human cumulus GCs, possibly reflecting a state of GC luteinization potentiation.

Comorbidities are a hallmark of stroke that both increase the incidence of stroke and worsen outcome. Hypertension is prevalent in the stroke population and the most important modifiable risk factor for stroke. Hypertensive disorders promote stroke through increased shear stress, endothelial dysfunction, and large artery stiffness that transmits pulsatile flow to the cerebral microcirculation. Hypertension also promotes cerebral small vessel disease through several mechanisms, including hypoperfusion, diminished autoregulatory capacity and localized increase in blood-brain barrier permeability. Preeclampsia, a hypertensive disorder of pregnancy, also increases the risk of stroke 4-5-fold compared to normal pregnancy that predisposes women to early-onset cognitive impairment. In this review, we highlight how comorbidities and concomitant disorders are not only risk factors for ischemic stroke, but alter the response to acute ischemia. We focus on hypertension as a comorbidity and its effects on the cerebral circulation that alters the pathophysiology of ischemic stroke and should be considered in guiding future therapeutic strategies.