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1. We characterized the vasoactive effects of OR-1896, the long-lived metabolite of the inodilator levosimendan, in coronary and skeletal muscle microvessels. 2. The effect of OR-1896 on isolated, pressurized (80 mmHg) rat coronary and gracilis muscle arteriole (approximately 150 microm) diameters was investigated by videomicroscopy. 3. OR-1896 elicited concentration-dependent (1 nM-10 microM) dilations in coronary (maximal dilation: 66+/-6%, relative to that in Ca2+-free solutions; pD2: 7.16+/-0.42) and gracilis muscle arterioles (maximal dilation: 73+/-4%; pD2: 6.71+/-0.42), these dilations proving comparable to those induced by levosimendan (1 nM-10 microM) in coronary (maximal dilation: 83+/-6%; pD2: 7.06+/-0.14) and gracilis muscle arterioles (maximal dilation: 73+/-12%; pD2: 7.05+/-0.1). 4. The maximal dilations in response to OR-1896 were significantly (P

BACKGROUND AND PURPOSE: Antagonists of angiotensin AT(1) receptors elicit beneficial vascular effects in diabetes mellitus. We hypothesized that diabetes induces sustained availability of AT(1) receptors, causing enhanced arterial constriction to angiotensin II. EXPERIMENTAL APPROACH: To assess functional availability of AT(1) receptors, constrictions to successive applications of angiotensin II were measured in isolated skeletal muscle resistance arteries (∼150 µm) of Zucker diabetic fatty (ZDF) rats and of their controls (+/Fa), exposed acutely to high glucose concentrations (HG, 25 mM, 1 h). AT(1) receptors on cell membrane surface were measured by immunofluorescence. KEY RESULTS: Angiotensin II-induced constrictions to first applications were greater in arteries of ZDF rats (maximum: 82 ± 3% original diameter) than in those from +/Fa rats (61 ± 5%). Constrictions to repeated angiotensin II administration were decreased in +/Fa arteries (20 ± 6%), but were maintained in ZDF arteries (67 ± 4%) and in +/Fa arteries vessels exposed to HG (65 ± 6%). In ZDF arteries and in HG-exposed +/Fa arteries, Rho-kinase activities were enhanced. The Rho-kinase inhibitor, Y27632 inhibited sustained constrictions to angiotensin II in ZDF arteries and in +/Fa arteries exposed to HG. Levels of surface AT(1) receptors on cultured vascular smooth muscle cells (VSMCs) were decreased by angiotensin II but were maintained in VSMCs exposed to HG. In VSMCs exposed to HG and treated with Y27632, angiotensin II decreased surface AT(1) receptors. CONCLUSIONS AND IMPLICATIONS: In diabetes, elevated glucose concentrations activate Rho-kinase which inhibits internalization or facilitates recycling of AT(1) receptors, leading to increased functional availability of AT(1) receptors and sustained angiotensin II-induced arterial constriction.

Although not complete, the above described cross section of avenues of today research in microcirculation, blood rheology and vascular biology - we believe - will lead us not only to a better understanding how circulation of organs are designed and regulated and affected by various conditions, but also will help us to design new modalities to temper pathophysiological alterations in microcirculation. © 2009 S. Karger AG, Basel.

Diabetes mellitus is associated with disturbed regulation in the microcirculation. A low-grade vascular inflammation has been implicated in the development of diabetes-related vascular complications, but the underlying molecular mechanisms has not yet been fully elucidated. It is known that cyclooxygenase-2 (COX-2) plays a key role in prostaglandin biosynthesis during the development of inflammation. Recent studies revealed that in diabetes increased synthesis of various prostanoids, via up-regulation of COX-2, interferes with the regulation of vasomotor function. In this review, we will summarize the current findings regarding the role of COX-2, and COX-2-derived prostanoids in the regulation of vascular tone, as well as the possible underlying mechanisms leading to COX-2 activation in diabetes mellitus.

Hyperhomocysteinemia (HHcy) is a newly recognized risk factor for myocardial infarction, however, the effect of HHcy on endothelium-dependent flow-induced dilation of coronary arteries is not known. Thus, changes in diameter of small intramural coronary arteries (diameter, approximately 145 microm) isolated from control rats and rats with methionine diet-induced HHcy were investigated by videomicroscopy. Increases in intraluminal flow (from 0 to 40 microl/min) elicited dilations of control vessels (maximum, 25 +/- 2 microm), responses that were absent in HHcy arteries. The nitric oxide (NO) synthase inhibitor L-NAME inhibited flow-induced dilation of control coronaries, whereas it had no effect on responses of HHcy arteries. Dilations of control and HHcy arteries to the NO donor sodium nitroprusside were not different. Responses to flow in HHcy coronary arteries were unaffected by administration of L-arginine or the prostaglandin H(2)/thromboxane A(2) receptor antagonist SQ 29,548. However, in the presence of superoxide dismutase (plus catalase) or the superoxide scavenger Tiron increases in flow elicited L-NAME-sensitive dilations of HHcy coronaries (maximum, 18 +/- 5 microm). Also, superoxide dismutase significantly reduced the enhanced superoxide production of HHcy coronaries (measured by the lucigenin chemiluminescence method). Single vessel Western blotting showed an increased tyrosine nitrosation (a stable biomarker of tissue peroxynitrite formation) in HHcy coronaries. Also, extensive prevalence of 3-nitrotyrosine immunoreactivity was observed in HHcy coronaries that was confined primarily to the subendothelial layers of smooth muscle. We propose that in HHcy an increased level of superoxide scavenges NO forming peroxynitrite, which increases protein nitrosation. The reduced bioavailability of NO impairs flow-induced dilations of coronary arteries, which may contribute to the development of coronary atherosclerosis and ischemic heart disease.