15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and Cerebrovascular-Disorders

Modern functional imaging techniques of the brain measure local hemodynamic responses evoked by neuronal activity. Capillary pericytes recently were suggested to mediate neurovascular coupling in brain slices, but their role in vivo remains unexplored. We used two-photon microscopy to study in real time pericytes and the dynamic changes of capillary diameter and blood flow in the cortex of anesthetized mice, as well as in brain slices. The thromboxane A(2) analog, 9,11-dideoxy-9α,11α-methanoepoxy Prostaglandin F2α (U46619), induced constrictions in the vicinity of pericytes in a fraction of capillaries, whereas others dilated. The changes in vessel diameter resulted in changes in capillary red blood cell (RBC) flow. In contrast, during brief epochs of seizure activity elicited by local administration of the GABA(A) receptor antagonist, bicuculline, capillary RBC flow increased without pericyte-induced capillary diameter changes. Precapillary arterioles were the smallest vessels to dilate, together with penetrating and pial arterioles. Our results provide in vivo evidence that pericytes can modulate capillary blood flow in the brain, which may be important under pathological conditions. However, our data suggest that precapillary and penetrating arterioles, rather than pericytes in capillaries, are responsible for the blood flow increase induced by neural activity.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Arterioles; Bicuculline; Blood Flow Velocity; Brain; Capillaries; Cerebrovascular Disorders; Female; GABA-A Receptor Antagonists; Hyperemia; Male; Mice; Mice, Transgenic; Microscopy, Fluorescence, Multiphoton; Pericytes; Receptors, GABA-A; Thromboxane A2; Vasoconstrictor Agents; Vasodilation

Diabetes mellitus produces abnormalities of the endothelium and impairs endothelium-dependent dilatation of large and small cerebral blood vessels. However, the effect of diabetes mellitus on cerebral vasoconstriction and the modulatory influence of nitric oxide on cerebral vasoconstriction is unclear. Thus, the first goal of this study was to examine the effect of diabetes mellitus on constrictor responses of the basilar artery in vivo. Our second goal was to examine a potential role for nitric oxide in modulating constrictor responses of the basilar artery. A craniotomy was performed over the ventral medulla to expose the basilar artery. The diameter of the basilar artery was measured using intravital microscopy in nondiabetic and diabetic (3-4 months after injection of streptozotocin; 50-60 mg/kg i.p.) rats in response to angiotensin II, arginine vasopressin, endothelin-1, and the thromboxane analogue, U-46619. Topical application of angiotensin II (10 and 100 nM) produced only minimal changes in diameter of the basilar artery which were similar in nondiabetic and diabetic rats (p>0.05). Arginine vasopressin (0.1 and 1.0 nM), endothelin-1 (10 and 50 nM), and U-46619 (10 and 100 nM) produced marked dose-related constriction of the basilar artery which also was similar in nondiabetic and diabetic rats (p>0.05). Next, we examine whether the synthesis/release of nitric oxide played a role in constriction of the basilar artery in response to the agonists. We found that L-NMMA (1.0 microM) did not alter constrictor responses of the basilar artery in nondiabetic and diabetic rats. Thus, responses of the basilar artery to important vasoactive agonists are not altered by diabetes mellitus. In addition, it does not appear that the synthesis/release of nitric oxide modulates constrictor responses of the basilar artery to angiotensin II, arginine vasopressin, endothelin-1 and U-46619. We suggest that preservation of vasoconstrictor responses, coupled with impaired vasodilator responses, may contribute to the pathogenesis of cerebrovascular abnormalities associated with diabetes mellitus.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Angiotensin II; Animals; Arginine Vasopressin; Basilar Artery; Blood Pressure; Cerebrovascular Disorders; Diabetes Mellitus, Experimental; Endothelin-1; Enzyme Inhibitors; Male; Muscle, Smooth, Vascular; Nitric Oxide Synthase; omega-N-Methylarginine; Rats; Thromboxanes; Vasoconstriction; Vasoconstrictor Agents

Aggregation and adherence of platelets to vascular endothelium are increased during diabetes mellitus, and thus responses of cerebral arteries to products released by platelets may have important implications for the pathogenesis of stroke during diabetes. The goal of this study was to determine whether responses of the basilar artery to products released by platelets are altered during diabetes.. A craniotomy was performed over the ventral medulla to expose the basilar artery. Diameter of the basilar artery was measured using intravital microscopy in nondiabetic and diabetic (50-60 mg/kg i.p. streptozotocin) rats in response to adenosine 5'-diphosphate, serotonin, and the thromboxane analogue U-46619.. Topical application of 10 and 100 microM adenosine 5'-diphosphate produced only minimal changes in diameter of the basilar artery that were similar in nondiabetic and diabetic rats (p greater than 0.05). At 0.01, 0.1, and 1.0 microM serotonin produced dose-related constriction of the basilar artery that was similar in nondiabetic and diabetic rats (p greater than 0.05). At 0.1 and 1.0 microM U-46619 also produced similar dose-related constriction of the basilar artery in nondiabetic and diabetic rats (p greater than 0.05).. These findings suggest that responses of the basilar artery to products released by platelets are not altered by diabetes mellitus. Thus, it does not appear that alterations in reactivity of the basilar artery to products released by platelets contribute to the pathogenesis of stroke during diabetes.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adenosine Diphosphate; Animals; Basilar Artery; Blood Platelets; Cerebrovascular Disorders; Diabetes Mellitus, Experimental; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Prostaglandin Endoperoxides, Synthetic; Rats; Serotonin; Vasodilation