1. “Neurovascular Coupling Research"

2. Am J Physiol Heart Circ Physiol. 2003 Aug;285(2):H507-15 Am J Physiol Heart Circ Physiol. 2003 Aug;285(2):H507-15 (PMID: 12860561) Reduced perivascular PO 2 increases nitric oxide (NO) release from endothelial cells. Endothelial cells can act as "oxygen sensors" to large reductions in O 2 availability by increasing NO production. Reduced O 2 availability, arteriolar and venular NO level significantly increased  Vasodilation (   ) ! NO level (nM) (mean +/- SE) O 2  O 2  Arteriolar 397 +/- 26695 +/- 79 (   15 +/- 3%) Venular 298 +/- 34534 +/- 66 (   14 +/- 5%) Parenchymal (tissue) 138 +/- 36144 +/- 34

3. Stroke. 2003 Jun;34(6):1547-52. Epub 2003 Apr 24 Stroke. 2003 Jun;34(6):1547-52. Epub 2003 Apr 24 (PMID: 12714709) ATP-sensitive potassium channels (KATP) in the cerebral circulation. KATP located in smooth muscle (media) and endothelium of brain vessels. Classic openers of KATP dilate brain arteries. Dilation can be blocked by glibenclamide (GLIB), a selective inhibitor of KATP opening! PH-sensitive site on the internal surface of KATP may explain the glibenclamide-inhibition produced by intracellular acidosis (PH  ) and perhaps by CO 2. KATP appears to be involved in the action of endothelium- derived mediators of cerebrovascular tone.

4. J Cereb Blood Flow Metab. 2003 Oct;23(10):1227-38J Cereb Blood Flow Metab. 2003 Oct;23(10):1227-38 (PMID: 14526233) Cerebrovascular vasodilation to extraluminal acidosis (PH  ) occurs via combined activation of KATP & K ca (Ca 2+ - activated potassium) channels. Potassium channels are important regulators of cerebrovascular tone and may be modulated by a perivascular NO (EDRF) level. Dilation can be blocked by tetraethylammonium (TEA), a selective inhibitor of K ca opening! Combined blockade of K ATP and K Ca channels further reduced resting diameter (vasoconstriction). Conclusion = K ATP and K Ca channels are responsible for vasodilation (   35 ± 10%) to acidosis.

5. Regulation of the cerebral circulation: role of endothelium and potassium channels. Endothelial- (e.g. EDRF) and potassium channel-based mechanisms are related because several endothelium- derived factors produce relaxation by activation of potassium channels. The influence of potassium channels may be altered by pathology: - chronic hypertension - subarachnoid hemorrhage - diabetes Physiol Rev. 1998 Jan;78(1):53-97Physiol Rev. 1998 Jan;78(1):53-97 (PMID:9457169)

6. Psychiatry Res. 2003 Apr 1;122(3):207-9 Psychiatry Res. 2003 Apr 1;122(3):207-9 (PMID: 12694895) Effect of sildenafil (Viagra) on cerebral blood flow velocity. SILDENAFIL did not result in any significant changes in blood flow velocity of the right middle cerebral artery. Future experiments: - Diameters of the cerebral arteries under the influence of sildenafil - CO 2 and cerebral blood flow velocity during sexual stimulation after sildenafil

7. Am J Physiol Heart Circ Physiol. 2003 Apr;284(4):H1073-9 Am J Physiol Heart Circ Physiol. 2003 Apr;284(4):H1073-9 (PMID: 12666665) Carbon monoxide (CO) mediates vasodilator effects of glutamate in isolated pressurized cerebral arterioles of newborn pigs. Neurotransmitter GLUTAMATE causes vasodilation of newborn pig cerebral arterioles by endothelium-dependent dilation that involves stimulation of CO production  resulting in CBF  Studies demonstrated that overactivation of glutamate receptors leads to nitric oxide (NO) production that contributes to the excitotoxic neuronal death ! (Therapie. 2002 Nov-Dec;57(6):548- 53)

8. Metab Brain Dis. 2002 Dec;17(4):229-35 Metab Brain Dis. 2002 Dec;17(4):229-35 (PMID: 12602500) Cerebral blood flow in hyperammonemia: heterogeneity and starling forces in capillaries. Diseases associated with HYPERAMMONEMIA (hepatitis, cirrose) often show a reduced CBF due to vasoconstriction. In the brain, hyperammonemia interferes with ion homeostasis, membrane potentials, neurotransmission, and neurotransmitter recycling and reduces metabolic rates for O 2 and glucose  Vasoconstriction.

9. Life Sci. 2003 Nov 14;73(26):3415-25Life Sci. 2003 Nov 14;73(26):3415-25 (PMID: 14572882) Impaired nitric oxide synthase-dependent dilatation of cerebral arterioles in type II diabetic rats. Results: -Type II diabetes mellitus harms NO responses of cerebral arterioles. - Endothelial NO synthase (eNOS) was significantly higher in diabetic obese Zucker rats than in lean Zucker rats. Cerebral arteriolar  (mean +/- SE) Lean Zucker ratsType II Diabetic obese Zucker rats Acetylcholine 10 +/- 3%2 +/- 2% Adenosinedifosfaat (ADP) 20 +/- 2%8 +/- 2% Nitroglycerin (NO) similar

10. Stroke. 2003 Feb;34(2):446-51 Stroke. 2003 Feb;34(2):446-51 (PMID: 12574558) Pathophysiology. 2003 Sep;9(4):207-214Pathophysiology. 2003 Sep;9(4):207-214 (PMID: 14567923) Effects of acute hyperhomocysteinemia on the neurovascular coupling mechanism. HYPERHOMOCYSTEINEMIA is a vascular risk factor that interfers with the NO (EDRF) signaling pathway of endothelial vasoregulation. Attenuation of homocysteine endothelial dysfunction by exercise training. Exposure of endothelial cells to homocysteine (HCY)  decreased NO and harmed vascular function Exercise training improves vascular function by increasing endothelial NO production secondary to an increase in the enzyme responsible for its synthesis, endothelial nitric oxide synthase (eNOS)

11. Am. J. Physiol. (Heart Circ. Physiology) Mechanisms of cerebral vasodilation by superoxide and hydrogen peroxide. Hydrogen peroxide dilate cerebral arterioles by activating ATP- sensitive potassium channels  probably through an oxidant mechanism. Superoxide dilates cerebral arterioles by opening calcium- activated potassium channels.

12. Neurolog. 2002 May;8(3):175-85Neurolog. 2002 May;8(3):175-85 (PMID: 12803689) Diagnosis and treatment of neurally mediated syncope. SYNCOPE by reduction in CBF (brain stem neurons) responsible for supporting consciousness. Symptoms with syncope  increase in parasympathetic efferent activity causing: - Bradycardia (< 60 contractions / min) - Reduction in sympathetic vasoconstrictor outflow  vasodilatation.

13. Measurements of CBF / Neuronal Activation / Coupling Stroke. 2003 Apr;34(4):945-9. Epub 2003 Mar 06Stroke. 2003 Apr;34(4):945-9. Epub 2003 Mar 06 PMID: 12624217 Transcranial Doppler  cerebral vasodilatory capacity (CVC) (non-invasive). http://www.thieme.de/aktneu/abstracts2003/daten/p386.html DC-MagnetoEncephaloGraphy (DC-MEG) and Near-InfraRed- Spectroscopy (NIRS)  coupling between neuronal activation and accompanying vascular response (non-invasive). Magn Reson Med. 2003 Aug;50(2):263-74Magn Reson Med. 2003 Aug;50(2):263-74 PMID: 12876702 VASO-fMRI  FMRI based on changes in vascular space occupancy (non-invasive).

14. Conclusions A lot of (unknown) factors, especially metabolic factors, can influence the level of vasoregulation & CBF. There are different ways to obtain CBF / Neuronal Activation / Coupling data. In the future maybe high res. molecular MRI can give insight into cellular metabolic processes, which then can be linked to vasodilatation / vasoconstriction and FMRI neuronal activation images. Examples: - NO (EDRF) production by “shear stress” / O 2  / overactivation of Glutamate receptors -O 2  then NO  / ATP  (ADP  & Adenosine  ) = vasodilation Further Investigation Required !