Điều chỉnh Dòng máu bởi S-Nitrosohemoglobin trong Gradient Oxy Sinh Lý

L. Stryer in Biochemistry L. Stryer Ed. (Freeman San Francisco CA 1981) pp. 43-82

A. C. Guyton in Textbook of Medical Physiology (Saunders Philadelphia PA 1981) pp. 208-215 224-225 230-245 and 344-355.

Duling B., Berne R. M., Circ. Res. 27, 669 (1970);

; A. S. Popel R. N. Pittman L. Ellsworth [erratum Am. J. Physiol. 261 (September 1991)] ibid. 256 H921 (1989); D. P. Swain and R. N. Pittman ibid. p. H247; I. Torres Filho

Kerger H., Intaglietta M., Microvasc. Res. 51, 202 (1996);

Buerk D., Shonat R., Riva C., Cranstoun S., ibid. 45, 134 (1993).

Intaglietta M., Johnson P., Winslow R., Cardiovasc. Res. 32, 632 (1996);

; E. Braunwald Ed. Heart Disease: A Textbook of Cardiovascular Medicine (Saunders Philadelphia PA 1988); E. Antonini and M. Brunori Hemoglobin and Myoglobin in Their Reactions with Ligands (Elsevier New York 1971).

M. F. Perutz in Molecular Basis of Blood Diseases G. Stammatayanopoulos Ed. (Saunders Philadelphia PA 1987) pp. 127-178

D. Voet and J. G. Voet (Wiley New York 1995) pp. 215-235.

10.1038/380221a0

A. C. Guyton in Textbook of Medical Physiology (Saunders Philadelphia PA 1981) pp. 504–513.

Methods of the ring bioassay can be found in

Stamler J. S., et al., Proc. Natl. Acad. Sci. U.S.A. 89, 444 (1992);

. P O 2 was measured as described in (11). Attempts were made to achieve equivalent baseline tone at the different P O 2 's by varying the concentration of phenylephrine. SNO–oxy Hb (SNO-Hb[FeII]O 2 ) and GSNO preparations were synthesized and quantified as described in (5).

J. S. Stamler et al. data not shown.

SNO-RBCs (∼1 μM) caused 32.5 ± 1.2% relaxation that lasted 14.5 ± 0.7 min in 95% O 2 versus 61 ± 10% relaxation that lasted 23 ± 2 min in <1% O 2 ( n = 3 to 4; P < 0.05). SNO-RBCs (∼0.1 μM) produced small relaxations in <1% O 2 and small contractions in 95% O 2 . In contrast RBCs containing no SNO-Hb produced small contractions (less than those of cell-free Hb) that were potentiated by hypoxia (13 ± 2.0% in 95% O 2 versus 25 ± 5% in <1% O 2 ; P < 0.05).

Protein modeling was done with SYBYL software from TRIPOS Inc. (St. Louis MO). Hemoglobin coordinates came from the Brookhaven Protein Data Bank (PDB): In oxy Hb 1HCO and other PDB coordinate files; in deoxy Hb 3HHB and other PDB files. NO was modeled onto oxy Hb and deoxy Hb with the use of the bond distances and angles recorded in S. Oae and K. Shinhama [ Org. Prep. Proc. Int. 15 165 (1983)] with rotational freedom about the Cα–Cβ Cβ Cβ–Sγ Sγ–Nδ bonds. Figures were prepared with the program VIEW (L. Bergman University of North Carolina).

Adult Sprague-Dawley rats (290 to 350 g) were anesthetized with sodium pentobarbital intubated and ventilated with a respirator to maintain the arterial CO 2 pressure at 35 to 45 mmHg. Drugs were infused through the femoral vein and blood pressure was monitored via the femoral artery as described in (5). Blood gas tensions and pH were measured periodically; the blood was replaced with three volumes of 0.9% saline. The tissue P O 2 was measured with platinum microelectrodes (50 μm outer diameter coated with Nafion) implanted stereotaxically in the right and left hippocampus (AP −3.4 mm; ML +2.2 mm) caudate putamen nucleus (CPN) and substantia nigra (SN) (see coordinates below) as described in

Piantadosi C. A., et al., Free Rad. Biol. Med. 22, 725 (1997);

. The P O 2 electrodes were polarized to −0.65 V against an Ag/AgCl reference and the current was measured with a low-impedance nanoampere meter. Arterial P O 2 was adjusted by changing the inspired O 2 concentration and atmospheric pressure. Hydrogen (H 2 )-sensitive platinum microelectrodes were implanted stereotaxically in the SN (AP −5.3 mm; ML −2.4 mm to the bregma depth 3.2 mm) CPN (AP +0.8 mm; ML −2.5 mm depth 5.2 mm) and parietal cortex for measurement of regional blood flow. The microelectrodes were insulated with epoxy with the exception of the Nafion-coated tip (1 mm). The electrodes were polarized to 400 mV against a reference electrode and the current was measured with a low-impedance nanoampere meter during and after the inhalation of hydrogen gas (2.5%) for 1 min. The H 2 -clearance curves and O 2 tracings were recorded with PC WINDAQ (software DI-200 AC; DATA Q Instruments OH). Cerebral blood flow was calculated with the initial slope method [

Heiss W. D., Traupe H., Stroke 12, 161 (1981);

Young W., ibid. 11, 552 (1980);

]. Regional blood flow was monitored for 30 min before and after drug administration (time 0).

Tibbles P. M., Edelsberg J. S., N. Engl. J. Med. 334, 1642 (1996).

Approximately 0.1 μM SNO-RBCs lowered blood pressure by 7 ± 1 mmHg and ∼0.5 μM SNO-RBCs lowered blood pressure by 16 ± 2 mmHg ( n = 8; P < 0.001 versus baseline).

Dewhirst M. W., Secomb T. W., Ong E. T., Hsu R., Gross J. F., Cancer Res. 54, 3333 (1994);

Kerger H., Torres Filho I., Rivas M., Winslow R., Intaglietta M., Am. J. Physiol. 268, H802 (1995).

Park K. H., Rubin L. E., Gross S. S., Levi R., Circ. Res. 71, 992 (1992);

Hampl V., Archer S. L., Nelson D. P., Weir E. K., J. Appl. Physiol. 75, 1748 (1993).

Casadevall M., et al., Gastroenterology 110, 1156 (1996);

Kasper S.-M., et al., Anesth. Analg. 83, 921 (1996);

Stamler J. S., Nature 380, 108 (1996);

Persson M. G., Gustafsson L. E., Wiklund N. P., Hedqvist P., Moncada S., Br. J. Pharmacol. 100, 463 (1990);

; D. Mitchell and K. Tyml Am. J. Physiol. 270 ( Heart Circ. Physiol. 39 ) H1696 (1996);

King C. E., et al., J. Appl. Physiol. 76, 1166 (1994).

We are indebted to M. Dewhirst for his insight. J.S.S. is a Pew scholar in the biomedical sciences and the recipient of grants from the National Heart Lung and Blood Institute (NHLBI) (HL 52529 and HR59130). C.A.P. is funded by the NHLBI.