The present study addresses the hypothesis that CO produced from endogenous heme oxygenase (HO) can dilate newborn cerebral arterioles. HO-2 protein was highly expressed in large and small blood vessels, as well as parenchyma, of newborn pig cerebrum. Topically applied CO dose-dependently dilated piglet pial arterioles in vivo over the range 10¹¹10⁹ M (maximal response). CO-induced cerebrovascular dilation was abolished by treatment with the Ca²⁺-activated K⁺ channel inhibitors tetraethylammonium chloride and iberiotoxin. The HO substrate heme-L-lysinate also produced tetraethylammonium-inhibitable, dose-dependent dilation from 5 × 10⁸ to 5 × 10⁷ M (maximal). The HO inhibitor chromium mesoporphyrin blocked dilation of pial arterioles in response to heme-L-lysinate. In addition to inhibiting dilation to heme-L-lysinate, chromium mesoporphyrin also blocked pial arteriolar dilations in response to hypoxia but did not alter responses to hypercapnia or isoproterenol. We conclude that CO dilates pial arterioles via activation of Ca²⁺-activated K⁺ channels and that endogenous HO-2 potentially can produce sufficient CO to produce the dilation.

heme oxygenase; potassium channels; cyclic nucleotides; brain blood flow

This article has been cited by other articles:

				N. G. Abraham, J. Cao, D. Sacerdoti, X. Li, and G. Drummond Heme oxygenase: the key to renal function regulation Am J Physiol Renal Physiol, November 1, 2009; 297(5): F1137 - F1152. [Abstract] [Full Text] [PDF]

				A. Kanu and C. W. Leffler Roles of Glia Limitans Astrocytes and Carbon Monoxide in Adenosine Diphosphate-Induced Pial Arteriolar Dilation in Newborn Pigs Stroke, March 1, 2009; 40(3): 930 - 935. [Abstract] [Full Text] [PDF]

				Corrigendum Am J Physiol Heart Circ Physiol, September 1, 2008; 295(3): H1369 - H1369. [Full Text] [PDF]

				A. Li, Q. Xi, E. S. Umstot, L. Bellner, M. L. Schwartzman, J. H. Jaggar, and C. W. Leffler Astrocyte-Derived CO Is a Diffusible Messenger That Mediates Glutamate-Induced Cerebral Arteriolar Dilation by Activating Smooth Muscle Cell KCa Channels Circ. Res., February 1, 2008; 102(2): 234 - 241. [Abstract] [Full Text] [PDF]

				A. Kanu and C. W. Leffler Carbon monoxide and Ca2+-activated K+ channels in cerebral arteriolar responses to glutamate and hypoxia in newborn pigs Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H3193 - H3200. [Abstract] [Full Text] [PDF]

				R. Bauer, B. Walter, and U. Brandl Intrauterine growth restriction improves cerebral O2 utilization during hypercapnic hypoxia in newborn piglets J. Physiol., October 15, 2007; 584(2): 693 - 704. [Abstract] [Full Text] [PDF]

				C. W. Leffler, H. Parfenova, A. L. Fedinec, S. Basuroy, and D. Tcheranova Contributions of astrocytes and CO to pial arteriolar dilation to glutamate in newborn pigs Am J Physiol Heart Circ Physiol, December 1, 2006; 291(6): H2897 - H2904. [Abstract] [Full Text] [PDF]

				S. Basuroy, S. Bhattacharya, D. Tcheranova, Y. Qu, R. F. Regan, C. W. Leffler, and H. Parfenova HO-2 provides endogenous protection against oxidative stress and apoptosis caused by TNF-{alpha} in cerebral vascular endothelial cells Am J Physiol Cell Physiol, November 1, 2006; 291(5): C897 - C908. [Abstract] [Full Text] [PDF]

				A. Kanu, J. Whitfield, and C. W. Leffler Carbon monoxide contributes to hypotension-induced cerebrovascular vasodilation in piglets Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2409 - H2414. [Abstract] [Full Text] [PDF]

				H. Ohata, S. Cao, and R. C. Koehler Contribution of adenosine A2A and A2B receptors and heme oxygenase to AMPA-induced dilation of pial arterioles in rats Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2006; 291(3): R728 - R735. [Abstract] [Full Text] [PDF]

				J. J. Andresen, N. I. Shafi, W. Durante, and R. M. Bryan Jr. Effects of carbon monoxide and heme oxygenase inhibitors in cerebral vessels of rats and mice Am J Physiol Heart Circ Physiol, July 1, 2006; 291(1): H223 - H230. [Abstract] [Full Text] [PDF]

				S. W. Ryter, J. Alam, and A. M. K. Choi Heme Oxygenase-1/Carbon Monoxide: From Basic Science to Therapeutic Applications Physiol Rev, April 1, 2006; 86(2): 583 - 650. [Abstract] [Full Text] [PDF]

				C. W. Leffler, H. Parfenova, J. H. Jaggar, and R. Wang Carbon monoxide and hydrogen sulfide: gaseous messengers in cerebrovascular circulation J Appl Physiol, March 1, 2006; 100(3): 1065 - 1076. [Abstract] [Full Text] [PDF]

				A. Rebel, S. Cao, H. Kwansa, S. Dore, E. Bucci, and R. C. Koehler Dependence of acetylcholine and ADP dilation of pial arterioles on heme oxygenase after transfusion of cell-free polymeric hemoglobin Am J Physiol Heart Circ Physiol, March 1, 2006; 290(3): H1027 - H1037. [Abstract] [Full Text] [PDF]

				A. Kanu, D. Gilpin, A. L. Fedinec, and C. W. Leffler Cyclooxygenase Products Stimulate Carbon Monoxide Production by Piglet Cerebral Microvessels Experimental Biology and Medicine, February 1, 2006; 231(2): 181 - 185. [Abstract] [Full Text] [PDF]

				M. Ishikawa, M. Kajimura, T. Adachi, K. Maruyama, N. Makino, N. Goda, T. Yamaguchi, E. Sekizuka, and M. Suematsu Carbon Monoxide From Heme Oxygenase-2 Is a Tonic Regulator Against NO-Dependent Vasodilatation in the Adult Rat Cerebral Microcirculation Circ. Res., December 9, 2005; 97(12): e104 - e114. [Abstract] [Full Text] [PDF]

				L. Wu and R. Wang Carbon Monoxide: Endogenous Production, Physiological Functions, and Pharmacological Applications Pharmacol. Rev., December 1, 2005; 57(4): 585 - 630. [Abstract] [Full Text] [PDF]

				C. W. Leffler, L. Balabanova, A. L. Fedinec, and H. Parfenova Nitric oxide increases carbon monoxide production by piglet cerebral microvessels Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1442 - H1447. [Abstract] [Full Text] [PDF]

				S. Turkseven, A. Kruger, C. J. Mingone, P. Kaminski, M. Inaba, L. F. Rodella, S. Ikehara, M. S. Wolin, and N. G. Abraham Antioxidant mechanism of heme oxygenase-1 involves an increase in superoxide dismutase and catalase in experimental diabetes Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H701 - H707. [Abstract] [Full Text] [PDF]

				C. W. Leffler, A. L. Fedinec, H. Parfenova, and J. H. Jaggar Permissive contributions of NO and prostacyclin in CO-induced cerebrovascular dilation in piglets Am J Physiol Heart Circ Physiol, July 1, 2005; 289(1): H432 - H438. [Abstract] [Full Text] [PDF]

				H. Parfenova, P. Carratu, D. Tcheranova, A. Fedinec, M. Pourcyrous, and C. W. Leffler Epileptic seizures cause extended postictal cerebral vascular dysfunction that is prevented by HO-1 overexpression Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2843 - H2850. [Abstract] [Full Text] [PDF]

				A. Ahmed, C. M. Waters, C. W. Leffler, and J. H. Jaggar Ionic mechanisms mediating the myogenic response in newborn porcine cerebral arteries Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H2061 - H2069. [Abstract] [Full Text] [PDF]

				E. Barkoudah, J. H. Jaggar, and C. W. Leffler The permissive role of endothelial NO in CO-induced cerebrovascular dilation Am J Physiol Heart Circ Physiol, October 1, 2004; 287(4): H1459 - H1465. [Abstract] [Full Text] [PDF]

				Y. Nishikawa, D. W. Stepp, D. Merkus, D. Jones, and W. M. Chilian In vivo role of heme oxygenase in ischemic coronary vasodilation Am J Physiol Heart Circ Physiol, June 1, 2004; 286(6): H2296 - H2304. [Abstract] [Full Text] [PDF]

				Q. Xi, D. Tcheranova, H. Parfenova, B. Horowitz, C. W. Leffler, and J. H. Jaggar Carbon monoxide activates KCa channels in newborn arteriole smooth muscle cells by increasing apparent Ca2+ sensitivity of {alpha}-subunits Am J Physiol Heart Circ Physiol, February 1, 2004; 286(2): H610 - H618. [Abstract] [Full Text] [PDF]

				P. Koneru and C. W. Leffler Role of cGMP in carbon monoxide-induced cerebral vasodilation in piglets Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H304 - H309. [Abstract] [Full Text] [PDF]

				F. Zhang, J. I. Kaide, L. Yang, H. Jiang, S. Quan, R. Kemp, W. Gong, M. Balazy, N. G. Abraham, and A. Nasjletti CO modulates pulmonary vascular response to acute hypoxia: relation to endothelin Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H137 - H144. [Abstract] [Full Text] [PDF]

				P. Carratu, M. Pourcyrous, A. Fedinec, C. W. Leffler, and H. Parfenova Endogenous heme oxygenase prevents impairment of cerebral vascular functions caused by seizures Am J Physiol Heart Circ Physiol, August 7, 2003; 285(3): H1148 - H1157. [Abstract] [Full Text] [PDF]

				C. W. Leffler, L. Balabanova, A. L. Fedinec, C. M. Waters, and H. Parfenova Mechanism of glutamate stimulation of CO production in cerebral microvessels Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H74 - H80. [Abstract] [Full Text] [PDF]

				J. S. Naik and B. R. Walker Heme oxygenase-mediated vasodilation involves vascular smooth muscle cell hyperpolarization Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H220 - H228. [Abstract] [Full Text] [PDF]

				C. W. Leffler, L. Balabanova, C. D. Sullivan, X. Wang, A. L. Fedinec, and H. Parfenova Regulation of CO production in cerebral microvessels of newborn pigs Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H292 - H297. [Abstract] [Full Text] [PDF]

				E. Fiumana, H. Parfenova, J. H. Jaggar, and C. W. Leffler Carbon monoxide mediates vasodilator effects of glutamate in isolated pressurized cerebral arterioles of newborn pigs Am J Physiol Heart Circ Physiol, April 1, 2003; 284 (4): H1073 - H1079. [Abstract] [Full Text] [PDF]

				J. S. Naik, T. L. O'Donaughy, and B. R. Walker Endogenous carbon monoxide is an endothelial-derived vasodilator factor in the mesenteric circulation Am J Physiol Heart Circ Physiol, March 1, 2003; 284(3): H838 - H845. [Abstract] [Full Text] [PDF]

				W. Durante Carbon monoxide and bile pigments: surprising mediators of vascular function Vascular Medicine, August 1, 2002; 7(3): 195 - 202. [Abstract] [PDF]

				J. S. Robinson, A. L. Fedinec, and C. W. Leffler Role of carbon monoxide in glutamate receptor-induced dilation of newborn pig pial arterioles Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2371 - H2376. [Abstract] [Full Text] [PDF]

				R. J. Gonzales and B. R. Walker Role of CO in attenuated vasoconstrictor reactivity of mesenteric resistance arteries after chronic hypoxia Am J Physiol Heart Circ Physiol, January 1, 2002; 282(1): H30 - H37. [Abstract] [Full Text] [PDF]

				H. Parfenova, R. A. Neff III, J. S. Alonso, B. V. Shlopov, C. N. Jamal, S. A. Sarkisova, and C. W. Leffler Cerebral vascular endothelial heme oxygenase: expression, localization, and activation by glutamate Am J Physiol Cell Physiol, December 1, 2001; 281(6): C1954 - C1963. [Abstract] [Full Text] [PDF]

				J. S. Naik and B. R. Walker Homogeneous segmental profile of carbon monoxide-mediated pulmonary vasodilation in rats Am J Physiol Lung Cell Mol Physiol, December 1, 2001; 281(6): L1436 - L1443. [Abstract] [Full Text] [PDF]

				Z.-Z. Yang and A.-P. Zou Transcriptional regulation of heme oxygenases by HIF-1alpha in renal medullary interstitial cells Am J Physiol Renal Physiol, November 1, 2001; 281(5): F900 - F908. [Abstract] [Full Text] [PDF]

				N. L. Jernigan, T. L. O'Donaughy, and B. R. Walker Correlation of HO-1 expression with onset and reversal of hypoxia-induced vasoconstrictor hyporeactivity Am J Physiol Heart Circ Physiol, July 1, 2001; 281(1): H298 - H307. [Abstract] [Full Text] [PDF]

				C. W. Leffler, A. Nasjletti, R. A. Johnson, and A. L. Fedinec Contributions of prostacyclin and nitric oxide to carbon monoxide-induced cerebrovascular dilation in piglets Am J Physiol Heart Circ Physiol, April 1, 2001; 280(4): H1490 - H1495. [Abstract] [Full Text] [PDF]

				S. W. Ryter, M. Si, C.-C. Lai, and C.-Y. Su Regulation of endothelial heme oxygenase activity during hypoxia is dependent on chelatable iron Am J Physiol Heart Circ Physiol, December 1, 2000; 279(6): H2889 - H2897. [Abstract] [Full Text] [PDF]

				T. L. O'Donaughy and B. R. Walker Renal vasodilatory influence of endogenous carbon monoxide in chronically hypoxic rats Am J Physiol Heart Circ Physiol, December 1, 2000; 279(6): H2908 - H2915. [Abstract] [Full Text] [PDF]

				J. S. Robinson, A. L. Fedinec, and C. W. Leffler Role of carbon monoxide in glutamate receptor-induced dilation of newborn pig pial arterioles Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2371 - H2376. [Abstract] [Full Text] [PDF]