(Hypertension. 1995;25:166-169.)
© 1995 American Heart Association, Inc.
Articles |
A Heme Oxygenase Product, Presumably Carbon Monoxide, Mediates a Vasodepressor Function in Rats
From the Department of Pharmacology, New York Medical College, Valhalla, and The Rockefeller University (N.G.A.), New York City.
Correspondence to Robert A. Johnson, PhD, Department of Pharmacology, New York Medical College, Valhalla, NY 10595.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract Heme oxygenase is a mammalian enzyme that converts heme to biliverdin and carbon monoxide. Carbon monoxide activates soluble guanylate cyclase and relaxes vascular smooth muscle, and it has been implicated as a potential neuromessenger. The regulatory functions of endogenous carbon monoxide on hemodynamics are not known. Zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG) inhibits heme oxygenase in rats and thus permits assessment of the hemodynamic response to inhibition of endogenous carbon monoxide synthesis. In chronically instrumented, awake male Sprague-Dawley rats, ZnDPBG (45 µmol/kg IP) increased mean arterial pressure (19±2%, P<.05) and total peripheral resistance (47±4%, P<.05), decreased cardiac output (-16±2%, P<.05), but did not affect heart rate. Another heme oxygenase inhibitor, zinc protoporphyrin IX (45 µmol/kg IP), also increased arterial pressure (17±5%, P<.05), with no effect on heart rate. In contrast, neither the nonmetallic deuteroporphyrin 2,4-bis glycol (45 µmol/kg IP) nor biliverdin (45 µmol/kg IP) had any effect on blood pressure or heart rate. These findings suggest that ZnDPBG and zinc protoporphyrin IX increase arterial pressure by inhibiting heme oxygenase activity. After pretreatment with chlorisondamine (5 mg/kg IP) or prazosin (5 mg/kg IP) to inhibit autonomic ganglionic or
1-adrenoceptor
functions, respectively, ZnDPBG did not affect arterial pressure or
heart rate. This suggests that ZnDPBG-induced increases in blood
pressure rely on autonomic nervous function. We conclude that the
pressor response to heme oxygenase inhibitors results from withdrawal
of the inhibitory influence of endogenous carbon monoxide on a pressor
mechanism mediated by the autonomic nervous system.
Key Words: blood pressure • carbon monoxide • heme oxygenase • autonomic nervous system
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Heme oxygenase is a widely distributed enzyme that daily converts almost 1% of the heme in blood to biliverdin and carbon monoxide.1 2 3 4 The biliverdin by-product, in mammals, is rapidly transformed into bile pigments for excretion, whereas the endogenously generated carbon monoxide binds avidly to a variety of heme- and sulfydryl-bearing structures until eliminated by ventilation.3 Carbon monoxide is an activator of soluble guanylate cyclase5 and relaxes vascular smooth muscle via a cGMP-dependent mechanism.6 A recent study has provided evidence that a subset of glutamate receptors, involved in the function of the afferent arm of the baroreceptor reflex, may be coupled with heme oxygenase–mediated production of carbon monoxide.7 There has been speculation that heme oxygenase–generated carbon monoxide production might play a physiological role in blood pressure (BP) regulation,3 8 but no such role has been established. Zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG) is an inhibitor of heme oxygenase activity.9 10 11 ZnDPBG has been shown to inhibit endogenous carbon monoxide production in rats12 and thus permits the physiological actions of heme oxygenase activity to be studied in vivo.
We designed the present study to assess the contribution of heme oxygenase activity to resting BP in the awake rat. To accomplish this, we contrasted hemodynamic measurements before and after short-term administration of ZnDPBG. We conducted additional experiments to assess potential involvement of the autonomic nervous system in ZnDPBG-induced BP effects.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Materials
Porphyrins and biliverdin were obtained from Porphyrin Products and chlorisondamine (Ecolid) from Ciba Pharmaceutical Products. All other drugs were purchased from Sigma Chemical Co. Porphyrins were prepared in 50 mmol/L Na2CO3 (15 µmol of drug per milliliter) immediately before use. Other drugs were dissolved in normal saline on the day of the experiment.
Animals
Sixty-five male Sprague-Dawley rats (Charles River,
Wilmington, Mass) ranging in weight from 300 to 375 g were used in
these studies. Rats were individually housed in a controlled
temperature of 27°C, with automatic lighting that provided a 12-hour
on-off cycle. Rats had free access to commercial rat chow (Ralston
Purina) and tap water.
Each animal was anesthetized with sodium pentobarbital (Anpro Pharmaceuticals, 60 mg/kg IP), and a chronic arterial catheter was implanted for BP and heart rate (HR) determinations. Each arterial catheter (PE-50) was filled with heparinized normal saline, introduced through a femoral artery, and advanced into the lower abdominal aorta. Each was tunneled subcutaneously to an exit point at the nape of the neck and sealed with a steel pin until use.
In some experiments, animals were also chronically instrumented with aortic flow probes (model 2.5S, Transonic Systems) for measurement of cardiac output. Each of these animals was temporarily intubated for mechanical ventilation (Rodent Ventilator, Harvard Bioscience) while the flow probe was placed around the ascending aorta. The probe electrical leads were guided through the right second intercostal space, tunneled subcutaneously, and exited at the nape of the neck. All animals received ampicillin (30 mg/kg per 12 hours SC) for at least 3 days after surgery. A postsurgical recovery period of at least 4 days was allowed before experiments.
Experimental Design
All experiments were conducted in awake, unrestrained rats.
Femoral arterial catheters were connected to pressure transducers
(model P23XL, Statham) coupled to a polygraph (model 7D, Grass
Instrument Co) for continuous arterial pressure measurements. The
aortic flow probes were connected to a flowmeter (Transonic model T208)
for cardiac output determinations.
In protocol 1, arterial pressure, HR, and cardiac output were measured
before and after injection of 50 mmol/L Na2CO3
(3 mL/kg IP) vehicle or ZnDPBG (45 µmol/kg IP) to inhibit heme
oxygenase activity.9 10 11 12 Another control group received
nonmetallic DPBG (45 µmol/kg IP), which does not affect heme
oxygenase activity (unpublished observations). Total peripheral
resistance was calculated as the ratio of mean arterial pressure (MAP)
to cardiac output and was expressed as millimeters of mercury per
milliliter per minute. In complementary experiments, rats were injected
with ZnDPBG (45 µmol/kg IP, n=3) or DPBG (45 µmol/kg IP, n=3).
Thirty minutes later, rats were given a sodium pentobarbital overdose
(150 mg/kg IP), and the brains were immediately removed for assay of
microsomal heme oxygenase activity as previously
described.9 10 The microsomal heme oxygenase activity was
not detectable in animals injected with ZnDPBG, whereas it averaged
0.160±0.025 nmol bilirubin/mg protein per hour in those injected with
DPBG. In protocol 2, arterial pressure and HR were measured before and
after an injection of 50 mmol/L Na2CO3 vehicle
alone (3 mL/kg IP); zinc protoporphyrin IX (ZnPP, 45 µmol/kg IP),
which inhibits heme oxygenase activity; or biliverdin (45 µmol/kg
IP), which is a heme oxygenase product.1 2 4 In protocol
3, rats were pretreated for 15 minutes with either chlorisondamine (5
mg/kg IP) or prazosin (5 mg/kg IP) to block autonomic ganglionic or
1-adrenoceptor functions,13 respectively.
Arterial pressure and HR were then measured before and after injection
of the vehicle alone (3 mL/kg IP) or ZnDPBG (45 µmol/kg IP) to
inhibit heme oxygenase activity. In some experiments, the effect of
ZnDPBG on the BP of rats pretreated with chlorisondamine was examined
in animals receiving phenylephrine at a rate (4±1 µg/kg per minute
IV) sufficient to offset the vasodepressor effect of the ganglionic
blocker. In protocol 4, rings of descending thoracic aorta from
untreated rats were prepared for recording of isometric tension in
organ baths filled with Krebs' bicarbonate buffer, according to
published procedures.13 In these rings we examined the
effect of ZnDPBG (50 µmol/L) on resting tension as well as on the
tension development induced by the cumulative addition of phenylephrine
(10-9 to 10-6 mol/L) to the bath.
Statistics
Results are expressed as mean±SEM. Data were analyzed by ANOVA,
with a value of P<.05 being significant. This was followed
by orthogonal contrasts (=0.05) with Bonferroni correction.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Fig 1 displays hemodynamic data before and after ZnDPBG or DPBG administration. ZnDPBG administration, to inhibit heme oxygenase activity, increased MAP (P<.05) and total peripheral resistance (P<.05). ZnDPBG decreased cardiac output (P<.05) but did not affect HR (P>.05). DPBG administration, which does not affect heme oxygenase activity, did not affect MAP, total peripheral resistance, cardiac output, or HR (P>.05 each). Also, vehicle administration did not affect (n=5, P>.05) MAP (104±1 versus 101±1 mm Hg), total peripheral resistance (1.40±0.02 versus 1.41±0.02 mm Hg/[mL/min]), cardiac output (76±1 versus 74±1 mL/min), or HR (437±1 versus 436±2 beats per minute).
|
Fig 2 shows the data on HR and MAP before and after administration of ZnPP, biliverdin, or vehicle. ZnPP administration, to inhibit heme oxygenase activity, increased MAP (P<.05) but did not affect HR (P>.05). Biliverdin administration, which is a heme oxygenase product, did not affect either MAP or HR (P>.05 each). Also, vehicle administration did not affect arterial pressure or HR (P>.05 each).
|
Fig 3 shows the data of MAP and HR before and after vehicle or ZnDPBG administration in rats pretreated with chlorisondamine to block ganglionic function. Chlorisondamine pretreatment lowered BP and decreased HR (P<.05 each). In chlorisondamine-pretreated animals, ZnDPBG administration had no effect on BP (P>.05) but did decrease HR (P<.05). Vehicle administration had no effect on BP or HR (P>.05). ZnDPBG did not affect the BP (105±5 versus 97±3 mm Hg, n=5) of rats in which the vasodepressor response to pretreatment with chlorisondamine was offset by infusion of phenylephrine.
|
Fig 4 shows the data of MAP and HR before and after
vehicle and ZnDPBG administration in rats pretreated with prazosin to
inhibit 1-adrenoceptor function. Prazosin pretreatment
reduced BP (P<.05) and increased HR (P<.05). In
prazosin-pretreated animals, neither vehicle nor ZnDPBG administration
had any affect on BP or HR (P>.05, each).
|
The resting tone of rings of descending thoracic aorta bathed in Krebs' bicarbonate buffer did not change with the addition of ZnDPBG (50 µmol/L) to the bath. Also, aortic constrictor responses to phenylephrine (1 µmol/L) were similar in the presence and absence of ZnDPBG (87±8% versus 83±5% of contractions induced by 120 mmol/L KCl).
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Since ZnDPBG and ZnPP inhibit heme oxygenase–mediated conversion of heme to carbon monoxide and biliverdin,9 10 11 12 the effects of these inhibitors on hemodynamics may provide insights into the physiological influence of heme oxygenase products on BP regulation. ZnDPBG and ZnPP administration produces pressor responses that are maximal within 5 minutes and maintained for approximately 1 hour. ZnDPBG-induced increases in arterial pressure are paralleled by increases in total peripheral resistance, establishing systemic vasoconstriction as the major hemodynamic determinant of the increase in BP. Importantly, nonmetallic DPBG, which does not inhibit heme oxygenase activity, does not affect hemodynamics. This strengthens the argument that the pressor effect of ZnDPBG is a consequence of decreased heme oxygenase activity. If so, these findings imply that heme oxygenase activity is subserving a vasodepressor function by promoting vasodilation.
Elevation of BP after pretreatment with an inhibitor of heme oxygenase may be a consequence of increased cellular levels of heme or diminished formation of biliverdin or carbon monoxide products. As heme turnover rate is slow,3 it is unlikely that the ZnDPBG- and ZnPP-induced pressor responses, which have a rapid onset, are a consequence of heme accumulation, secondary to decreased heme degradation. Although biliverdin is an antioxidant and may potentially lower BP by inhibiting lipid peroxidation and/or by prolonging the half-life of nitric oxide,5 14 in our studies biliverdin does not decrease BP. Therefore, ZnDPBG- and ZnPP-induced increases in arterial pressure are more likely to be the consequence of a diminished carbon monoxide production than of heme accumulation or decreased biliverdin production.
According to the present study, inhibitors of heme oxygenase
increase BP via mechanisms that rely on autonomic nervous function.
This conclusion is based on the observation that the ZnDPBG-induced
rise in BP is prevented by pretreatment with chlorisondamine to block
ganglionic function. Also, the ZnDPBG-induced increase in arterial
pressure is prevented by pretreatment with prazosin, to block
1-adrenoceptors, implying that the pressor effect of the
heme oxygenase inhibitor depends on 1-adrenoceptor
function. That ZnDPBG does not affect constrictor responses of aortic
smooth muscle to phenylephrine, or increase the BP of
chlorisondamine-pretreated rats undergoing infusion of
phenylephrine, argues against the possibility that the inhibitor
of heme oxygenase acts postsynaptically to increase sympathetically
mediated vasoconstrictor tone. Rather, the results of the present
study are consistent with the notion that inhibitors of heme oxygenase
affect presynaptic events leading to augmentation of sympathetic
activity and BP. Of note, an inhibitor of heme oxygenase was recently
shown to block the effect of metabotropic glutamate receptor activation
in the nucleus tractus solitarii of rats,7 implicating
carbon monoxide in the function of the afferent arm of the baroreceptor
reflex and, consequently, in the neurogenic control of BP.
To the extent that carbon monoxide arising from heme oxygenase activity subserves a vasodepressor function, interventions that increase heme oxygenase–catalyzed conversion of heme to carbon monoxide may be expected to lower BP. A previous study15 has shown that increased heme oxygenase activity produced by tin chloride treatment is associated with a lowering of BP in spontaneously hypertensive rats. Another study16 demonstrated that heme arginate treatment, which also increased heme oxygenase activity, similarly lowered BP in that rat strain.
In summary, ZnDPBG and ZnPP, known to inhibit heme oxygenase–mediated conversion of heme to carbon monoxide, increase arterial pressure. Pretreatment with chlorisondamine or prazosin prevents ZnDPBG from increasing arterial pressure, implying that the pressor effect of this agent relies on autonomic nervous function. We conclude that the pressor response to heme oxygenase inhibitors results from withdrawal of the inhibitory influence of endogenous carbon monoxide on a pressor mechanism mediated by the autonomic nervous system. A corollary of this conclusion is that carbon monoxide arising from heme via metabolism by heme oxygenase exerts a tonic counterregulatory influence on autonomic mechanisms that promote elevation of BP.
|
Acknowledgments |
|---|
This research was supported by grants 5PO1 HL-34300, HL-36670, and HL-18579 from the National Institutes of Health, Bethesda, Md. We would like to thank Jennifer Brown for assistance in preparing the manuscript.
Received June 16, 1994; first decision August 16, 1994; accepted October 25, 1994.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Abraham NG, Lin JH-C, Schwartzman ML, Levere RD, Shibahara S. The physiological significance of heme oxygenase. Int J Biochem. 1988;20:543-558. [Medline] [Order article via Infotrieve]
2. Maines MD. Heme oxygenase: function, multiplicity, regulatory mechanisms, and clinical applications. FASEB J. 1988;2:2557-2568. [Abstract]
3. Marks GS, Brien JF, Nakatsu K, McLaughlin BE. Does carbon monoxide have a physiological function? Trends Pharmacol Sci. 1991;12:185-188. [Medline] [Order article via Infotrieve]
4. Moore MR, McColl KEL, Rimington C, Goldberg A. Porphyrins and enzymes of the heme biosynthetic pathway. In: Wintrobe MM, ed. Disorders of Porphyrin Metabolism. New York, NY: Plenum Medical Book Co; 1987:21-44.
5. Schmidt HHHW. NO, CO and HO endogenous soluble guanylyl cyclase-activating factors. FEBS Lett. 1992;307:102-107.[Medline] [Order article via Infotrieve]
6. Graser T, Vedernikov YP, Li DS. Study on the mechanism of carbon monoxide induced endothelium-independent relaxation in porcine coronary artery and vein. Biomed Biochim Acta. 1990;49:293-296. [Medline] [Order article via Infotrieve]
7. Glaum SR, Miller RJ. Zinc protoporphyrin-IX blocks the effects of metabotropic glutamate receptor activation in the rat nucleus tractus solitarii. Mol Pharmacol. 1993;43:965-969. [Abstract]
8.
Verma A, Hirsch DJ, Glatt CE, Ronnett GV, Snyder SH. Carbon
monoxide: a putative neural messenger. Science. 1993;259:381-384.
9. Mitrione SM, Villalon P, Lutton JD, Levere RD, Abraham NG. Inhibition of human adult and fetal heme oxygenase by new synthetic heme analogues. Am J Med Sci. 1988;296:180-186. [Medline] [Order article via Infotrieve]
10. Chernick RJ, Martasek P, Levere RD, Margreiter R, Abraham NG. Sensitivity of human tissue heme oxygenase to a new synthetic metalloporphyrin. Hepatology. 1989;10:365-369. [Medline] [Order article via Infotrieve]
11. Vreman HJ, Ekstrand BC, Stevenson DK. Selection of metalloporphyrin heme oxygenase inhibitors based on potency and photoreactivity. Pediatr Res. 1993;33:195-200. [Medline] [Order article via Infotrieve]
12. Vreman HJ, Lee OK, Stevenson DK. In vitro and in vivo characteristics of a heme oxygenase inhibitor: ZnBG. Am J Med Sci. 1991;302:335-341. [Medline] [Order article via Infotrieve]
13.
Pucci ML, Lin L, Nasjletti A. Pressor and renal
vasoconstrictor effects of NG-nitro-L-arginine as affected
by blockade of pressor mechanisms mediated by the sympathetic nervous
system, angiotensin, prostanoids and vasopressin. J Pharmacol Exp
Ther. 1992;261:240-245.
14. Stocker R, McDonagh AF, Glazer AN, Ames BN. Antioxidant activities of bile pigments: biliverdin and bilirubin. Methods Enzymol. 1990;186:301-311. [Medline] [Order article via Infotrieve]
15.
Sacerdoti D, Escalante B, Abraham NG, McGiff JC, Levere RD,
Schwartzman ML. Treatment with tin prevents the development of
hypertension in spontaneously hypertensive rats. Science. 1989;243:388-390.
16. Levere RD, Martasek P, Escalante B, Schwartzman ML, Abraham NG. Effect of heme arginate administration on blood pressure in spontaneously hypertensive rats. J Clin Invest. 1990;86:213-219.
This article has been cited by other articles:
 |
|
 |
|
  G. L. Volti, L. Vanella, D. Gazzolo, and F. Galvano Carbon monoxide: vasoconstrictor or vasodilator? That's the question Am J Physiol Renal Physiol, October 1, 2008; 295(4): F901 - F903. [Full Text] [PDF]
|
|
|
|
 |
|
 T. Chang, L. Wu, and R. Wang Inhibition of vascular smooth muscle cell proliferation by chronic hemin treatment Am J Physiol Heart Circ Physiol, September 1, 2008; 295(3): H999 - H1007. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. G. Abraham and A. Kappas Pharmacological and Clinical Aspects of Heme Oxygenase Pharmacol. Rev., March 1, 2008; 60(1): 79 - 127. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Yang, P. J. Lee, L. Long, R. C. Trembath, and N. W. Morrell BMP4 Induces HO-1 via a Smad-Independent, p38MAPK-Dependent Pathway in Pulmonary Artery Myocytes Am. J. Respir. Cell Mol. Biol., November 1, 2007; 37(5): 598 - 605. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. T. Botros and L. G. Navar Interaction between endogenously produced carbon monoxide and nitric oxide in regulation of renal afferent arterioles Am J Physiol Heart Circ Physiol, December 1, 2006; 291(6): H2772 - H2778. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Hirakawa and Y. Hayashida Autonomic Cardiovascular Responses to Heme Oxygenase Inhibition in Conscious Rats Hypertension, December 1, 2006; 48(6): 1124 - 1129. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W.-C. Lo, P.-J. Lu, W.-Y. Ho, M. Hsiao, and C.-J. Tseng Induction of Heme Oxygenase-1 Is Involved in Carbon Monoxide-Mediated Central Cardiovascular Regulation J. Pharmacol. Exp. Ther., July 1, 2006; 318(1): 8 - 16. [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]
|
|
|
|
 |
|
 F. K. Johnson, R. A. Johnson, W. Durante, K. E. Jackson, B. K. Stevenson, and K. J. Peyton Metabolic syndrome increases endogenous carbon monoxide production to promote hypertension and endothelial dysfunction in obese Zucker rats Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2006; 290(3): R601 - R608. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Achouh, S. Simonet, C. Badier-Commander, C. Chardigny, C. Vayssettes-Courchay, R. Zegdi, Z. Khabbaz, J.-N. Fabiani, and T. J. Verbeuren The induction of heme oxygenase 1 decreases contractility in human internal thoracic artery and radial artery grafts J. Thorac. Cardiovasc. Surg., December 1, 2005; 130(6): 1573 - 1580. [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]
|
|
|
|
 |
|
 H. Resch, C. Zawinka, G. Weigert, L. Schmetterer, and G. Garhofer Inhaled Carbon Monoxide Increases Retinal and Choroidal Blood Flow in Healthy Humans Invest. Ophthalmol. Vis. Sci., November 1, 2005; 46(11): 4275 - 4280. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Morse and A. M. K. Choi Heme Oxygenase-1: From Bench to Bedside Am. J. Respir. Crit. Care Med., September 15, 2005; 172(6): 660 - 670. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Roman Gene Therapy and Heme Oxygenase Coming of Age Hypertension, June 1, 2004; 43(6): 1173 - 1174. [Full Text] [PDF]
|
|
|
|
|
|
L. Yang, S. Quan, A. Nasjletti, M. Laniado-Schwartzman, and N. G. Abraham Heme Oxygenase-1 Gene Expression Modulates Angiotensin II-Induced Increase in Blood Pressure Hypertension, June 1, 2004; 43(6): 1221 - 1226. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Sacerdoti, N. G. Abraham, A. O. Oyekan, L. Yang, A. Gatta, and J. C. McGiff Role of the Heme Oxygenases in Abnormalities of the Mesenteric Circulation in Cirrhotic Rats J. Pharmacol. Exp. Ther., February 1, 2004; 308(2): 636 - 643. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. A. D. T. G. Wagener, H.-D. Volk, D. Willis, N. G. Abraham, M. P. Soares, G. J. Adema, and C. G. Figdor Different Faces of the Heme-Heme Oxygenase System in Inflammation Pharmacol. Rev., September 1, 2003; 55(3): 551 - 571. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Wang, H. Sterling, W. A. Shao, Q. Yan, M. A. Bailey, G. Giebisch, and W.-H. Wang Inhibition of heme oxygenase decreases sodium and fluid absorption in the loop of Henle Am J Physiol Renal Physiol, September 1, 2003; 285(3): F484 - F490. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-H. Lin, W.-C. Lo, M. Hsiao, and C.-J. Tseng Interaction of Carbon Monoxide and Adenosine in the Nucleus Tractus Solitarii of Rats Hypertension, September 1, 2003; 42(3): 380 - 385. [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]
|
|
|
|
 |
|
 Y.-H. Chen, S.-F. Yet, and M. A. Perrella Role of Heme Oxygenase-1 in the Regulation of Blood Pressure and Cardiac Function Experimental Biology and Medicine, May 1, 2003; 228(5): 447 - 453. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. I. Goodman, S. Quan, L. Yang, A. Synghal, and N. G. Abraham Functional Expression of Human Heme Oxygenase-1 Gene in Renal Structure of Spontaneously Hypertensive Rats Experimental Biology and Medicine, May 1, 2003; 228(5): 454 - 458. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. F. Ndisang and R. Wang Alterations in Heme Oxygenase/Carbon Monoxide System in Pulmonary Arteries in Hypertension Experimental Biology and Medicine, May 1, 2003; 228(5): 557 - 563. [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]
|
|
|
|
|
|
J. S. Winestone, C. Bonner, and C. W. Leffler Carbon Monoxide as an Attenuator of Vasoconstriction in Piglet Cerebral Arterioles Experimental Biology and Medicine, January 1, 2003; 228(1): 46 - 50. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. G. Abraham, S. Quan, P. A. Mieyal, L. Yang, T. Burke-Wolin, C. J. Mingone, A. I. Goodman, A. Nasjletti, and M. S. Wolin Modulation of cGMP by human HO-1 retrovirus gene transfer in pulmonary microvessel endothelial cells Am J Physiol Lung Cell Mol Physiol, November 1, 2002; 283(5): L1117 - L1124. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. F. Ndisang, W. Zhao, and R. Wang Selective Regulation of Blood Pressure by Heme Oxygenase-1 in Hypertension Hypertension, September 1, 2002; 40(3): 315 - 321. [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]
|
|
|
|
 |
|
 X.-m. Liu, G. B Chapman, K. J Peyton, A. I Schafer, and W. Durante Carbon monoxide inhibits apoptosis in vascular smooth muscle cells Cardiovasc Res, August 1, 2002; 55(2): 396 - 405. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Morse and A. M. K. Choi Heme Oxygenase-1 . The "Emerging Molecule" Has Arrived Am. J. Respir. Cell Mol. Biol., July 1, 2002; 27(1): 8 - 16. [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]
|
|
|
|
 |
|
 K. J. Peyton, S. V. Reyna, G. B. Chapman, D. Ensenat, X.-m. Liu, H. Wang, A. I. Schafer, and W. Durante Heme oxygenase-1-derived carbon monoxide is an autocrine inhibitor of vascular smooth muscle cell growth Blood, May 29, 2002; 99(12): 4443 - 4448. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Roman P-450 Metabolites of Arachidonic Acid in the Control of Cardiovascular Function Physiol Rev, January 1, 2002; 82(1): 131 - 185. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X.-m. Liu, G. B. Chapman, H. Wang, and W. Durante Adenovirus-Mediated Heme Oxygenase-1 Gene Expression Stimulates Apoptosis in Vascular Smooth Muscle Cells Circulation, January 1, 2002; 105(1): 79 - 84. [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]
|
|
|
|
|
|
H. E. Sabaawy, F. Zhang, X. Nguyen, A. ElHosseiny, A. Nasjletti, M. Schwartzman, P. Dennery, A. Kappas, and N. G. Abraham Human Heme Oxygenase-1 Gene Transfer Lowers Blood Pressure and Promotes Growth in Spontaneously Hypertensive Rats Hypertension, August 1, 2001; 38(2): 210 - 215. [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]
|
|
|
|
|
|
F. Zhang, J.-I. Kaide, Y. Wei, H. Jiang, C. Yu, M. Balazy, N. G. Abraham, W. Wang, and A. Nasjletti Carbon monoxide produced by isolated arterioles attenuates pressure-induced vasoconstriction Am J Physiol Heart Circ Physiol, July 1, 2001; 281(1): H350 - H358. [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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
W.-C. Lo, C.-R. Jan, H.-T. Chiang, and C.-J. Tseng Modulatory Effects of Carbon Monoxide on Baroreflex Activation in Nucleus Tractus Solitarii of Rats Hypertension, June 1, 2000; 35(6): 1253 - 1257. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. R. Grover, R. L. Rairigh, J. P. Zenge, S. H. Abman, and J. P. Kinsella Inhaled carbon monoxide does not cause pulmonary vasodilation in the late-gestation fetal lamb Am J Physiol Lung Cell Mol Physiol, April 1, 2000; 278(4): L779 - L784. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Takeda, G. Perry, N. G. Abraham, B. E. Dwyer, R. K. Kutty, J. T. Laitinen, R. B. Petersen, and M. A. Smith Overexpression of Heme Oxygenase in Neuronal Cells, the Possible Interaction with Tau J. Biol. Chem., February 25, 2000; 275(8): 5395 - 5399. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Togane, T. Morita, M. Suematsu, Y. Ishimura, J.-I. Yamazaki, and S. Katayama Protective roles of endogenous carbon monoxide in neointimal development elicited by arterial injury Am J Physiol Heart Circ Physiol, February 1, 2000; 278(2): H623 - H632. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. LYALL, A. BARBER, L. MYATT, J. N. BULMER, and S. C. ROBSON Hemeoxygenase expression in human placenta and placental bed implies a role in regulation of trophoblast invasion and placental function FASEB J, January 1, 2000; 14(1): 208 - 219. [Abstract] [Full Text]
|
|
|
|
 |
|
 W. Durante, K. J. Peyton, and A. I. Schafer Platelet-Derived Growth Factor Stimulates Heme Oxygenase-1 Gene Expression and Carbon Monoxide Production in Vascular Smooth Muscle Cells Arterioscler. Thromb. Vasc. Biol., November 1, 1999; 19(11): 2666 - 2672. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. A. D. T. G. Wagener, J.-L. da Silva, T. Farley, T. de Witte, A. Kappas, and N. G. Abraham Differential Effects of Heme Oxygenase Isoforms on Heme Mediation of Endothelial Intracellular Adhesion Molecule 1 Expression J. Pharmacol. Exp. Ther., October 1, 1999; 291(1): 416 - 423. [Abstract] [Full Text]
|
|
|
|
|
|
C. W. Leffler, A. Nasjletti, C. Yu, R. A. Johnson, A. L. Fedinec, and N. Walker Carbon monoxide and cerebral microvascular tone in newborn pigs Am J Physiol Heart Circ Physiol, May 1, 1999; 276(5): H1641 - H1646. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Kozma, R. A. Johnson, F. Zhang, C. Yu, X. Tong, and A. Nasjletti Contribution of endogenous carbon monoxide to regulation of diameter in resistance vessels Am J Physiol Regulatory Integrative Comp Physiol, April 1, 1999; 276(4): R1087 - R1094. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. O. Oyekan, K. McAward, J. Conetta, L. Rosenfeld, and J. C. McGiff Endothelin-1 and CYP450 arachidonate metabolites interact to promote tissue injury in DOCA-salt hypertension Am J Physiol Regulatory Integrative Comp Physiol, March 1, 1999; 276(3): R766 - R775. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. C.M. Siow, H. Sato, and G. E. Mann Heme oxygenase-carbon monoxide signalling pathway in atherosclerosis: anti-atherogenic actions of bilirubin and carbon monoxide? Cardiovasc Res, February 1, 1999; 41(2): 385 - 394. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. K. Caudill, T. C. Resta, N. L. Kanagy, and B. R. Walker Role of endothelial carbon monoxide in attenuated vasoreactivity following chronic hypoxia Am J Physiol Regulatory Integrative Comp Physiol, October 1, 1998; 275(4): R1025 - R1030. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Motterlini, A. Gonzales, R. Foresti, J. E. Clark, C. J. Green, and R. M. Winslow Heme Oxygenase-1–Derived Carbon Monoxide Contributes to the Suppression of Acute Hypertensive Responses In Vivo Circ. Res., September 7, 1998; 83(5): 568 - 577. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. W. De Keulenaer, D. C. Chappell, N. Ishizaka, R. M. Nerem, R. W. Alexander, and K. K. Griendling Oscillatory and Steady Laminar Shear Stress Differentially Affect Human Endothelial Redox State : Role of a Superoxide-Producing NADH Oxidase Circ. Res., June 1, 1998; 82(10): 1094 - 1101. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Chlorakos, B. L. Langille, and S. L. Adamson Cardiovascular responses attenuate with repeated NO synthesis inhibition in conscious fetal sheep Am J Physiol Heart Circ Physiol, May 1, 1998; 274(5): H1472 - H1480. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Johnson, E. Colombari, D. S. A. Colombari, M. Lavesa, W. T. Talman, and A. Nasjletti Role of Endogenous Carbon Monoxide in Central Regulation of Arterial Pressure Hypertension, October 1, 1997; 30(4): 962 - 967. [Abstract] [Full Text]
|
|
|
|
|
|
N. Ishizaka, H. De Leon, J. Bech Laursen, T. Fukui, J. N. Wilcox, G. De Keulenaer, K. K. Griendling, and R. W. Alexander Angiotensin II–Induced Hypertension Increases Heme Oxygenase-1 Expression in Rat Aorta Circulation, September 16, 1997; 96(6): 1923 - 1929. [Abstract] [Full Text]
|
|
|
|
|
|
M. Hausberg and V. K. Somers Neural Circulatory Responses to Carbon Monoxide in Healthy Humans Hypertension, May 1, 1997; 29(5): 1114 - 1118. [Abstract] [Full Text]
|
|
|
|
|
|
W. Durante, M. H. Kroll, N. Christodoulides, K. J. Peyton, and A. I. Schafer Nitric Oxide Induces Heme Oxygenase-1 Gene Expression and Carbon Monoxide Production in Vascular Smooth Muscle Cells Circ. Res., April 19, 1997; 80(4): 557 - 564. [Abstract] [Full Text]
|
|
|
|
|
|
N. Ishizaka and K. K. Griendling Heme Oxygenase-1 Is Regulated by Angiotensin II in Rat Vascular Smooth Muscle Cells Hypertension, March 1, 1997; 29(3): 790 - 795. [Abstract] [Full Text]
|
|
|
|
|
|
S.-F. Yet, A. Pellacani, C. Patterson, L. Tan, S. C. Folta, L. Foster, W.-S. Lee, C.-M. Hsieh, and M. A. Perrella Induction of Heme Oxygenase-1 Expression in Vascular Smooth Muscle Cells. A LINK TO ENDOTOXIC SHOCK J. Biol. Chem., February 14, 1997; 272(7): 4295 - 4301. [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]
|
|
|
|
|
|
P. Wiesel, A. P. Patel, I. M. Carvajal, Z. Y. Wang, A. Pellacani, K. Maemura, N. DiFonzo, H. G. Rennke, M. D. Layne, S.-F. Yet, et al. Exacerbation of Chronic Renovascular Hypertension and Acute Renal Failure in Heme Oxygenase-1-Deficient Mice Circ. Res., May 25, 2001; 88(10): 1088 - 1094. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Imai, T. Morita, T. Shindo, R. Nagai, Y. Yazaki, H. Kurihara, M. Suematsu, and S. Katayama Vascular Smooth Muscle Cell-Directed Overexpression of Heme Oxygenase-1 Elevates Blood Pressure Through Attenuation of Nitric Oxide-Induced Vasodilation in Mice Circ. Res., July 6, 2001; 89(1): 55 - 62. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||