Biotransformation of glyceryl trinitrate to glyceryl dinitrate by human hemoglobin

1984 ◽  
Vol 62 (6) ◽  
pp. 704-706 ◽  
Author(s):  
Brian M. Bennett ◽  
Kanji Nakatsu ◽  
James F. Brien ◽  
Gerald S. Marks
Keyword(s):  
Carbon Monoxide ◽  
Cardiac Output ◽  
Glyceryl Trinitrate ◽  
Human Erythrocytes ◽  
Supernatant Fraction ◽  
Human Hemoglobin

The elimination of glyceryl trinitrate (GTN) by man is rapid and its clearance exceeds cardiac output. It is therefore clear that a variety of tissues in addition to liver are involved in the biotransformation of GTN. Incubation of GTN with the 25 000 × g supernatant fraction of lysed human erythrocytes resulted in a 39.6% ± 5.5 (SD) elimination of GTN after 40 min. After pretreatment of the lysate supernatant fraction with carbon monoxide, GTN elimination was only 26% ± 4.5. These data indicated that hemoglobin might be involved in GTN elimination. When purified hemoglobin was incubated with GTN, a 77.1% ± 6.4 elimination of GTN was observed, accompanied by glyceryl dinitrate formation. The biotransformation of GTN was inhibited by pretreatment with carbon monoxide. The results indicate that the biotransformation of GTN by human erythrocytes is due, at least in part, to interaction with hemoglobin.

Differential biotransformation of glyceryl trinitrate by red blood cell – supernatant fraction and pulmonary vein homogenate

1989 ◽  
Vol 67 (5) ◽  
pp. 417-422 ◽  
Author(s):  
Gerald S. Marks ◽  
Brian E. McLaughlin ◽  
Heather F. MacMillan ◽  
Kanji Nakatsu ◽  
James F. Brien
Keyword(s):  
Carbon Monoxide ◽  
Blood Cell ◽  
Glyceryl Trinitrate ◽  
Pulmonary Vein ◽  
Red Blood Cell ◽  
Supernatant Fraction ◽  
Preferential Formation ◽  
Dependent Process ◽  
Enzymatic Mechanisms ◽  
Cell Supernatant

We have demonstrated previously that glyceryl trinitrate (GTN) undergoes biotransformation to two glyceryl dinitrate (GDN) metabolites in the human red blood cell – supernatant fraction (RBC–SF) by hemoglobin-mediated and sulfhydryl-dependent enzymatic mechanisms. In the present study, we have shown that biotransformation of GTN in rabbit RBC–SF yields a glyceryl-1,2-dinitrate (1,2-GDN)/glyceryl-1,3-dinitrate (1,3-GDN) ratio of 5.3. Following inhibition of hemoglobin-mediated biotransformation of GTN by carbon monoxide (CO), the 1,2-GDN/1,3-GDN ratio was 2.1. Following inhibition of sulfhydryl-dependent biotransformation by N-ethylmaleimide (NEM), the 1,2-GDN/1,3-GDN ratio was 30.0. We have demonstrated previously that for GTN-induced vasodilation of isolated bovine pulmonary vein (BPV), the 1,2-GDN/1,3-GDN ratio was 7.1, which indicated that a hemoprotein-dependent process was involved in GTN biotransformation. To determine if this was the case, the biotransformation of GTN (0.51 μM) was studied in BPV homogenates; 31.1 pmol GDN/mg BPV protein was formed in 20 min. The 1,2-GDN/1,3-GDN ratio was 1.1, which indicated that hemoprotein-mediated biotransformation did not occur. This conclusion was supported by the fact that CO did not inhibit GTN biotransformation. GTN biotransformation by BPV homogenate was inhibited 62% by NEM, 89% by boiling of the homogenate, and almost completely by boiling plus NEM. These results indicated that biotransformation of GTN by the BPV homogenate involved in a combination of enzymatic and nonenzymatic processes that were mostly sulfhydryl dependent. It is concluded that the mechanism for GTN biotransformation in isolated intact BPV, which yielded preferential formation of 1,2-GDN, was rendered nonfunctional upon tissue homogenization.Key words: glyceryl trinitrate, glyceryl dinitrate, biotransformation, erythrocyte, pulmonary vein.

scholarly journals The Binding of Carbon Monoxide by Human Hemoglobin

1968 ◽  
Vol 243 (11) ◽  
pp. 2918-2920 ◽  
Author(s):  
S R Anderson ◽  
E Antonini
Keyword(s):  
Carbon Monoxide ◽  
Human Hemoglobin

scholarly journals The Reactions of the Isolated α and β Chains of Human Hemoglobin with Oxygen and Carbon Monoxide

1966 ◽  
Vol 241 (22) ◽  
pp. 5238-5243 ◽  
Author(s):  
Maurizio Brunori ◽  
Robert W. Noble ◽  
Eraldo Antonini ◽  
Jeffries Wyman
Keyword(s):  
Carbon Monoxide ◽  
Human Hemoglobin

Whole body and hindlimb cardiovascular responses of the anesthetized dog during CO hypoxia

1984 ◽  
Vol 62 (7) ◽  
pp. 769-774 ◽  
Author(s):  
C. E. King ◽  
S. M. Cain ◽  
C. K. Chapler
Keyword(s):  
Carbon Monoxide ◽  
Blood Flow ◽  
Cardiac Output ◽  
Sympathetic Innervation ◽  
Cardiovascular Responses ◽  
The Body ◽  
Whole Body ◽  
Total Resistance ◽  
Intact Group ◽  
Anesthetized Dogs

To compare with earlier studies of anemic hypoxia obtained by hemodilution, O2 carring capacity was decreased by carbon monoxide (CO) hypoxia. Arterial O2 content was reduced either 50% (moderate CO) or 65% (severe CO). In two groups of anesthetized dogs (moderate and severe CO) hindlimb innervation remained intact while in a third group (moderate CO) the hindlimb was denervated. Measurements were obtained prior to and at 30 and 60 min of CO hypoxia. Cardiac output was elevated at 30 min of CO hypoxia in all groups (p < 0.01) and in the severe CO group at 60 min (p < 0.01). Hindlimb blood flow remained unchanged during CO hypoxia in the intact groups. In the denervated group, hindlimb blood flow was greater (p < 0.05) than that in the intact groups throughout the experiment. A decrease in mean arterial pressure (p < 0.01) in all groups was associated with a fall in total resistance (p < 0.01). Hindlimb resistance remained unchanged during moderate CO hypoxia in the intact group but increased (p < 0.05) in the denervated group. In the severe CO group hindlimb resistance was decreased (p < 0.05) at 60 min. The results indicate that the increase in cardiac output during CO hypoxia was directed to nonmuscle areas of the body and that intact sympathetic innervation was required to achieve this redistribution.

Erythrocytes decrease myocardial hydrogen peroxide levels and reperfusion injury

1989 ◽  
Vol 256 (2) ◽  
pp. H584-H588 ◽  
Author(s):  
J. M. Brown ◽  
M. A. Grosso ◽  
L. S. Terada ◽  
C. J. Beehler ◽  
K. M. Toth ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Carbon Monoxide ◽  
Superoxide Dismutase ◽  
Reperfusion Injury ◽  
Ventricular Function ◽  
Anion Channel ◽  
Human Erythrocytes ◽  
Rat Hearts ◽  
Perfused Hearts ◽  
Isolated Rat

Reperfusion with untreated, carbon monoxide-treated, or glutaraldehyde-fixed human erythrocytes (RBC) increased ventricular function and decreased myocardial hydrogen peroxide (H2O2) levels [assessed by H2O2-dependent aminotriazole (AMT) inactivation of myocardial catalase activities] of ischemic, isolated rat hearts. In contrast, reperfusion with RBC that lacked catalase (AMT treated) and/or glutathione (N-ethylmaleimide treated) did not increase ventricular function or decrease myocardial H2O2 levels as much as reperfusion with untreated RBC. By comparison, reperfusion with superoxide dismutase-depleted (diethyldithiocarbamate-treated) or anion channel-inhibited (diisothiocyanodisulfonic acid stilbene-treated) RBC increased ventricular function and decreased myocardial H2O2 levels the same as untreated RBC. The results suggest that catalase and/or glutathione in intact RBC can decrease endogenously generated H2O2 and related reperfusion injury in ischemic, isolated perfused hearts.

Intrapulmonary blood flow redistribution during hypoxia increases gas exchange surface area

1982 ◽  
Vol 52 (6) ◽  
pp. 1575-1580 ◽  
Author(s):  
R. L. Capen ◽  
W. W. Wagner
Keyword(s):  
Carbon Monoxide ◽  
Blood Flow ◽  
Cardiac Output ◽  
Gas Exchange ◽  
Surface Area ◽  
Vascular Resistance ◽  
Diffusing Capacity ◽  
Capillary Recruitment ◽  
Blood Flow Redistribution ◽  
Exchange Surface

We have previously shown that airway hypoxia causes pulmonary capillary recruitment and raises diffusing capacity for carbon monoxide. This study was designed to determine whether these events were caused by an increase in pulmonary vascular resistance, which redistributed blood flow toward the top of the lung, or by an increase in cardiac output. We measured capillary recruitment at the top of the dog lung by in vivo microscopy, gas exchange surface area of the whole lung by diffusing capacity for carbon monoxide, and blood flow distribution by radioactive microspheres. During airway hypoxia recruitment occurred, diffusing capacity increased, and blood flow was redistributed upward. When a vasodilator was infused while holding hypoxia constant, these effects were reversed; i. e., capillary “derecruitment” occurred, diffusing capacity decreased, and blood flow was redistributed back toward the bottom of the lung. The vasodilator was infused at a rate that left hypoxic cardiac output unchanged. These data show that widespread capillary recruitment during hypoxia is caused by increased vascular resistance and the resulting upward blood flow redistribution.

Effect of inhibitors of glutathione S-transferase on glyceryl trinitrate activity in isolated rat aorta

1993 ◽  
Vol 71 (2) ◽  
pp. 179-184 ◽  
Author(s):  
Rita Nigam ◽  
Tracy Whiting ◽  
Brian M. Bennett
Keyword(s):  
Glyceryl Trinitrate ◽  
Cyclic Gmp ◽  
Guanylyl Cyclase ◽  
Rat Aorta ◽  
Supernatant Fraction ◽  
Organic Nitrates ◽  
Transferase Activity ◽  
Glutathione S Transferase ◽  
Glutathione S Transferases

We investigated the role of glutathione S-transferases (enzymes known to biotransform organic nitrates) in the vascular action of glyceryl trinitrate (GTN). Relaxation of phenylephrine-contracted rat aortic strips was assessed in the presence or absence of the glutathione S-transferase inhibitors Basilen Blue, bromosulfophthalein, Rose Bengal, hematin, chlorotriphenyltin, and (octyloxy)benzoylvinylglutathione. Whereas none of the inhibitors increased the EC50 for GTN relaxation, glutathione S-transferase activity in the 100 000 × g supernatant fraction of rat aorta was inhibited markedly by most of the inhibitors. In addition, GTN-stimulated activation of aortic guanylyl cyclase in broken-cell preparations was attenuated by all of the glutathione S-transferase inhibitors, suggesting a direct inhibitory action on guanylyl cyclase. In other experiments using aortic strips preexposed to phenylephrine, the inhibitors had no effect on GTN-induced cyclic GMP accumulation or on vascular biotransformation of GTN. In contrast, both Basilen Blue and bromosulfophthalein significantly inhibited GTN-induced relaxation of K+-contracted aortic strips, and Basilen Blue significantly inhibited GTN biotransformation in aortic strips preexposed to 25 mM K+. This may be due to a more favourable electrochemical gradient for entry of the inhibitors into membrane-depolarized tissues. We conclude that vascular glutathione S-transferases play a role in mediating the vasodilator actions of GTN in intact tissues in vitro, but that this appears to depend upon the nature of the contractile agent used in such studies.Key words: glyceryl trinitrate, glutathione S-transferase, cyclic GMP, vascular smooth muscle, biotransformation.

The role of α-adrenergic receptors in carbon monoxide hypoxia

1986 ◽  
Vol 64 (11) ◽  
pp. 1442-1446 ◽  
Author(s):  
S. M. Villeneuve ◽  
C. K. Chapler ◽  
C. E. King ◽  
S. M. Cain
Keyword(s):  
Carbon Monoxide ◽  
Blood Flow ◽  
Cardiac Output ◽  
Adrenergic Receptors ◽  
Muscle Blood Flow ◽  
Control Period ◽  
Arterial Oxygen ◽  
Adrenergic Blockade ◽  
Limb Blood Flow ◽  
Arterial Oxygen Content

The importance of α-adrenergic receptors in the cardiac output and peripheral circulatory responses to carbon monoxide (CO) hypoxia was studied in anesthetized dogs. Phenoxybenzamine (3 mg/kg i.v.) was injected to block α-receptor activity and the data obtained were then compared with those from a previous study of CO hypoxia in unblocked animals. Values for cardiac output, hindlimb blood flow, vascular resistance, and oxygen uptake were obtained prior to and at 30 and 60 min of CO hypoxia which reduced arterial oxygen content by approximately 50%. α-Adrenergic blockade resulted in a lower (p < 0.05) control value for cardiac output than observed in unblocked animals, but no differences were present between the two groups at 30 or 60 min of CO hypoxia. Similarly, limb blood flow was lower (p < 0.05) during the control period in the α-blocked group but rose to the same level as that in the unblocked animals at 60 min of COH. No change in limb blood flow occurred during CO hypoxia in the unblocked group. These findings demonstrated that during CO hypoxia (i) α-receptor mediated venoconstriction does not contribute to the cardiac output response and (ii) α-receptor mediated vasoconstriction probably does prevent a rise in hindlimb skeletal muscle blood flow.

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