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G S Marks

Publications and source records attributed to G S Marks.

At least 73 records · Page 4Linked to original sources
PubMed1993

Effect of temperature on glyceryl trinitrate induced relaxation of rabbit aorta.

It has previously been shown that the vasodilatory response to glyceryl trinitrate (GTN) was decreased during hypothermic cardiopulmonary bypass. The purpose of these experiments was to determine the effect of temperature on GTN-induced relaxation and on GTN biotransformation in rabbit aorta. It was determined that the EC50 of GTN on rabbit aortic rings (RARs) was increased significantly from 1.8 x 10(-8) M at 37 degrees C to 3.4 x 10(-8) M at 27 degrees C (p < 0.05). The production of NO by rabbit aortic strips (RASs) was significantly less at 27 degrees C compared with 37 degrees C after 80 min, being 9.62 x 10(-11) +/- 13.2 x 10(-11) mol NO/g wet wt. RASs compared with 5.71 x 10(-10) +/- 9.43 x 10(-11) mol NO/g wet wt. RASs, respectively (p < 0.05), after 80 min incubation. There was no difference in the amount of glyceryl-1,2-dinitrate (1,2-GDN) produced from GTN at the two temperatures. The ED20 for NO-induced relaxation of RARs increased from 3.46 x 10(-10) +/- 2.24 x 10(-10) mol at 37 degrees C to 1.01 x 10(-9) +/- 4.51 x 10(-10) mol at 27 degrees C (p < 0.05). These data indicate that the biotransformation of GTN and the release of NO were impaired by hypothermia, and that this, as well as a decrease in the tissue response to NO at 27 degrees C, explains the decrease in GTN activity at reduced body temperatures.

Animals↗
PubMed1993

Selective sequestration of nitric oxide by subcellular components of vascular smooth muscle and platelets: relationship to nitric oxide stimulation of the soluble guanylyl cyclase.

Sequestration of nitric oxide (NO) by subcellular fractions isolated from bovine pulmonary arterial medial layer (BPA) and rabbit platelets (RP) was studied utilizing a novel chemiluminescence--headspace gas technique. Sequestration in all fractions was similarly rapid (5 min) and remained constant for at least 30 min. When incubated with 108 pmol of NO, the BPA mitochondrial, microsomal, and nuclear fractions sequestered 22.8 +/- 1.9, 20.5 +/- 2.2 and 15.2 +/- 3.6% of the NO, respectively (n = 14). However, significantly more of the 108 pmol of NO, 36.8 +/- 2.8 and 32.9 +/- 3.6%, respectively, was sequestered by the BPA homogenate (about 2 mg protein/mL) and BPA cytosolic fraction (about 1 mg protein/mL) (n = 19). Also, RP cytosolic fraction (about 3 mg protein/mL) sequestered a greater amount of NO than any BPA fraction when incubated with 108 pmol of NO (83.0 +/- 1.0%; n = 3). Analysis of the binding data obtained for the BPA homogenate and cytosolic fraction was consistent with the existence of two binding sites, one site with a Kd of approximately 100 nM and another with a Kd of approximately 1 microM. Both the BPA homogenate fraction and the cytosolic fraction as well as the RP cytosolic fraction were shown to have soluble guanylyl cyclase activity. The nitrovasodilator sodium nitroprusside (SNP) caused a concentration-dependent increase in the activity of this enzyme in all these fractions. Maximum stimulations caused by 1 mM SNP in BPA homogenate fraction, BPA cytosolic fraction, and RP cytosolic fraction were equivalent to 2-, 4- and 3-fold increases in catalytic activity, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Lack of evidence for the involvement of cytochrome P-450 or other hemoproteins in metabolic activation of glyceryl trinitrate in rabbit aorta.

The present study was conducted to test the hypothesis that glyceryl trinitrate (GTN) metabolic activation in blood vessels is mediated by cytochrome P-450 or some other hemoprotein. The effects of cytochrome P-450 inhibitor [2-dimethylaminoethyl-2,2-diphenyl-n-pentanoate (SKF-525A) and metyrapone] on the response of rabbit aortic rings to GTN was determined by recording cumulative GTN dose-response curves in the presence of either or both inhibitors. The cytochrome P-450 inhibitors did not interfere with the ability of GTN to relax rabbit aortic rings. Treatment of rabbit aortic strips (RAS) with carbon monoxide (CO) was undertaken to elucidate a potential role of ferrous hemoproteins in mediating GTN-induced relaxation. CO did not significantly inhibit GTN-induced vasodilation of RAS. Biotransformation of GTN to glyceryl dinitrates by RAS exposed to CO for 5 min or nitric oxide (NO) for 10 min was determined by incubation of the tissues with 0.5 microM [3H]- or [14C]-GTN in the presence of CO or NO for 10 sec, 30 sec or 2 min. Neither CO nor NO exposure inhibited glyceryl-1,2- or -1,3-dinitrate formation by RAS after the 10-sec or 2-min incubation with RAS. For the 30-sec incubation, NO exposure did inhibit glyceryl dinitrate formation by RAS. This was deemed to be less important than the 10-sec data, the time just before the onset of relaxation. Therefore, emphasis is placed on lack of inhibition by NO at this earlier time point.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Carbon monoxide does not inhibit glyceryl trinitrate biotransformation by or relaxation of aorta.

Carbon monoxide (CO) was employed to assess the role of ferrous hemoproteins in the vasodilation and biotransformation of glyceryl trinitrate (GTN) in rabbit aortic strips. These tissues were contracted submaximally with phenylephrine, exposed to CO for 5 min, and then incubated with 0.5 microM [1,3(14) C]GTN in the presence of CO for 2 min or 30 s. The [14C]GTN-induced relaxation of the strips was recorded, and [14C]GTN biotransformation to [14C]glyceryl dinitrate metabolites by the tissues was determined by thin-layer chromatographic-liquid scintillation spectrometric analysis. CO treatment inhibited neither GTN-induced relaxation nor GTN biotransformation to glycerol dinitrate metabolites. These results indicate that ferrous hemoproteins are probably not involved in the biotransformation of GTN that is associated with relaxation of the rabbit aortic strips.

Animals↗
PubMed1992

Plasma disposition and hemodynamic effects of a single oral dose of isosorbide dinitrate in human males and females.

The goal of the present work was to determine the plasma disposition and hemodynamic effects of isosorbide dinitrate (ISDN) in human males and females. Fourteen healthy human volunteers took part in the study; seven males, 21.7 +/- 2.5 y (SD), and seven females, 20.7 +/- 3.4 y. Measurements of forearm blood flow (FBF), vascular conductance (FVC), and venous capacitance (Cv) were obtained by venous occlusion plethysmography, whereas blood pressure was measured by automatic sphygmomanometry. Blood samples were taken through a catheter placed in the antecubital vein at 0, 15, 30, 45, 60, 90, 120, 360, 480, 720, and 1440 min following a single 10 mg oral dose of ISDN. Plasma concentrations of ISDN and its mononitrate metabolites, isosorbide-2-mononitrate (2-ISMN) and isosorbide-5-mononitrate (5-ISMN), were determined by large bore capillary column gas-liquid chromatography. Hemodynamic measurements were made at corresponding experimental times up to 480 min. No differences were observed in the disposition of ISDN, 2-ISMN or 5-ISMN between the male and female volunteers. In addition, the plasma concentrations of ISDN and its mononitrate metabolites did not consistently correlate with the hemodynamic changes of the individual subjects. Diastolic blood pressure was significantly decreased for a 0.5 h period starting at 30 min, which was the time at which plasma ISDN concentrations peaked, and which preceded the time when the plasma concentrations of 2-ISMN and 5-ISMN were maximal. These observations indicate that, for a single 10 mg oral dose of ISDN, there were no gender-dependent differences in the plasma disposition of the parent drug or its mononitrate metabolites, and the vascular changes responsible for the decrease in diastolic blood pressure in these volunteers occurred in vascular beds other than those of skeletal muscle as represented by forearm blood flow.

Administration, Oral↗
PubMed1992

Thin-layer chromatographic separation of the ferrochelatase-inhibitory ring A and ring B regioisomers of N-ethylprotoporphyrin from a mixture of the four regioisomers.

When N-alkylprotoporphyrins are prepared synthetically or biologically, a mixture of four regioisomers is obtained. For our studies, separation of the potent ferrochelatase-inhibitory ring A (NA) and ring B (NB) regioisomers from the ring C (NC) and ring D (ND) regioisomers of low potency is required. Previously this separation required two successive high-performance liquid chromatography procedures. We now report that the separation of the zinc complexes of the NA and NB regioisomers from the NC and ND regioisomers can be achieved by a rapid and inexpensive thin-layer chromatography procedure.

Animals↗
PubMed1992

Direct evidence for nitric oxide formation from glyceryl trinitrate during incubation with intact bovine pulmonary artery.

It has been proposed that the mechanism of the vasodilator action of glyceryl trinitrate (GTN) involves biotransformation to nitric oxide. A sensitive chemiluminescence method for nitric oxide determination was used to test this hypothesis. In four experiments, bovine pulmonary artery (BPA) was incubated with GTN (0.1 mM) in Krebs' solution (2 mL) containing 30 mM KCl, and in anaerobic conditions using 95% Ar - 5% CO2, in a sealed micro-Fernbach flask (6.2-mL volume). After incubation for 2, 5, 10, or 20 min at 37 degrees C, 400-microL aliquots of headspace gas were removed and injected into a redox chemiluminescence detector. Nitric oxide formation was first measurable at 5 min (76 +/- 53 pmol/g wet wt. BPA), and increased with incubation time (174 +/- 46 pmol/g wet wt. BPA after 10 min and 310 +/- 67 pmol/g wet wt. BPA after 20 min). This is the first direct chemical measurement of nitric oxide formation during interaction of GTN with vascular smooth muscle. These data support the concept that GTN is a nitrovasodilator prodrug acting via the formation of nitric oxide.

Animals↗
PubMed1992

Biotransformation of glyceryl trinitrate by rat brain homogenate.

Incubation of glyceryl trinitrate (GTN) with 5% (w/v) rat brain homogenate (RBH) resulted in biotransformation of the organic nitrate vasodilator drug to a mixture of glyceryl-1,2-dinitrate (1,2-GDN) and glyceryl-1,3-dinitrate (1,3-GDN). Heating of the RBH at 100 degrees C for 5 min and (or) pretreatment with 5 mM N-ethylmaleimide at 37 degrees C for 10 min demonstrated that about two-thirds of the GTN biotransformation activity was due to a sulfhydryl-dependent enzymatic process resulting in the predominant formation of 1,2-GDN, and that the remaining biotransformation activity was due to a sulfhydryl-dependent nonenzymatic process resulting in the selective formation of 1,3-GDN. In a preliminary experiment, nitric oxide formation was observed during the incubation of GTN with RBH under anaerobic conditions. These data support the idea that some of the therapeutic and adverse effects of GTN are mediated through its action in the central nervous system.

Animals↗
PubMed1992

Inhibition of chick embryo hepatic uroporphyrinogen decarboxylase by components of xenobiotic-treated chick embryo hepatocytes in culture. II.

A variety of xenobiotics, viz., 3,3',4,4'-tetrachlorobiphenyl (TCBP), sodium phenobarbital (PB), 3,5-diethoxycarbonyl-2, 4,6-trimethylpyridine (OX-DDC), and nifedipine, cause a decrease in uroporphyrinogen decarboxylase (UROG-D) activity, accompanied by uroporphyrin accumulation, in chick embryo hepatocytes in culture. In this study the activity of 17-day-old chick embryo hepatic UROG-D was determined by measuring the conversion of pentacarboxylporphyrinogen I to coproporphyrinogen I, and it was shown that a UROG-D inhibitor, previously reported to accumulate in TCBP-treated and PB-treated chick embryo hepatocytes in culture, also accumulates in OX-DDC-treated and nifedipine-treated chick embryo hepatocytes in culture. It was concluded that the accumulation of a UROG-D inhibitor provides an explanation for the UROG-D inhibition observed in this culture system with xenobiotics that cause uroporphyrin accumulation. Studies of the UROG-D inhibitory fraction isolated from the 10,000 x g, 40,000 x g, and 100,000 x g supernatant fractions of cultured chick embryo hepatocyte homogenate led to the conclusion that the UROG-D inhibitor is derived from a soluble component of the homogenate.

Animals↗
PubMed1992

Inactivation of cytochrome P450 and inhibition of ferrochelatase by analogues of 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine with 4-nonyl and 4-dodecyl substituents.

Cytochrome P450- and heme-destructive effects of the 4-nonyl and 4-dodecyl analogues of 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine (DDC) were determined using hepatic microsomal preparations obtained from untreated, beta-naphthoflavone-treated, and phenobarbital-treated chick embryos. The 4-nonyl analogue of DDC was less efficacious than 4-ethyl DDC and 4-hexyl DDC, but more efficacious than 4-dodecyl DDC with respect to cytochrome P450-destructive activity. In all hepatic microsomal preparations, cytochrome P450 destruction by 4-nonyl DDC was accompanied by loss of microsomal heme. In contrast, 4-dodecyl DDC caused loss of heme only in hepatic microsomal preparations obtained from phenobarbital-treated chick embryos. The ability of 4-nonyl DDC and 4-dodecyl DDC to lower ferrochelatase activity was compared with that of 4-ethyl DDC and 4-hexyl DDC in cultured chick embryo hepatocytes. As the length of the 4-alkyl group was increased, the ferrochelatase-lowering efficacy and potency of the DDC analogue decreased. The 4-dodecyl DDC analogue was unable to lower ferrochelatase activity, which accorded with the finding that the administration of 4-dodecyl DDC to phenobarbital-treated rats did not lead to the accumulation of an N-alkylprotoporphyrin. The ability of 4-nonyl DDC to lower ferrochelatase activity was attributed to the formation of N-nonylprotoporphyrin IX following the administration of 4-nonyl DDC to phenobarbital-treated rats.

Animals↗
PubMed1992

Evidence for the stereoselective inhibition of chick embryo hepatic ferrochelatase by N-alkylated porphyrins. II.

N-Ethylprotoporphyrin (N-ethyl-PP) was isolated from the livers of phenobarbital-pretreated rats after the administration of 3,5-diethoxycarbonyl-1,4-dihydro-2,6-dimethyl-4-ethylpyridine, separated into its four regioisomers by high performance liquid chromatography, and quantitated. The percentage ratio, in the chromatogram, of the peak areas of the ring A-substituted (NA) and the ring B-substituted (NB) regioisomers was 80:20, compared with 50:50 for synthetic N-ethyl-PP. The NA regioisomer of N-ethyl-PP isolated from rat liver was found to be approximately 5 times more potent an inhibitor of ferrochelatase than was the NB regioisomer. Because the synthetic NA regioisomer (an equal mixture of the NA and the epi-NA enantiomers) is equipotent with the synthetic NB regioisomer (an equal mixture of the NB and the epi-NB enantiomers), epi-NB must be more potent than epi-NA. The higher potency previously observed with the NA plus NB regioisomers of N-ethyl-PP isolated from rat liver, compared with the NA plus NB regioisomers of synthetic N-ethyl-PP, is explained by the fact that the biological preparation contains 80% of the potent NA, compared with 25% of the potent NA and 25% of the potent epi-NB in the synthetic preparation. The critical features for optimal ferrochelatase-inhibitory activity are the ring A N-ethyl group facing downward in the NA isomer and the ring B N-ethyl group in the epi-NB isomer being rotated through 180 degrees to occupy the same position. According to one proposed mechanism, N-alkylprotoporphyrins inhibit ferrochelatase by serving as transition state analogues for the iron insertion step. X-ray crystallography shows that the N-alkyl group-bearing pyrrole ring and the pyrrole ring opposite to the N-alkyl group are tilted out of planarity in opposite directions. We suggest that this tilting reflects the normal conformational changes required for the insertion of iron into the protoporphyrin IX ring by ferrochelatase and that the greater inhibitory activity of NA and epi-NB isomers, compared with epi-NA and NB isomers, is due to the fact that the normal mechanism for ferrochelatase-catalyzed iron insertion has preference for an A-C ring tilt over a B-D ring tilt.

Animals↗
PubMed1991

Elevation of delta-aminolevulinic acid synthase and cytochrome PB1 P450 messenger RNA levels by dihydropyridines, dihydroquinolines, sydnones, and N-ethylprotoporphyrin IX.

A series of compounds that increase the activity of delta-aminolevulinic acid synthase (ALAS) in chick embryo hepatocyte cultures were studied for their effects on steady-state levels of mRNA for ALAS and phenobarbital-inducible cytochrome PB1 P450. N-Ethylprotoporphyrin IX (N-EtPP), which is believed to lower heme levels by inhibition of ferrochelatase (FC), had little effect on steady-state ALAS mRNA levels. 3,5-Diethoxycarbonyl-1,4-dihydro-2,6-dimethyl-4- isobutylpyridine (4-isobutyl DDC), which is believed to lower heme levels by repetitive destruction of the heme moiety of cytochrome P450, increased steady-state levels of ALAS mRNA levels approximately 2-fold. 3,5-Diethoxycarbonyl-1,4-dihydro-2,6-dimethyl-4-ethylpyridine (4-ethyl DCC) which inhibits FC activity and destroys the heme moiety of cytochrome P450, increased ALAS mRNA levels approximately 4-fold. A combination of N-EtPP and 4-isobutyl DDC produced a synergistic increase in ALAS mRNA levels to approximately 6-fold over control levels. The synergistic increase in ALAS activity observed previously with this combination can be explained, at least in part, by a synergistic increase in ALAS mRNA levels. Other porphyrinogenic agents, which function as mechanism-based inactivators of cytochrome P450 and elevate ALAS activity, were found to elevate ALAS mRNA. These compounds included 3-[2-(2,4,6-trimethylphenyl)thioethyl]-4-methylsydnone (TTMS), 2,4-diethyl-2-methyl-1,2-dihydroquinoline (DMDQ), and 2,2,4-trimethyl-1,2,dihydroquinoline (TMDQ). The elevation of ALAS mRNA by these porphyrinogenic agents is probably due to their lowering of cellular heme levels by a combination of ferrochelatase inhibition and repetitive destruction of the heme moiety of cytochrome P450. The lowering of heme levels should result in an enhancement of ALAS mRNA half-life as it has been demonstrated by others that heme shortens the half-life of ALAS mRNA. It was of interest that some of these drug treatments also caused an elevation in steady-state levels of cytochrome PB1 P450 mRNA; the exception was TTMS, which along with its analogue 3-(2-phenylethyl)-4-methylsydnone (PEMS), did not alter cytochrome PB1 P450 mRNA levels. Increases in steady-state levels of cytochrome PB1 P450 mRNA subsequent to increases in steady-state levels of ALAS mRNA were observed with 4-ethyl DDC, 4-isobutyl DDC, DMDQ, and TMDQ. The data obtained with N-EtPP and a combination of N-EtPP and 4-isobutyl DDC on cytochrome PB1 P450 mRNA levels do not support the contention that heme functions as a positive regulator of cytochrome P450 gene expression.

5-Aminolevulinate Synthetase↗
PubMed1991

Quantitation of nitric oxide formation from nitrovasodilator drugs by chemiluminescence analysis of headspace gas.

A rapid and reliable method has been developed for the quantitation of nitric oxide by chemiluminescence analysis of headspace gas. Aqueous nitric oxide standards are used to calibrate the method. There is a linear relationship between the amount of nitric oxide and the redox chemiluminescence detector response over the range of 52-2445 pmol of nitric oxide in 2.0 mL of deionized water contained in a sealed 6.2-mL flask. The intra-day and inter-day coefficient of variation values of the method do not exceed 4% and 9%, respectively. The lower limit of quantitative sensitivity and the lower limit of qualitative detection are 52 pmol and 26 pmol of nitric oxide, respectively. This method has been used to measure nitric oxide formation during the incubation of glyceryl trinitrate or sodium nitroprusside in the presence of cysteine. This method has two major advantages over the currently available procedures for the quantitation of nitric oxide, viz., no artifactual formation of nitric oxide during sample preparation and decreased instrumental contamination.

Cysteine↗
PubMed1991

Does carbon monoxide have a physiological function?

Recently endothelium-derived relaxing factor (EDRF) has been identified as nitric oxide. The source of the nitric oxide is L-arginine, and the L-arginine-nitric oxide pathway has been proposed to function as a widespread transduction mechanism for the regulation of cell function and communication. Gerald Marks and colleagues suggest that carbon monoxide, which is formed endogenously from heme catabolism and which shares some of the chemical and biological properties of nitric oxide, may play a similar role. This would be achieved by carbon monoxide binding to the iron atom of the heme moiety of soluble guanylyl cyclase and to the iron-sulfur centers of macrophage enzymes.

Animals↗
PubMed1991

Porphyrinogenic effects in chick embryo liver cell culture of chloramphenicol analogues that are mechanism-based inactivators of cytochrome P-450.

Structural analogues of chloramphenicol (CAP) cause mechanism-based inactivation of rat liver cytochrome P-450 (P450) either via protein acylation or destruction of the heme prosthetic group. The goal of the present work was to determine whether CAP analogues that cause loss of the P450 heme moiety also cause porphyrin accumulation in chick embryo liver cell culture. The porphyrin profiles produced by exposure of cells to CAP analogues (160 microM) were determined by high-performance liquid chromatography with fluorescence detection. Of three CAP analogues that do not cause loss of the heme moiety of rat liver P450IIB1, two dichloroacetamides were not porphyrinogenic. The third compound, a chlorofluoroacetamide, caused porphyrin accumulation. This result may be due to the presence of P450 isozymes in chick embryo hepatocytes, distinct from rat liver P450IIB1, that are susceptible to destruction by this analogue. Of four CAP analogues that inactivate rat liver P450IIB1 with concomitant heme loss, a dichloroacetamide and two chlorofluoroacetamides caused porphyrin accumulation. The remaining compound, a monochloroacetamide, was not porphyrinogenic, perhaps because the P450 apoprotein cannot be reconstituted with fresh heme drawn from the regulatory "free heme pool" following inactivation by this analogue. Alternatively, there may be no P450 isozyme in chick embryo liver cell culture that is susceptible to inactivation by this compound.

Animals↗
PubMed1991

Adrenoceptors of the human internal thoracic artery.

Adrenoceptor function in the human internal thoracic artery (ITA) was characterized in vitro using segments of the artery obtained during coronary bypass operations. Specimens were prepared as isolated arterial rings mounted in a tissue bath, and mechanical activity (isometric tension) was measured in response to drugs. The ITA responded to phenylephrine (PE), epinephrine, and norepinephrine with concentration-dependent contractions. The PE-induced contractions were antagonized by phenoxybenzamine, prazosin, and high concentrations of yohimbine. The ITA was not effectively contracted by clonidine in the concentration range normally associated with alpha 2-adrenoceptor stimulation. The beta-adrenoceptor agonist, isoproterenol, had a weak and variable effect on the ITA; samples from 9 out of 12 subjects did not respond to isoproterenol, whereas samples from 3 subjects responded with relaxations of between 33 and 42%. These in vitro studies indicate that the most important adrenoceptors of the human ITA are alpha-adrenoceptors; this may be relevant for the pharmacologic management of patients undergoing coronary bypass surgery using the ITA.

Adrenergic alpha-Antagonists↗
PubMed1991

Interaction of glyceryl trinitrate and sodium nitroprusside with bovine pulmonary vein homogenate and 10,000 x g supernatant: biotransformation and nitric oxide formation.

The current proposed mechanism of action of nitrovasodilator drugs involves biotransformation to nitric oxide, which is postulated to be the active vasodilator substance. Our objective was to determine whether nitric oxide was formed from two prototype nitrovasodilator drugs, glyceryl trinitrate (GTN) and sodium nitroprusside (SNP), after incubation with bovine pulmonary vein (BPV) preparations. GTN or SNP was incubated in an argon atmosphere with phosphate buffer, BPV homogenate, or the 10,000 x g supernatant fraction of the homogenate. Nitric oxide formation, as determined by a chemiluminescence-headspace gas method, was measurable following the incubation of SNP with BPV homogenate and 10,000 x g supernatant. There was no detectable formation of nitric oxide from the incubation of GTN with the two BPV preparations, although GTN was biotransformed to glyceryl dinitrate, as determined by gas-liquid chromatography. There was decreased recovery of nitric oxide during the incubation of authentic nitric oxide with the two BPV preparations as compared with buffer. In conclusion, formation of nitric oxide was measured for the interaction of SNP, but not GTN, with BPV preparations. However, the data do not exclude the possible formation of nitric oxide from GTN, as nitric oxide was shown to be sequestered or transformed by the BPV preparations.

Animals↗