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Carbon monoxide and cardiovascular control Brazilian Journal of Medical and Biological Research (1999) 32: 1-14 Carbon monoxide: from toxin
to endogenous modulator of
cardiovascular functions
Departamento de Fisiologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brasil2 Experimental Research Department, 2nd Institute of Physiology, Semmelweis University of Medicine, Budapest, Hungary Abstract
Correspondence
Carbon monoxide (CO) is a pollutant commonly recognized for its Key words
toxicological attributes, including CNS and cardiovascular effects.
But CO is also formed endogenously in mammalian tissues. Endog- enously formed CO normally arises from heme degradation in a reaction catalyzed by heme oxygenase. While inhibitors of endoge- nous CO production can raise arterial pressure, heme loading can enhance CO production and lead to vasodepression. Both central and peripheral tissues possess heme oxygenases and generate CO from heme, but the inability of heme substrate to cross the blood brain barrier suggests the CNS heme-heme oxygenase-CO system may be independent of the periphery. In the CNS, CO apparently acts in the nucleus tractus solitarii (NTS) promoting changes in glutamatergic neurotransmission and lowering blood pressure. At the periphery, the heme-heme oxygenase-CO system can affect cardiovascular functions in a two-fold manner; specifically: 1) heme-derived CO generated within vascular smooth muscle (VSM) can promote vasodilation, but 2) its actions on the endothelium apparently can promote vasocon- striction. Thus, it seems reasonable that the CNS-, VSM- and endothe- lial-dependent actions of the heme-heme oxygenase-CO system may all affect cardiac output and vascular resistance, and subsequently Changing personalities
neural pathologies and elicit changes in car- for its toxic effects. Its colorless and odorless properties, combined with its tenacious abil- bin is inevitably detected in most mamma- ity to compete with oxygen for binding to lian species. While initially thought to be a hemoglobin, can lull its victims into a gradual manifestation of widespread environmental contamination, it was eventually realized that which all too often are fatal. Less appreci- these persistent carboxyhemoglobin levels ated is the tendency for long periods of low arise from carbon monoxide which is formed level carbon monoxide exposure to promote within the host. This endogenously formed carbon monoxide arises primarily as a prod- uct of heme metabolism (3). Until recently, metabolic activities (7-10). Accordingly, any or all heme proteins would seem particularly regarded simply as a waste product, but there well suited to be potentially involved in the biological actions of carbon monoxide.
influence biological functions (4).
considered candidate (4,8). Carbon monox- ide activates purified soluble guanylate cy- clase to increase cGMP formation approxi- and about the biochemistry related to endog- mately two-fold, which is relatively modest enous carbon monoxide formation, only re- when compared to the 100-fold greater in- cent studies have tried to functionally link creases that may be obtained by activation these two areas. The purpose of this review with nitric oxide (8). However, such differ- is to highlight some of the important physi- ences in efficacy do not preclude the possi- cal properties and the biochemical actions of bility that functional effects may still arise from the increases in cGMP production which tools used to investigate the endogenous car- bon monoxide system, and to summarize the duced activation of soluble guanylate cy- apparent acute effects of this system as they verse models of distribution kinetics, the blue, an inhibitor of soluble guanylate cy- performance of dose-time related actions, clase (11). Consequently, it was suggested and the identification of multiple organ in- that carbon monoxide-induced vasodilation volvement are evidence that the actions of of vascular smooth muscle was soluble guan- carbon monoxide can be quite complex (5).
ylate cyclase-dependent. But recent studies While the critical details of the toxicological actions of carbon monoxide are admittedly soluble guanylate cyclase have shown that well beyond the scope of the current review, carbon monoxide-induced dilation may pro- and cardiovascular effects of carbon monox- ide intoxication have been published else- findings suggest that carbon monoxide, at where (1,2,5,6). Since the toxicology litera- ture serves as a basis for many of the known actions of carbon monoxide, a few features processes which are soluble guanylate cy- culled from those studies should still be mentioned to appreciate some of the poten- tial actions of endogenously formed carbon (cytP450), which collectively display a spec- tral shift in response to carbon monoxide binding, are another class of enzymes pro- Messenger systems
posed as potential mediators of carbon mon- oxide-induced effects (7). However, it has been suggested that the CO/O2 ratio required their tendency to bind carbon monoxide (7).
to produce significant binding to most types of cytP450 enzymes would also be likely to properties, the binding of carbon monoxide overwhelm the O2-carrying capacity of cir- Carbon monoxide and cardiovascular control culating hemoglobin to a fatal extent (2,5).
activities of some mitochondrial cytochrome bin levels in the blood are quite common, oxidases may be affected by levels of carbon this constitutes a minimum load of approxi- monoxide which fall short of producing fatal mately 100 µmol/l carbon monoxide trapped apparently further enhanced during increased monoxide arises almost exclusively from the least three isoforms of heme oxygenase have chromes of the mitochondrial membrane are been identified (3,20) which originate from involved in electron transport and in the generation of ATP, disruption of the associ- als, metalloporphyrins, as well as heme, have ated electron shuttling may in turn lead to been shown to chronically induce heme oxy- multiple functional effects by interfering with genase-1 while having relatively little effect kinase- and other ATP-dependent processes.
on the expression of heme oxygenase-2 (21).
Prostaglandin G/H synthase (14), cata- Very little is known about the recently dis- lases (15), and potassium channels (16) are covered heme oxygenase-3 isoform (20). The also amongst the suggested potential targets regulation of heme oxygenase expression is for the actions of carbon monoxide. In addi- quite complex (21), but it is clear that the sues may allow them to participate in the thus may also participate in the biological local generation of carbon monoxide where they otherwise might be limited by a defi- contributions of each of these systems to the biological effects of carbon monoxide, if any, have yet to be fully understood.
protein is not the only means for stimulating the generation of carbon monoxide and other Endogenous sources of carbon
monoxide and their regulation
bilirubin (23) in a manner which precedes discernable induction of the enzyme. Since the provision of the substrate rapidly in- monomeric free heme and is generated in a reaction catalyzed by the heme oxygenases.
products, it is clear that heme availability can be a rate-limiting step for the endoge- release equimolar quantities of iron, biliver- primarily recycled into the formation of new ies of delta aminolevulinic acid (dALA) syn- heme while the biliverdin is rapidly con- thase and its feedback inhibition by heme verted to bilirubin by an abundance of biliver- (24) imply that normal resting levels of free heme may be in the vicinity of 0.5-1.0 µmol/ product eventually binds to circulating he- l. Oddly, heme loading in 50-fold excess of these levels typically increases plasma bi- boxyhemoglobin until it is excreted through lirubin levels and CO production by only 2- ventilation. Heme oxygenase activity in some 3-fold (23). The reason for these divergent tissue homogenates is sufficient to generate trends may be related to the physical proper- ties of heme. In aqueous solutions at physi- important differences. Nitric oxide is highly ological pH, monomeric free heme has been labile, exhibiting a biological half-life of characterized as reaching saturation at around 2 µmol/l (25). Heme which is loaded beyond unusually stable and highly resistant to trans- this limit progressively forms dimeric struc- formation (1,2). As mentioned earlier, nitric tures and polymeric chains (25). While these oxide is a powerful activator of soluble guan- ylate cyclase, whereas carbon monoxide is a constitute “heme stores”, they apparently do weak activator of this cGMP-generating en- not function as substrates for heme oxyge- zyme (8). Under most conditions the consti- nase (3,26). Consequently, it can make sense tutive forms of nitric oxide synthase are that heme loading might only double or triple primarily found in neurons and endothelium (29) but are relatively absent from vascular in tissues. In turn, this increase in heme oxygenase substrate availability should be isoform of heme oxygenase is similarly preva- paralleled by increases in carbon monoxide/ lent in neuronal and endothelial tissue do- mains (30), it differs from its nitric oxide- does not arise solely from the degradation of heme. In fact, inhibition of heme oxygenase muscle domain of most blood vessels, con- or dysfunction may potentially disrupt some source of endogenously formed carbon mon- aspects of the nitric oxide-generating system oxide, the blockade of heme oxygenase ac- while leaving the heme-derived carbon mon- tivity initiates the generation of carbon mon- oxide from alternative sources including a process involved in fatty acid metabolism Studying the heme-heme oxygenase-
carbon monoxide system: tools and
shifts in carbon monoxide sources are poorly approaches
Chronic heme oxygenase induction
carbon monoxide might participate in bio- logical functions was highlighted in a semi- nal work by Gerald Marks (4). Noting that is often accompanied by an array of “heat carbon monoxide is an activator of soluble shock” stress-related proteins and functional guanylate cyclase, and that carbon monox- derangements (21,30). Heavy metal salts and ide is endogenously formed as part of heme other stress-related events are often used to induce expression of heme oxygenase-1 pro- rived carbon monoxide might function in a manner synonymous to that of nitric oxide.
(30,31). While such chronic inductions may Indeed both systems produce low molecular reflect potential pathological states which weight gasses which are activators of soluble could lead to persistent elevations in endog- guanylate cyclase, and the catalytic forma- enous carbon monoxide production, this tech- nique may be less than optimal to distinguish the actions of heme oxygenase-derived car- bon monoxide from those of the other simul- ide-generating systems also exhibit some very taneously expressed heat-shock proteins.
Carbon monoxide and cardiovascular control Acute manipulations of the heme-heme
of dALA (24), the rate-limiting step in the oxygenase-carbon monoxide system
carbonate has been used to solubilize hema- tin for clinical applications (24), the result- effects of endogenously formed carbon mon- ing preparation is still susceptible to degra- increasing and decreasing tissue levels of The solubility limitations associated with heme can easily be overcome by dissolving oxide. Unfortunately, no selective chelators it in an amino acid solution. Heme-L-arginate or metabolizing agents are currently avail- is one such commercially available prepara- able to inactivate carbon monoxide once it tion (32,33) which is used in the treatment of has been formed. But the formation of heme- preparation boosts the solubility of heme to (3,23,26) or conversely decreased by using availability, and yields a preparation which can be stored for months without discernible (13,19,21,23,24,27). Such a strategy has been protocols, heme-L-arginate may create meth- used to identify heme-induced effects which odological problems, since L-arginine is a substrate for nitric oxide synthase-mediated product (19,23). Specifically, heme-induced formation of nitric oxide (29). Alternatively, effects which can be prevented and/or re- lysinate can be made by replacing L-arginine are likely to be consequent to the formation with L-lysine (32). Since heme-L-arginate of a heme oxygenase product. As iron, biliver- and heme-L-lysinate each demonstrate heme din and carbon monoxide are the metabolic oxygenase substrate activities identical to that of hematin (32), these preparations seem tabolism of heme (3,21), the actions of these particularly well suited as sources of heme pared to identify the specific product which is most likely to account for the heme oxyge- endogenous formation of carbon monoxide.
These pharmacological tools resemble heme in their porphyrin structure, but the iron core nase activity in experimental settings is com- is substituted by a heavy metal such as Zn, plicated by its tendency to aggregate in aque- Sn, Cr, Co or Cu (19,21,27,30,34). The ten- ous solutions at physiological pH (25,32) dency for some of these substituted porphy- and to degrade during storage (32). An acetic rins to compete with heme for binding to the heme oxygenase enzyme has led to their use increase porphyrin solubility, but such con- as heme oxygenase inhibitors. Accordingly, ditions may also damage porphyrin integrity such inhibitors can also be used to inhibit the (25). Alternatively, bases such as Tris and crease the solubility of porphyrins, but these caustic solvents may also promote substan- phyrins, most notably those which are tin- soluble in ethanol, but ethanol can alter por- bearing, can undergo non-enzymatic degra- phyrin metabolism by driving the synthesis cies may not plateau for hours (2). The de- have also been raised over the potential in- layed transit of this water soluble and low teractions of metalloporphyrins with soluble molecular weight gas from the peritoneum to guanylate cyclase (36,37). It is abundantly the vascular space strongly suggests that the clear that the substituted metalloporphyrins extravascular tissues also possess a marked do not participate in the activation of soluble affinity for carbon monoxide. Furthermore, it supports what toxicologists have empha- sized for years, that carboxyhemoglobin lev- substituted metalloporphyrins produce func- els are of limited value when judging the tional effects which arise from their direct carbon monoxide content of the extravascu- action on soluble guanylate cyclase have not The heme-heme oxygenase-carbon
to confirm that a heme-induced effect may monoxide system and cardiovascular
functions
carbon monoxide product. An array of tech- niques for preparing and administering car- Since blood pressure is calculated as the product of cardiac output and total peripher- in vitro studies, carbon monoxide is water al resistance, cardiovascular functional stud- soluble and thus can be easily prepared in ies accordingly focus on these determinants.
physiological buffer solutions. In contrast, Based upon the toxicological literature and administration of carbon monoxide for in vivo studies can be substantially compli- Marks (2,4,8), it appears that heme-derived cated by its distribution kinetics which are carbon monoxide might serve as a vasodila- markedly influenced by the affinity of this tor and accordingly tend to be vasodepressive.
gas for heme proteins (1,2). Carbon monox- ide has been administered through inhala- Chronic blood pressure effects of the heme-
tion (1), but the delivery of carbon monoxide heme oxygenase-carbon monoxide system
to the tissues by this method is reliant on its delivery as carboxyhemoglobin. This means aspects of heme oxygenase induction (21,30).
globin before it can be delivered to the tis- Studies preceding the overt suggestion that sues. In turn, this event produces hypoxia that must precede appreciable accumulations pate in biological functions showed that in- of carbon monoxide in the tissues. Intrave- could chronically slow the development of solutions is equally disadvantageous because hypertension in spontaneously hypertensive rats (SHR) (31). Since the vasodepressive The intraperitoneal administration of car- bon monoxide may offer some advantages.
microsomal cytochrome content, those early Using this simple and efficient technique, studies attributed the blood pressure lower- marked changes in cardiovascular function ing effects of heme oxygenase induction to a can precede dramatic changes in carboxyhe- reduction of the formation of cytP450-de- ide gas is injected into the peritoneum, its rived vasoconstrictive eicosanoids (31).
appearance in the vasculature as carboxyhe- While this explanation was consistent with moglobin is not immediate and in some spe- the findings, those corollary studies did not Carbon monoxide and cardiovascular control directly verify a state of free heme depletion.
oxygenase activity constitutes a major de- velopment for studying the biological ac- similarly slow down the development of hy- the ability to examine heme oxygenase-re- free heme is the substrate for heme oxyge- lated effects in a setting which maximally increase bilirubin production, this suggests shifting in carbon monoxide sources. By so that heme substrate availability is not im- doing, these inhibitors of heme oxygenase paired by these treatments. Rather, it sup- may also be used to evaluate the contribu- ports the idea that a heme oxygenase product such as carbon monoxide may be involved in Certainly such evidence does not preclude a role for cytP450-derived eicosanoids in heme rapidly produce vasoconstriction and raise oxygenase-induced vasodepression. Indeed, blood pressure in rats (40). This suggests changes in cytP450 and heme oxygenase con- tent accompany a variety of chronic disease reduce vascular tone. In contrast, heme prepa- states (21,30,31). Nonetheless, studies which rations that drive heme oxygenase-mediated rely solely on chronic corollaries between in- formation of carbon monoxide, such as heme- duction and functions are not able to distin- L-lysinate, lower blood pressure in chroni- guish the effects of heme oxygenase activity from those of the other simultaneously ex- models and in rats made acutely hyperten- pressed heat-shock proteins. Interpretations of sive by phenylephrine infusion (23). These studies using chronic treatment of heme oxy- genase inhibitors are similarly complicated as can be prevented by pretreatment with in- such inhibitors tend to induce heme oxyge- hibitors of heme oxygenase. This suggests nase along with other heat-shock proteins that the vasodepressive actions of heme are (21,31), while at the same time directly inhib- consequent to the formation of a heme oxy- iting heme oxygenase. In addition, these chronic treatments may potentially produce effects by It is well established that the heme oxy- altering other less investigated functional as- genase-mediated degradation of heme forms pects of porphyrin metabolism-dependent pro- three products: iron, biliverdin and carbon cesses such as dALA synthase activity or glu- monoxide (3). Iron chelation does not pre- tathione metabolism (24). Furthermore, chronic inhibition of heme oxygenase activity through (23), and biliverdin does not acutely pro- the use of metalloporphyrins or even highly mote vasodepression in either normotensive specific antibodies may have limited influence on total carbon monoxide production as sources intraperitoneal injection of carbon monox- of nonheme-derived carbon monoxide may be ide does preferentially lower blood pressure greatly amplified during such conditions (27).
in hypertensive models (23). Thus, it ap- pears that the heme-induced vasodepression Acute blood pressure effects of the heme-
is more likely to arise from the formation of heme oxygenase-carbon monoxide system
and inhibitors to acutely manipulate heme vasodepression (23). While this might sug- gest that the hypertensive models such as the can inhibit heme oxygenase activity both at the periphery and in the brain, decrease the strains do not differ in plasma bilirubin con- (27), and increase the blood pressure of the awake rat in a manner which is paralleled by with heme preferentially lower blood pres- an increase in total peripheral resistance (40).
sure in the hypertensive models despite simi- This pressor response can be prevented by lar 2-3-fold elevations in the plasma biliru- alpha-1-adrenergic receptor antagonists or bin content in both normotensive and hyper- tensive strains. A variety of hypertensive function, but not by bilateral sino-aortic deaf- models have been found to be both acutely (23) and chronically (1) more sensitive to the vasodepressive actions of exogenously ap- sure may involve a heme oxygenase-related plied carbon monoxide than their normoten- sive counterparts. These tendencies indicate the site of termination of cardiovascular and models do not appear to differ in their abili- respiratory afferent fibers in the medulla ties to generate heme oxygenase products, oblongata (44) and is a key structure in glu- including carbon monoxide. Rather they sug- tamatergic-mediated cardiovascular afferents gest that SHRs, and perhaps other hyperten- and an integrative region of baroreceptor sive models as well, may be more sensitive and chemoreceptor responses (45). Systemic to the vasodepressant actions of the carbon inhibition of heme oxygenase has been shown to attenuate the pressure-bradycardia rela- CNS involvement in heme oxygenase-related
(43). Inhibitors of heme oxygenase can af- cardiovascular effects
fect glutamatergic-mediated depolarization in isolated NTS preparations (46). Since iso- lated NTS tissues respond to manipulations been identified in the brain (21,40-42), but its distribution is such that it forms distinct oxide system, and since the NTS is involved tracts (41). While some metalloporphyrins both in the modulation of baroreceptor re- like ZnDPBG have been designed to pass the flex activity and in the establishment of blood blood brain barrier to inhibit heme oxyge- nase activity in the brain (27,40), studies using radiolabeled tags show that heme does not pass the blood brain barrier (33). In addition, dALA synthase, the rate-limiting the NTS are able to increase blood pressure the other enzymes involved in heme synthe- in a manner that can be reversed by microin- sis have been identified in brain tissues (24).
jections of carbon monoxide (43). Likewise, The finding that the brain is insulated from microinjections of carbon monoxide into the infiltration by circulating heme but locally NTS can reverse the elevation in blood pres- possesses the metabolic processes for heme sure produced by systemic administration of synthesis suggests that the CNS may consti- ZnDPBG (43). Thus it appears that the heme tute a heme oxygenase functional unit which oxygenase product formed in the NTS exerts is distinct from that of peripheral tissues.
a vasodepressive influence; it also appears Carbon monoxide and cardiovascular control that the heme oxygenase product is likely to be less complicated by CNS-related effects since heme does not cross the blood brain barrier (33). However, inhibitors of heme volved in NTS-mediated afferent barorecep- oxygenase which cross the blood brain bar- tor activity. NTS microinjections of heme rier (40), and carbon monoxide as well (1,2), oxygenase inhibitors do attenuate the pres- can potentially affect the blood pressure by sor responses to microinjections of L-gluta- acting directly on the NTS or other central mate (47) and interfere with baroreceptor structures. Since the CNS exerts a powerful activity. Such findings suggest that heme influence on cardiovascular functions, the metabolism may locally interact with gluta- actions of the heme-heme oxygenase-carbon matergic transmission in the NTS. Even so, monoxide system directly on vascular activ- it remains unclear if these glutamatergic- ity may be best addressed by using isolated linked effects arise solely from its influences vessel preparations which are devoid of cen- on carbon monoxide product formation.
neuromodulatory roles for heme oxygenase- Endogenous carbon monoxide and
vascular tone: dual actions
should be observed when designing and in- terpreting CNS studies using metalloporphy- Carbon monoxide as a vasoconstrictor
rins. The potential of metalloporphyrin and in arteriolar and venular smooth muscle, and a highly complicated topic. In the porphyrin has also been located in arteriolar endotheli- um (48). The findings that carbon monoxide is enzymatically mediated and constitutes can stimulate soluble guanylate cyclase (8) the rate-limiting step in the formation of new and relax preparations of vascular smooth heme (24). In turn, the concentration of free muscle (11) have prompted suggestions that heme serves as a feedback inhibitor of dALA synthase activity. This is the mechanism by by promoting vasodilation (4). In contrast, which tissue levels of heme are effectively earlier studies (7,49-52) have provided ample maintained. This heme precursor, dALA, is evidence that carbon monoxide can bind to structurally related to gamma aminobutyric nitric oxide synthase and inhibit the produc- acid (GABA). In addition, heme itself dem- tion of nitric oxide, a vasodilator. If so, it onstrates affinity for benzodiazepine recep- tors. It is accepted that GABA and benzodi- could block basal nitric oxide production azepine receptor functions are cooperative and may play important roles in central regu- quent increase in blood pressure. While these lation of blood pressure. While the effects of two functionally opposing roles of endog- dALA on GABA receptors and the effects of heme on benzodiazepine receptor functions lar tone are equally plausible, several studies have not been fully characterized, it should using isolated vessels and perfused prepara- tions (7,53-56) have suggested that heme- fluences heme availability may also poten- tory. Such reports have understandably typi- fied carbon monoxide as a vasodilator.
systemic administration of heme are likely to to elucidate the endothelial-dependent roles seem reasonable that the blockade of nitric from those which are endothelium-independ- oxide formation should allow the vasodila- ent. In an attempt to clarify this issue, we tory influences of heme-derived carbon mon- recently found that heme can elicit vasodila- tion of isolated superfused rat gracilis first- In vessels with intact endothelium and in order arterioles denuded of endothelium, in hibit nitric oxide synthesis, we find that heme inhibitor of heme oxygenase (57). In that does elicit vasodilation in a manner which is study, carbon monoxide similarly elicited vasodilation in the preparations denuded of (12,53,57). Blockade of nitric oxide synthases endothelium. These observations suggest that similarly allows the vasodilatory effects of a heme oxygenase product, apparently car- carbon monoxide to be displayed even when bon monoxide, can produce vasodilation of the endothelium is present (12,53,57). Ac- these resistance vessels in a manner which is cordingly, the simplest explanation is that endothelium-independent. It also suggests heme-derived carbon monoxide, specifical- that the vasodilatory actions of heme can be ly that formed in smooth muscle, may serve independent of the generation of endotheli- to promote vasodilation by a local action.
Simultaneously these vasodilatory actions elicited a vasoconstriction in similarly pre- drawal of the vasodilatory influences of en- pared arterioles when the endothelium was left intact (57). In addition, we found that readily reversed by the further inclusion of oxide synthase, they are admittedly in sharp more, in similarly prepared vessels in which the endothelium was left intact, we found lights the vasodilatory actions of carbon mon- oxide. Coceani et al. (54) have reported that could also elicit a vasoconstrictive response.
vasodilation can be elicited by heme sub- These frankly unexpected findings suggested strate in intact lamb ductus arteriosus ves- sels. Such findings may seem in contrast to our recent findings, but they have carefully elicit vasoconstriction by 1) facilitating the release of a vasoconstrictive agent from the ized in the smooth muscle domain of their endothelium or by 2) interfering with the ductus vessels, but not present in the endo- release of an endothelium-derived relaxing the nitric oxide system for multiple biologi- relaxing factor (29). In addition, nitric oxide cal processes (29), the possibility of a carbon synthase-mediated formation of nitric oxide monoxide/nitric oxide interaction should be has been repeatedly shown to be inhibited by explored to determine its hemodynamic func- carbon monoxide (7,49-52). If the observed tional significance. Consideration of this potential interaction is crucial, since igno- constriction of the gracilis arteriole prepara- rance of this feature might seriously con- tions were a consequence of inhibition of found the interpretations of key experiments in this newly emerging area of endogenous Carbon monoxide and cardiovascular control Vasodilatory influences of endogenous
37). However, the arteriolar constriction pro- carbon monoxide
fected by an inhibitor of soluble guanylate cyclase (12). Furthermore, vasodilatory ac- tions of exogenously applied carbon monox- interfering with the vasodilatory influences ide or heme also appear to be unaffected by of the nitric oxide system, that suggestion an inhibitor of soluble guanylate cyclase in was certainly not intended to overlook the isolated arteriolar preparations (12). Accord- ingly, it appears that heme, at least in some ent effects of carbon monoxide attenuating the vasodilatory influences of the nitric ox- unrelated to soluble guanylate cyclase activ- ide vasodilatory system, the vasodilatory ef- ity. While the mechanisms underlying acute carbon monoxide-induced relaxation of vas- preparations in which the nitric oxide system cular smooth muscle have yet to be clarified, they apparently arise independently from P- In isolated superfused rat gracilis first- 450-, endothelin- or soluble guanylate cy- order arterioles with intact endothelium, in an environment containing L-NAME to maxi- mally inhibit nitric oxide synthase, heme Proposed organization for
does promote vasodilation in a manner which endogenously derived carbon
is readily reversed by inhibitors of heme monoxide effects on cardiovascular
functions
induced vasodilatory response arises from the generation of a heme oxygenase product.
These heme-induced vasodilatory effects are lated describing intricate details of mecha- not prevented by an iron chelator or mim- icked by biliverdin. However, carbon mon- expression. There has also been a virtually endless trail of proposed biochemical inter- tion of similar preparations. This is the evi- dence that the vasodilatory heme oxygenase tabolites with almost every imaginable mes- product is most likely to be carbon monox- certainly of tremendous importance, there In similarly prepared resistance vessels, may have been a tendency for the biochem- in which the nitric oxide system has been istry to overwhelm the functional effects of maximally inhibited, inhibitors of heme oxy- this newly explored system. The identifica- tion of the primary functions of endogenously striction (12). This vasoconstrictive effect can be both prevented and reversed by car- point of orientation in the search to identify bon monoxide, but cannot be prevented by a nitric oxide donor. These findings suggest that the basal production of carbon monox- an approach, the physiological contributions ide may exert a substantial vasodilatory in- fluence on these resistance vessels.
oxide system may best be appreciated.
potential interactions between metallopor- emphasized the apparent functional conse- phyrins and soluble guanylate cyclase (36, bon monoxide system in an attempt to orga- the carbon monoxide- and nitric oxide-gen- erating systems should be seriously consid- ered, especially when isolated preparations monoxide on cardiovascular functions. What dependent and -independent actions of car- bon monoxide exerts effects on cardiovas- bon monoxide on vascular tone, it appears that carbon monoxide can affect blood pres- vascular tone and baroreceptor reflex func- muscle appears to be vasodilatory. This va- tions. One region in the brain that has been strongly implicated as participating in these carbon monoxide-induced withdrawal of the endothelium-dependent vasodilatory influ- actions of the CNS may exert a third influ- ence of the nitric oxide system. This sug- ence which “tips the balance” of the directly offsetting endothelium-dependent and -in- monoxide may have little direct effect on basal vascular tone. Even so, such condi- tions could still interfere with the dynamic While the search for functional roles for influences related to shear force-mediated changes of the nitric oxide system and con- ide system remains in its infancy, the ac- sequently amplify the vasoactive actions of crued evidence strongly suggests that the that carbon monoxide, even the endogenously waste product. More specifically, the evi- vasospasms. Since carbon monoxide has been shown to compete with L-arginine for bind- monoxide may exert effects on blood pres- ing to nitric oxide synthase, then L-arginine may potentially protect nitric oxide synthase pendent and -independent functions in the from the inhibitory actions of carbon mon- vasculature, and these periferal effects may oxide. It should be emphasized that it is not clear to what extent the nitric oxide and induced influences arising through the cen- carbon monoxide systems interact in vivo.
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