Renal vasodilatory influence of endogenous carbon monoxide in chronically hypoxic rats

O'Donaughy, Theresa L.; Walker, Benjimen R.

doi:10.1152/ajpheart.2000.279.6.h2908

Cited by 48 publications

(73 citation statements)

References 44 publications

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“…Even so, it remains clear that the antinatriuretic/antidiuretic effects of the HO inhibitor can occur independently of changes in RBF and GFR. Furthermore, our results are in agreement with a study showing that the HO inhibitor zinc protoporphyrin had no effect on baseline RBF (23).…”

Section: Discussionsupporting

confidence: 93%

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Inhibition of heme oxygenase augments tubular sodium reabsorption

Jackson

Quadri³

et al. 2011

American Journal of Physiology-Renal Physiology

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Jackson KE, Jackson DW, Quadri S, Reitzell MJ, Navar LG. Inhibition of heme oxygenase augments tubular sodium reabsorption. Am J Physiol Renal Physiol 300: F941-F946, 2011. First published February 2, 2011 doi:10.1152/ajprenal.00024.2010.-Heme oxygenase (HO) catalyzes the degradation of heme to form iron, biliverdin, and carbon monoxide (CO). The vascular actions of CO include direct vasodilation of vascular smooth muscle and indirect vasoconstriction through inhibition of nitric oxide synthase (NOS). This study was performed to examine the effects in the kidney of inhibition of heme oxygenase alone or combined with NOS inhibition. Chromium mesoporphyrin (CrMP; 45 mol/kg ip), a photostable HO inhibitor, was given to control rats and N G -nitro-L-arginine methyl ester (L-NAME)-treated hypertensive rats (50 mg·kg Ϫ1 ·day Ϫ1 , 12 h, 4 days). In control animals, CrMP decreased CO levels, renal HO-1 levels, urine volume, and sodium excretion, but had no effect on arterial pressure, renal blood flow (RBF), plasma renin activity (PRA), or glomerular filtration rate (GFR). In L-NAME-treated hypertensive rats, CrMP decreased endogenous CO and renal HO-1 levels and had no effect on arterial pressure, RBF, or GFR but decreased sodium and water excretion in a similar manner to control animals. An increase in PRA was observed in untreated rats but not in L-NAME-infused rats, indicating that this effect is associated with an absent NO system. The results suggest that inhibition of HO promotes water and sodium excretion by a direct tubular action that is independent of renal hemodynamics or the NO system. renal hemodynamics; natriuresis; renal blood flow; plasma renin activity THE UBIQUITOUS ENZYME HEME oxygenase (HO) catalyzes the enzymatic degradation of heme to free iron, biliverdin, and carbon monoxide (CO) (20, 32). Two major isoforms of HO, the inducible HO-1 and the constitutive HO-2, are currently recognized (20). HO-1 is induced by a variety of stimuli, such as ischemia, hypoxia, oxidative stress, inflammation, and hypertension, while HO-2 is constitutively present. These isoforms are present in the renal vasculature, as well as in other vascular beds (2,8,14,17,32). HO activity is partly regulated by substrate availability, thus both isoforms can increase endogenous CO levels (9, 11). Pharmacological manipulation of HO has been shown to selectively influence blood flow systemically and in the kidney (18). In addition, manipulation of HO activity alters tissue CO concentrations (34).There is abundant evidence indicating that CO plays an important dual role in regulating normal vascular tone (13,14,16). CO has been shown to promote relaxation of vascular smooth muscle (7), but can also cause endothelium-dependent vasoconstriction (11, 12) through inhibition of nitric oxide synthase (NOS) (13). Renal vascular resistance responses to CO have been variable ranging from a biphasic response (31) to NOS-dependent vasoconstriction (24) and direct vasodilation (4).The renal vasculature and tubules express HO (1,5,10,18,31), a...

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Section: Discussionsupporting

confidence: 93%

“…However, other investigators found that HO inhibition had no effect on basal renal hemodynamics (23). It has also been reported that HO inhibition by zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG) promotes regional differences in RBF by decreasing medullary blood flow with no significant changes in cortical blood flow (37).…”

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confidence: 99%

Inhibition of heme oxygenase augments tubular sodium reabsorption

Jackson

Quadri³

et al. 2011

American Journal of Physiology-Renal Physiology

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“…18 HOdependent generation of CO and other products is relevant to the regulation of renal function, because pharmacological inhibition of HO isoforms results in renal vasoconstriction and increased reactivity of the renal vasculature to constrictor agonists. 3,5,20 The present study demonstrates for the first time that the status of NO synthesis influences the urinary concentration Figure 2. Effect of SNAP on CO-generating activity of renal homogenates derived from rats treated with L-NAME for 2 days.…”

Section: Discussionmentioning

confidence: 56%

“…3,5,8,20 For example, it is conceivable that upregulation of renal CO production during NOS inhibition brings about attenuation of the renal vasoconstriction known to be associated with diminished production of NO. 4,5 This notion is in keeping with a recent report that the renal vasoconstriction ensuing after administration of the HO inhibitor SnMP is greatly magnified in rats pretreated with L-NAME.…”

Section: Discussionmentioning

confidence: 99%

Nitric Oxide Synthesis Inhibition Promotes Renal Production of Carbon Monoxide

et al. 2004

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Abstract-We tested the hypothesis that the status of NO synthesis influences the renal heme-heme oxygenase system.Studies were conducted in untreated rats and rats treated with the NO synthesis inhibitor N G -nitro-L-arginine methyl ester for 2 days. Treated and untreated rats were contrasted in terms of renal expression of heme oxygenase-1 and -2, renal carbon monoxide (CO)-generating activity, and urinary CO concentration and excretion rate. Heme oxygenase-1 and -2 proteins were similarly expressed in the kidneys of untreated and treated rats. In contrast, the NADPH-dependent component of the CO-generating activity of renal homogenates incubated with heme (a measure of heme oxygenase activity) was higher (PϽ0.05) in kidneys from rats treated with the NO synthesis inhibitor relative to corresponding data in untreated rats (1015Ϯ95 versus 379Ϯ111 pmol CO/mg per hour). Similarly, relative to corresponding data in untreated rats, rats treated with the NO synthesis inhibitor displayed increased (PϽ0.05) urinary CO concentration (920Ϯ174 versus 2286Ϯ472 pmol/mL) and urinary CO excretion (4.7Ϯ0.4 versus 14.3Ϯ2.7 pmol/min). This study demonstrates that NO synthesis inhibition upregulates the urinary concentration and excretion rate of CO, and the HO-dependent generation of CO by renal homogenates, without affecting the expression of renal heme oxygenase isoforms. Our findings imply that endogenous NO is an inhibitory regulator of renal CO generation by HO. Key Words: kidney Ⅲ carbon monoxide Ⅲ nitric oxide Ⅲ heme oxygenase C arbon monoxide (CO), a product of heme metabolism by heme oxygenase isoforms (HO)-1 and -2, 1 has been linked to the regulation of arterial tone and/or reactivity. 2,3 Nitric oxide (NO), a product of L-arginine metabolism by NO synthase isoforms (NOS), is a major contributor to mechanisms of vasodilation in several vascular beds. 4 The heme-HO and the L-arginine-NOS pathways interact at multiple sites and influence each other's level of activity and function. 1,[5][6][7] On one hand, ex vivo studies indicate that CO inhibits NOS activity and attenuates the expression of vasodilatory mechanisms mediated by NO. 8 On the other hand, NO decreases the catalytic activity of HO, 9,10 promotes HO-1 protein expression 6,7,11 and cellular uptake of heme, 6 and interferes with the ability of CO to stimulate large conductance Ca ϩϩ -activated K ϩ channels in vascular smooth muscle cells 12 and produce vasodilation. 5,13 It is difficult to predict the impact of variations in NO synthesis on the activity of the heme-HO system, because NO downregulates the activity of constitutively-expressed HO-2 while upregulating HO-1 protein expression. 6,7,10,11 Information on this point is relevant to the notion that the status of NO synthesis conditions the vasomotor response to HO inhibition in gracilis muscle arterioles and renal interlobular arteries ex vivo, and in the rat kidney and hind limb in vivo. 5,14 For example, after NOS inhibition, an increase in HO product generation may help condition the associated intens...

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“…HO-1 is normally low and contributes to HO activity only when it is induced as a result of some pathological condition (8). In vivo studies suggest that endogenous HO products can cause renal vasodilatation, diuresis, and natriuresis because metalloporphyrins (which inhibit HOs) increase blood pressure (14) and decrease renal blood flow (25,42), glomerular filtration rate (4), and pressure natriuresis (18).…”

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confidence: 99%

Heme oxygenase metabolites inhibit tubuloglomerular feedback in vivo

Wang

Garvin

D’Ambrosio

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Tubuloglomerular feedback (TGF) is a renal autoregulatory mechanism that constricts the afferent arteriole in response to increases in distal NaCl. Heme oxygenases (HO-1 and HO-2) release carbon monoxide (CO) and biliverdin, which may help control renal function. We showed in vitro that HO products inhibit TGF; however, we do not know whether this also occurs in vivo or the mechanism(s) involved. We hypothesized that in vivo HO-1 and HO-2 in the nephron inhibit TGF via release of CO and biliverdin. We first performed laser capture microdissection followed by real-time PCR and found that both HO-1 and HO-2 are expressed in the macula densa. We next performed micropuncture experiments in vivo on individual rat nephrons, adding different compounds to the perfusate, and found that an HO inhibitor, stannous mesoporphyrin (SnMP), potentiated TGF (P Ͻ 0.05, SnMP vs. control). The CO-releasing molecule (CORM)-3 partially inhibited TGF at 50 mol/l (P Ͻ 0.01, CORM-3 vs. control) and blocked it completely at higher doses. A soluble guanylyl cyclase (sGC) inhibitor, LY83583, blocked the inhibitory effect of CORM-3 on TGF. Biliverdin also partially inhibited TGF (P Ͻ 0.01, biliverdin vs. control), most likely attributable to decreased superoxide (O 2 Ϫ ) because biliverdin was rendered ineffective by tempol, a O 2 Ϫ dismutase mimetic. We concluded that HO-1 and HO-2 in the nephron inhibit TGF by releasing CO and biliverdin. The inhibitory effect of CO on TGF is mediated by the sGC/cGMP signaling pathway, whereas biliverdin probably acts by reducing O 2 Ϫ .stop-flow pressure; afferent arteriole; carbon monoxide; biliverdin AFFERENT ARTERIOLE (Af-Art) resistance determines renal blood flow and glomerular hydrostatic pressure and thus plays a central role in the development of hypertension and hypertensive nephropathy. Af-Art resistance is controlled by myogenic tone (19), vasoactive hormones (24), tubuloglomerular feedback (TGF) (35), and connecting tubule glomerular feedback (31). TGF is the mechanism by which the macula densa (MD) senses increases in luminal NaCl and signals the Af-Art to constrict (34). It is blocked by nitric oxide (NO) produced by the thick ascending loop of Henle and/or the MD (30,38). NO inhibits TGF by increasing cGMP in the MD, whereas superoxide (O 2 Ϫ ) potentiates TGF by scavenging NO (28). Heme oxygenases (HOs) are enzymes that catalyze conversion of heme to carbon monoxide (CO), biliverdin, and ferrous iron. Two active isoforms of HO, HO-1 and HO-2, have been described (2). The kidney constitutively expresses HO-2 mainly within epithelial cells of the thick ascending limb, distal convoluted and connecting tubules, and preglomerular arterioles (8, 12). HO-1 is normally low and contributes to HO activity only when it is induced as a result of some pathological condition (8). In vivo studies suggest that endogenous HO products can cause renal vasodilatation, diuresis, and natriuresis because metalloporphyrins (which inhibit HOs) increase blood pressure (14) and decrease renal blood flow (25, 42), gl...

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Renal vasodilatory influence of endogenous carbon monoxide in chronically hypoxic rats

Cited by 48 publications

References 44 publications

Inhibition of heme oxygenase augments tubular sodium reabsorption

Inhibition of heme oxygenase augments tubular sodium reabsorption

Nitric Oxide Synthesis Inhibition Promotes Renal Production of Carbon Monoxide

Heme oxygenase metabolites inhibit tubuloglomerular feedback in vivo

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