Heme oxygenase-mediated vasodilation involves vascular smooth muscle cell hyperpolarization

2003 ◽  
Vol 285 (1) ◽  
pp. H220-H228 ◽  
Author(s):  
Jay S. Naik ◽  
Benjimen R. Walker
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Heme Oxygenase ◽  
Vascular Reactivity ◽  
Protoporphyrin Ix ◽  
Zinc Protoporphyrin ◽  
Spin Traps ◽  
Enhanced Production ◽  
Vasodilatory Response ◽  
Presence And Absence

Chronic hypoxia is associated with both blunted agonist-induced and myogenic vascular reactivity and is possibly due to an enhanced production of heme oxygenase (HO)-derived carbon monoxide (CO). However, the mechanism of endogenous CO-meditated vasodilation remains unclear. Isolated pressurized mesenteric arterioles from chronically hypoxic rats were administered the HO substrate heme-l-lysinate (HLL) in the presence or absence of iberiotoxin, 1 H-[1,2,4]oxadiazolo[4,3- a]quinoxalin-1-one (ODQ), ryanodine, or free radical spin traps ( N- tert-butyl-α-phenylnitrone and 4,5-dihydroxy-1,3-benzenedisulfonic acid disodium salt). The effects of HLL administration on vascular smooth muscle (VSM) membrane potential were assessed in superior mesenteric artery strips in the presence and absence of zinc protoporphyrin IX or iberiotoxin. The vasodilatory responses to exogenous CO were assessed in the presence and absence of ODQ or iberiotoxin. HLL administration produced a dose-dependent vasodilatory response that was nearly eliminated in the presence of iberiotoxin. Neither ODQ, spin traps, nor ryanodine altered the vasodilatory response to HLL, although ODQ abolished the vasodilatory response to S-nitroso- N-acetyl-penicillamine. HLL administration produced a zinc protoporphyrin IX- and iberiotoxin-sensitive VSM cell hyperpolarization. Iberiotoxin and ODQ inhibited the vasodilatory response to exogenous CO. Thus the vasodilatory response to endogenous CO involves cGMP-independent activation of VSM large-conductance Ca2+-activated K+ channels and does not likely involve the formation of Ca2+ sparks emanating from ryanodine-sensitive stores.

Inhibitory effect of CO on internal anal sphincter: heme oxygenase inhibitor inhibits NANC relaxation

1993 ◽  
Vol 265 (4) ◽  
pp. G799-G804 ◽  
Author(s):  
S. Rattan ◽  
S. Chakder
Keyword(s):  
Smooth Muscle ◽  
Anal Sphincter ◽  
Heme Oxygenase ◽  
Nerve Stimulation ◽  
Internal Anal Sphincter ◽  
Direct Action ◽  
Second Messengers ◽  
Protoporphyrin Ix ◽  
Zinc Protoporphyrin ◽  
Before And After

We examined the effect and role of CO in opossum internal anal sphincter (IAS) relaxation in response to nonadrenergic noncholinergic (NANC) nerve stimulation. Effects of NANC nerve stimulation on the IAS tension and second messengers (cAMP and cGMP) were examined before and after the selective heme oxygenase (HO) inhibitor zinc protoporphyrin IX (Zn PP-IX). The HO activity of the IAS smooth muscle was determined before and after NANC nerve stimulation. CO caused a concentration-dependent and tetrodotoxin-resistant fall in the resting tension of the IAS. The direct action of CO was confirmed by its relaxant action on the isolated smooth muscle cells. Furthermore, CO caused an increase in the tissue cGMP levels comparable to that observed with nerve stimulation. Zn PP-IX caused suppression of IAS relaxation caused by NANC nerve stimulation and vasoactive intestinal polypeptide (VIP) but not by peptide histidine-isoleucine and suppression of the increase in cGMP in response to NANC nerve stimulation. Zn PP-IX had no significant effect on the IAS responses to CO, nitric oxide (NO), and the beta-adrenoceptor agonist isoproterenol. The IAS responses to CO were not modified by the NO synthase inhibitor NG-nitro-L-arginine. Significant HO activity was detected in the IAS, which increased further in response to NANC nerve stimulation and VIP. The direct relaxant actions of CO and the suppression of NANC-mediated relaxation of the IAS by the HO inhibitor suggest the involvement of CO in the neurally mediated IAS relaxation.

Endogenous carbon monoxide is an endothelial-derived vasodilator factor in the mesenteric circulation

2003 ◽  
Vol 284 (3) ◽  
pp. H838-H845 ◽  
Author(s):  
Jay S. Naik ◽  
Theresa L. O'Donaughy ◽  
Benjimen R. Walker
Keyword(s):  
Carbon Monoxide ◽  
Cellular Localization ◽  
Vascular Reactivity ◽  
Protoporphyrin Ix ◽  
Physiological Saline ◽  
Mesenteric Arteries ◽  
Zinc Protoporphyrin ◽  
Sprague Dawley ◽  
Vasodilator Response ◽  
Enhanced Production

Chronic hypoxia (CH) is associated with both blunted agonist-induced and myogenic vascular reactivity, possibly due to an enhanced production of heme oxygenase (HO)-derived carbon monoxide (CO). However, the cellular location of the HO responsible for these effects has not been clearly established. Therefore, we examined the response to administration of the substrate for HO, heme-l-lysinate (HLL), in endothelium-intact and endothelium-denuded small mesenteric arteries from CH male Sprague-Dawley rats. Mesenteric arteries were isolated and mounted on glass cannulas, pressurized to 60 mmHg, and superfused with physiological saline solution. All experiments were performed in the presence of 100 μM N ω-nitro-l-arginine. The vasodilator response to HLL or exogenous CO was examined. HLL experiments were performed in the presence and absence of the HO inhibitor zinc protoporphyrin IX (ZnPPIX). HLL administration resulted in a dose-dependent vasodilator response that was abolished in the presence of ZnPPIX or by endothelial removal. Exogenous CO produced a vasodilator response that was independent of an intact endothelium. Cellular localization of HO was verified through immunohistochemistry in sections of the gut and aorta from CH and control animals. Staining for HO-1, HO-2, and endothelial nitric oxide synthase was confined to the endothelium. Thus we conclude that CO is a product of HO located within the endothelium.

cAMP induces heme oxygenase-1 gene expression and carbon monoxide production in vascular smooth muscle

1997 ◽  
Vol 273 (1) ◽  
pp. H317-H323 ◽  
Author(s):  
W. Durante ◽  
N. Christodoulides ◽  
K. Cheng ◽  
K. J. Peyton ◽  
R. K. Sunahara ◽  
...  
Keyword(s):  
Carbon Monoxide ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Heme Oxygenase ◽  
Muscle Cells ◽  
Heme Oxygenase 1 ◽  
Zinc Protoporphyrin ◽  
Intracellular Camp

Recent studies indicate that vascular smooth muscle cells generate carbon monoxide (CO) via the action of heme oxygenase (HO). Because adenosine 3',5'-cyclic monophosphate (cAMP) is an important intracellular signaling molecule in the regulation of vascular cell function, we examined whether this second messenger modulates the expression of HO and the production of CO by rat aortic smooth muscle cells. Treatment of smooth muscle cells with the membrane-permeable cAMP derivative dibutyryl cAMP or with compounds that increase intracellular cAMP levels (isoproterenol and forskolin) resulted in a concentration- and time-dependent increase in the levels of HO-1 mRNA and protein, whereas the expression of HO-2 remained unchanged. Both actinomycin D and cycloheximide blocked the basal expression of HO-1 mRNA and protein and prevented the cAMP-mediated induction of HO-1. Incubation of platelets with cAMP-treated smooth muscle cells resulted in a significant increase in platelet cGMP concentration that was partially reversed by treatment of smooth muscle cells with the nitric oxide synthase inhibitor NG-monomethyl-L-arginine or the HO blocker zinc protoporphyrin-IX. However, the combined addition of these two inhibitors to cAMP-treated smooth muscle cells or the addition of the CO and NO scavenger hemoglobin to platelets completely blocked the stimulatory effect on platelet cGMP levels. These results demonstrate that cAMP induces the expression of the HO-1 gene and stimulates the formation of CO and NO in vascular smooth muscle cells. The capacity of cAMP to induce the synthesis of guanylate cyclase-stimulatory CO from smooth muscle cells may represent a novel mechanism by which this nucleotide regulates vascular tone.

Mechanism of inhibition of VIP-induced LES relaxation by heme oxygenase inhibitor zinc protoporphyrin IX

1999 ◽  
Vol 276 (1) ◽  
pp. G138-G145 ◽  
Author(s):  
Satish Rattan ◽  
Ya-Ping Fan ◽  
Sushanta Chakder
Keyword(s):  
Smooth Muscle ◽  
G Protein ◽  
Heme Oxygenase ◽  
Inhibitory Action ◽  
Muscle Relaxation ◽  
Protoporphyrin Ix ◽  
Significant Inhibition ◽  
Smooth Muscle Relaxation ◽  
Zinc Protoporphyrin ◽  
Protein Activation

The putative heme oxygenase inhibitor zinc protoporphyrin IX (ZnPP IX) is known to exert diverse actions, including inhibitory action on smooth muscle relaxation by vasoactive intestinal polypeptide (VIP). The studies were performed in the opossum lower esophageal sphincter (LES) smooth muscle to determine the site of the inhibitory action of ZnPP IX in the smooth muscle relaxation by VIP. We also examined the effect of a direct Gs protein activator, cholera toxin (CTX), known to stimulate adenylate cyclase (AC). CTX caused relaxation of the LES smooth muscle by its action directly at the smooth muscle cells. The convergence of the common mechanisms of actions of VIP and CTX on AC was determined by the suppression of their effects by the AC inhibitor and CTX desensitization. ZnPP IX caused attenuation of the LES smooth muscle relaxation by VIP but not by CTX. ZnPP IX but not zinc deuteroporphyrin IX caused significant inhibition of VIP binding to the membrane receptor. We conclude that ZnPP IX attenuates VIP-induced LES smooth muscle relaxation by inhibition of VIP binding to G protein-coupled receptors linked to AC at a point proximal to G protein activation.

Mechanisms of Direct Inhibitory Action of Isoflurane on Vascular Smooth Muscle of Mesenteric Resistance Arteries

2003 ◽  
Vol 99 (3) ◽  
pp. 666-677 ◽  
Author(s):  
Takashi Akata ◽  
Tomoo Kanna ◽  
Jun Yoshino ◽  
Shosuke Takahashi
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Vascular Reactivity ◽  
Channel Blocker ◽  
Isometric Force ◽  
Systemic Resistance ◽  
Resistance Arteries ◽  
Voltage Gated ◽  
Fura 2 ◽  
Force Relation

Background Isoflurane has been shown to directly inhibit vascular reactivity. However, less information is available regarding its underlying mechanisms in systemic resistance arteries. Methods Endothelium-denuded smooth muscle strips were prepared from rat mesenteric resistance arteries. Isometric force and intracellular Ca2+ concentration ([Ca2+]i) were measured simultaneously in the fura-2-loaded strips, whereas only the force was measured in the beta-escin membrane-permeabilized strips. Results Isoflurane (3-5%) inhibited the increases in both [Ca2+]i and force induced by either norepinephrine (0.5 microM) or KCl (40 mM). These inhibitions were similarly observed after depletion of intracellular Ca2+ stores by ryanodine. Regardless of the presence of ryanodine, after washout of isoflurane, its inhibition of the norepinephrine response (both [Ca2+]i and force) was significantly prolonged, whereas that of the KCl response was quickly restored. In the ryanodine-treated strips, the norepinephrine- and KCl-induced increases in [Ca2+]i were both eliminated by nifedipine, a voltage-gated Ca2+ channel blocker, whereas only the former was inhibited by niflumic acid, a Ca2+-activated Cl- channel blocker. Isoflurane caused a rightward shift of the Ca2+-force relation only in the fura-2-loaded strips but not in the beta-escin-permeabilized strips. Conclusions In mesenteric resistance arteries, isoflurane depresses vascular smooth muscle reactivity by directly inhibiting both Ca2+ mobilization and myofilament Ca2+ sensitivity. Isoflurane inhibits both norepinephrine- and KCl-induced voltage-gated Ca2+ influx. During stimulation with norepinephrine, isoflurane may prevent activation of Ca2+-activated Cl- channels and thereby inhibit voltage-gated Ca2+ influx in a prolonged manner. The presence of the plasma membrane appears essential for its inhibition of the myofilament Ca2+ sensitivity.

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