Peroxynitrite does not impair pulmonary and systemic vascular responses

2004 ◽  
Vol 96 (2) ◽  
pp. 455-462 ◽  
Author(s):  
B. D. Nossaman ◽  
P. A. Dabisch ◽  
J. T. Liles ◽  
S. R. Baber ◽  
H. C. Champion ◽  
...  
Keyword(s):  
Perfusion Pressure ◽  
Systemic Arterial Pressure ◽  
Vascular Responses ◽  
Arterial Perfusion ◽  
Intravenous Injections ◽  
Vasoconstrictor Response ◽  
Vasodilator Activity ◽  
Vascular Responsiveness ◽  
Pulmonary Arterial ◽  
Vasoactive Agonists

The effects of peroxynitrite (ONOO-) on vascular responses were investigated in the systemic and hindquarters vascular bed and in the isolated perfused rat lung. Intravenous injections of ONOO- decreased systemic arterial pressure, and injections of ONOO- into the hindquarters decreased perfusion pressure in a dose-related manner. Injections of ONOO- into the lung perfusion circuit increased pulmonary arterial perfusion pressure. Responses to ONOO- were rapid in onset, short in duration, and repeatable without exhibiting tachyphylaxis. Repeated injections of ONOO- did not alter systemic, hindquarters, or pulmonary responses to endothelium-dependent vasodilators or other vasoactive agonists and did not alter the hypoxic pulmonary vasoconstrictor response. Injections of sodium nitrate or nitrite or decomposed ONOO- had little effect on vascular pressures. Pulmonary and hindquarters responses to ONOO- were not altered by a cyclooxygenase inhibitor in a dose that attenuated responses to arachidonic acid. These results demonstrate that ONOO- has significant pulmonary vasoconstrictor, systemic vasodepressor, and vasodilator activity; that short-term repeated exposure does impair vascular responsiveness; and that responses to ONOO- are not dependent on cyclooxygenase product release.

Analysis of pulmonary and systemic vascular responses to cromakalim, an activator of K+ATP channels

1991 ◽  
Vol 260 (3) ◽  
pp. H957-H966 ◽  
Author(s):  
R. K. Minkes ◽  
P. Kvamme ◽  
T. R. Higuera ◽  
B. D. Nossaman ◽  
P. J. Kadowitz
Keyword(s):  
Arterial Pressure ◽  
Perfusion Pressure ◽  
Antihypertensive Agents ◽  
Blocking Agent ◽  
High Dose ◽  
Arterial Perfusion ◽  
Intravenous Injections ◽  
Vasodilator Activity ◽  
Pulmonary Arterial ◽  
Dose Dependent

Cardiovascular and pulmonary responses to cromakalim, a member of a novel class of antihypertensive agents that open ATP-sensitive K+ (K+ATP) channels, were investigated in the anesthetized cat. Intravenous injections of cromakalim in doses of 30-300 micrograms/kg decreased arterial pressure (AP), pulmonary arterial pressure (PAP), and increased cardiac output (CO), while producing small changes in right and left atrial pressures. Pulmonary and systemic vascular resistances were decreased and vasodilator responses to cromakalim were blocked by glybenclamide, a K+ATP channel-blocking agent. The low dose of cromakalim caused a reflex increase in heart rate (HR) and right ventricular contractile force (RVCF), whereas the high dose decreased HR and RVCF. Under constant-flow conditions the K+ATP channel opener caused dose-dependent decreases in hindquarters perfusion pressure, and when tone was elevated in the pulmonary vascular bed, dose-dependent decreases in pulmonary lobar arterial perfusion pressure. Hindquarters and pulmonary lobar vasodilator responses to cromakalim were inhibited in a specific manner by glybenclamide. The present data show that cromakalim has significant vasodilator activity in both the systemic and pulmonary vascular beds and suggest that responses to this agent result from activation of glybenclamide-sensitive K+ATP channels. These data show that cromakalim can cause substantial decreases in systemic and pulmonary vascular resistance in a dose that has little effect on RVCF.

scholarly journals Pulmonary and systemic vasodilator responses to the soluble guanylyl cyclase stimulator, BAY 41-8543, are modulated by nitric oxide

2010 ◽  
Vol 299 (4) ◽  
pp. H1153-H1159 ◽  
Author(s):  
Adeleke M. Badejo ◽  
Vaughn E. Nossaman ◽  
Edward A. Pankey ◽  
Manish Bhartiya ◽  
Chandrika B. Kannadka ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Arterial Pressure ◽  
Guanylyl Cyclase ◽  
Pulmonary Arterial Pressure ◽  
Soluble Guanylyl Cyclase ◽  
Systemic Arterial Pressure ◽  
Intravenous Injections ◽  
Vasodilator Activity ◽  
Pulmonary Arterial ◽  
Vascular Beds

BAY 41-8543 is a nitric oxide (NO)-independent stimulator of soluble guanylyl cyclase (sGC). Responses to intravenous injections of BAY 41-8543 were investigated under baseline and elevated tone conditions and when NO synthase (NOS) was inhibited with Nω-nitro-l-arginine methyl ester (l-NAME). Under baseline conditions, intravenous injections of BAY 41-8543 caused small decreases in pulmonary arterial pressure, larger decreases in systemic arterial pressure, and increases in cardiac output. When pulmonary arterial pressure was increased to ∼30 mmHg with an intravenous infusion of U-46619, intravenous injections of BAY 41-8543 produced larger dose-dependent decreases in pulmonary arterial pressure, and the relative decreases in pulmonary and systemic arterial pressure in response to the sGC stimulator were similar. Treatment with l-NAME markedly decreased responses to BAY 41-8543 when pulmonary arterial pressure was increased to similar values (∼30 mmHg) in U-46619-infused and in U-46619-infused plus l-NAME-treated animals. The intravenous injection of a small dose of sodium nitroprusside (SNP) when combined with BAY 41-8543 enhanced pulmonary and systemic vasodilator responses to the sGC stimulator in l-NAME-treated animals. The present results indicate that BAY 41-8543 has similar vasodilator activity in the systemic and pulmonary vascular beds when pulmonary vasoconstrictor tone is increased with U-46619. These results demonstrate that pulmonary and systemic vasodilator responses to BAY 41-8543 are significantly attenuated when NOS is inhibited by l-NAME and show that vasodilator responses to BAY 41-8543 are enhanced when combined with a small dose of SNP in l-NAME-treated animals. The present results are consistent with the concept that pulmonary and systemic vasodilator responses to the sGC stimulator are NO-independent; however, the vasodilator activity of the compound is greatly diminished when endogenous NO production is inhibited with l-NAME. These data show that BAY 41-8543 has similar vasodilator activity in the pulmonary and systemic vascular beds in the rat.

scholarly journals Pulmonary and systemic vasodilator responses to the soluble guanylyl cyclase activator, BAY 60–2770, are not dependent on endogenous nitric oxide or reduced heme

2011 ◽  
Vol 300 (3) ◽  
pp. H792-H802 ◽  
Author(s):  
Edward A. Pankey ◽  
Manish Bhartiya ◽  
Adeleke M. Badejo ◽  
Umair Haider ◽  
Johannes-Peter Stasch ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Arterial Pressure ◽  
Sodium Nitroprusside ◽  
Pulmonary Arterial Pressure ◽  
Soluble Guanylyl Cyclase ◽  
Systemic Arterial Pressure ◽  
Intravenous Injections ◽  
Pulmonary Vasodilator ◽  
Vasodilator Activity ◽  
Pulmonary Arterial

4-({(4-Carboxybutyl)[2-(5-fluoro-2-{[4′-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}methyl)benzoic acid (BAY 60–2770) is a nitric oxide (NO)-independent activator of soluble guanylyl cyclase (sGC) that increases the catalytic activity of the heme-oxidized or heme-free form of the enzyme. In this study, responses to intravenous injections of the sGC activator BAY 60–2770 were investigated under baseline and elevated tone conditions induced by the thromboxane mimic U-46619 when NO synthesis was inhibited by Nω-nitro-l-arginine methyl ester hydrochloride (l-NAME), when sGC activity was inhibited by 1H-[1,2,4]-oxadizaolo[4,3]quinoxaline-1-one (ODQ), an agent that oxidizes sGC, and in animals with monocrotaline-induced pulmonary hypertension. The intravenous injections of BAY 60–2770 under baseline conditions caused small decreases in pulmonary arterial pressure, larger decreases in systemic arterial pressure, and no change or small increases in cardiac output. Under elevated tone conditions during infusion of U-46619, intravenous injections of BAY 60–2770 caused larger decreases in pulmonary arterial pressure, smaller decreases in systemic arterial pressure, and increases in cardiac output. Pulmonary vasodilator responses to BAY 60–2770 were enhanced by l-NAME or by ODQ in a dose that attenuated responses to the NO donor sodium nitroprusside. ODQ had no significant effect on baseline pressures and attenuated pulmonary and systemic vasodilator responses to the sGC stimulator BAY 41–8543 2-{1-[2-(fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5(4-morpholinyl)-4,6-pyrimidinediamine. BAY 60–2770 and sodium nitroprusside decreased pulmonary and systemic arterial pressures in monocrotaline-treated rats in a nonselective manner. The present data show that BAY 60–2770 has vasodilator activity in the pulmonary and systemic vascular beds that is enhanced by ODQ and NOS inhibition, suggesting that the heme-oxidized form of sGC can be activated in vivo in an NO-independent manner to promote vasodilation . These results show that BAY 60–2770 and sodium nitroprusside decreased pulmonary and systemic arterial pressures in monocrotaline-treated rats, suggesting that BAY 60–2770 does not have selective pulmonary vasodilator activity in animals with monocrotaline-induced pulmonary hypertension.

Comparison of responses to sarafotoxins 6a and 6c in pulmonary and systemic vascular beds

1992 ◽  
Vol 262 (3) ◽  
pp. H852-H861
Author(s):  
R. K. Minkes ◽  
J. A. Bellan ◽  
T. R. Higuera ◽  
P. J. Kadowitz
Keyword(s):  
Arterial Pressure ◽  
Vascular Resistance ◽  
Perfusion Pressure ◽  
Venous Pressure ◽  
Constant Flow ◽  
Flow Conditions ◽  
Arterial Perfusion ◽  
Intravenous Injections ◽  
Autonomic Reflexes ◽  
Pressure Changes

Cardiovascular and pulmonary responses to sarafotoxin (S) 6a and S6c were investigated in the anesthetized cat. Intravenous injections of the peptides in doses of 0.1-1.0 nmol/kg caused decreases or biphasic changes in arterial pressure (AP) and increases in central venous pressure, pulmonary arterial pressure (PAP), and cardiac output (CO). Secondary decreases in CO were observed in response to higher doses, and biphasic changes in systemic (SVR) and pulmonary (PVR) vascular resistances were observed. Under constant-flow conditions, the peptides only increased pulmonary lobar arterial perfusion pressure and lobar vascular resistance. AP responses to S6a, S6c, endothelin (ET)-1, ET-2, vasoactive intestinal contractor (VIC), and Lys7-ET-1 were similar, whereas AP responses to S6b and ET-3 were similar. S6a, S6b, S6c, ET-1, ET-2, ET-3, VIC, Lys7-ET-1, and big ET-1 increased PAP. S6a and S6c increased distal aortic and superior mesenteric arterial (SMA) blood flow and caused biphasic changes at the highest doses. Under constant-flow conditions, S6a and S6c produced dose-dependent biphasic changes in hindquarters perfusion pressure. Changes in SVR and PVR in response to the peptide were not affected by hexamethonium, glyburide, or meclofenamate, indicating that responses are independent of autonomic reflexes, activation of ATP-regulated K+ channels, or release of cyclooxygenase products. In contrast, N-nitro-L-arginine methyl ester decreased hindquarters vasodilator response to S6a and S6c. The present data show that S6a and S6c produce both vasodilation and vasoconstriction in the systemic vascular bed and increase lobar vascular resistance and that hindquarters vasodilator responses are mediated, in part, by the release of endothelium-derived relaxing factor.

Rho kinase and Ca2+ entry mediate increased pulmonary and systemic vascular resistance in l-NAME-treated rats

2007 ◽  
Vol 293 (5) ◽  
pp. L1306-L1313 ◽  
Author(s):  
Jasdeep S. Dhaliwal ◽  
David B. Casey ◽  
Anthony J. Greco ◽  
Adeleke M. Badejo ◽  
Thomas B. Gallen ◽  
...  
Keyword(s):  
Cardiac Output ◽  
Arterial Pressure ◽  
Systemic Vascular Resistance ◽  
Vascular Resistance ◽  
Pulmonary Arterial Pressure ◽  
Rho Kinase ◽  
Systemic Arterial Pressure ◽  
Intravenous Injections ◽  
Pulmonary Arterial ◽  
Dose Dependent

The small GTP-binding protein and its downstream effector Rho kinase play an important role in the regulation of vasoconstrictor tone. Rho kinase activation maintains increased pulmonary vascular tone and mediates the vasoconstrictor response to nitric oxide (NO) synthesis inhibition in chronically hypoxic rats and in the ovine fetal lung. However, the role of Rho kinase in mediating pulmonary vasoconstriction after NO synthesis inhibition has not been examined in the intact rat. To address this question, cardiovascular responses to the Rho kinase inhibitor fasudil were studied at baseline and after administration of an NO synthesis inhibitor. In the intact rat, intravenous injections of fasudil cause dose-dependent decreases in systemic arterial pressure, small decreases in pulmonary arterial pressure, and increases in cardiac output. l-NAME caused a significant increase in pulmonary and systemic arterial pressures and a decrease in cardiac output. The intravenous injections of fasudil after l-NAME caused dose-dependent decreases in pulmonary and systemic arterial pressure and increases in cardiac output, and the percent decreases in pulmonary arterial pressure in response to the lower doses of fasudil were greater than decreases in systemic arterial pressure. The Ca++ entry blocker isradipine also decreased pulmonary and systemic arterial pressure in l-NAME-treated rats. Infusion of sodium nitroprusside restored pulmonary arterial pressure to baseline values after administration of l-NAME. These data provide evidence in support of the hypothesis that increases in pulmonary and systemic vascular resistance following l-NAME treatment are mediated by Rho kinase and Ca++ entry through L-type channels, and that responses to l-NAME can be reversed by an NO donor.

Inhibitory effect of hypertonic mannitol on vasoconstrictor and vasodilator responses of isolated coronary arteries

1978 ◽  
Vol 235 (6) ◽  
pp. H728-H735 ◽  
Author(s):  
V. S. Krishnamurty ◽  
H. R. Adams ◽  
G. H. Templeton ◽  
J. T. Willerson
Keyword(s):  
Coronary Arteries ◽  
Perfusion Pressure ◽  
Inhibitory Effect ◽  
Vasoactive Agents ◽  
Future Studies ◽  
Beta Adrenoceptor ◽  
Vasoconstrictor Response ◽  
Pressor Responses ◽  
Vascular Responsiveness

The effect of hypertonic mannitol on pressor responses to vasoactive agents was studied in isolated canine coronary arteries perfused with physiologic salt solution at a constant flow. When perfusion pressure was increased with 60 mM KCl, mannitol (50 mosM) consistently caused a decrease in perfusion pressure that lasted for at least 1 h. Withdrawal of mannitol from the perfusion media was associated with a vasoconstrictor response that was not prevented by alpha- or beta-adrenoceptor blockade or by the presence of either nitroglycerin or norepinephrine. Hypertonic mannitol also reduced the responsiveness of the isolated smooth muscle preparations to several different mechanistically unrelated vasodilator agents. The mechanism(s) responsible for the paradoxical ability of hypertonic mannitol to reduce vascular responsiveness to both vasoconstrictor and vasodilator interventions in isolated canine coronary arteries is not known, but future studies should be directed at elucidating it as well as determining whether similar phenomena occur in vivo.

scholarly journals Analysis of responses to the Rho-kinase inhibitor Y-27632 in the pulmonary and systemic vascular bed of the rat

2010 ◽  
Vol 299 (1) ◽  
pp. H184-H192 ◽  
Author(s):  
David B. Casey ◽  
Adeleke M. Badejo ◽  
Jasdeep S. Dhaliwal ◽  
James L. Sikora ◽  
Alex Fokin ◽  
...  
Keyword(s):  
Arterial Pressure ◽  
Guanylate Cyclase ◽  
Kinase Inhibitor ◽  
Pulmonary Arterial Pressure ◽  
Rho Kinase ◽  
Hypoxic Exposure ◽  
Intravenous Injections ◽  
Vasoconstrictor Response ◽  
Rho Kinase Inhibitor ◽  
Pulmonary Arterial

Responses to the Rho kinase inhibitor Y-27632 were investigated in the anesthetized rat. Under baseline conditions intravenous injections of Y-27632 decreased pulmonary and systemic arterial pressures and increased cardiac output. The decreases in pulmonary arterial pressures were enhanced when baseline tone was increased with U-46619, and under elevated tone conditions Y-27632 produced similar percent decreases in pulmonary and systemic arterial pressures. Injections of Y-27632 prevented and reversed the hypoxic pulmonary vasoconstrictor response. The increase in pulmonary arterial pressure in response to ventilation with a 10% O2-90% N2 gas mixture was not well maintained during the period of hypoxic exposure. Treatment with the nitric oxide (NO) synthase (NOS) inhibitor nitro-l-arginine methyl ester (l-NAME) increased pulmonary arterial pressure and prevented the decline or fade in the hypoxic pulmonary vasoconstrictor response. The hypoxic pulmonary vasoconstrictor response was reversed by Y-27632 in control and in l-NAME-treated animals. The Rho kinase inhibitor attenuated increases in pulmonary arterial pressures in response to intravenous injections of serotonin, angiotensin II, and Bay K 8644. Y-27632, sodium nitrite, and BAY 41-8543, a guanylate cyclase stimulator, decreased pulmonary and systemic arterial pressures and vascular resistances in monocrotaline-treated rats. These data suggest that Rho kinase is involved in the regulation of baseline tone and in the mediation of pulmonary vasoconstrictor responses. The present data suggest that the hypoxic pulmonary vasoconstrictor response is modulated by the release of NO that mediates the nonsustained component of the response in the anesthetized rat. These data suggest that Rho kinase and NOS play important roles in the regulation of vasoconstrictor tone in physiological and pathophysiological states and that monocrotaline-induced pulmonary hypertension can be reversed by agents that inhibit Rho kinase, generate NO, or stimulate soluble guanylate cyclase.

Analysis of responses to angiotensin I-(3-10) in the hindlimb vascular bed of the cat

1996 ◽  
Vol 270 (4) ◽  
pp. H1172-H1177 ◽  
Author(s):  
E. A. Garrison ◽  
P. J. Kadowitz
Keyword(s):  
Perfusion Pressure ◽  
Systemic Arterial Pressure ◽  
Flow Conditions ◽  
Angiotensin I ◽  
Response Curves ◽  
Angiotensin Iv ◽  
Intravenous Injections ◽  
Vascular Bed ◽  
Dependent Pathway ◽  
Anesthetized Cat

Responses to angiotensin I-(3-10), the precursor for angiotensin IV, were investigated in the anesthetized cat. Intravenous injections of the precursor caused dose-related increases in systemic arterial pressure that were similar to responses elicited by angiotensin i.v. and that were inhibited by captopril. in the hindlimb vascular bed of the cat under constant-flow conditions, injections of the substrate into the perfusion circuit in doses of 3-100 micrograms caused dose-related increases in hindlimb perfusion pressure that were rapid in onset and were not altered by the presence of a time-delay coil in the perfusion circuit. Dose-response curves for the precursor and angiotensin i.v. were parallel, and the precursor was approximately twofold less potent than angiotensin i.v. in its ability to increase hindlimb perfusion pressure. Responses to the precursor were inhibited by captopril in a dose that attenuated hindlimb vasoconstrictor responses to angiotensin I. Increases in hindlimb perfusion pressure in response to angiotensin I-(3-10) were inhibited by DuP-532 in a dose that attenuated the response to angiotensin i.v. PD-123,319, an AT2 receptor antagonist, had no significant effect on responses to angiotensin I-(3-10). The present results suggest that angiotensin I-(3-10) is rapidly and efficiently converted by an angiotensin converting enzyme-dependent pathway into an active peptide, which induces vasoconstriction by activating AT1 receptors in the peripheral vascular bed of the cat.

d-[Ala2]endomorphin 2 and endomorphin 2 have nitric oxide-dependent vasodilator activity in rats

1998 ◽  
Vol 274 (5) ◽  
pp. H1690-H1697 ◽  
Author(s):  
Hunter C. Champion ◽  
Philip J. Kadowitz
Keyword(s):  
Nitric Oxide ◽  
Opioid Receptor ◽  
Peripheral Resistance ◽  
Systemic Arterial Pressure ◽  
Nitric Oxide Synthase Inhibitor ◽  
Intravenous Injections ◽  
Similar Dose ◽  
Vasodilator Activity ◽  
Synthase Inhibitor ◽  
Oxide Synthase

Endomorphin 1 and 2, newly discovered endogenous ligands for the μ-opioid receptor, have vasodepressor activity in the rat. In the present study, the mechanism mediating hemodynamic responses to endomorphin 2 and the endomorphin analog [D-Ala2]endomorphin 2 (TAPP) was investigated in the rat. Intravenous injections of TAPP and endomorphin 2 produced similar dose-dependent decreases in systemic arterial pressure and were ∼10-fold more potent than Met-enkephalin. TAPP and endomorphin 2 decreased heart rate, cardiac output, and total peripheral resistance. Under constant-flow conditions, injections of TAPP and endomorphin 2 into the perfusion circuit produced decreases in hindquarter perfusion pressure, and vasodilator responses were attenuated by the opioid receptor antagonist naloxone. Hindquarter vasodilator responses to TAPP and endomorphin 2 were attenuated by the nitric oxide synthase inhibitor N ω-nitro-l-arginine methyl ester (L-NAME; 50 mg/kg iv), whereas responses to the endothelium-independent vasodilators calcitonin gene-related peptide, diethylamine/nitric oxide, and isoproterenol were not changed. Hindquarter vasodilator responses to TAPP and endomorphin 2 were not altered by the cyclooxygenase inhibitor sodium meclofenamate, the ATP-dependent K+ channel antagonist U-37883A, or the presence of a time-delay coil in the perfusion circuit. These results indicate that vasodilator responses to TAPP and endomorphin 2 are mediated by the activation of a naloxone-sensitive opioid receptor and the release of nitric oxide from the endothelium within the hindquarter vascular bed of the rat.

Pulmonary vascular responsiveness in cold-exposed calves

1985 ◽  
Vol 63 (2) ◽  
pp. 131-135 ◽  
Author(s):  
K. J. Greenlees ◽  
A. Tucker ◽  
D. Robertshaw ◽  
C. R. Vader
Keyword(s):  
Heart Rate ◽  
Blood Flow ◽  
Cold Exposure ◽  
Vascular Reactivity ◽  
Acute Hypoxia ◽  
Systemic Arterial Pressure ◽  
Venous Circulation ◽  
Vascular Responsiveness ◽  
Pulmonary Arterial ◽  
Neutral Conditions

The pulmonary vascular responses to acute hypoxia and to infusions of histamine and 5-hydroxytryptamine (5-HT) were recorded in unanesthetized standing bull calves under neutral (16–18 °C) and cold (3−5 °C) temperature conditions. Cold exposure alone resulted in a significant increase in pulmonary arterial wedge pressure from 10.2 ± 3.5 to 15.9 ± 4.9 Torr (1 Torr = 133.322 Pa). Resistance to blood flow between the pulmonary wedge and the left atrium significantly increased from 0.50 ± 0.51 to 1.21 ± 0.78 mmHg∙L−1∙min−1 (1 mmHg = 133.322 Pa) with cold exposure. This apparent pulmonary venoconstrictor response to cold exposure was further evaluated to determine if hypoxia, histamine, or 5-HT responsiveness was altered by cold exposure. Twelve minutes of hypoxia increased pulmonary arterial and systemic arterial pressures, heart rate, and respiratory rate similarly in cold and neutral temperatures. Cold exposure did not alter the dose-related reductions of systemic arterial and pulmonary arterial pressures in response to histamine. Similarly, the decreases in systemic arterial pressure and heart rate and increases in pulmonary arterial and left atrial pressures in response to 5-HT were not significantly different in cold and neutral conditions. It was concluded that acute, mild cold exposure results in an increase in resistance to blood flow in the pulmonary venous circulation without a general increase in pulmonary vascular reactivity, as measured by responses to hypoxia, histamine, and 5-HT.

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