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Publication Record


Effect of a phosphodiesterase 5 inhibitor on pulmonary and cerebral arteries of newborn piglets with chronic hypoxia-induced pulmonary hypertension.
Fike CD, Kaplowitz M, Zhang Y, Dantuma M, Madden JA
(2012) Neonatology 101: 28-39
MeSH Terms: 3',5'-Cyclic-AMP Phosphodiesterases, Animals, Animals, Newborn, Chronic Disease, Disease Models, Animal, Hypertension, Pulmonary, Hypoxia, Middle Cerebral Artery, Phosphodiesterase Inhibitors, Pulmonary Artery, Purinones, Swine, Vasodilation
Show Abstract · Added May 20, 2014
BACKGROUND - The use of phosphodiesterase 5 (PDE5) inhibitors to treat newborns with pulmonary hypertension is increasing. The effect of PDE5 inhibitors on the neonatal cerebral circulation remains unknown. The neonatal piglet model of chronic hypoxia-induced pulmonary hypertension allows the study of the effects of PDE5 inhibitors on both the pulmonary and cerebral circulations.
OBJECTIVES - To determine whether the PDE5 inhibitor, zaprinast, causes dilation in pulmonary and middle cerebral arteries (MCA) of normoxic newborn piglets and those with chronic hypoxia-induced pulmonary hypertension, and to evaluate whether zaprinast alters responses to increased pressure (autoregulatory ability) of the MCA.
METHODS - Two-day-old piglets were raised in normoxia or hypoxia for 3 or 10 days. Pulmonary arteries and MCA were isolated and pressurized, after which changes in diameter to zaprinast were measured. MCA pressure-diameter relationships were determined.
RESULTS - Dilation to zaprinast was similar in pulmonary arteries from normoxic and hypoxic piglets. Zaprinast dilated MCA from all groups but the response was diminished in MCA from piglets raised in hypoxia for 10 days. MCA pressure-diameter relationships (autoregulation) did not differ between the groups.
CONCLUSIONS - Pulmonary artery dilation to zaprinast supports the use of PDE5 inhibitors to treat pulmonary hypertension in neonates. PDE5 inhibitors function as MCA dilators but do not impair the pressure-diameter behavior of the cerebral circulation of either normoxic newborn piglets or those with chronic hypoxia-induced pulmonary hypertension. These findings suggest that cerebral autoregulation is likely to be intact with acute PDE5 inhibitor treatment in infants with pulmonary hypertension in conditions associated with chronic hypoxia.
Copyright © 2011 S. Karger AG, Basel.
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13 MeSH Terms
Detection of an interchain carbinolamine cross-link formed in a CpG sequence by the acrolein DNA adduct gamma-OH-1,N( 2)-propano-2'-deoxyguanosine.
Kim HY, Voehler M, Harris TM, Stone MP
(2002) J Am Chem Soc 124: 9324-5
MeSH Terms: Acrolein, CpG Islands, DNA Adducts, Nuclear Magnetic Resonance, Biomolecular, Purinones
Show Abstract · Added May 29, 2014
Spectroscopic evidence is presented for the formation of a carbinolamine interchain cross-link in 5'-CpG-3' sequences, arising from the acrolein adduct gamma-OH-PdG. This may be important in understanding biological processing of acrolein-induced DNA damage in CpG sequences.
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5 MeSH Terms
Cessation of platelet-mediated cyclic canine coronary occlusion after thrombolysis by combining nitric oxide inhalation with phosphodiesterase-5 inhibition.
Schmidt U, Han RO, DiSalvo TG, Guerrero JL, Gold HK, Zapol WM, Bloch KD, Semigran MJ
(2001) J Am Coll Cardiol 37: 1981-8
MeSH Terms: Administration, Inhalation, Animals, Blood Platelets, Coronary Thrombosis, Dipyridamole, Dogs, Drug Therapy, Combination, Nitric Oxide, Phosphodiesterase Inhibitors, Purinones, Thrombolytic Therapy
Show Abstract · Added May 27, 2014
OBJECTIVES - We sought to evaluate the ability of type 5 phosphodiesterase (PDE5) inhibitors to augment the antithrombotic effects of inhaled nitric oxide (NO) in a canine model of platelet-mediated coronary thrombosis after thrombolysis.
BACKGROUND - Type 5 phosphodiesterase inhibitors potentiate the ability of NO to inhibit platelet aggregation in vitro by preventing platelet cyclic guanosine monophosphate catabolism. We previously reported that breathing low concentrations of NO gas attenuated, but did not prevent, cyclic flow reductions (CFRs) in a canine model of coronary thrombosis after thrombolysis.
METHODS - Cyclic flow reductions were induced after creation of a left anterior descending coronary artery stenosis, endothelial injury, thrombus formation and thrombolysis. Dogs were either untreated or treated with inhaled NO (20 ppm by volume), intravenous zaprinast, intravenous dipyridamole or the combination of inhaled NO with either PDE5 inhibitor (n = 4 per group).
RESULTS - Cyclic flow reductions ceased, and complete coronary patency was achieved in all dogs after they breathed NO combined with zaprinast (by 12.0+/-4.7 min [mean +/- SEM]) or dipyridamole (by 9.8+/-4.7 min). The frequency of CFRs was unaffected by NO, dipyridamole or zaprinast alone. Systemic arterial blood pressure and bleeding time were unchanged with any treatment. Ex vivo thrombin-induced platelet aggregation in dogs breathing NO and receiving dipyridamole was reduced by 75+/-7% (p < 0.05).
CONCLUSIONS - The PDE5 inhibitors potentiated the antithrombotic properties of inhaled NO in a canine model of platelet-mediated coronary artery thrombosis after thrombolysis, without prolonging the bleeding time or causing systemic hypotension.
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11 MeSH Terms
Evidence that additional mechanisms to cyclic GMP mediate the decrease in intracellular calcium and relaxation of rabbit aortic smooth muscle to nitric oxide.
Weisbrod RM, Griswold MC, Yaghoubi M, Komalavilas P, Lincoln TM, Cohen RA
(1998) Br J Pharmacol 125: 1695-707
MeSH Terms: 1-Methyl-3-isobutylxanthine, 3',5'-Cyclic-GMP Phosphodiesterases, Angiotensin II, Animals, Aorta, Calcium, Cyclic GMP, Dose-Response Relationship, Drug, Enzyme Inhibitors, Guanylate Cyclase, Manganese, Muscle Relaxation, Muscle, Smooth, Nitric Oxide, Oxadiazoles, Phosphodiesterase Inhibitors, Protein Kinase C, Purinones, Quinoxalines, Rabbits, Thionucleotides, Vasoconstrictor Agents, Vasodilator Agents
Show Abstract · Added March 11, 2015
1. The role of cyclic GMP in the ability of nitric oxide (NO) to decrease intracellular free calcium concentration [Ca2+]i and divalent cation influx was studied in rabbit aortic smooth muscle cells in primary culture. In cells stimulated with angiotensin II (AII, 10(-1) M), NO (10(-10) - 10(-6) M) increased cyclic GMP levels measured by radioimmunoassay and decreased [Ca2+]i and cation influx as indicated by fura-2 fluorimetry. 2. Zaprinast (10(-4) M), increased NO-stimulated levels of cyclic GMP by 3-20 fold. Although the phosphodiesterase inhibitor lowered the level of [Ca2+]i reached after administration of NO, the initial decreases in [Ca2+]i initiated by NO were not significantly different in magnitude or duration from those that occurred in the absence of zaprinast. 3. The guanylyl cyclase inhibitor, H-(1,2,4) oxadiazolo(4,3-a) quinoxallin-1-one (ODQ, 10(-5) M), blocked cyclic GMP accumulation and activation of protein kinase G, as measured by back phosphorylation of the inositol trisphosphate receptor. ODQ and Rp-8-Br-cyclic GMPS, a protein kinase G inhibitor, decreased the effects of NO, 10(-10) - 10(-8) M, but the decrease in [Ca2+]i or cation influx caused by higher concentrations of NO (10(-7) - 10(-6) M) were unaffected. Relaxation of intact rabbit aorta rings to NO (10(-7) - 10(-5) M) also persisted in the presence of ODQ without a significant increase in cyclic GMP. Rp-8-Br-cyclic GMPS blocked the decreases in cation influx caused by a cell permeable cyclic GMP analog, but ODQ and/or the protein kinase G inhibitor had no significant effect on the decrease caused by NO. 4. Although inhibitors of cyclic GMP, protein kinase G and phosphodiesterase can be shown to affect the decrease in [Ca2+]i and cation influx via protein kinase G, these studies indicate that when these mechanisms are blocked, cyclic GMP-independent mechanisms also contribute significantly to the decrease in [Ca2+]i and smooth muscle relaxation to NO.
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23 MeSH Terms