ABSTRACT
An infant with subvalvar and valvar pulmonary stenosis, subvalvar, and valvar aortic stenosis and hypertrophic cardiomyopathy, who presented with pulmonary hemorrhage, is reported. He had right ventricular hypertrophy, thickened pulmonary valve leaflets, severe asymmetric left ventricular hypertrophy with outflow tract obstruction, and a thickened and dysplastic aortic valve.
Subject(s)
Aortic Valve Stenosis/surgery , Heart Defects, Congenital/surgery , Heart Transplantation/methods , Hypertrophy, Left Ventricular/surgery , Pulmonary Valve Stenosis/surgery , Ventricular Outflow Obstruction/surgery , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/surgery , Angiography , Aortic Valve Stenosis/congenital , Aortic Valve Stenosis/diagnosis , Disease Progression , Echocardiography, Doppler , Fatal Outcome , Heart Defects, Congenital/diagnosis , Hemorrhage/diagnosis , Humans , Hypertrophy, Left Ventricular/congenital , Hypertrophy, Left Ventricular/diagnosis , Infant, Newborn , Lung Diseases/diagnosis , Male , Pulmonary Valve Stenosis/congenital , Pulmonary Valve Stenosis/diagnosis , Risk Assessment , Severity of Illness Index , Ventricular Outflow Obstruction/congenital , Ventricular Outflow Obstruction/diagnosisABSTRACT
BACKGROUND: The purpose of this study was to examine the effects of cyclooxygenase (COX) deficiency on baseline functional characteristics and on recovery of left ventricular developed pressure (LVDP) after 20 minutes of global ischemia and 40 minutes of reperfusion in untreated and preconditioned hearts. METHODS AND RESULTS: Compared with hearts from wild-type (WT) and COX-2(-/-) mice, baseline cardiac prostaglandin (PG) E(2) and 6-keto-PGF(1alpha) levels were significantly decreased in hearts from COX-1(-/-) mice. After ischemia, cardiac PGE(2) levels increased in WT, COX-1(-/-), and COX-2(-/-) mice (P<0.05). Recovery of function (LVDP) after global ischemia in hearts from COX-1(-/-) and COX-2(-/-) mice was significantly less than in WT hearts. Pretreatment of WT mice with indomethacin for 2 days before ischemia significantly decreased LVDP recovery; however, perfusion of WT hearts with indomethacin for 40 minutes before ischemia did not significantly alter LVDP recovery. Postischemic recovery of LVDP in COX-1(-/-) and COX-2(-/-) was unchanged by perfusion with 5 micromol/L PGE(2), PGD(2), PGF(2alpha), or carboprostacyclin. Hearts from COX-2(-/-) mice showed an increase in ischemic contracture compared with hearts from WT and COX-1(-/-) mice; however, hearts did not differ in intracellular pH, ATP, or inorganic phosphate during ischemia. Ischemic preconditioning significantly improved postischemic LVDP recovery in COX-1(-/-), COX-2(-/-), and WT mice. CONCLUSIONS: Genetic disruption or 2-day chemical inhibition of COX-1 and COX-2 decreases recovery of LVDP after ischemia; however, acute perfusion with indomethacin is not detrimental. These data are consistent with protection due to the altered expression of some protein that is modulated by COX or its metabolites.
Subject(s)
Ischemic Preconditioning, Myocardial , Isoenzymes/genetics , Isoenzymes/physiology , Myocardial Reperfusion Injury/etiology , Prostaglandin-Endoperoxide Synthases/genetics , Prostaglandin-Endoperoxide Synthases/physiology , Animals , Cyclooxygenase 1 , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Cyclooxygenase Inhibitors/pharmacology , Hemodynamics , Hydrogen-Ion Concentration , Indomethacin/pharmacology , Isoenzymes/antagonists & inhibitors , Kinetics , Membrane Proteins , Mice , Mice, Knockout , Myocardial Contraction , Myocardial Reperfusion Injury/physiopathology , Myocardial Reperfusion Injury/therapy , Organ Culture Techniques , Phosphates/metabolism , Prostaglandins/pharmacology , Ventricular PressureABSTRACT
NADPH-cytochrome P450 reductase (CPR; NADPH:ferrihemoprotein reductase, EC 1.6.2.4) catalyzes the transfer of electrons to all known microsomal cytochromes P450. CPR is unique in that it is one of only two mammalian enzymes known to contain both flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), the other being the various isoforms of nitric oxide synthase. Similarities in amino acid sequence and in functional domain arrangement with other key flavoproteins, including nitric oxide synthase, make CPR an excellent prototype for studies of interactions between two flavin cofactors. We have obtained diffraction-quality crystals of rat liver CPR, expressed in Escherichia coli and solubilized by limited proteolysis with trypsin. The crystals were grown in Hepes buffer (pH 7.0), containing polyethylene glycol 4500 and NaCl. The crystals belong to the orthorhombic space group P2(1)2(1)2(1), with unit cell dimensions a = 103.3 A, b = 116.1 A, and c = 120.4 A. If we assume that there are two molecules of the 72-kDa CPR polypeptide per asymmetric unit, the calculated value of Vm is 2.54 A3/Da.