High serum levels of procollagen type III N-terminal amino peptide in patients with congenital heart disease.

OBJECTIVE: The serum concentration of aminoterminal procollagen type III (PIIIP) is considered a useful marker of tissue fibrogenesis. The present study tested the hypothesis that: serum PIIIP levels are elevated in patients with congenital heart disease (CHD) and abnormal haemodynamic loading and/or hypoxaemia; PIIIP levels are associated with the severity of haemodynamic load or hypoxaemia, both of which enhance myocardial fibrosis. METHODS AND RESULTS: Serum PIIIP levels were measured in five groups of CHD patients (42 patients with ventricular septal defect (VSD), 26 with coarctation of the aorta (COA, n = 19) or aortic stenosis (AS, n = 7), 36 with atrial septal defect (ASD), 39 with pulmonary stenosis (PS) and 20 with tetralogy of Fallot (TOF)). PIIIP levels of CHD patients were significantly higher than those of 42 control subjects (p<0.05, each). Serum PIIIP levels increased in parallel with increased ventricular volume load in VSD and ASD, and with the severity of PS. In TOF patients, PIIIP levels correlated negatively with arterial oxygen saturation. Treatment with an angiotensin-converting enzyme inhibitor (ACEI) was associated with low levels of PIIIP in COA/AS patients despite the existing haemodynamic load. CONCLUSION: The increased serum PIIIP levels in proportion to the severity of ventricular load or cyanosis suggest enhanced myocardial synthesis of collagen type III in patients with CHD. Suppression of the PIIIP level by ACEI suggests the involvement of the renin-angiotensin-aldosterone system in myocardial fibrosis. These data provide the basis for the development of new diagnostic and therapeutic strategies in patients with CHD.

Factors that increase the contractile tone of the ductus arteriosus also regulate its anatomic remodeling.

Permanent closure of the full-term newborn ductus arteriosus (DA) occurs only if profound hypoxia develops within the vessel wall during luminal obliteration. We used fetal and newborn baboons and lambs to determine why the immature DA fails to remodel after birth. When preterm newborns were kept in a normoxic range (Pa(O(2)): 50-90 mmHg), 86% still had a small patent DA on the sixth day after birth; in addition, the preterm DA wall was only mildly hypoxic and had only minimal remodeling. The postnatal increase in Pa(O(2)) normally induces isometric contractile responses in rings of DA; however, the excessive inhibitory effects of endogenous prostaglandins and nitric oxide, coupled with a weaker intrinsic DA tone, make the preterm DA appear to have a smaller increment in tension in response to oxygen than the DA near term. We found that oxygen concentrations, beyond the normoxic range, produce an additional increase in tension in the preterm DA that is similar to the contractile response normally seen at term. We predicted that preterm newborns, kept at a higher Pa(O(2)), would have increased DA tone and would be more likely to obliterate their lumen. We found that preterm newborns, maintained at a Pa(O(2)) >200 mmHg, had only a 14% incidence of patent DA. Even though DA constriction was due to elevated Pa(O(2)), obliteration of the lumen produced profound hypoxia of the DA wall and the same features of remodeling that were observed at term. DA wall hypoxia appears to be both necessary and sufficient to produce anatomic remodeling in preterm newborns.

Characterization of PGE2 receptors in fetal and newborn lamb ductus arteriosus.

Although the role of PGE2 in maintaining ductus arteriosus (DA) patency is well established, the specific PGE2 receptor subtype(s) (EP) involved have not been clearly identified. We used late gestation fetal and neonatal lambs to study developmental regulation of EP receptors. In the fetal DA, radioligand binding and RT-PCR assays virtually failed to detect EP1 but detected EP2, EP3D, and EP4 receptors in equivalent proportions. In the newborn lamb, DA total density was one-third of that found in the fetus and only EP2 was detected. Stimulation of EP2 and EP4 increased cAMP formation and was associated with DA relaxation. Though stimulation of EP3 inhibited cAMP formation, it surprisingly relaxed the fetal DA both in vitro and in vivo. This EP3-induced relaxation was specifically diminished by the ATP-sensitive K(+) (K(ATP)) channel blocker glibenclamide. In conclusion, PGE2 dilates the late gestation fetal DA through pathways that involve either cAMP (EP2 and EP4) or K(ATP) channels (EP3). The loss of EP3 and EP4 receptors in the newborn DA is consistent with its decreased responsiveness to PGE2.

Synthesis and systemic fungicidal activity of silicon-containing azole derivatives.

A new series of azole derivatives containing silicon were synthesized and evaluated for fungicidal activity against rice sheath blight by submerged application. Among them, 2-(4-fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-trimethylsilylpr opan-2-ol (9a) exhibited satisfactory efficacy at 12.5 grams per 10 ares.

Tissue hypoxia inhibits prostaglandin and nitric oxide production and prevents ductus arteriosus reopening.

Regulation of ductus arteriosus (DA) tension depends on a balance between oxygen-induced constriction and PG and nitric oxide (NO)-mediated relaxation. After birth, increasing Pa(O(2)) produces DA constriction. However, as the full-term ductus constricts, it develops severe tissue hypoxia in its inner vessel wall (oxygen concentration <0.2%). We used isolated rings of fetal lamb DA to determine why the constricted ductus does not relax and reopen as it becomes hypoxic. We used a modification of the 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide (EF5) technique (Clyman RI, Chan CY, Mauray F, Chen YQ, Cox W, Seidner SR, Lord EM, Weiss H, Wale N, Evan SM, and Koch CJ. Pediatr Res 45: 19-29, 1999) to determine mean tissue oxygen concentration. A decrease in the ductus' mean tissue oxygen concentration from 1.4 to 0.1% lowers the isometric tone of the ductus by 15 +/- 10% of its maximal active tension (the maximal tension that can be produced by the ductus). Although decreases in oxygen concentration diminish ductus tension, most of the vasoconstrictor tone in the ductus is independent of ambient oxygen concentration. This oxygen-independent tone is equivalent to 64 +/- 10% of the maximal active tension. At mean tissue oxygen concentrations >0.2%, endogenous PGs and NO inhibit more than 40% of the active tension developed by the ductus. However, when tissue oxygen concentrations drop below 0.2%, the constitutive relaxation of the ductus by endogenous PGs and NO is lost. In the absence of PG and NO production, tension increases to a level normally observed only after treatment of the ductus with indomethacin and nitro-L-arginine methyl ester (inhibitors of PG and NO production). Therefore, under conditions of severe hypoxia (tissue oxygen concentration <0.2% oxygen), the loss of PG- and NO-mediated relaxation more than compensates for the loss of oxygen-induced tension. We hypothesize that this increased ductus tone enables the vessel to remain closed as it undergoes tissue remodeling.

Synthesis of Novel 25-Substituted Milbemycin A4 Derivatives and Their Acaricidal Activity against Tetranychus urticae.

Novel 25-substituted milbemycin A4 derivatives were synthesized from 25a-hydroxymilbemycin A4 and 25b-hydroxymilbemycin A4, which had been obtained by the microbial oxidation of milbemycin A4. The acaricidal activity of each synthesized derivative was tested against Tetranychus urticae, and all of the synthesized derivatives showed higher activity than parent milbemycin A4. Some of the derivatives had higher acaricidal activity than milbemycin D, which had higher acaricidal activity than milbemycin A4. Among them, 25b-methylmilbemycin A4 was the most active derivative, with 100% mortality of the mite at a concentration of 1 ppm, and 63% mortality at 0.1 ppm.

[Left ventricular function in essential hypertension during isoproterenol infusion].

The left ventricular function of 23 patients with essential hypertension was investigated during infusion of isoproterenol (ISP). These patients consisted of 13 without cardiac hypertrophy (Group NH) and 10 with cardiac hypertrophy (Group HH). Ten normotensive subjects served as normal controls. To assess left ventricular functions, M-mode echocardiograms were recorded at rest and after ISP infusion for 5 minutes (0.005 and 0.01 microgram/kg/min). There were no significant differences in peak negative dD/dt in all groups at rest. But peak negative dD/dt of Group HH significantly decreased after an infusion of 0.005 microgram/kg/min ISP (Group N: 3.43 +/- 0.69, Group NH: 3.15 +/- 0.61, and Group HH: 2.49 +/- 0.48 cm/sec, respectively). The peak negative dD/dt of Group HH was also significantly decreased after a dose of 0.01 microgram/kg/min. Among all patients with hypertension, peak negative dD/dt correlated inversely with left ventricular mass (LVM) after the infusion of ISP (0.005 microgram/kg/min: r = -0.64, p less than 0.001, 0.01 microgram/kg/min: r = -0.68, p less than 0.001). The peak positive dD/dt of Group HH was significantly decreased only when compared with that of Group N at rest (Group N: 3.15 +/- 0.75, Group NH: 3.02 +/- 0.86, and Group HH: 1.92 +/- 0.68 cm/sec, respectively). The difference between the peak positive dD/dt of Group HH and that of Group N was more prominent after the infusion of ISP than at rest. Among all patients with hypertension, the peak positive dD/dt was inversely related to LVM at rest (r = -0.64, p less than 0.002). There was a similar relation between the two indexes after the infusion of ISP. Peak positive dD/dt was related to peak negative dD/dt after a dose of 0.01 microgram/kg/min in Group HH (r = 0.67, p less than 0.05). There was no significant difference in heart rate, change in blood pressure, or total peripheral vascular resistance after the infusion of ISP. It is concluded that diastolic left ventricular dysfunction and latent systolic left ventricular dysfunction are related to increased LVM in Group HH. It seems that after the infusion of ISP severe diastolic left ventricular dysfunction is related to latent systolic left ventricular dysfunction.