Streptozotocin treatment upregulates uncoupling protein 3 expression in the rat heart.

Diabetic rats have a deficiency in their heart ATP concentrations, and although the mechanism remains to be elucidated, this deficiency may involve increased uncoupling of oxidative phosphorylation. To investigate whether heart uncoupling proteins (UCPs) are subject to transcriptional regulation in diabetes, we examined changes in UCP mRNA expression in the heart of streptozotocin-induced diabetic (STZ-DM) rats. Heart UCP3 mRNA expression significantly increased by 9.4-fold in STZ-DM rats, while levels of UCP2 mRNA expression were not significantly altered. Insulin supplementation in STZ-DM rats returned UCP3 mRNA concentrations to control levels. The expression of UCP3 mRNA was similarly elevated in the heart of fasted rats, which also have hypoinsulinemia and hyper-free fatty acidemia but, unlike the STZ-DM rats, are hypoglycemic. Since hyperinsulinemia alone was previously reported to not affect UCP3 gene expression in the muscle, these results indicate that hyper-free fatty acidemia is a potent enhancer of UCP3 gene expression in the diabetic rat heart. Interestingly, we found no changes in UCP3 mRNA levels in Zucker fatty (fa/fa) rats with excessive chronic hyper-free fatty acidemia, which suggests that upregulation of heart UCP3 mRNA may depend on an acute change in free fatty acid concentrations rather than on their sustained elevation. High-energy ATP deficiencies in the diabetic rat heart may primarily result from proton leakage due to the upregulation of UCP3 expression.

Protein surface amino acid compositions distinctively differ between thermophilic and mesophilic bacteria.

One of the well-known observations of proteins from thermophilic bacteria is the bias of the amino acid composition in which charged residues are present in large numbers, and polar residues are scarce. On the other hand, it has been reported that the molecular surfaces of proteins are adapted to their subcellular locations, in terms of the amino acid composition. Thus, it would be reasonable to expect that the differences in the amino acid compositions between proteins of thermophilic and mesophilic bacteria would be much greater on the protein surface than in the interior. We performed systematic comparisons between proteins from thermophilic bacteria and mesophilic bacteria, in terms of the amino acid composition of the protein surface and the interior, as well as the entire amino acid chains, by using sequence information from the genome projects. The biased amino acid composition of thermophilic proteins was confirmed, and the differences from those of mesophilic proteins were most obvious in the compositions of the protein surface. In contrast to the surface composition, the interior composition was not distinctive between the thermophilic and mesophilic proteins. The frequency of the amino acid pairs that are closely located in the space was also analyzed to show the same trend of the single amino acid compositions. Interestingly, extracellular proteins from mesophilic bacteria showed an inverse trend against thermophilic proteins (i.e. a reduced number of charged residues and rich in polar residues). Nuclear proteins from eukaryotes, which are known to be abundant in positive charges, showed different compositions as a whole from the thermophiles. These results suggest that the bias of the amino acid composition of thermophilic proteins is due to the residues on the protein surfaces, which may be constrained by the extreme environment.

Congenital 17 alpha-hydroxylase deficiency: a clinicopathologic study.

The histopathologic features of the adrenal glands in three cases of congenital 17 alpha-hydroxylase deficiency are described in relation to clinical and endocrine findings. Diffuse or nodular adrenocortical hyperplasia, particularly in the zonae fasciculata and reticularis, was observed in all cases examined. The hyperplastic adrenal cortices were composed of cells with morphologic features of hypercorticism and hyperstimulation. Myelolipomatous lesions were detected in two cases. These morphologic findings were consistent with excessive adrenocorticotropic hormone secretion in this disorder. In all the cases examined, the plasma aldosterone concentration was within normal limits, and plasma renin activity was suppressed prior to dexamethasone treatment. Morphologically, however, hyperplasia of the cells with abundant mitochondria and smooth endoplasmic reticulum seemed to involve the zona glomerulosa. Nonencapsulated nests of hypertrophied cortical cells in periadrenal tissue were remarkable in one case. From these morphologic findings, we postulated hyperfunction of the zona glomerulosa as well as involvement of corticosteroids from the zona glomerulosa in the pathophysiology of this disorder.

Ten-year follow-up after valve replacement with the St. Jude Medical prosthesis in children.

Since 1979, 50 children, 4 months to 15 years of age, have successfully undergone cardiac valve replacement with the St. Jude Medical prosthesis (St. Jude Medical, Inc., St. Paul, Minn.). There were 24 boys and 26 girls. The valve replaced was mitral in 28 children, aortic in 15, mitral and aortic in 1, and mitral and tricuspid in 1. A left-sided tricuspid valve was replaced in 3 children. Anticoagulant therapy was maintained in all children; 40 children were treated with warfarin, whereas 10 children who underwent aortic or mitral valve replacement were on a regimen of aspirin combined with dipyridamole. The follow-up period, comprising 224 patient-years, ranged from 1 to 10 years. There were four valve-related complications: one from thromboembolism, two from valve thrombosis, and the other one from prosthetic valve endocarditis. Actuarial rate free from all valve-related complications at 10 years was 84.7%. There were four late deaths: one from valve thrombosis and the others from non-valve-related complications. Actuarial survival rate at 10 years was 90.8%. All surviving children are in functional class I, and no child so far has needed replacement of a prosthesis because of somatic growth. These results indicate that the St. Jude Medical prosthesis is a cardiac valve substitute of choice for valve replacement in children.

Septation and Fontan repair of univentricular atrioventricular connection.

From April 1986 to September 1988, 12 patients with double- or common-inlet left ventricle and left anterior rudimentary right ventricle underwent septation while 17 patients with double- or common-inlet left or right ventricle underwent the Fontan operation. In the septation group, three patients who had pressure gradients ranging from 10 to 85 mm Hg between the left ventricle and the aorta underwent enlargement of the outlet foramen, and all survived. One of the 12 patients had a common atrioventricular valve that was repaired by separating the atrioventricular valve by the procedure used for atrioventricular septal defect. One had complete heart block before septation and the other one had it after separation. One 17-year-old woman, who had the smallest left ventricle (168% of normal), died in the hospital (mortality, 8.3%). In the Fontan group, one patient who died in the hospital (5.9%) had high pulmonary resistance of 4.4 U/m2, and one late death (5.9%) occurred in a patient who had complete heart block and a high mean pulmonary arterial pressure of 20 mm Hg. Because of suprasystemic pressure in the pulmonary ventricle, two patients had immediate takedown of the septation repair and substitution of the Fontan repair. Although right atrial pressure was almost equal in both groups after operation, the cardiac index was significantly higher in the septation group than in the Fontan repair group (p less than 0.01). These data suggest that patients who are candidates for either septation or Fontan repair might fare better with septation.

The antihypertensive mechanism of delapril, a newly developed converting enzyme inhibitor, is related to the suppression of vascular angiotensin II release in the spontaneously hypertensive rat.

Accumulating evidence suggests an important role of vascular renin-angiotensin system (RAS) in the local control of arterial tone. To further gain insight into the significance of vascular RAS in hypertension, we investigated the relationship between the antihypertensive action of delapril, a newly developed converting enzyme inhibitor (CEI), and its effects on vascular angiotensin II (Ang II) release in spontaneously hypertensive rats (SHR). Male SHRs were given delapril or its active metabolite (5-hydroxydelapril diacid; 5-hydroxy-DPD) orally (10 mg/kg/day) for 2 weeks. Isolated hind legs of these rats were perfused with angiotensinogen-free Krebs-Ringer solution, and Ang II released into the perfusate was directly determined by extraction with Sep-Pak C18 cartridges connected to the perfusion system. Both delapril and 5-hydroxy-DPD produced a sustained antihypertensive action. The spontaneous release of Ang II from isolated perfused hind legs of control SHRs was about 50 to 110 pg during the first 30 min of perfusion, and it remained stable up to 3 h. Another active metabolite, delapril diacid (DPD), when added to the perfusion medium (10(-9) to 5 x 10(-5) mol/L), suppressed the Ang II release in a dose-dependent manner. The maximal percent inhibition of Ang II released evoked by DPD (5 x 10(-6) mol/L) was approximately 51%. Oral pretreatment of either delapril or 5-hydroxy-DPD for 2 weeks suppressed the Ang II release by 61% and 73% for delapril and 5-hydroxy-DPD, respectively. These results suggest the presence of a functional RAS in vascular tissues, and that delapril exerts its antihypertensive effect through inhibition of vascular Ang II release in SHRs.

Multiple arterial thromboembolisms in a patient with the 20210 A prothrombin gene mutation.

The most recently characterized genetic defect contributing to venous thrombophilia is the 20210 A prothrombin gene mutation. We describe a patient with this defect who had arterial thrombosis resulting in considerable mesenteric ischemia. Several environmental factors, which might otherwise be considered of low thrombotic risk, may also have contributed to her condition. The recognition of the potential for novel presentations of hypercoagulable states may contribute to a reduction in the morbidity associated with acute mesenteric ischemia.

Gene expression of aromatic L-amino acid decarboxylase mRNA in the kidney of normotensive and hypertensive rats.

Peripheral dopamine (DA) synthesis and release increase during hypertensive stage of spontaneously hypertensive rats (SHR). DA is generated from 3,4-dihydroxyphenylalanine by L-amino acid decarboxylase (AADC). We have studies urinary DA and DA metabolites and the gene expression of neuron and non-neuron specific AADC mRNA in the kidney of SHR. Compared to Wister-Kyoto rats (WKY), there was an increased urinary free DA and DOPAC excretions in 8 and 12 week-old SHR. At the age of 16 weeks, the difference in free DA excretion between SHR and WKY rats disappeared, although the urinary DOPAC excretion remained significantly higher in SHR, but urinary HVA excretion did not differ from WKY rats. The expression of the neuron specific AADC mRNA in the kidney of SHR and WKY rats was not detected, but the non-neuron specific AADC mRNA in the kidney of SHR and WKY rats was detected. The gene expression of the non-neuron specific AADC mRNA tended to decrease with age in SHR. The results suggest that a decrease in renal DA production with age may be caused by diminished expression of non-neuron specific AADC mRNA in kidney.

Postprandial changes in noradrenergic and dopaminergic activity in patients with essential hypertension.

In order to elucidate the role of noradrenergic and dopaminergic activity in the pathogenesis of postprandial hypotension, the effect of feeding of ordinary diet on blood pressure, pulse rate, plasma catecholamine and other circulating vasoactive substances such as insulin were examined in mild essential hypertensive patients (EH) and their age-matched control subjects (N). Mean blood pressure significantly decreased in both N and EH after feeding, and the decrease tended to be greater in EH than in N. Feeding induced a marked increase in plasma norepinephrine in both N and EH. Plasma dopamine significantly increased following feeding was observed in N, while the increase in plasma dopamine following feeding was blunted in EH. The ratio of norepinephrine to dopamine following in EH was significantly greater than that in N. From these results, it is suggested that the feeding-induced stimulation of noradrenergic activity may be a result from the decrease in blood pressure, and that the blunted response of dopaminergic activity in EH may reflect the enhanced conversion of dopamine to norepinephrine probably due to the enhanced activity of dopamine beta-hydroxylase in the sympathetic nerves.

Dopaminergic activity and endorenal dopamine synthesis in non-insulin dependent diabetes mellitus.

In the present study we tried to clarify the differences of the cardiovascular and renal responses to feeding in relation to the peripheral dopamine system. In control subjects (C), ingestion of protein (100 g) induced an increase in Ccr accompanied by an increase in tubular sodium excretion (FENa+). Patients with non-insulin dependent diabetic (NIDDM), a protein-induced increase in Ccr was comparable to that in C, while FEN+ did not change following protein. Since an increase in urinary 3,4-dihydroxyphenylacetic acid was blunted in NIDDM, an impaired natriuretic response to high protein may be results from an insufficient synthesis of renal dopamine. Plasma dopamine and its metabolites in NIDDM following protein tended to be greater than in C. Protein induced a greater decrease in blood pressure (BP) in NIDDM, but no increase in pulse rate was observed. An ordinary diet containing 10 g of protein also induced a decrease in BP. A reflex tachycardia was observed in C and normotensive NIDDM but not in hypertensive one. In normotensive NIDDM, plasma dopamine and norepinephrine increased after the diet, while in hypertensive NIDDM there were no increases in catecholamines. From these results it is suggested that the relatively elevated peripheral dopaminergic activity and the blunted dopamine synthesis in the kidney may be responsible for the abnormal cardiovascular and renal responses to feeding in patients with NIDDM.

Palliative repair of aortic atresia associated with tricuspid atresia and transposition of the great arteries.

Successful palliative repair of aortic atresia and hypoplastic aortic arch associated with tricuspid atresia in a neonate is described. The repair consisted of reconstruction of the hypoplastic aortic arch with an equine pericardial patch, division of the patient ductus arteriosus, connection of the pulmonary artery to the aorta, implantation of the proximal part of the ascending aorta into the main pulmonary artery, and anastomosis of a polytetrafluoroethylene graft 5 mm in diameter between the right ventricular outflow tract and the central pulmonary artery, which was transferred anteriorly to the main pulmonary artery.

Effect of delapril hydrochloride on angiotensin II release from isolated rat hind legs.

The effect of the newly developed angiotensin-converting enzyme (ACE) inhibitor, delapril hydrochrolide (CV-3317), on the release of immunoreactive angiotensin II (irAng II) from isolated rat hind legs was compared with that of captopril. Both ACE inhibitors, added to the perfusion medium (2 X 10(-9) - 10(-6) M), suppressed irAng II release in a dose-dependent manner, but the inhibition was greater with delapril than with captopril. The results provide further support for the concept that vascular tissues produce Ang II and release it in a regulated fashion. The results also suggest a possible link between the antihypertensive mechanism of ACE inhibitors, including delapril, and the suppression of vascular Ang II release.

Antihypertensive and hormonal activity of MK 954 in spontaneously hypertensive rats.

MK 954 (DuP 753), a recently developed angiotensin II (Ang II) receptor antagonist, was administered orally for 2 weeks to spontaneously hypertensive (SHR) and Wistar-Kyoto rats (WKY). Whereas the basal levels of plasma Ang II were lower in SHR than in WKY, treatment with MK 954 markedly reduced blood pressure in SHR but not in WKY. Plasma renin activity, Ang I and Ang II were increased, while plasma aldosterone was decreased in both strains. These results no only indicate therapeutic efficacy of this agent in the chronic treatment of human hypertension, but also support the idea that the renin-angiotensin system plays an important role in the control of blood pressure in SHR.

Bone metastasis from colorectal cancer in autopsy cases.

The incidence of bone metastasis from colorectal cancer is reported to be 10.7% in autopsy cases. However, the characteristics of the primary cancers, as well as the patterns of bone metastasis, remain unclear. We analyzed the clinical and autopsy records of 118 patients with primary colorectal cancer treated either surgically or conservatively and eventually autopsied between 1970 and 1987 at Toranomon Hospital in Tokyo. Bone metastasis was detected in 23.7% (28/118). The average age of patients with bone metastasis was lower than that in patients without bone metastasis (P < 0.02). Cancers to the rectum and cecum were accompanied by bone metastasis more frequently than cancers of other portions of the colon. Signet-ring cell carcinoma showed a high incidence of bone metastasis (P = 0.041). Bone metastasis from colorectal cancer was associated with liver or lung metastases (P < 0.0001). These results indicated that bone metastasis from colorectal cancer is not as infrequent as previously described.

Gastrojejunal fistula caused by gastric ulcer.

We report a case of gastrojejunal fistula caused by benign gastric ulcer, a very rare condition. The patient was an 81-year-old-woman who had had multiple recurrences of gastric ulcer. She also had diabetes mellitus. She was admitted to our hospital because of a left femoral head fracture, necessitating a mechanical bone head exchange operation. She had severe abdominal pain and anemia on the 48th postoperative day. Gastroendoscopic examination revealed a giant ulcer with a long-axis diameter of more than 5cm on the lesser curvature of the gastric body. She was treated with intravenous famotidine and all oral intake was restricted; her symptoms were alleviated. Two weeks later, a fistula had formed between the stomach and the jejunum just anal to the duodeno-jejunal flexure. She was placed on an ulcer diet, and was discharged with no symptoms on the 151st postoperative day. She has remained asymptomatic for 1 1/2, years to date. Lack of H2-antagonist administration, operative stress, and administration of ipriflavone appeared to have induced gastric ulcer recurrence, and formation of the fistula between the stomach and the jejunum seemed to have been facilitated by the patient being very lean and having minimal mesenteric adipose tissue.

TCV-116, a newly developed angiotensin II receptor antagonist, induces regression of cardiac hypertrophy through suppression of the tissue renin-angiotensin system in spontaneously hypertensive rats.

Previously, we reported that an orally active angiotensin II (Ang II) receptor antagonist Losartan induces regression of left ventricular hypertrophy with reduction in the tissue Ang II contents in spontaneously hypertensive rats (SHR). To further address the role of the cardiac renin-angiotensin system in the pathophysiology of hypertensive left ventricular hypertrophy, we examined the effects of TCV-116, a newly developed, highly specific nonpeptide Ang II receptor antagonist, on cardiac hypertrophy and the tissue angiotensin I (Ang I) and Ang II, as well as plasma renin activity (PRA) and Ang II, were determined. Treatment with TCV-116 (1 mg/kg per day) lowered blood pressure markedly. TCV-116 reduced significantly the left ventricular weight by about 11% compared with control animals. The left ventricular Ang I and Ang II contents were lowered by TCV-116 (12.9 +/- 1.4 vs. 30.4 +/- 2.5 pg/tissue, control, p < 0.01, for Ang I; 15.1 +/- 0.6 vs. 18.7 +/- 0.4 pg/tissue, control, p < 0.01, for Ang II), whereas PRA and plasma Ang II concentration were increased by the treatment. With the control and TCV-116-treated animals, there was a significant positive correlation between the left ventricular weight and the tissue Ang II content (r = 0.681, p < 0.01). These results not only further support the view that cardiac Ang II, rather than circulating Ang II, plays an important role in the pathophysiology of left ventricular hypertrophy of this animal model of human hypertension, but imply also that TCV-116 induces regression of hypertensive left ventricular hypertrophy through suppression of the tissue renin-angiotensin system.

Demonstration and characterization of angiotensin-converting enzyme in human pituitary tissue.

High activity of angiotensin-converting enzyme was demonstrated in human pituitary tissue. This activity required the presence of chloride ion and was almost completely inhibited by a specific converting enzyme inhibitor captopril (10 nM), indicating that the activity measured is indeed angiotensin-converting enzyme. The specific activity of the enzyme was 1.68 +/- 1.20 nmol hippuric acid generated mg of protein-1 min-1 (mean +/- SD, for 11 specimens). The biochemical features of the enzyme were closely related to the well-characterized human lung converting enzyme, such as molecular weight (290,000), optimum pH (8.0-8.5), the presence of glycoprotein residues, and dependence on chloride ion concentration. These results provide definitive evidence for the presence of angiotensin-converting enzyme in human pituitary tissue.

Multiple forms of immunoreactive renin in human pituitary tissue.

Immunoreactive renin was demonstrated in pituitary tissues of postmortem human subjects with different diseases. The specific immunoreactive renin activity comprised the majority of the tissue renin-like activity (mean, 83%), indicating the absence of nonspecific actions of proteases such as cathepsin D. We used three pituitary specimens with high levels of the specific renin activity for further biochemical characterization of the enzyme. Small differences were found in the molecular mass (45 K, 42 K and 37 K), binding to concanavalin A-Sepharose, and isoelectric points (pI) (4.72, 4.78, 4.86, 5.06, 5.28 and 5.44). These results seem to be interpreted as evidence for the presence of specific renin in the human pituitary with microheterogeneity.

Effects of losartan, a nonpeptide angiotensin II receptor antagonist, on cardiac hypertrophy and the tissue angiotensin II content in spontaneously hypertensive rats.

Losartan, a recently developed nonpeptide angiotensin II (Ang II) receptor antagonist, was administered orally to 10-week-old spontaneously hypertensive rats (SHR) for 2 weeks. Cardiac weight and tissue Ang II, as well as plasma renin activity (PRA) and Ang II, were determined. Treatment with Losartan (10 mg/kg per day) lowered blood pressure markedly. Losartan reduced significantly the left ventricular weight by 11% compared with control rats. The left ventricular Ang II content was lowered by Losartan (18.6 +/- 0.9 pg/tissue; 21.9 +/- 0.9 pg/tissue, control, p less than 0.05), whereas PRA and plasma Ang II concentration were increased by the treatment. With the control and Losartan-treated animals, there was a significant positive correlation between the left ventricular weight and the tissue Ang II content (r = 0.563, p less than 0.05). These results provide evidence that cardiac tissue Ang II, rather than circulating Ang II, plays an important role in the pathophysiology of left ventricular hypertrophy of this animal model of human hypertension.

Direct evidence for erythropoietin-induced release of endothelin from peripheral vascular tissue.

The effect of recombinant human erythropoietin (r-HuEPO, 0.1 to 2.0 U/ml) on endothelin-1 (ET-1) release was examined in isolated hind legs perfused with Krebs-Ringer solution from normal rats. r-HuEPO increased immunoreactive (ir-) ET-1 release in a dose-dependent fashion; the maximal percent increment in ir-ET-1 release evoked by r-HuEPO (2.0 U/ml) was about +210% over the basal rate of release. However, r-HuEPO showed no effect on release of angiotensin II, thromboxane B2 or vasodilatory prostaglandin I2 from the vasculature. These results not only provide direct evidence that r-HuEPO has the potential to specifically stimulate release of ET-1 from peripheral vascular beds, but, hence, suggest a contributory role of ET-1 in r-HuEPO-induced hypertension in anemic human subjects undergoing r-HuEPO therapy.