Efficacy and effect on plasma B-type natriuretic peptide concentration of losartan-hydrochlorothiazide for hypertension uncontrolled by losartan-based therapy: subanalysis of a Multicentre Prospective Observational Study.

Many patients with hypertension have difficulty achieving their target blood pressure (BP). Therefore combination therapy, for example with an angiotensin II receptor blocker (ARB) and a diuretic, may be recommended. We previously evaluated the efficacy and safety of losartan (LOS) 50 mg - hydrochlorothiazide (HCTZ) 12.5 mg, as well as its effect on the plasma concentration of B-type natriuretic peptide (BNP, a prognostic marker for cardiovascular events), in patients with hypertension uncontrolled by ≥3 months of ARB-based therapy. The present subanalysis used data from patients who received LOS-based therapy before switching to LOS-HCTZ. Efficacy, safety, and changes in blood biochemical variables including BNP were evaluated. After excluding 4 patients with protocol violations, data from 35 patients (aged 36-79 years, mean 63 years; 66% male) were used in the safety analysis. The efficacy analysis used data from the 30 patients who were followed up for 12 months. Systolic/diastolic BP decreased from 156±12/87±11 mmHg at baseline to 125±11/73±10 mmHg at 12 months (p<0.001). After 12 months, half of the patients achieved their target BP as defined by the Japanese Society of Hypertension Guidelines for the Management of Hypertension 2004. In 12 patients with baseline plasma BNP concentration ≥20 pg/mL, BNP decreased from 78.3±18.8 pg/mL to 57.3±17.7 pg/mL (p<0.01). 3 patients experienced adverse events, one of which was cardiovascular. LOS-HCTZ is efficacious, has a good safety profile, and decreases plasma BNP concentration.

Acute renal infarction in a patient with left atrial myxoma.

A 24-year-old male first attended our hospital with acute onset of right flank pain radiating to the right lower quadrant of the abdomen. A contrast-enhanced computer tomography (CT) scan showed renal infarction, and he was admitted immediately for treatment. On admission, the right lower abdominal pain diminished gradually. On the second day in hospital, a left atrial echogenic mass was detected which filled the left atrial cavity; it appeared to be a left atrial myxoma measuring 3.9+/-4.9 cm. The patient was immediately transferred and underwent emergency surgery. Histologic examination confirmed the diagnosis of myxoma. Post-operatively, he recovered well and was discharged from hospital without any further specific treatment.

Study on the packing geometry, stoichiometry, and membrane interaction of three analogs related to a pore-forming small globular protein.

A de novo designed pore-forming small globular protein (SGP) with antitumor activity consists of four helices: 3 basic amphipathic helices composed of Leu and Lys surrounding a central hydrophobic helix composed of oligoalanine. These helices are connected by a beta-turn-forming sequence and two beta-turn-unfavorable ones (S. Lee, T. Kiyota, T. Kunitake, E. Matsumoto, S. Yamashita, K. Anzai, and G. Sugihara Biochemistry 1997, Vol. 36, pp. 3782-3791). In the present work, we designed and synthesized three new SGP analogs in order to study the stoichiometric packing geometry and stability of SGP. The replacement of alanines in the central helix of SGP with leucines (SGP-L), which make the helix much larger in size and more hydrophobic, resulted in an equilibrium of monomeric-trimeric structure. The replacement of some Lys residues by Glu residues in the hydrophilic regions of the amphipathic helices (SGP-E) led to a decrease in helical content and the formation of an equilibrium of monomeric-trimeric structure. The alteration of beta-turn regions with Gly residues, which makes these regions flexible (SGP-G), established an equilibrium of monomeric-dimeric states in buffer. The hydrophobic alpha-helix of SGP-L penetrated into the lipid bilayers in a manner that stabilized model membranes and biomembranes, whereas the central helices of SGP-G and -E destabilized them by forming channels. SGP and its analogs may be a useful model to study the role of the hydrophobic and hydrophilic regions in the formation of monomer-oligomer of proteins and to better understand the insertion of membrane targeting proteins into biomembranes.

Coronary vasomotor response to acetylcholine late after angioplasty.

To elucidate the changes in coronary vasomotion in a previously balloon-dilated segment, we examined the vasoconstricting response of previously balloon-dilated and non-dilated segments to acetylcholine. Acetylcholine was administered into coronary arteries cumulatively (left and right coronary artery: 10-100 micrograms) in 15 patients (age: 60 +/- 3 years, 12 males and 3 females) at 7.4 +/- 1.5 months after successful percutaneous transluminal coronary angioplasty (PTCA). In PTCA segments with no restenosis, does-dependent constriction in response to acetylcholine was observed in only 1 patient. In non-PTCA segments of PTCA and non-PTCA arteries, 12 patients showed dose-dependent vasoconstriction in response to acetylcholine. Coronary spasm, which was defined as a more than 75% reduction in coronary diameter compared with that after isosorbide dinitrate, was provoked in one PTCA segment (7%). In non-PTCA segments of PTCA and non-PTCA arteries, 15 of 44 arteries (34%) demonstrated coronary spasm in 9 of 15 patients (60%, p < 0.005 vs PTCA segment). In conclusion, PTCA segments free of restenosis showed no hyper-reactivity to acetylcholine, while non-PTCA segments showed hypercontractility in response to acetylcholine. Coronary balloon angioplasty may alter the coronary vasomotor reaction to acetylcholine several months after angioplasty.

[A case of successful operation for chronic aortic dissection (DeBakey 1 type) complicated with cerebral infarction].

We report a successful operation for a patient of chronic aortic dissection complicated with cerebral infarction. A 60-year-old woman has been treated suffering from cerebral infarction for 7 years. She was referred to our hospital for abnormal chest X-ray and complaint of dry cough. The enhanced CT scan and aortogram demonstrated chronic aortic dissection (DeBakey I) extending from ascending aorta to the abdominal aortic bifurcation with occlusion of right common carotid artery and dilated ascending aorta and aortic arch. The onset of aortic dissection seemed to be, from a clinical point of view, coincident with the onset of cerebral infarction seven years ago. The replacement of the ascending aorta and aortic arch with woven Dacron velour graft were performed under hypothermic and selective cerebral perfusion. The postoperative course was uneventful although complicated with transient recurrence nerve palsy and she has been doing well.

Complete obstruction of right proximal pulmonary artery: a case report.

A fifty-five-year-old woman had worried about dyspnea for three years. A chest x-ray appeared normal except for hypovascularity of the upper lung field. On angiograms, a wedge-shaped obstruction was observed at the left proximal pulmonary artery, and well-developed collateral circulation from the right thoracic artery to the internal costal arteries was observed. On the exercise test, exertional dyspnea developed with tachycardia and a decreased saturation of arterial oxygen.

[A case report of primary pulmonary hypertension: congestive heart failure induced by pregnancy and delivery].

A thirty-year-old woman had complaints of general fatigue and gain in body weight, which had developed since the third trimester of pregnancy. On admission, she had lip cyanosis, general edema, and tachycardia. A chest rentogenogram showed cardiomegaly and dilatation of the pulmonary arteries. On cardiac catheterization, pulmonary artery pressure and pulmonary vascular resistance were elevated moderately. A pulmonary perfusion scintigram revealed a defect in the left lower lung field with no evidence of thrombus in a pulmonary artery angiogram. In this case, an underlying disease which caused pulmonary hypertension might have been the underfined cause. For this reason, primary pulmonary hypertension was the diagnosis. In the present case there is a danger that congestive heart failure may be induced by pregnancy and delivery and, furthermore, there is a possibility that during the clinical course of the illness pulmonary infarction might occur.

Developmental changes of sarcolemmal Na+-H+ exchange.

We previously demonstrated that the effect of respiratory acidosis on cardiac contractility in the newborn was less than in the adult rabbit, and these data suggested a higher [Na+]i and [Na+]i-[Ca2+]o exchange in the newborn as compared to the adult. In this study, we investigated developmental changes of Na+-H+ exchange in isolated sarcolemmal vesicles. Sarcolemmal purification for Na+-K ATPase was 61.9 and 67.1 fold in the newborn and the adult rabbit heart, respectively. In the presence of an outwardly directed proton gradient across the vesicular membrane, sarcolemmal 22Na uptake rate in the newborn (0.22 +/- 0.01 nmol Na+/mg prot/s) was significantly higher than than in the adult (0.16 +/- 0.01 nmol Na+/mg prot/s). 1.0 mM amiloride inhibited 22Na uptake by 75% and 80% in the newborn and the adult, respectively. In the absence of a pH gradient, vesicular 22Na uptake in the newborn and the adult were not significantly different. In conclusion, the higher Na+-H+ exchange in the newborn may lead to a higher [Na+]i and subsequent calcium influx via Na+-Ca2+ exchange as compared with the adult during acidosis. This may explain the greater recovery of mechanical function in the newborn heart as compared to the adult heart during acidosis.

Effect of ischemia on sarcolemmal Na+-Ca2+ exchange in neonatal hearts.

We studied the effect of cardiac ischemia on sarcolemmal enzymes, Na+-Ca2+ exchange, Ca2+ binding, and Ca2+ efflux in the newborn and adult rabbit. Rabbit ventricle was made ischemic by incubation in hypoxic, glucose-free Tyrode solution at 37 degrees C for 60-120 min. Ischemia inhibited Na+-K+-ATPase and K+-p-nitrophenylphosphatase (PNPPase) activity in the adult myocardium more than in the newborn. In the oxygenated (control) hearts, Na+-Ca2+-exchange activity in the newborn sarcolemma [Michaelis constant (Km) 18 microM; maximum velocity (Vmax) 33] was similar to that in the adult (Km = 16 microM, Vmax = 32). After 60 min ischemia, however, Na+-Ca2+ exchange in the newborn (Km = 16 microM, Vmax = 18) was inhibited less than in the adult (Km = 25 microM, Vmax = 18). In the two age groups, Ca2+ binding and efflux rate were not increased after ischemia, which suggested that Ca2+ permeability did not increase during ischemia. In conclusion, ischemia inhibited sarcolemmal enzymes and Na+-Ca2+ exchange in the newborn less than in the adult, and this lesser inhibition might contribute to or be caused by the greater tolerance of the newborn heart to ischemia.

Sarcolemmal calcium kinetics in the neonatal heart.

We characterized sarcolemmal enzymes, Na+-Ca2+ exchange, Ca2+ efflux, and Ca2+ binding in the neonatal rabbit heart. Sarcolemmal vesicles were isolated by differential and sucrose gradient centrifugation. The sarcolemmal purification factor for K+-p-nitro-phenylphosphatase (pNPPase) was 38.8 and 34.5 in the newborn and the adult, respectively. Contamination by mitochondria and sarcoplasmic reticulum was minimal. Specific activities of Na+-K+ ATPase and K+-pNPPase in the newborn were significantly lower than those in the adult. In the newborn, maximal Na+-Ca2+ exchange was 24.6 +/- 1.1 nmol Ca2+/mg/1.5 s, passive Ca2+ efflux rate was 14.6 +/- 2.2 nmol Ca2+/mg/min and Ca2+ binding was 69.4 +/- 3.3 nmol Ca2+/mg/4 min. These values were not significantly different from the adult values. At pH 6.0, Na+-Ca2+ exchange and Ca2+ binding were approximately 60% of control values (pH = 7.4) in two age groups. These values were stimulated at pH 8.0 and 9.0. In conclusion, Na+-Ca2+ exchange, Ca2+ efflux, passive Ca2+ binding and the effect of pH on Na+-Ca2+ exchange and Ca2+ binding in the newborn were similar to those in the adult.

Metabolic and physical changes during calcium paradox induced in the rat heart.

Early changes in metabolic and physical properties were determined in rat hearts during calcium paradox. Calcium paradox was induced under constant perfusion pressure (60 mmHg) or constant coronary flow rate (9.8 ml/min). Within 30 s after calcium repletion, in either case, NADH increased, despite a decrease in ATP and increases in ADP and AMP. Surface spectrophotometry showed a deoxygenation of the myoglobin, thereby indicating myocardial oxygen depletion. These changes were predominant under conditions of constant pressure perfusion. In association with a rapid development of contracture, there were also a reduction in coronary flow (18%) in constant pressure perfusion, and an increase in perfusion pressure (208%) under constant flow perfusion. Thus, tissue deoxygenation has to be given due attention in the early development of calcium paradox, particularly in case of a constant pressure perfusion. Under constant flow perfusion, the physical stress due to high pressure perfusion against contracture may play an important role in the development of calcium paradox. This may be the first reported evidence for tissue anoxia in calcium paradox.

Adriamycin and altered membrane functions in rat hearts.

To evaluate the potential roles of alterations of membrane functions and resulting calcium overload in the pathogenesis of acute adriamycin cardiotoxicity, we observed sarcolemmal, sarcoplasmic reticular and mitochondrial functions in isolated hearts perfused by the Langendorff technique and exposed to adriamycin. Myocardial tissue calcium content was increased to 120 and 130% of the control level after 30 and 60 min perfusion with adriamycin (50 micrograms/ml), respectively. Sarcolemmal ouabain-sensitive Na+,K+-ATPase activity was decreased by 46% after 30 min perfusion, compared with the control. Mitochondrial calcium uptake was also depressed but sarcoplasmic reticular calcium uptake and binding remained unaltered. Mitochondrial respiratory activity was depressed after 60 min perfusion, when glutamate was used as a substrate, thereby indicating that adriamycin had an inhibitory effect on the NADH-dehydrogenase system. Thus, among membrane functions directly or indirectly regulating calcium movement, the inhibition of enzyme systems susceptible to lipid peroxidation may play important roles in calcium overload induced by adriamycin.

Changes in subcellular calcium transport in rat hearts during the calcium paradox.

Changes in the transport of calcium in the sarcoplasmic reticulum (SR) and mitochondria (MT), of the rat heart during calcium paradox were investigated. Calcium binding and uptake by SR in the paradox hearts were from about 1.5 to 2 times greater than in normal hearts, whereas in the MT of the paradox hearts they were about half those of normal hearts. There was no difference between paradox and normal hearts in calcium stimulated ATPase activity in the SR. The ultrastructure of the MT was disrupted in calcium paradox, but the SR was essentially the same as in normal hearts. We propose that during calcium paradox, the intracellular calcium overload damages both calcium transport and the ultrastructure of the MT, but that calcium transport by the SR is accelerated to compensate for the calcium overload.

Total adenine nucleotide stores and sarcoplasmic reticular Ca transport in ischemic rat heart.

We studied the relation between the contractility and metabolic changes in reperfusion after ischemia, and the effect of diltiazem on these changes, in an isolated rat heart perfused using the Langendorff method. After aerobic perfusion at 80 cmH2O, the perfusion pressure was reduced to 10 cmH2O to induce global ischemia. Substrate was removed from the perfusate during ischemia. After 30 or 60 min of ischemia, the heart was reperfused in an aerobic condition. During ischemia, the total adenine nucleotide level (TAN: sum of ATP, ADP, and AMP) was progressively reduced and the ATP-to-ADP ratio was one-third of the value obtained in an aerobic condition. With 30 min of subsequent reperfusion, ATP increased, and the shorter the duration of ischemia, the closer ATP/ADP approached the value of an aerobic condition, whereas TAN was equivalent to the value shown immediately before reperfusion. Thus the degree of ATP recovery by reperfusion mainly depends on the amount of TAN immediately before reperfusion and the mitochondrial function of oxidative phosphorylation that determines ATP/ADP. The calcium transport activity of the sarcoplasmic reticulum of myocardial cells was affected by ischemia and showed no amelioration or further deterioration by subsequent reperfusion. When diltiazem (10(-5)M) was added to the perfusate continuously from 5 min before ischemia, during ischemia, and until 10 min of reperfusion, the amount of TAN in ischemia and reperfusion and the calcium transport activity during reperfusion were maintained at relatively high levels. The degree of contractility recovery by reperfusion showed direct correlations with both the tissue ATP amount and the level of calcium transport activity in the sarcoplasmic reticulum.

Effects of diltiazem on the calcium paradox in isolated rat hearts.

Effects of diltiazem (10(-5) M) on the calcium paradox were studied in isolated, perfused rat hearts. After 4 min of calcium-free perfusion, the hearts were reperfused with medium containing 2.5 mM calcium for 15 min at 37 degrees C. During this perfusion, the coronary flow rate was maintained either high (10 ml/min) to produce severe tissue injury of calcium paradox or low (5 ml/min) to produce mild injury. In the high flow rate group, administration of diltiazem during the calcium-free period and calcium-repletion period failed to reduce the overall level of tissue injury caused by calcium-repletion. In the low coronary flow rate group, diltiazem markedly prevented the development of the calcium paradox, in terms of calcium-induced creatine kinase release, recovery of contractile tension development, tissue high-energy phosphate stores and tissue calcium accumulation. These events were irrespective of whether the drug was administered only during the calcium-free period, the calcium-free period and initial 2 min of the calcium-repletion period or the calcium-free period and totality of the calcium-repletion period. Thus, diltiazem appears to exert its protective effect against the mild calcium paradox phenomenon by regulating the ionic environment of myocardial cells during the calcium-free period.