Akio Kuroiwa

Reduced baroreceptor sensitivity in borderline hypertension.

The sensitivity of the baroreceptor reflex in nine patients with borderline hypertension (mean age 19.1 plus or minus 0.2 years) was compared to that in six normal subjects of comparable age (mean 18.8 plus or minus 0.3 years) and that in 14 patients with established hypertension (mean age 48.3 plus or minus 3.1 years). The sensitivity of the baroreceptor reflex was assessed by determining the slope of the regression line relating the rise of systolic pressure to the prolongation of the R-R Interval during the transient rise of arterial pressure induced by an intravenous injection of phenylephrine. The average baroreceptor slope in nine patients with borderline hypertension was 9.1 plus or minus 0.8 msec/mm Hg, which was significantly less than that in six normal subjects (16.0 plus or minus 2.0; P smaller than 0.01), but was greater than that in 14 patients with established hypertension (4.9 plus or minus 0.7; P smaller than 0.01). The significant negative correlation was found as the baroreceptor slope was related to the mean arterial pressure in patients with borderline hypertension and normal subjects, all of whom were 20 years old or less. Attenuation of the baroreceptor sensitivity may influence the maintenance of raised arterial pressure in borderline hypertension.

Optimal dialysis improves uremic pruritus

The authors analyzed data on 59 hemodialyzed patients who did not have significant disorders of calcium and phosphate metabolism and found that more than 60% suffered from disabling pruritus possibly related to chronic uremia. Both biochemical correlates of the prevalence of pruritus and dialysis efficacy calculated by urea kinetics were investigated. Significantly higher values of blood urea nitrogen and plasma beta 2-microglobulin just before the dialysis session were observed in pruritic patients with lower dialysis efficacy estimated by Kt/V urea and normalized protein catabolic rate (nPCR). After 3 months without changing the dialysis prescriptions, 16 patients with a mean Kt/V urea and a normalized protein catabolic rate (nPCR) of 1.28 and 1.22 g/kg/d, respectively, experienced significant reductions in the degree of pruritus estimated by the pruritic score, from 12.6 +/- 5.1 to 6.3 +/- 3.2. Twenty-two patients with a mean Kt/V urea and an nPCR of 1.09 and 1.01, respectively, continued to have severe pruritus (score: 12.3 +/- 4.7 to 12.7 +/- 6.4). In 9 of 22 patients with prolonged severe pruritus, dialysis efficacy was heightened with an increase in dialyzer membrane area of more than 0.3 m2. Seven of nine patients with increased dialysis prescriptions had significant reductions of the mean pruritic score, from 12.6 +/- 4.8 to 6.3 +/- 2.4, which inversely related to the significant increase of Kt/V urea from 1.05 +/- 0.25 to 1.24 +/- 0.33; among patients whose dialysis prescriptions were not changed, only one had a significant reduction in score. The authors concluded that higher dialysis efficacy with good nutritional state reduces the prevalence and degree of pruritus in hemodialyzed patients.

Weight reduction regresses left ventricular mass regardless of blood pressure level in obese subjects

The effects of weight reduction on left ventricular mass in obese normotensive and hypertensive subjects were investigated. Previous studies have shown that weight reduction in hypertensive (HT) obese patients is associated with decreased left ventricular mass (LVM) and decreased blood pressure (BP). This study was performed to examine whether weight reduction would also regress LVM in normotensive (NT) obese subjects and to clarify the mechanisms of these effects if they occurred. A weight-reduction program consisted of mild exercise and mild hypocaloric intake. M-mode echocardiography was performed to estimate the LVM. After the 12-week intervention, the mean reductions in body weight (BW) in the NT (n = 11) and HT (n = 11) groups were 4.9 kg (p < 0.005) and 4.6 kg (p < 0.0005), respectively. Systolic, diastolic, and mean BP were significantly reduced by 13, 9, and 11 mm Hg, respectively, in the HT group. By contrast, no significant changes in systolic, diastolic, or mean BP were observed in the NT group. LVM was significantly reduced from 176 +/- 26 gm to 159 +/- 26 gm (p < 0.05) in the HT group and from 167 +/- 33 gm to 145 +/- 34 gm (p < 0.02) in the NT group. These results suggest that weight reduction in obese subjects by mild exercise and mild hypocaloric intake can lead to a reduction in LVM, regardless of whether the subjects have normal or high blood pressure.

Comparison of Dobutamine Stress Echocardiography and Stress Thallium-201 Single-Photon Emission Computed Tomography for Detecting Coronary Artery Disease

Dobutamine stress echocardiography and stress thallium-201 single-photon emission computed tomography (SPECT) were compared for detecting coronary artery disease in 120 consecutive patients who underwent concomitant quantitative coronary angiography. The left ventricle was divided into anterior, inferior, and lateral regions. Wall motion or perfusion abnormalities observed within each region were classified as ischemia or fixed abnormality. Both tests showed 81% agreement in all 120 patients. Complete agreement was observed in 77% of the 360 regions analyzed. The overall sensitivity of dobutamine stress echocardiography and thallium-201 SPECT for the detection of coronary artery disease was 85% and 89%, and the specificity was 93% and 85%, respectively. A good correlation was found between the wall motion score index and perfusion defect size at peak stress and at rest (r = 0.70). Dobutamine stress echocardiography and thallium-201 SPECT exhibit a comparable accuracy for diagnosing coronary artery disease, localizing coronary artery stenosis, and detecting regional myocardial abnormalities. The wall motion score index may be useful for evaluating the myocardial area at risk.

Inhibitory Effect of Adrenomedullin on Rat Mesangial Cell Mitogenesis

We investigated the effects of adrenomedullin on rat mesangial cell proliferation. Adrenomedullin (10(-10)-10(-7) M inhibited both [3H]thymidine incorporation into cultured rat mesangial cells and cell proliferation in a concentration-dependent manner. Adrenomedullin (10(-10)-10(-6) M) stimulated cyclic adenosine monophosphate accumulation in rat mesangial cells in a concentration-dependent manner. These findings suggest that adrenomedullin inhibits proliferation of rat mesangial cells probably through a cyclic adenosine monophosphate-dependent mechanism.

Adrenomedullin-sensitive receptors are preferentially expressed in cultured rat mesangial cells

By using cultured rat mesangial cells, we compared the effects on cyclic nucleotide levels of adrenomedullin with those of the structurally related peptides, calcitonin gene-related peptide (CGRP) and amylin. Adrenomedullin potently increased cAMP levels 7-fold in a time- and concentration-dependent manner. Its EC50 was 3 x 10(-9) M. CGRP was less potent (2-fold) with an EC50 of 10(-7) M, and amylin had no effect on cAMP levels. All three peptides failed to increase cGMP levels. Treatment of cells with near maximal concentrations of adrenomedullin (10(-7) M) and CGRP (10(-6) M) had no additive effect on cAMP levels. Human adrenomedullin-(22-52)-NH2, a putative adrenomedullin receptor antagonist, inhibited the production of cAMP elicited by adrenomedullin (IC50: 7 x 10(-8) M) and CGRP (IC50: 5 x 10(-8) M). Human CGRP-(8-37), a CGRP receptor antagonist, conversely, reduced the cAMP elevation caused by these peptides with a lower potency (IC50: 10(-6) M for both peptides). This demonstrated that human adrenomedullin-(22-52)-NH2 was a more effective antagonist for adrenomedullin- and CGRP-specific receptors than human CGRP-(8-37). Results suggest that receptors sensitive to adrenomedullin are preferentially expressed in cultured rat mesangial cells. Immunohistochemical study showed almost no immunoreactive adrenomedullin and CGRP, if any, in the cells. Adrenomedullin may regulate mesangial function as either a paracrine or circulating hormone via a cAMP- but not a cGMP-dependent mechanism.

Usefulness of the Valsalva maneuver in management of the long QT syndrome.

Exercise or isoproterenol infusion may evoke ventricular arrhythmias in patients with the long QT syndrome. We examined the electrocardiographic effects of the Valsalva maneuver in eight patients with the long QT syndrome and nine healthy subjects. The Valsalva maneuver lengthened the QTc interval in both groups, but the lengthening was greater in the patients. In the patients who were having frequent attacks of ventricular tachycardia, the Valsalva-induced prolongation of the QTc interval was particularly remarkable and was associated with the development of T-wave alternans and short runs of ventricular tachycardia. Propranolol effectively suppressed the lengthening of the QTc interval during Valsalva strain and prevented Valsalva-induced ventricular arrhythmia. These results suggest that the Valsalva maneuver may be useful in evaluating the risk of ventricular tachyarrhythmias and the efficacy of drug treatment in patients with the long QT syndrome.

Differential induction of constitutive and inducible nitric oxide synthases by distinct inflammatory stimuli in bovine aortic endothelial cells

Exposure to various combinations of cytokines and lipopolysaccharide (LPS) has been reported to increase NO production in vascular endothelial cells. The molecular entity of the newly expressed nitric oxide synthase (NOS) in endothelial cells, however, has not yet been examined in detail. In this report, we carried out biochemical characterizations and molecular identification of NOS isoform(s) expressed in cytokine/LPS-treated bovine aortic endothelial cells (BAEC). The increased NOS activity in tumor necrosis factor-alpha (TNF-alpha)/LPS-treated BAEC was localized mainly in the cytosolic fraction and Ca2+-independent, whereas that in interferon-alpha,beta(IFN-alpha,beta)/LPS-treated BAEC was preferentially in the membrane fraction and Ca2+-dependent, suggesting that TNF-alpha/LPS increased an inducible NOS (iNOS)-like activity, and IFN-alpha,beta/LPS increased an endothelial constitutive NOS (ecNOS)-like activity. Correspondingly, the different responses to the cytokine/LPS pretreatment were demonstrated in semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) using primers specific for iNOS or ecNOS, that is, TNF-alpha/LPS elicited the expression of iNOS mRNA whereas IFN-alpha,beta/LPS increased that of ecNOS mRNA. A nuclear run-on transcription assay and an inhibition experiment by actinomycin D indicated that the apparent increase of ecNOS in the IFN-alpha,beta/LPS-treated BAEC was at least in part ascribed to the transcriptional activation. The nucleotide sequences of the amplified PCR products in TNF-alpha/LPS- and IFN-alpha,beta/LPS-treated BAEC were 93% and 99% identical to the corresponding regions of human hepatocyte iNOS and bovine ecNOS, respectively. These findings indicated that, in cytokine/LPS-treated BAEC, two NOS isoforms whose molecular natures were closely homologous to the conventional isoforms of iNOS and ecNOS were differently induced in response to distinct inflammatory stimuli.

Effects of nifedipine on platelet function.

Effects of nifedipine on platelet aggregation were studied both in vitro and in vivo. From in vitro experiments, nifedipine inhibited platelet aggregation in a dose-dependent manner. The inhibition by nifedipine (final concentration 10 micrograms/ml) on epinephrine-induced and collagen-induced platelet aggregation was more than 90%, greater than that on adenosine diphosphate (ADP)-induced aggregation. The consumption ratio of small platelets (less than or equal to 6.4 fL) was higher than that of large platelets (greater than 6.4 fL), suggesting that nifedipine inhibits the aggregation of large platelets more effectively. Changes in the effects of nifedipine on platelet aggregation associated with exercise were also studied in six healthy volunteers. While platelet aggregability increased after exercise without administration of nifedipine, it was inhibited 90 minutes after the drugs administration (10 mg). The inhibition of collagen-induced and ADP-induced (2 microM) aggregation by nifedipine was particularly significant.

Long-lasting effect of oral molsydomine on exercise performance: a new antianginal agent.

This study examines whether the beneficial effects of molsydomine, a recently introduced antianginal agent, on exercise performance of patients with angina pectoris are long lasting. The hemodynamic effects are known to persist for several hours. The effects of molsydomine on the duration of exercise and the time to the onset of ST depression were compared to those of placebo during two hours after oral administration. Molsydomine prolonged the duration of exercise in all eight patients (average 2.8 min, P < 0.001) and delayed the onset of ST depression (average 2.2 min, P < 0.001), while the placebo failed to alter these measurements. The increment of the duration of exercise produced by 2 mg of molsydomine in two hours following oral administration was comparable to the increment produced in a few minutes after 0.3 mg of nitroglycerin given sublingually. The results indicate that molsydomine offers prophylaxis for angina pectoris that lasts at least two hours after oral administration.