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The L-arginine/nitric oxide (NO) pathway plays a key role in a number of biological processes within most organs and systems. Increasing attention has been addressed to its involvement in the pathogenesis of various human diseases. In this review we examine the enzymology of different NO-synthase isoforms, the major NO detection techniques as well as the possible clinical and pharmacological implications of this new metabolic pathway.

An endothelin urinary hyperexcretion, which is not counterbalanced by an adequate increase in cGMP biosynthesis, was previously detected in some patients with IgA Nephropathy (IgAN). Since this imbalance might potentiate local ET1-mediated hemodynamics effects, 9 IgAN patients with an increased (> or = 0.1) urinary ET1/cGMP ratio (group 1) and 5 IgAN patients with comparable renal function and reduced ET1/cGMP ratio (group 2) were given standard doses of isosorbide 5 mononitrate (as a nitric oxide source). Blood nitric oxide (NO) levels, as detected by electron paramagnetic resonance, significantly increased after isosorbide administration (p < 0.01) and decreased after drug discontinuation in both groups. Nitric oxide levels were significantly related with those of the effective renal plasma flow (p < 0.02), but not with the glomerular filtration rate. Proteinuria levels significantly decreased after drug administration (p < 0.009) in group 1 and returned to baseline levels thereafter, except two cases showing persisting low levels. Values of filtration fraction in the same group decreased after iso5M administration (p < 0.02 compared to basal levels). These results may possibly be related to the counterbalancing effects of nitric oxide on endothelin-mediated mesangial contraction.

The relationships between rest conditions of myocardial asynergy, response to dobutamine administration, perfusion and glucose metabolism were examined in 12 patients with chronic coronary artery disease and left ventricular dysfunction. We evaluated (1) rest and stress myocardial perfusion by 99Tcm-methoxyisobutylisonitrile (MIBI) and single photon emission tomography (SPET), (2) rest myocardial segmental wall motion by trans-thoracic echocardiography and low-dose dobutamine, and (3) myocardial metabolism by [18F]-2-fluoro-2-deoxy-D-glucose (18-FDG) and positron emission tomography (PET), in the fasting state. The analysis was carried out on 16 left ventricular myocardial segments. The SPET studies were analysed semi-quantitatively by normalization to the peak activity. Wall motion was assessed by a visual score. An 18FDG index was determined as the tissue/blood pool radioactivity ratio in each segment. The results showed: (1) remarkably good agreement between the number of dobutamine responsive segments and 18FDG positive segments among those that were only moderately hypoperfused and hypokinetic; (2) a smaller number of dobutamine responsive segments than 18FDG positive segments among those that were hypoperfused and akinetic; and (3) the presence of 18FDG in 50% of the segments that were severely hypoperfused and akinetic or dyskinetic and without improvement with dobutamine. These results indicate that in severely hypoperfused and akinetic or dyskinetic segments, trans-thoracic echocardiography under inotropic stimulation provides little additional information compared with that obtained with rest echocardiography and perfusion studies; the assessment of 18FDG uptake provides information that is complementary to that obtained by perfusion assessment, rest and dobutamine trans-thoracic echocardiography.

Neuropeptide Y, a potent vasoconstrictor peptide with 36 amino acid residues, is co-stored and released with catecholamines in sympathetic nerve endings. In this study responses in circulating neuropeptide Y induced by baroreceptor activation during change from the supine to the head-up position was measured in normal subjects and untreated essential hypertensives. Furthermore, the relationships with plasma catecholamines, endothelin-1, renin and serotonin were studied. No significant differences of plasma neuropeptide Y were found between normotensive and hypertensive subjects, before or after postural changes, and there was no correlation with a range of the vasoactive substances studied. Our results suggest that plasma neuropeptide Y does not increase with noradrenaline on sympathetic activation during postural stress both in normals and in hypertensive subjects. In man, measurement of plasma neuropeptide Y during head-up tilt does not provide a useful estimation of sympathetic nervous activity.

The distinction between fibrotic and viable myocardium is a key issue in patients with coronary artery disease and left ventricular dysfunction. Metabolic imaging with positron emission tomography (PET) and labeled tracers, along with the study of myocardial perfusion, is now available to identify hibernating myocardium. However, PET imaging of myocardial metabolism is a high-cost and time-consuming technique, and requires an on-site cyclotron. The aim of this study is to test the reliability of dobutamine echocardiography (DE) compared with PET imaging, for the identification of hibernating myocardium. In 16 patients, scheduled for myocardial revascularization, left ventricular shapes were divided in eight segments both for echocardiographic and nuclear study evaluation. All patients underwent a technetium 99m MIBI single-photon emission tomography stress-rest study of perfusion, a fluorine-18-labeled deoxyglucose (FDG(/PET study of metabolism, and a DE test (baseline, at a 5 micrograms/kg/min infusion of dobutamine for 8 minutes and at a 10 micrograms/kg/min dose for additional 8 minutes). Neither myocardial ischemia nor arrhythmia occurred during the DE test. Baseline echocardiograms showed 90 segments with wall motion abnormalities: wall motion impairment was decreased or reversed in 33 of 90 segments; it remained unchanged in 57 of 90 segments. In 32 of 33 segments considered viable on the basis of DE and in 21 of 57 segments with unchanged kinesis, some degree of FDG was detected. Thus, sensitivity and specificity of DE compared with nuclear studies was 60% and 97% respectively. Moreover, a good correlation and agreement (kappa = 0.51) between DE and the presence of FDG were found. We conclude that DE is a safe and reliable test for the screening of hibernating myocardium in patients with chronic coronary artery disease and left ventricular dysfunction.

The peroxidative breakdown of membrane polyunsaturated fatty acids leads to the production of various carbonylic compounds: among these, 4-hydroxynonenal (HNE) displays many biological properties related to neutrophil functions. It stimulates rat and human polymorphonuclear (PMN) cell migration and has been detected during inflammation. The aim of this study was to elucidate and well characterize the mechanism of action of HNE. We observed that micromolar HNE concentrations that influence migration do not stimulate differently from many other chemoattractants the human PMN chemiluminescence (CL) induced by opsonized zymosan or phorbol 12-myristate 13-acetate (PMA). Higher HNE concentrations inhibit the light emission of stimulated PMN. Addition of 0.5 mM L-arginine (L-arg), the substrate of nitric oxide synthase, into the incubation medium had the effect of modifying human CL. In fact, HNE at 10-6 M, a concentration which is ineffective in absence of L-Arg, at 10-5 M reduces CL emission of PMA-stimulated human PMN. These observations have been confirmed by electron-spin resonance (ESR) analysis. HNE, according to other stimuli, induced PMN phosphoinositide-specific phospholipase C (PL-C). All these results considered together suggest the conclusion that HNE represents an interesting endogenous molecule that plays a role as an inflammatory mediator involved a) in the recruitment of phagocytic cells at the inflamed area, and b) in the modulation of respiratory burst and of nitric oxide (NO) production.

1. The purpose of the present study was to analyse the effects of the alpha 2-adrenoceptor agonist medetomidine and the antagonist yohimbine on gastrin release in conscious dogs. 2. Gastrin secretion was investigated under both basal conditions and stimulation by 2-deoxy-D-glucose, food or bombesin. 3. Basal gastrin under fasting conditions was significantly reduced by medetomidine and increased by yohimbine. 4. 2-deoxy-D-glucose-induced gastrin increase was fully inhibited by medetomidine; this effect was antagonized by yohimbine. 5. Medetomidine significantly inhibited food-induced increase in plasma gastrin; under these conditions yohimbine was without effect per se, but significantly antagonized the inhibitory action of medetomidine. 6. Gastrin release induced by bombesin was not affected by medetomidine or yohimbine. 7. These results suggest that alpha 2-adrenoceptors play an inhibitory role under conditions in which gastrin release is mainly mediated through cholinergic and non-cholinergic nervous pathways; in contrast, they do not indicate the presence of alpha 2-adrenoceptors on G cells of the dog stomach.

To evaluate the role and mechanism of action of calcitriol on glucose-induced insulin secretion in uremia, 17 patients with severe chronic renal failure were studied. Glucose metabolism was investigated by the intravenous glucose tolerance test (IVGTT) before and after treatment for 21 days with 0.5 microgram/day of calcitriol and 500 mg/day of calcium (C+Ca) (6 cases) or 0.5 microgram/day of calcitriol alone (C) (11 cases). After these evaluations the patients on C+Ca were shifted to C and 6 patients on C were shifted to C+Ca, and IVGTT was repeated 21 days after the shift. For each test plasma glucose (G), immunoreactive insulin (IRI) and C-peptide (C-p) were measured at -30, 0, 2, 5, 15, 30, 45, 60 min, and baseline plasma values of 1 alpha,25(HO)2-vitamin D3, C-terminal parathyroid hormone (PTH-C), intact parathyroid hormone (PTH-I), calcitonin, and serum values of total and ionized calcium were dosed. Also, glucose constant decay (K-G), insulin response (IRI area), C-p production (C-p area), insulinogenic index (IGI) and insulin resistance index (RI) were calculated. A historical group of 21 healthy volunteers formed the normal controls. 1 alpha,25(HO)2-vitamin D3 plasma levels in uremic patients before treatment were significantly lower than normal range. As compared to controls, uremic patients showed significantly lower K-G, IRI area and IGI values and significantly higher RI values. After treatment with C or C+Ca, the insulin response improved significantly at 2 and 5 min and G decrement was more marked at 30, 45 and 60 min.(ABSTRACT TRUNCATED AT 250 WORDS)

The peripheral opioid receptor subtypes involved in the regulation of gastric acid secretion were studied in dogs with both a gastric fistula and a Heidenhain pouch, by using the putative mu-opioid receptor agonist dermorphin, the delta-opioid receptor agonist [D-Ala2,D-Leu5]enkephalin (DADLE) and the kappa-opioid receptor agonist dynorphin-(1-13). Dermorphin caused a significant increase in basal acid secretion from both the gastric fistula and the Heidenhain pouch, while DADLE and dynorphin-(1-13) did not. Acid secretion stimulated by 2-deoxy-D-glucose from the gastric fistula was not modified by dermorphin and dynorphin-(1-13), while DADLE significantly inhibited it; at the same time gastric secretion from the Heidenhain pouch was significantly increased by dermorphin and unmodified by DADLE and dynorphin-(1-13). Dermorphin, DADLE or dynorphin-(1-13) did not modify plasma gastrin during basal or 2-deoxy-D-glucose-stimulated conditions. Submaximal bethanechol-stimulated secretion was increased by dermorphin and DADLE but unaffected by dynorphin-(1-13). Acid secretion from the gastric fistula stimulated by pentagastrin was enhanced by dermorphin, inhibited by DADLE and unaffected by dynorphin-(1-13). Dermorphin and DADLE significantly increased acid secretion from the Heidenhain pouch stimulated by pentagastrin, while dynorphin-(1-13) was ineffective. Naloxone prevented the stimulatory effects of dermorphin and DADLE on the Heidenhain pouch, but it reduced acid secretion from the gastric fistula further when given with DADLE. The inhibitory effects of DADLE on secretion from the gastric fistula were prevented by naltrindole, a selective antagonist of delta-opioid receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Idrapril is the prototype of a new class of angiotensin converting enzyme (ACE) inhibitors. Its pharmacokinetics and pharmacodynamics (plasma ACE activity) were investigated in rats, dogs (after intravenous and oral doses), and human volunteers (after oral doses). Following intravenous administration (1 mg/kg) to rats and dogs, elimination half-lives were 96 and 52 min, systemic clearance 19.6 and 9.5 ml/min kg, and volume of distribution 2.7 and 0.8 liters/kg, respectively. Pharmacokinetics appeared linear in dogs, within the dose range of 0.1-10 mg/kg. After oral administration of similar doses (approximately 2 mg/kg) in the three species studied, peak plasma concentrations were 182, 567, and 726 ng/ml; AUCs 25, 85, and 182 micrograms min/ml; and elimination half-lives 82, 54, and 174 min in rats, dogs, and healthy volunteers, respectively. Absolute oral bioavailability was calculated to be approximately 24% in rats and dogs. Idrapril did not bind to plasma proteins of the species studied. Plasma ACE was fully inhibited following oral administration of approximately 2 mg/kg in rats and humans, but in dogs maximal inhibition did not exceed 85%. Duration of action, measured as time for ACE to recover to 70% of initial activity, was approximately 5, 3, and 22 hr in rats, dogs, and humans, respectively. Idrapril plasma levels appeared correlated in a saturable way with inhibition of plasma ACE in all three species, yielding ex vivo IC50 values of approximately 7 ng/ml for both the rat and humans, and 91 ng/ml for dogs.

The effects of esaprazole, a novel antiulcer drug, on gastric acid secretion and plasma gastrin levels were investigated in dogs provided with a gastric fistula or Heidenhain pouch. Esaprazole affected in a different extent the tests performed on dogs with a gastric fistula. The greatest inhibitory effect was obtained against 2-deoxy-D-glucose-induced acid output and gastrin release. An intermediate inhibition by esaprazole was detected on bethanechol-evoked secretion, and the lowest activity was found versus histamine-stimulated secretion. All these responses were strongly inhibited by the antimuscarinic drug pirenzepine used as reference drug. Moreover, both esaprazole and pirenzepine prevented the acid secretory response to a test meal in dogs with a Heidenhain pouch, without significantly affecting plasma gastrin levels. The present results suggest that the depressant action of esaprazole on gastric secretion depends on its peripheral anticholinergic activity, consisting of a partial blockade of acid output and a main reduction of vagally mediated gastrin release. On the basis of these findings, the antiulcer activity of esaprazole might be in part ascribed to its inhibitory effects on gastric secretion.

In order to evaluate effects of metabolic acidosis on glucose metabolism in uremia, we studied, by an intravenous glucose tolerance test (IVGTT), 46 patients with severe chronic renal failure divided into three groups according to their blood bicarbonate (BB) values: group A formed by 15 patients without or with light metabolic acidosis (BB > or = 20 mEq/1); group B formed by 18 patients with moderate metabolic acidosis (16 < or = BB < 20 mEq/1); group C formed by 13 patients with severe metabolic acidosis (BB < 16 mEq/1). In 8 patients of group B (subgroup B1) and in 8 of group C (subgroup C1), IVGTT was also repeated after adjustment of acid-base balance by intravenous or oral bicarbonate administration. Twenty-nine healthy volunteers formed the normal controls. For each test, glucose constant decay (K), immunoreactive insulin (IRI) area and C-peptide (C-p) area response, insulinogenic index (IGI) and insulin resistance index (RI) were calculated. Compared to controls, all uremic groups showed significantly lower values of K and IGI and significantly higher values of C-p area and RI. In group C, RI was significantly higher than in groups A and B. No differences were found in the other glucose metabolism parameters among the uremic groups. After bicarbonate administration, subgroup C1 showed a significant decrease in RI and a rise in K values, while subgroup B1 showed no changes in glucose metabolism parameters. From these data, we infer that abnormalities of acid-base balance do not affect insulin response but severe metabolic acidosis may play an additional role in the insulin resistance of uremic patients.

The effect of (R)alpha-methylhistamine (MH) and thioperamide (selective agonist and antagonist respectively of histamine H3 receptors) was examined in conscious gastric fistula dogs to investigate the role of histamine H3 receptors in the control of basal and stimulated gastric acid secretion. Intravenous infusion of MH at 0.3 and 0.6 mumol/kg/h caused a significant reduction of the 2-deoxy-D-glucose (2-DG)-stimulated acid output, maximal inhibition being 60%. The inhibitory effect of MH was counteracted by thioperamide (0.1 mumol/kg/h), which, by itself, did not modify the 2-DG-induced acid secretion. The increase in plasma gastrin levels induced by 2-DG was not significantly affected either by MH or by thioperamide. Under basal conditions MH (0.3 mumol/kg/h) did not induce any significant change in acid secretion and in plasma gastrin levels; by contrast, thioperamide (0.1 mumol/kg/h) produced a significant increase both in acid output and in plasma gastrin. These results suggest that activation of H3 receptors can exert a negative control in stimulated acid secretion in conscious dogs, when cholinergic pathways to acid secretion are activated by 2-DG; moreover, the slight, but significant, stimulatory effect of thioperamide on basal acid output and basal plasma gastrin may be suggestive for a tonic inhibitory role of H3 receptors in the regulation of basal acid secretion, however, a nonspecific effect of this drug cannot be excluded.

Altered sympathetic activity may play an important role in the pathogenesis of hypertrophic obstructive cardiomyopathy (HOCM). Spectral analysis of heart rate variability was employed to assess the sympatho-vagal function and balance in 18 patients with HOCM (11 males, 7 females, mean age 42 years, range 19-59) and in 15 healthy control subjects (9 males, 6 females, mean age 44 years, range 18-65). Electrocardiographic recordings obtained both at rest and during 60 degrees passive tilt, were digitized and analyzed by fast Fourier transform in order to obtain the power spectrum of heart rate variability. The low-frequency band (LF: 0.05-0.17 Hz) and the high-frequency band (HF: 0.18-0.34) of power spectrum were considered as indexes of sympathetic and vagal activities respectively. A semiquantitative two-dimensional echocardiographic score (SES) was used to assess the entity of myocardial hypertrophy whereas the entity of the intraventricular gradient was determined by continuous wave Doppler. Low-frequency band at rest was slightly but significantly reduced in HOCM group with respect to controls (35.2 +/- 2.0 vs 45.0 +/- 2.5 nu, respectively; p < 0.01), whereas the HF band and the LF/HF ratio were not different in the 2 groups. During tilt, control subjects showed a significant reduction of the HF band (-35%, p < 0.001), an increase in the LF band (+36%, p < 0.001) and a sharp increase in the LF/HF ratio (+105%, p < 0.001). On the contrary the baroreflex increase in the LF band and LF/HF ratio during tilt was markedly blunted, or even reverted, in patients with HOCM (-9%, NS and +5%, NS, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

To evaluate the changes of left ventricular diastolic and systolic function and the timing of these changes in the early stages of acute myocardial infarction, serial echocardiograms were performed in 10 male patients (mean age of 56 years) with acute myocardial infarction, undergoing reperfusion by thrombolysis (recombinant tissue plasminogen activator). Echocardiograms were performed before reperfusion and 3, 6, 12, 24, 48, 72 hours, 7 and 14 days after thrombolysis. Significant differences of heart rate, systolic and diastolic blood pressure, left ventricular end diastolic volume, end-systolic volume and ejection fraction were not found. The mean regional wall motion index improved from 1.02 +/- 0.50 to 0.89 +/- 0.51 (p less than 0.05) at 48 hours; to 0.79 +/- 0.46 (p less than 0.01) at 72 hours; to 0.69 +/- 0.43 (p less than 0.001) at 7 days and to 0.61 +/- 0.40 at 14 days (p less than 0.001). The deceleration time decreased from 223 +/- 33 to 169 +/- 30 ms (p less than 0.001) 24 hours after reperfusion without further improvement. E peak velocity and E/A ratio significantly increased at 72 hours, while A peak velocity was not statistically different. A slow and progressive recovery of left ventricular function occurred after thrombolysis in acute myocardial infarction. Left ventricular diastole improves earlier while regional systolic function improves slowly till the hospital discharge.

The study was carried out in order to evaluate in maintenance hemodialysis (MH) patients: (1) the reliability of serum ferritin (SF) measurement in iron deficiency diagnosis and therapy; (2) the possibility to improve iron stores assessment through laboratory indexes routinely used in clinical practice; (3) the most effective iron deficiency treatment. After a preliminary assessment of SF reference values in 250 healthy volunteers, we studied 72 MH patients divided into three groups according to their SF baseline values: high (group A), normal (group B), low (group C) (normal range 19-191 ng/ml). Each group was further divided into three subgroups receiving three different iron treatments for 6 months: (1) oral administration of 67.5 mg/day of Fe3+ as Fe-ferritin (subgroups A1, B1, C1); (2) oral administration of 60 mg/day of Fe3+ as Fe-chondroitin sulfate (subgroups A2, B2, C2); (3) i.v. administration at the end of each dialytic session of 31 mg of Fe3+ as Fe-gluconate-Na (subgroups A3, B3, C3). The response to the iron therapy was considered positive when the hemoglobin (Hb) and the hematocrit (Ht) increased to greater than or equal to 15% of the baseline values. The rate of positive responses in each subgroup was as follows: A1 0/5, A2 0/5, A3 0/7, B1 2/10, B2 1/6, B3 5/11, C1 1/7, C2 3/7, C3 10/16. We concluded that SF values above 191 ng/ml allow to exclude iron deficiency whereas SF values less than or equal to the normal range are inadequate. In an attempt to improve diagnostic sensitivity we divided patients of subgroup B3 and C3 into responders (R) and nonresponders (NR).(ABSTRACT TRUNCATED AT 250 WORDS)

To explain mechanisms responsible for derangement of insulin release in uremia, we investigated glucose metabolism through three different tests in 14 patients with end-stage chronic renal failure. These tests were: intravenous glucose tolerance test with 0.33 g/kg of glucose solution (IVGTT); IVGTT with 0.5 g/kg of glucose solution (IVGTT2); IVGTT during aminophylline infusion (IVGTT + A). Twelve of the patients had IVGTT repeated after two to four months of thrice-weekly regular hemodialysis (IVGTT3). In each test we measured plasma glucose (G), immunoreactive insulin (IRI) and C-peptide. We also calculated glucose constant decay (K), insulin production (IRI area), insulinogenic index (IGI), and insulin resistance index (RI). Twenty-nine healthy volunteers formed the normal controls for IVGTT. As compared to controls, during IVGTT uremic patients showed significantly lower values in K, IRI area and IGI, and showed a significant RI value increase. During IVGTT2, IRI are values were higher than during IVGTT but IGI and K values were unchanged. During IVGTT + A both IRI area and IGI values were higher than during IVGTT. After hemodialysis treatment (IVGTT3) K, IRI areas and IGI increased significantly as compared to the predialysis period. K increase after hemodialysis correlated directly to IGI increase and inversely to RI changes. IGI increase during IVGTT3 was directly correlated to IGI rise during IVGTT + A. From these data we infer that defective insulin release in uremia is due to a decrease of beta-cell glucose sensitivity rather than to their functional exhaustion. An impaired adenyl cyclase-cAMP system may have an important role in the pathogenesis of this abnormality.

To evaluate the utility of echo-Doppler (ED; PW, CW and color), 67 patients affected by pure mitral stenosis (20 M, 47 F, mean age 52 years) were submitted to ED examination. Right and left cardiac catheterization were performed in 20 patients within 24 hours before ED. Mitral area obtained by Doppler method (Hatle's formula) correlated highly with both echo-2 dimensional and hemodynamic area (r = 0.93, p less than 0.001; r = 0.95, p less than 0.001 respectively). It was possible to calculate systolic pulmonary pressure, in patients with tricuspid incompetence, (43.9 +/- 14.9 mmHg, range 25-80) which correlated significantly (r = 0.95, p less than 0.001) with hemodynamic data (40.2 +/- 12.7 mmHg, range 20-70). The left atrial-left ventricular pressure gradient was 15.6 +/- 6.9 mmHg, range 6-32; the mean pressure gradient was 8.4 +/- 3.7 mmHg, range 3-17; the pressure half time 170.2 +/- 62.3 ms, range 83-330. We observed different types of direction of transmitral jets: centrally directed (n = 34); forward antero-lateral wall (n = 28); toward interventricular septum (n = 5). The transmitral jets presented 4 different appearances: scimitar-shaped (n = 28); candle flame (n = 24); mushroom (n = 9); double-jets (n = 6). No correlation was observed between the different types of transmitral jets (direction and appearance) and the parameters obtained by Doppler (PW and CW): velocities, pressure half-time, gradients. Thus, Doppler echocardiography permits a complete anatomic and functional evaluation of patients with pure mitral stenosis. We have not observed any correlation between the hemodynamic data and the different types of transmitral jets visualized by color Doppler.

The effects of oral diethylaminoethyl-dextran (3 g total), taken 30 min before a standard mixed test meal, on plasma glucose, total cholesterol, triglycerides, total lipids, gastrin-like immunoreactivity, bombesin-like immunoreactivity, gastric-inhibitory-polypeptide-like immunoreactivity and neurotensin-like immunoreactivity were evaluated in eight healthy volunteers following a double-blind protocol. Incremental peak plasma concentrations of total lipids and triglycerides were significantly reduced by pretreatment with diethylaminoethyl-dextran pretreatment, while peaks of plasma glucose and total cholesterol were not significantly affected. Diethylaminoethyl-dextran also inhibited postprandial gastrin-like gastric-inhibitory-polypeptide-like and neurotensin-like immunoreactivity; by contrast, bombesin-like immunoreactivity was not significantly modified. The present study indicates that diethylaminoethyl-dextran is able to regulate some postprandial metabolic and hormonal parameters in man; consequently it might be useful in the treatment of hyperlipoproteinaemia and obesity.

We studied metabolic and hormonal patterns in 11 patients on hemodialysis for over 10 years (group A) to determine whether some metabolic abnormalities worsen with long-term dialysis or whether a particular endocrine-metabolic pattern discriminates long-term hemodialysis survivors. Data were compared to those of 14 subjects of similar age and sex on dialysis for 1-3 years (group B) and to those measured in the same patients during the 1st year of dialytic treatment. As to glucose metabolism, group A showed elevation of fasting plasma glucose and a decrease of glucose constant decay (K) and insulin production (IIG) values as compared to the 1st year of dialysis. No difference was found between group A now and group B. However in the 1st year of dialysis group A showed significantly higher K values than group B. As regards lipid metabolism, group A presented higher alpha-lipoprotein values and high-density lipoprotein-cholesterol/cholesterol, high-density lipoprotein-cholesterol/apoprotein A, and apoprotein A/apoprotein B ratios, while low-density lipoprotein-cholesterol and apoprotein B values and beta/alpha-lipoprotein ratio were lower. These data demonstrate less vascular risk in group A. We explain these results as depending on natural selection. Multivariate analysis of survival confirmed that survival in hemodialysis patients is influenced negatively by glucose and lipid metabolism abnormalities. As to Ca-P metabolism, group A showed higher carboxy-terminal parathyroid hormone and alkaline phosphatase values than group B. However, these data may be superimposed to those determined in the same patients in 1981, when we began the regular use of 1 alpha,25-(OH)2-vitamin D3.(ABSTRACT TRUNCATED AT 250 WORDS)

Sixteen patients affected by congestive cardiomyopathy were studied by means of right and left cardiac catheterization and cineangiocardiography. Cardiac output and mean pulmonary circulation time were determined by the radiocardiographic method. Left ventriculograms were obtained in all the patients in the 45 degrees RAO projection; the left ventricular end diastolic and end systolic volumes were calculated both by the area-length and by the slice method. Among the several hemodynamic data (stroke index, mean pulmonary circulation time, left ventricular end diastolic pressure, left ventricular volumes and ejection fraction) the most early impaired and therefore usefull for an early diagnosis, were: the left ventricular end-systolic volume, the left ventricular end-diastolic volume and the left ventricular ejection fraction.

The effects of dermorphin and morphine on gastric acid secretion were studied in conscious dogs with both gastric fistulas (GF) and Heidenhain pouches (HP). Under basal conditions dermorphin and morphine, infused systemically at graded doses, produced a significant increase in acid secretion from both GF and HP. This increase was significantly inhibited by naloxone, naltrexone methylbromide and N-methyl-levallorphan methanesulphonate. Dermorphin did not modify the acid output stimulated by 2-deoxy-D-glucose from GF, while morphine significantly inhibited it; on the contrary acid secretion from HP was increased in this test by both dermorphin and morphine. Acid secretion from GF stimulated by pentagastrin was unaffected by morphine and significantly enhanced by dermorphin. Under these conditions a significant increase in acid secretion from HP was recorded with dermorphin and morphine. Naloxone and N-methyl-levallorphan methanesulphonate, given during pentagastrin-stimulated secretion, significantly inhibited acid output 'per se' from GF and HP and prevented the stimulatory effect of dermorphin and morphine. Bethanechol-induced secretion from GF and HP was significantly increased by both dermorphin and morphine. The present results demonstrate that opioids have simultaneous yet opposite effects on acid secretion in the dog and that mu receptors are involved in both the excitatory and inhibitory effects. Excitatory effects do not seem to be mediated via a vagal pathway (peripheral ?), in contrast to the inhibitory effects (central ?). The inhibitory effects of opiate antagonists on pentagastrin-stimulated secretion suggest a physiological role of peripheral opioid receptors in gastric acid secretion.

The effects of galanin on gastric acid secretion and plasma levels of gastrin were studied in conscious dogs chronically fitted with gastric fistulas. Continuous i.v. infusion of galanin (2 micrograms.kg-1.h-1) for 2 h did not affect unstimulated total acid output or plasma levels of gastrin. In contrast, simultaneous i.v. infusion of galanin (1-2 micrograms.kg-1.h-1) inhibited the bombesin-stimulated output of acid whereas the effects of bombesin on gastrin output were not significantly modified. Galanin (2-4 micrograms.kg-1 i.v.) also depressed the secretory response to 2-deoxy-D-glucose without significantly affecting plasma gastrin levels. Galanin (2-4 micrograms.kg-1 i.v.) did not depress bethanechol-stimulated gastric acid output or inhibit histamine-stimulated gastric acid secretion. These findings indicate that glanin inhibits the bombesin- and 2-deoxy-D-glucose-stimulated secretion of gastric acid in conscious dogs by an action which is probably exerted at the level of the cholinergic nerve terminals.

The effects of three types of white wine (10% ethanol; pH 2.84-3.26), Coke (pH 2.45) and water (pH 8.03) on basal and food-stimulated gastric acid secretion in dogs were investigated. Water and Coke did not significantly modify acid secretion and gastrin release under basal conditions. By contrast, white wine or water +10% ethanol significantly increased acid secretion, with a tendency to elevate plasma gastrin concentrations. Acid secretion and gastrin release induced by a standard meal were not significantly modified by previous administration of Coke and water. In contrast, white wine and water +10% ethanol significantly increased food-stimulated total acid output, without changing plasma gastrin levels. It is concluded that Coke and water have only trivial effects on basal and on food-stimulated gastric acid secretion and gastrin release in the dog. The gastric stimulant effect of white wine is mainly related to its percentage of alcohol regardless of the slight differences in pH of the solutions.