Prognostic value of captopril renal scintigraphy in renovascular hypertension.

This study evaluates the prognostic value of captopril renal scintigraphy in hypertensive patients undergoing renal artery revascularization. Preoperative studies of 51 patients were correlated with blood pressure results at 6- and 12-mo follow-up. Captopril-renal scintigraphy was carried out 1 hr after oral administration of 50 mg of captopril, using either 220 MBq of 99mTc-DTPA or 74 MBq of 99mTc-MAG3, followed by a baseline study in case of abnormal results. Evidence of amelioration or normalization in relation to captopril study was considered predictive of blood pressure control following treatment. Blood pressure response was favorable in 37 patients, but failed to show any improvement in 14. The scintigraphic test was positive in 33 patients (15 cured, 17 improved, 1 failed) and negative in 18 (3 cured, 2 improved, 13 failed). Sensitivity and specificity for renovascular hypertension was 86.5% and 93%, respectively. For blood pressure cure and improvement, the test had positive and negative predictive values of 97% and 72%, respectively. A positive preoperative captopril renal scintigraphic result is a strong predictor of hypertension curability by renal artery revascularization.

Evaluation of hypertensive patients by means of captopril enhanced renal scintigraphy with technetium-99m DTPA.

One-hundred five hypertensive patients underwent conventional renal scintigraphy followed 2 or 3 days later by Captopril-enhanced renal scintigraphy, performed 1 hr after premedication with 50 mg of Captopril per os. All patients were then submitted to renal arteriography, performed within 15-30 days. Fifty-five patients had no renal artery stenosis, 29 had unilateral disease, and 21 bilateral. Overall, 34/37 patients were diagnosed by the provocative test as having at least one renal artery affected by a stenosis greater than 50%. Of those with no stenosis (n = 55) or stenosis less than 50% (n = 13) only two cases were falsely positive. Thus sensitivity was 92% and specificity 97%. For single kidney identification with stenosis greater than 50%, sensitivity of renal scintigraphy after Captopril administration was 94% and specificity 98%. Captopril enhanced renal scintigraphy is thus suggested as the first test to be performed in hypertensive patients referred for renal scintigraphic studies. Only those cases with equivocal results require a baseline study for better assessment.

The deletion polymorphism of the angiotensin-converting enzyme is associated with nephroangiosclerosis.

The D allele of the angiotensin-converting enzyme (ACE) gene has been linked with diabetic nephropathy and IgA glomerulonephritis and with faster renal disease progression. The association of this allele with nephroangiosclerosis has been scarcely investigated. We have tested this association in 45 hypertensive patients (all whites) with well defined nephroangiosclerosis (diagnosis established on the basis of renal biopsy in all cases) and moderate to severe renal failure. As studies of genetic association of small size often produce conflicting results, besides a control group of 343 Italian patients with essential hypertension and normal renal function, we elected to use also a very large control group of race-matched subjects taken from a meta-analysis of 27,565 whites. The proportion of patients with the D allele (64%) was higher in patients with nephroangiosclerosis than that in Italian hypertensives (54%) and in whites (54%). DD and DI genotypes were more prevalent in patients than in control groups. The dominant model (DD and DI v II: nephroangiosclerosis v Italian controls: chi2 = 6.19, P = .012; nephroangiosclerosis v whites chi2 = 6.86, P = .009) fitted the data better than the codominant and the recessive model (P < or = .022). The D allele is associated with nephroangiosclerosis with a dominant effect in the sample of patients studied. Although intervention studies are needed to see whether these findings imply a causal association, our data suggest that this allele may at least act as disease marker in nephroangiosclerosis.

Antidepressant versus neuroleptic activities of sulpiride isomers on four animal models of depression.

The atypical neuroleptic sulpiride is also prescribed for depression because of its activating effect. However, such an effect does not necessarily imply an action identical to that of classical antidepressants, and a laboratory comparison of the neuroleptic and antidepressant activities of sulpiride may contribute to a better definition of its psychotherapeutic profile. Sulpiride isomers were studied in the rat in four behavioural models of depression which are thought to be influenced by neuroleptics in different ways. Desipramine (imipramine) and haloperidol were employed in each test as a standard antidepressant and neuroleptic, respectively. The four tests were: 1) prevention of apomorphine-induced sedation: 2) antagonism of apomorphine-induced hypothermia; 3) behavioural despair (swim test); 4) learned helplessness ( FR2 lever pressing escape). Desipramine ameliorated behaviour in all tests; haloperidol ameliorated the response to test 1, influenced that to test 2 in a neuroleptic-like way and worsened the responses to tests 3 and 4. (-)-Sulpiride worked in a similar way to haloperidol in all tests. (+)-Sulpiride significantly and dose-dependently ameliorated the responses to test 3 and was inactive in the others. No conclusion was drawn from test 1 owing to its lack of specificity; the results of the remaining tests indicated a neuroleptic profile of (-)-sulpiride and suggested a potential "antidepressant" activity of (+)-sulpiride which merits further investigation.

Effects of calcium antagonists on biogenic amines in discrete brain areas.

Discrete brain sections were obtained from rats given i.p. verapamil, nifedipine, diltiazem or flunarizine (0, 10, 20 or 40 mg/kg). The biogenic amines and metabolites in the hypothalamus, brainstem hippocampus, striatum, thalamus-midbrain and cortex were determined by high-performance liquid chromatography with electrochemical detection. The treatments induced several changes in the levels of neurotransmitters and metabolites, displaying regional specificity and differences according to the various compounds. It was speculated that some effects could have been due to indirect actions and/or to interactions of the compounds with receptors other than the voltage-sensitive calcium channels. However blockade of these channels could account for the following effects. (a) The nifedipine-induced increases in the 5-hydroxy-3-indoleacetic acid levels and, in general, the signs of activation of the serotonergic systems. (b) The fall in the 3,4-dihydroxyphenylacetic acid levels and, in general, the signs of attenuation of dopaminergic neurotransmission induced by nifedipine, verapamil and diltiazem. (c) The fall in the norepinephrine levels induced by all the compounds studied.

Effects of isradipine and darodipine on serotonergic system of the rat brain.

Isradipine and darodipine are dihydropyridine calcium antagonists that easily pass into the brain, showing high affinity for cerebral L-type voltage-sensitive calcium channel (VSCC). These drugs were IP administered to rats to study their effects on serotonergic systems of discrete brain areas. Isradipine (0.05-5.0 mg/kg) and darodipine (0.3-20 mg/kg) increased the 5-HIAA/5-HT ratio, mostly enhancing the metabolite (5-HIAA) content in various brain areas, suggesting that serotonin (5-HT) turnover was increased. This increase appeared to depend on facilitation of serotonergic neurotransmission, because low doses of isradipine (< 0.075 mg/kg) or darodipine (< 0.6 mg/kg) enhanced the number of head twitches induced by L-5-hydroxytryptophan (L-5-HTP). However, higher doses of isradipine (1.5 mg/kg) or darodipine (5 mg/kg) also appeared to stimulate a negative feedback mechanism, which predominated over the facilitation when the serotonergic neurotransmission was strongly activated. Thus, higher drug doses decreased both the serotonin turnover and the number of head twitches on rats treated with L-5-HTP. It was speculated that the observed effects were due to brain VSCC blockade, although the studied compounds showed a peculiar profile of properties when compared to other previously studied calcium antagonists. Moreover, it was concluded that darodipine appeared to be more effective and selective than isradipine regarding the effects on brain serotonergic systems.

Interactions between darodipine or isradipine and the 5-HT1A receptor agonist 8-OHDPAT in rat brain.

Isradipine and darodipine are dihydropyridine calcium antagonists that affect the serotonergic pathways with a peculiar profile of effects because, at low dose (0.08 and 0.3 mg/kg, respectively) they facilitate, but at high dose (1.60 and 5.0 mg/kg, respectively) they inhibit the serotonergic neurotransmission. To investigate the mechanisms of these effects, the selective 5-HT1A receptor agonist 8-OHDPAT was injected S.C. to rats pretreated I.P. with isradipine (0.04-1.60 mg/kg) or darodipine (0.3-5.0 mg/kg). By stimulating presynaptic 5-HT1A autoreceptor, 8-OHDPAT induced signs of inhibition of the serotonergic neutransmission (i.e., decrease of the 5-HIIA/5-HT ratio), but it also produced behavioral effects by stimulating postsynaptic 5-HT1A receptors (i.e., forepaw treadings). A low dose of isradipine (0.08 mg/kg) or darodipine (0.3 mg/kg) antagonized the presynaptic, but enhanced the postsynaptic effects of 8-OHDPAT, suggesting relief of the autoreceptor-mediated inhibition of the 5-HT release. Thus, the amine released could stimulate postsynaptic receptors, adding its action to that of 8-OHDPAT. A high dose of isradipine (1.60 mg/kg) or darodipine (5.0 mg/kg) left unchanged, or also enhanced, the signs of inhibition of serotonergic neurotransmission displayed by 8-OHDPAT, reducing but not suppressing the increase in the behavioral response to the stimulation of postsynaptic 5-HT1A receptors. It was speculated that the effects of isradipine and darodipine on scrotonergic pathways of rat brain could be due to changes in the back-regulation of the neurotransmission, mediated by 5-HT1A autoreceptors. This mechanism of action could be extended to other dihydropyridine calcium antagonists, because blockade of L-type VSCC by these compounds appears to be involved in their effects on brain 5-HT turnover.

Renal functional reserve in patients with a reduced number of functioning glomeruli.

Renal functional reserve (RFR) has been reported to be either reduced or absent in patients with renal insufficiency. Our study consisted in measuring RFR by acute protein load (PL) in 3 groups of patients: the first one was composed of 20 patients (pts) with biopsy-proven glomerular disease (GN) and a varying percentage of sclerotic glomeruli (15-70%); the second one consisted of 10 patients with acquired single kidney (SK) and the third group contained 5 patients with surgical ablation of more than 50% renal tissue (LRRM). Twenty-four healthy volunteers were studied as control subjects. The GFR percentage increase (delta GFR%) after PL in CS did not differ from that of the three groups of patients, despite a significant difference in resting GFR (CS = 113 +/- 11 ml/min/1.73 m2: GN 72 +/- 28 ml/min/1.7, p less than 0.01 vs CS; SK 81 +/- 20 ml/min/1.73 m2, p less than 0.01 vs CS; LRRM 45 +/- 10 ml/min/1.7, p less than 0.01 vs CS; Moreover, an inverse correlation was not found either between GFR and the percentage of sclerotic glomeruli in GN (r = 0.01, p = NS) or between GFR and the extent of excised renal tissue in the other two groups (r = 0.38, p = NS). In conclusion, our data do not confirm that RFR is necessarily reduced or absent in patients with a reduced number of functioning glomeruli, nor do they uphold the hypothesis of constant hyperfiltration in the remaining glomeruli.

Mid-dilution: the perfect balance between convection and diffusion.

Although hemodiafiltration (HDF) offers the advantage of increased convective clearance for middle molecules, there is still controversy as to whether reinfusion should occur pre- or post-filter. Mid-dilution hemodiafiltration (MD HDF) is a new HDF technique that uses a special dialyzer, MD190, which allows both pre- and post-reinfusion. While externally the dialyzer looks similar to conventional hemodialyzers, the internal fibers are divided into two bundles by a special annular header that first lets the blood pass through the peripheral bundle in post-dilution, mix with the reinfusion fluid at the opposite end of the dialyzer and then proceed (after pre-dilution) to the dialyzer blood exit. The dialyzer is able to support substantially higher reinfusion rates (10-12 l/h). We have compared the removal characteristics of several small solutes and larger middle-molecular-weight toxins by examining instantaneous clearance at 45 min, the dialysis reduction ratio and total mass removal (by spilling) in a three-center prospective cross-over study. Twenty patients were randomized to a treatment sequence of one-week high-flux bicarbonate hemodialysis (HD) followed by MD HDF, or vice versa. The parameters evaluated included urea, creatinine, beta2-microglobulin, angiogenin, leptin, retinol-binding protein, and the effects on sodium, potassium, bicarbonate and calcium. Blood flow rates ranged between 300-450 ml/min (mean 359 +/- 44 HD, 367 +/- 35 MD HDF). The mean reinfusion for MD HDF was 166 +/-17 ml/min. MD HDF had a significantly better instantaneous clearance for urea (328 +/- 28 vs 277 +/- 40); creatinine (292 +/- 32 vs. 212 +/- 66); phosphate (324 +/- 38 vs. 242 +/- 63); beta2-microglobulin (249 +/- 27 vs. 100 +/- 24); angiogenin (173 +/- 27 vs. 28 +/- 32); and leptin (202 +/- 29 vs. 63 +/- 43). Treatments were well tolerated with no adverse reactions occurring during any of the treatments. The MD HDF filter's unique configuration is designed to deliver high-efficiency HDF with a significant improvement in small and middle molecule removal. MD HDF supports substantially higher ultrafiltration rates, and as such, results in a higher removal of middle-molecular-weight toxins.

Electrophysiological response to dialysis: the role of dialysate potassium content and profiling.

UNLABELLED: The task of dialysis therapy is, amongst other things, to remove excess potassium (K+) from the body. The need to achieve an adequate K+ removal with the risk of cardiac arrhythmias due to sudden intra-extracellular K+ gradient advises the distribution of the removal throughout the dialysis session instead of just in the first half. The aim of the study was to investigate the electrical behavior of two different K+ removal rates on myocardial cells (risk of arrhythmia and ECG alterations). Constant acetate-free biofiltration (AFB) and profiled K+ (decreasing during the treatment) AFB (AFBK) were used in a patient sample to understand, first of all, the effect on premature ventricular contraction (PVC) and on repolarization indices [QT dispersion (QTd) and principal component analysis (PCA)]. The study was divided into two phases: phase 1 was a pilot study to evaluate K+ kinetics and to test the effect on the electrophysiological response of the two procedures. The second phase was set up as an extended cross-over multicenter trial in patient subsets prone to arrhythmias during dialysis. Phase 1: PVC increased during both AFB and AFBK but less in the latter in the middle of dialysis (298 in AFB vs. 200 in AFBK). The PVC/h in a subset of arrhythmic patients was 404 +/- 145 in AFB and 309 +/- 116 in AFBK (p = 0.0028). QT interval (QTc) prolongation was less pronounced in AFBK than in AFB. Phase 2: The PVC again increased in both AFB and AFBK but less in the latter mid-way through dialysis (79 +/- 19 AFB vs. 53 +/- 13 AFBK). Moreover, in the most arrhythmic patients the benefit accruing from the smooth K+ removal rate was more pronounced (103 +/- 19 in AFB vs. 78 +/- 13 in AFBK). CONCLUSION: It is not the K+ dialysis removal alone that can be destabilizing from an electrophysiological standpoint, but rather its removal dynamics. This is all the more evident in patients with arrhythmias who benefit from the K+ profiling during their dialysis treatment.

Effects of brain biogenic amines of repeated treatments with calcium antagonists.

Discrete brain sections were obtained from rats once or repeatedly (once a day for 5 days) given i.p. nifedipine, verapamil or diltiazem at doses ranging from 5 to 20 mg/kg. The biogenic amines and metabolites in the hypothalamus, brainstem, hippocampus, striatum, cortex and thalamus-midbrain were determined by high-performance liquid chromatography with electrochemical detection. The drug-induced changes, displaying regional specificity and differences according to the various compounds, suggested that: (a) serotonergic systems were activated, especially in fasted rats or after repeated treatment; (b) the dopaminergic system of the striatum was inhibited by nifedipine which did reduce the HVA levels and the HVA/DA, as well as the DOPAC/DA, ratio. These effects disappeared after repeated treatment. It was also speculated that the data obtained could be of great interest in view of the possible use of calcium antagonists to treat disorders of the central nervous system.

Salmon calcitonin induced head twitch in the rat.

The intracerebroventricular administration of salmon calcitonin (sCT) to rats induced a dose-dependent increase in the number of head twitches and potentiated such a response elicited by L-5-hydroxytryptophan (L-5-HTP). Subcutaneously administered sCT was ineffective "per se" but could again potentiate the head twitch response elicited by L-5-HTP. Since these data suggest a stimulation of the brain serotonergic pathways, the obtained results support the hypothesis that some central actions of sCT may involve activation of serotonergic systems in the rat brain.

[Preparation and beta adrenolytic activity of some derivatives of naphthol-[2,1-b]furan]. / Preparazione ed attività beta-adrenolitica di alcuni derivati del nafto[2,1-b]furano.

Some 1-(naphtho[2,1-b]furan-2-yl)-2-(t-butylamino)ethanols were synthesized for possible beta-adrenergic receptor blockade. The compounds may be considered to be derived from naphthyloxypropanolamines, the side chain of which is partially included in a furan ring. The pharmacological profile of 1-(naphtho[2,1-b]furan-2-yl)-2-(t-butylamine)ethanol (I b) is quite similar to that of propranolol without cardiac depressant properties.

Blockade of the serotonergic system counteracts the dizocilpine-induced changes in dopaminergic function.

The administration of dizocilpine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist acting at the associated ion channel, increased the grooming time induced in rats by the D1 dopamine receptor agonist SKF 38393 and the stereotyped behaviour elicited by the D1/D2 dopamine receptor agonist apomorphine, and reduced the locomotor response to the D2 dopamine receptor agonist quinpirole. This supports the view that glutamate deficiency plays an important role in the pathogenesis of schizophrenia by altering the balance between glutamatergic and dopaminergic systems. Blockade of serotonin receptors counteracted the effect of dizocilpine on dopaminergic responses. Both the non-selective 5HT1/5HT2 antagonist methysergide, and ketanserin, which more specifically blocks 5HT2 receptors, given at doses inhibiting serotonin-mediated behaviours but which did not affect spontaneous motility and dopaminergic behaviours, hampered the dizocilpine-induced potentiation of responses elicited by the stimulation of D1 or D1/D2 dopamine receptors and counteracted the dizocilpine-induced reduction of hyperactivity observed following quinpirole administration. The results suggest that the functional integrity of the serotonergic system is fundamental for the occurrence of dopaminergic changes resulting from non-competitive NMDA blockade.

The non-competitive NMDA receptor blocker dizocilpine potentiates serotonergic function.

Forepaw treading induced in rats by the 5HT1A agonist 8-OH-DPAT, and head shakes caused by the administration of the 5HT2A receptor against DOI, and by the 5HT precursor (-)5HTP, were significantly increased by pretreatment with the non-competitive N-methyl-D-aspartate (NMDA) antagonist dizocilpine. Dizocilpine administration also significantly increased the locomotor activity induced by the serotonin agonists. The competitive NMDA receptor antagonist CGP 43487 increased only the head shakes induced by DOI, but did not alter the behavior elicited by 8-OH-DPAT, or (-)5HTP, and did not modify locomotor responses to any of the agonists used. The dizocilpine-induced potentiation of head shakes elicited by DOI and (-)5HTP was inhibited by the 5HT2 agonist ketanserin, but was not modified by the selective dopamine D1 and D2 receptor blockers SCH 23390 and (-)sulpiride. The dopamine receptor antagonists did, however, counteract the dizocilpine facilitation of both forepaw treading induced by 8-OH-DPAT, and the locomotor response to all the serotonergic agonists. The results indicate that, unlike competitive NMDA receptor antagonists, the non-competitive antagonists enhanced the expression of serotonergic stimulation, and suggest that a glutamate deficiency could contribute to the pathogenesis of schizophrenia, not only through dopaminergic, but also through serotonergic, hyperactivity.