Irene S. Hoffmann

Efficacy of ondansetron (GR 38032F) and the role of serotonin in cisplatin induced nausea and vomiting

We compared the efficacy and safety of ondansetron (GR 38032F), a selective antagonist of serotonin S3 receptors, with that of placebo in controlling the nausea and vomiting induced by cisplatin treatment in 28 patients with cancer. The patients received either three intravenous doses of ondansetron (0.15 mg per kilogram of body weight) or normal saline (placebo) at four-hour intervals, beginning 30 minutes before the administration of cisplatin. Nausea and vomiting were markedly diminished in the group given ondansetron. The median time to the first episode of emesis was 2.8 hours in the placebo group and 11.6 hours in the ondansetron group (P less than 0.001); the median number of episodes in 24 hours was 5.5 in the placebo group and 1.5 in the ondansetron group (P less than 0.001); the mean (+/- SEM) number of regurgitations or dry heaves per episode was 3.2 +/- 0.5 in the placebo group and 1.17 +/- 0.1 in the ondansetron group (P less than 0.001). None of the 14 patients given ondansetron, but 12 of 14 given placebo, required treatment with antiemetic-rescue agents for the control of nausea and vomiting. There were no adverse effects attributable to ondansetron. The urinary excretion of 5-hydroxyindoleacetic acid, the main metabolite of serotonin, was increased in all patients two to six hours after they received cisplatin chemotherapy, and the increases paralleled the episodes of emesis. We conclude that ondansetron is an effective and safe agent for controlling the nausea and vomiting induced by cisplatin treatment. We suggest that cisplatin treatment increases the release of serotonin from enterochromaffin cells, and that ondansetron acts by blocking S3 receptors for serotonin.

Salt and the metabolic syndrome

BACKGROUND AND AIMS High blood pressure in subjects with the metabolic syndrome (MS) is largely related to dietary salt. We investigated in free-living men and women whether increase in dietary salt intake is associated with the presence and severity of the MS. METHODS AND RESULTS A total of 766 subjects (251M, 515F) of 44.9+/-0.5 years/age and SBP/DBP of 120+/-0.6/77+/-0.4 mmHg were studied. Twenty-four hour urinary sodium (UNa(+)) and potassium (UK(+)) excretions were 143+/-2.5 mmol (median: 131.5) and 48+/-0.9 mmol (median: 44). UNa(+) was higher in men than in women (median: 155.5 vs. 119.8 mmol/day; P<0.0001). UK(+) (r=0.34; P<0.0001), measures of obesity (r=0.26; P<0.0001) and BP (r=0.15; P<0.0001) were significantly associated with UNa(+). The association with BP was lost after adjusting for weight. Of the 766 subjects, 256 (33.4%) met the NCEP-ATPIII criteria for the MS. Median UNa(+) in men and women with no traits of the MS was 140 and 116.7 mmol/day, respectively (P<0.001), increasing to 176 in men and 135 mmol/day in women with 4-5 components of the syndrome (P<0.001). Weight, BMI and waist increased significantly across the quartiles of UNa(+) both in men and women; whereas, age, lipids and fasting glucose did not. SBP and DBP were associated with UNa(+) in men but not in women. UK(+) correlated with age in men and women (r=023; P<0.0001) and with obesity in women (r=0.14; P=0.001). CONCLUSIONS UNa(+) a measure of dietary sodium intake in free-living subjects was markedly increased in subjects with the MS. Higher UNa(+) was associated with obesity and higher BP, but not with age, dyslipidemia or fasting glucose.

Frequency-Dependent Release of Acetylcholine and Dopamine From Rabbit Striatum: Its Modulation by Dopaminergic Receptors

Abstract: The release of [3H]dopamine (DA) and [14C]acetylcholine (ACh) was monitored from single slices of the rabbit striatum. In all cases, the evoked overflow of ACh showed a higher peak and was of shorter duration than that of 3H products. For ACh, the release per pulse showed a marked decline with increasing frequency of stimulation, whereas flat frequency‐release curves were obtained for DA. At 0.1 and 1 Hz the evoked overflows of ACh were 15 and 7 times greater, respectively, than those of DA. Haloperidol (0.03 μM) and sulpiride (1 μM) produced large increases in the evoked overflow of DA and ACh at 3 and 10 Hz; little effect was observed at lower frequencies. These results indicate that the frequency‐release curves for DA and ACh are different and that at high frequencies the slope of the curves is modified by activation of pre‐ and postsynaptic DA receptors. Apomorphine inhibited in a concentration‐dependent fashion the evoked overflow of DA and ACh; greater inhibition was obtained at lower frequencies of stimulation. At 0.3 Hz the‐ DA agonist was two times more potent in inhibiting DA than ACh overflow (IC50: 12.0 ± 2.2 versus 22.0 ± 2.8 nM; p < 0.01). The greater sensitivity of pre‐than postsynaptic sites to apomorphine was also seen at higher frequencies (3 Hz). Benztropine (1/μ) reduced the evoked overflow of ACh at 10 Hz, and enhanced that of 3H products at all rates of stimulation (0.3–10 Hz). These results suggest that the release of DA and ACh is regulated by dopaminergic receptors. They also indicate that the effects of DA agonists and antagonists and of uptake inhibitors on DA and ACh release are highly dependent on the frequency of stimulation used.

Endothelial nitric oxide synthase polymorphism, nitric oxide production, salt sensitivity and cardiovascular risk factors in Hispanics

Mutations in the endothelial nitric oxide synthase (eNOS) gene may be associated with abnormal nitric oxide (NO) production and cardiovascular diseases. In this study, we investigated the prevalence of two eNOS polymorphisms, the Glu298Asp variant on exon 7, and the 4a/b variable number of tandem repeats (VNTR) on intron 4, and their association with blood pressure (BP), NO production, salt sensitivity and cardiovascular risk factors in healthy Venezuelans. The prevalence of both polymorphisms in Venezuelans was comparable to that described for Caucasians, but significantly different from that known for African-Americans and Japanese. The 4a/b genotype was associated with reduced levels of NO metabolites (25% decrease), larger BP lowering in response to salt restriction (9.0 vs 4.8 mmHg, P<0.05), greater prevalence of salt sensitivity (39% in 4a/b and 27% in 4b/b; P<0.05) and with higher LDL-cholesterol levels. The Glu298T polymorphism did not affect NO production, nor it was associated with salt sensitivity. Glu298Asp polymorphism was positively associated with higher weight, triglycerides and LDL-cholesterol. Neither polymorphism was associated with changes in fasting or postload serum glucose, BP, obesity and albuminuria. In conclusion, the prevalence of eNOS polymorphisms is strongly determined by ethnic factors. The 4a/b gene polymorphism could be a genetic susceptibility factor for the BP response to salt intake and for the genetic control of NO production. The reduced NO production in subjects with the 4a/b genotype may be responsible for the increased sensitivity of their BP to salt.

Dopamine autoreceptors modulate dopamine release from the prefrontal cortex

Abstract: Electrical stimulation (at 0.3, 1, or 10 Hz, 120 pulses each) produced a calcium‐dependent overflow of radioactivity from slices of the rabbit prefrontal cortex preloaded with [3H]3,4‐dihydroxyphenylethylamine ([3H]DA, [3H]dopamine) in the presence of desipramine. Flat frequency‐release curves were observed. Apomorphine and LY‐171555 inhibited in a concentration‐dependent fashion the evoked overflow of DA, an effect antagonized by haloperidol. Stimulation frequencies comparable to normal firing rates of mesocortical neurons (10 Hz) drastically reduced apomorphine‐induced inhibition of DA overflow. Haloperidol produced greater facilitation of DA overflow at 10 than at 1 Hz. Nomifensine, a neuronal uptake inhibitor, enhanced DA overflow. These results indicate that mesocortical DA neurons projecting to the prefrontal cortex have release modulatory autoreceptors of the D2 subtype.

Nitric oxide and salt sensitivity.

Studies in laboratory animals suggest that altered nitric oxide (NO) production may be associated with salt sensitivity. In this investigation we determined whether the endogenous NO production was altered in salt-sensitive human subjects when salt intake was changed. Salt sensitivity was assessed from the magnitude of the blood pressure (BP) lowering obtained when the salt intake was reduced from high to a low intake. The combined urinary excretion of nitrites and nitrates, the major metabolites of NO, was employed as an index of endogenous NO production. Salt-sensitive subjects (n = 23) were older, heavier, and had greater waist-to-hip ratios and higher baseline BP than salt-resistant individuals (n = 25). In salt-sensitive subjects, mean blood pressure (MBP) decreased 11.8+/-0.7 mm Hg, and NO metabolite excretion increased from 823+/-102 to 1530+/-148 mmol/24 h, when salt intake was reduced from 316 to 28 micromol/day. NO metabolite excretion was 45% lower during high salt (0.66+/-0.1 micromol/mg creatinine) than during low salt intake (1.12+/-0.1 micromol/mg creatinine) (P < .001). In contrast, when salt intake was reduced, salt-resistant subjects exhibited no significant mean changes in BP or NO metabolite excretion. During low salt intake, NO metabolite excretion (micromol/ day) was significantly higher in salt-sensitive individuals. The magnitude of decrease of systolic blood pressure, diastolic blood pressure, or MBP induced by reducing salt intake was not related to the increase in urinary excretion of NO metabolite levels (r2 = 0.009; P = .66). In summary, to the extent that urinary NO metabolite levels reflect the activity of the endogenous NO system, our results support the view that salt sensitivity may in part be determined by an inability to increase or to sustain NO production in response to high salt. Insufficient NO production during high salt may in turn lead to altered pressure-natriuresis relationships and to an increase in BP. The possibility that the increase in BP induced by high salt intake in salt-sensitive individuals could be the key factor in reducing NO metabolite levels can not be ruled out.

Participation of Serotonin on Early and Delayed Emesis Induced by Initial and Subsequent Cycles of Cisplatinum‐Based Chemotherapy: Effects of Antiemetics

The role of serotonin as the possible trigger mechanism of vomiting associated with chemotherapeutic drugs was further investigated in cancer patients (n=86). Increases in 5‐hydroxyindoleacetic acid (5‐HIAA) excretion rates (2.5–2.9 times baseline values) were observed 4 to 8 hours after high‐dose cisplatinum (≥50 mg/m2). The daily excretion of 5‐HIAA from 24–48, 48–72, and 72–96 hours after cisplatinum was not different from pre‐cisplatinum levels. These results, together with the efficacy data for 5‐HT3 antagonists, suggests that serotonin may trigger the early, intense period of emesis, but not the period of delayed emesis, following high‐dose cisplatinum. Compared with the first cycle of chemotherapy, higher peak levels and more sustained elevations of 5‐HIAA excretion were found after subsequent cycles, with high‐dose cisplatinum. Further, no evidence of serotonin depletion was found after a single or after repeated cycles of treatment with high‐dose cisplatinum. These data suggest that the more intense emetic response associated to repeated cycles of treatment may be triggered by greater changes in serotonin release. No significant differences in the rate and amount of 5‐HIAA excreted induced by low‐dose (30±2 mg/m2) and high‐dose (84±3 mg/m2) cisplatinum were found between those patients who received dexamethasone (D) (20 mg IV) and those who received metoclopramide (M) (2 mg/kg, IV), irrespectively of the cycle of treatment. Interestingly, for M but not for D, best antiemetic protection was observed when lower amounts of serotonin were released (i.e., low‐dose cisplatinum and initial cycles of treatment). This suggests, that contrary to D, the effects of M, a purported antagonist of 5‐HT3 receptors, are highly dependent on the quantity of serotonin release induced by a chemotherapeutic drug. Finally, our data suggest that D does not interfere with cisplatinum‐induced serotonin release.

Urinary albumin excretion in lean, overweight and obese glucose tolerant individuals: its relationship with dyslipidaemia, hyperinsulinaemia and blood pressure.

The presence of microalbuminuria has become an important tool for therapeutic intervention. In this study we investigated whether the dysmetabolic syndrome of obesity was associated with or could occur in the absence of microalbuminuria. The study was conducted in 71 clinically healthy, glucose tolerant Hispanics (age: 43 ± 1.4 years, body mass index (BMI): 28.7 ± 0.6 kg/m2, systolic blood pressure (SBP): 117 ± 2 mm Hg, diastolic blood pressure (DBP): 77 ± 1.3 mm Hg, urinary albumin excretion: 10.2 ± 0.6 mg/24 h). Subjects were classified as lean (BMI <25), overweight (BMI >25 <30) and obsese (BMI >30 kg/m2). Greater BMI was associated with higher body weight, waist-to-hip ratio (WHR), BP, fasting insulin, triglyceride, post glucose load insulin and glucose, and lower high-density lipoprotein (HDL) cholesterol levels. However, no significant differences in the urinary albumin excretion (mg/24 h) were found between lean (9.0 ± 0.9; median: 9.1), overweight (11.3 ± 1.2; median: 10.5) and obese (11.1 ± 1.2; median: 9.7) subjects. In addition, microalbuminuria (urinary albumin excretion >30 mg/24 h) was not found in any of the study subjects. For all subjects combined, as well as for each of the groups separately, the urinary albumin excretion was unrelated to the BMI, WHR, body weight, triglyceride, cholesterol (total, LDL or HDL), fasting or post-load glucose and insulin plasma concentrations. Neither in females nor in males, abdominal fat accumulation was associated with an increase in the urinary albumin excretion. However, in the obese groups, urinary albumin excretion was strongly related to the level of SBP (r2: 0.67; P < 0.0001) and DBP (r2: 0.55; P < 0.0001). In summary, obesity, hyperinsulinaemia and dyslipidaemia per se are not determinants of increased albumin excretion. However, in the obese subjects, the BP, particularly the SBP, was a strong determinant of the level of albumin in the urine. Microalbuminuria may occur later in the course of the dysmetabolic syndrome, due to worsening of hypertension and development of hyperglycaemia.

Role of salt sensitivity, blood pressure, and hyperinsulinemia in determining high upper normal levels of urinary albumin excretion in a healthy adult population☆

BACKGROUND The objective of this study was to investigate the role of blood pressure (BP), salt sensitivity (SS), and the cardiovascular metabolic syndrome in determining the urinary albumin excretion (UAE) in glucose-tolerant, normoalbuminuric (<20 mg/day) healthy adults. METHODS AND RESULTS We evaluated 177 healthy subjects (age, 38.3 +/- 0.9 years; weight, 75.2 +/- 1.1 kg; body mass index, 28.8 +/- 0.4 kg/m(2); systolic BP, 117 +/- 1 mm Hg; diastolic BP, 77.5 +/- 0.8 mm Hg; UAE, 8.2 +/- 0.3 mg/24 h). Subjects with UAE levels of 15 to 20 mg/day had higher systolic BP, diastolic BP, and pulse pressures than those with UAE levels less than 15 mg/day (P <.0001). Hypertension (HT) and SS were more prevalent in the high normal UAE group (15 to 20 mg/day) than in groups with lower UAE (47% v 8% for HT and 67% v 24% for SS). In normotensives (n = 156), no differences in BP were observed among the different UAE strata; yet, the prevalence of SS was greater in the high (57%) compared to the low normal (17% to 21%) UAE groups. Similar levels of UAE, BP, and similar prevalence of SS were found in men with and without abdominal obesity, despite the fact that obesity was associated with hypertriglyceridemia and hyperinsulinemia. CONCLUSIONS In healthy normoalbuminuric adults, high normal UAE is associated with SS in normotensives and with SS and higher BP in a mixed population (88% normotensive and 12% hypertensive). Abdominal obesity, hypertriglyceridemia, and hyperinsulinemia were not related to UAE. Therefore, UAE levels of 15 to 20 mg/day should be accepted as microalbuminuria, and these subjects may benefit from early intervention (ie, salt restriction and BP lowering).

Rate and duration of stimulation determine presynaptic effects of haloperidol on dopaminergic neurons.

Abstract: Superfused rabbit neostriatal slices prelabeled with [3H]dopamine ([3H]DA) were depolarized with electrical pulses (12 V, 1 ms). Although transmitter release showed a proportional increase with a greater number of pulses (30‐360 pulses), flat frequency‐release curves were obtained. Haloperidol (0.03–0.3 μm) enhanced 3H overflow without affecting its metabolism or time course, and antagonized apomorphine‐induced inhibition of transmitter release. Maximal enhancement of release by haloperidol was obtained with 30–60 pulses delivered at a rate of 3 Hz, whereas much less facilitation of release was seen at 0.3 and 1 Hz (30–90 pulses) or with 360 pulses at either of the three frequencies. Therefore, the slope of the frequency‐release curve was markedly increased by haloperidol. These results indicate that activation of presynaptic DA receptors, and thus facilitation of release by haloperidol was highly dependent on the rate and duration of stimulation of striatal dopaminergic terminals. In these neurons the feedback loop seems to act physiologically to depress the slope of the frequency‐release curve.