Endothelium-dependent vascular relaxation in patients with type I diabetes.

The endothelium plays an important role in the regulation of vascular tone. Although animal data show evidence for an impaired endothelium-dependent vasodilation in diabetes, human in vivo data are scarce. We investigated 11 type I diabetic patients and 11 matched healthy control subjects. The diabetic patients were selected on their relatively poor metabolic regulation (HbA1c > 8.5%), but none showed signs of microvascular complications. In all subjects, we recorded the forearm vasodilator responses to three different stimuli: 1) 5 min of forearm ischemia to obtain a maximal vasodilator response; 2) infusion of MCh into the brachial artery (dosages: 0.03-0.3-1.0 micrograms.min-1.100 ml-1 forearm volume) to evaluate endothelium-dependent vasodilation; and 3) intra-arterial infusion of SNP (dosages: 0.06-0.2-0.6 micrograms.min-1.100 ml-1) to evaluate endothelium-independent vasodilation. The diabetic patients had their usual subcutaneous insulin dose and breakfast 90 min before the start of the test. Baseline levels of BP and FBF were similar in both groups. The PORH response was similar in both groups, with a percentage fall in FVR of 92 +/- 1% in diabetic patients and 94 +/- 1% in control subjects. In the control subjects, MCh infusions exerted a dose-dependent vasodilator response with a maximal fall in the FVR of 90 +/- 2%. The highest dose of SNP induced a fall in FVR of 81 +/- 6% in this group. In diabetic patients, the percentage decrements in FVR during the several dosages of MCh and SNP were similar when compared with the control group. We conclude that chronic hyperglycemia, as occurred in our patients with uncomplicated diabetes mellitus, does not impair endothelium-dependent vasodilation in vivo.

Adrenomedullary secretion of epinephrine is increased in mild essential hypertension.

To assess whether patients with mild essential hypertension have excessive activities of the sympathoneuronal and adrenomedullary systems, we examined total body and forearm spillovers and norepinephrine and epinephrine clearances in 47 subjects with mild essential hypertension (25 men, 22 women, aged 38.1 +/- 6.7 years) and 43 normotensive subjects (19 men, 24 women, aged 36.5 +/- 5.9 years). The isotope dilution method with infusions of tritiated norepinephrine and epinephrine was used at rest and during sympathetic stimulation by lower body negative pressure at -15 and -40 mm Hg. Hypertensive subjects had a higher arterial plasma epinephrine concentration (0.20 +/- 0.01 nmol.L-1: mean +/- SE) than normotensive subjects (0.15 +/- 0.01) (P < .01). The increased arterial plasma epinephrine levels appeared to be due to a higher total body epinephrine spillover rate in the hypertensive subjects (0.23 +/- 0.02 nmol.min-1.m-2) than the normotensive subjects (0.18 +/- 0.01) (P < .05) and not to a decreased plasma clearance of epinephrine. The arterial plasma norepinephrine level, total body and forearm norepinephrine spillover rates, and plasma norepinephrine clearance were not altered in the hypertensive subjects. The responses of the catecholamine kinetic variables to lower body negative pressure were not consistently different between normotensive and hypertensive individuals. These data indicate that individuals with mild essential hypertension (1) have elevated arterial plasma epinephrine concentrations that are due to an increased total body epinephrine spillover rate, indicating an increased adrenomedullary secretion of epinephrine; (2) have no increased generalized sympathoneuronal activity and no increased forearm norepinephrine spillover; and (3) have similar responses of both the sympathoneuronal and adrenomedullary systems to sympathetic stimulation by lower body negative pressure.

Regional release and removal of catecholamines and extraneuronal metabolism to metanephrines.

Norepinephrine (NE) and epinephrine (E) are metabolized extraneuronally by catechol-O-methyl-transferase to the metanephrines (MNs), normetanephrine (NMN) and metanephrine (MN). Subjects in this study received infusions of tritium-labeled NE and E. Concentrations of MNs and catecholamines were measured in plasma flowing into and out of the heart, forearm, lungs, kidneys, mesenteric organs (gastrointestinal tract, spleen, and pancreas), liver, and adrenals to examine the regional production of MNs from circulating and locally released catecholamines. NE spillover from mesenteric organs and kidneys accounted for 64% of the spillover from all tissues. There was detectable spillover of E from most extraadrenal tissues, but 91% was from the adrenals. The production of MNs from locally released and circulating catecholamines varied widely among tissues. The liver made the largest contribution to removal of circulating NE (57%) and E (32%) and the largest contribution to the production of NMN (54%) and MN (37%) from metabolism of circulating catecholamines. In all other tissues more NMN was produced from locally released than from circulating NE. Thus, the metabolism of circulating NE was responsible for only 19% of the total production of NMN. An even smaller portion (6%) of plasma MN was derived from metabolism of circulating E. Most plasma MN (91%) was produced within the adrenals, which also provided the largest single source (23%) of NMN. The regional variation in extraneuronal production of MNs indicates considerable heterogeneity in how circulating and locally released catecholamines are handled by different tissues. The substantial contribution of the adrenals to the production of MNs explains the extraordinary sensitivity of these metabolites for the diagnosis of pheochromocytoma.

Carboplatin (CBDCA) and radiotherapy for stage IV carcinoma of the head and neck: a phase I-II study.

The prognosis of patients with squamous cell carcinoma (SQC) of the head and neck (H&N) depends on the primary site and anatomical extent of the disease. Recurrence rates after conventional surgery (S) and/or radiotherapy (RT) remain low for localized tumors, whereas in advanced loco-regional disease they occur in over 60% of all cases. Several combinations of treatment modalities have been attempted in order to improve local control in Stages III and IV. Unfortunately, the recurrence rate remains high with added morbidity when conventional surgery is combined with pre or post-operative radiotherapy. Induction chemotherapy (CT) with Cisplatinum and Bleomycin has resulted in severe toxicities when combined with radiotherapy. To evaluate the toxicity of Carboplatin (CBDCA), a second generation platinum analog, when given simultaneously with conventional doses of radiotherapy, 26 patients with Stage IV SQC of the head and neck were treated at the University of Maryland Medical Systems. There were 23 males and 3 females; median age was 59 years and median Karnofski performance status was 60. Twenty patients had received no prior therapy; six had surgical exploration and excision with measurable residual disease. Anatomically, six patients had tumors of the oral cavity, twelve in the pharynx, one in the nasopharynx, four in the larynx, one in the hypopharynx, one in the maxillary antrum, and one was an unknown primary. These patients were treated as out-patients with weekly injections of Carboplatin. The dose was escalated: two patients received 60 mg/M2, seven received 75 mg/M2, thirteen were treated with 100 mg/M2, and four with 400 mg/M2. The radiotherapy was given daily with conventional fractions of 180 cGy and total tumor doses of 60-75 Gy. Toxicities were mainly hematological with median nadirs decreasing with increasing doses of Carboplatin. Mucositis was seen in over 80% of the patients, but interestingly enough, it has never been more severe than that observed with radiotherapy alone. So far, there has not been any kidney, ear, or neurotoxicities. Of 25 evaluable patients, 19 (76%) responded with 13 (52%) showing complete response. The overall median survival time is 266+ days (324+ for responders and 179+ for non-responders). The follow-up is still short, 10-14 months, but 9 of 13 patients with complete response have not yet progressed.

The use of carboplatin and paclitaxel with daily radiotherapy in patients with locally advanced squamous cell carcinomas of the head and neck.

PURPOSE: Unresectable squamous cell carcinomas of the head and neck (SCCHN) continue to pose a significant therapeutic challenge. This report defines the toxicities, efficacy, and prognostic factors associated with the combination of carboplatin (CBDCA), paclitaxel, and once-daily radiation for patients with locally advanced disease. Additionally, the pharmacokinetics of paclitaxel were investigated. METHODS AND MATERIALS: From 1993-1998, 62 patients with Stage III-IV SCCHN were treated with 70.2 Gy of RT at 1.8 Gy/fraction/day to the primary site. Weekly chemotherapy was given during RT consisting of paclitaxel (45 mg/m(2)/wk) and CBDCA (100 mg/m(2)/wk). All patients presented with locally advanced disease; 77% had T4 disease and 21% had T3 disease. Fifty-eight percent had N2b-N3 disease. RESULTS: Sixty patients were evaluable for response and survival with a median follow-up of 30 months (range 7-70). Ninety-eight percent of patients completed prescribed therapy. One patient died after refusing medical management for pseudomembranous colitis and is scored as a Grade 5 toxicity. Two patients suffered Grade 4 leukopenia. Median number of break days was two. A clinical complete response (CR) at the primary site was obtained in 82%, with a total (primary site and neck) CR rate of 75%. The median survival for the entire cohort is 33 months. Response to therapy and status of the neck at presentation were the only prognostic factors found to influence survival. The median survival for patients who attained a CR is 49 months versus 9 months in those who did not attain a CR (p < 0.0001). The 2- and 3-year overall survival for complete responders are 79% and 61%. Plasma paclitaxel concentrations in the range shown to be radiosensitizing were achieved. CONCLUSIONS: Weekly carboplatin and paclitaxel given concurrently with definitive once-daily external beam radiation therapy is well tolerated with over 90% of patients completing prescribed therapy. An ultimate CR rate of greater than 70% was obtained, which translated directly into improved survival. With 48% 3-year overall survival for the entire group, this regimen is an excellent option for this group of patients with a historically poor prognosis.

Chronic alpha-1-adrenergic blockade increases sympathoneural but not adrenomedullary activity in patients with essential hypertension.

OBJECTIVE: Doxazosin, a selective alpha1-adrenoceptor antagonist, lowers blood pressure by reducing peripheral vascular resistance without causing reflex tachycardia. To discover whether antihypertensive treatment with an alpha1-adrenoceptor blocker is accompanied by an increase in sympathoadrenomedullary activity, we studied plasma catecholamine kinetics before and during treatment with doxazosin. PATIENTS AND METHODS: Eleven patients with essential hypertension were studied before and after 3 months' treatment with doxazosin (4-8 mg a day). 3H-noradrenaline and 3H-adrenaline were infused simultaneously and blood samples were collected to calculate plasma catecholamine kinetics before and during sympatho-adrenomedullary stimulation (lower-body negative pressure). RESULTS: Doxazosin decreased systolic and diastolic blood pressure and forearm vascular resistance, whereas the heart rate did not change significantly. During doxazosin, baseline arterial plasma noradrenaline increased from 0.97 +/- 0.07 to 1.21 +/- 0.07 nmol/l, and this appeared to be due to an increase in total body noradrenaline spillover from 1.54 +/- 0.15 to 1.84 +/- 0.16 nmol/min; noradrenaline clearance did not change significantly. Forearm noradrenaline spillover also increased, from 0.89 +/- 0.18 to 1.48 +/- 0.23 pmol/100 ml per min. In contrast, arterial plasma adrenaline, total body adrenaline spillover and adrenaline clearance were not significantly affected by doxazosin treatment. The response of plasma noradrenaline and total body and forearm spillover of noradrenaline to lower-body negative pressure (-40 mmHg) was significantly increased during doxazosin administration, whereas the response of the adrenaline kinetic parameters were not altered. CONCLUSIONS: The blood pressure reduction induced by a chronic administration of the alpha1-adrenoceptor blocker doxazosin elicits a baroreceptor-mediated reflexive increase in sympathoneural but not in adrenomedullary activity. The latter finding might partly explain why the heart rate is not increased during chronic treatment with this alpha1-adrenoceptor blocking drug.

Rodent cell transformation and immediate early gene expression following 60-Hz magnetic field exposure.

Some epidemiological studies suggest that exposure to power frequency magnetic fields (MFs) may be associated with an elevated risk of human cancer, but the experimental database remains limited and controversial. We investigated the hypothesis that 60-Hz MF action at the cellular level produces changes in gene expression that can result in neoplastic transformation. Twenty-four hour 200 microT continuous MF exposure produced negative results in two standard transformation systems (Syrian hamster embryo cells and C3H/10T1/2 murine fibroblasts) with or without postexposure to a chemical promoter. This prompted a reexamination of previously reported MF-induced changes in gene expression in human HL60 cells. Extensive testing using both coded and uncoded analyses was negative for an MF effect. Using the same exposure conditions as in the transformation studies, no MF-induced changes in ornithine decarboxylase expression were observed in C3H/10T1/2 cells, casting doubt on a promotional role of MF for the tested cells and experimental conditions.

Combined carboplatin plus bleomycin and conventional radiotherapy for advanced carcinomas of the head and neck.

In a previous study, we reported a 72% response rate (CR = 52%) in patients with unresectable head and neck (H&N) carcinomas treated with simultaneous carboplatin (CBDCA) and radiotherapy (RT). Bleomycin (Bleo), a known radiosensitizing agent, has been shown to increase response rates when given together with RT in similar patients. To explore the nonoverlapping toxicities of these two agents, we combined i.v. CBDCA (100 mg/m2/week), Bleo (5 units on day 1 and 4/weekly) and standard doses of RT in patients with unresectable H&N carcinomas. Chemotherapy (CT) was continued until completion of RT. Twenty-three (13 males, 10 females) previously untreated patients with stage IV squamous cell carcinoma of the H&N were treated at the University of Maryland Medical Center: 61% had oropharyngeal cancers; 26%, hypopharynx; 9%, oral cavity; and 4%, an unknown primary. Moderate to severe mucositis developed in 90%, which required RT interruptions of up to 3 weeks. After a median follow-up (FU) of 18 months, 35% achieved a complete response (CR) and 65% died from progressive disease. These preliminary data suggest that the addition of Bleo increases mucosal toxicity substantially and, while a moderate response rate was observed, it is unlikely that the CR rate will be higher than CBDCA/RT, which was also better tolerated and hence more suitable to multimodal approaches.

Embryotoxicity of human sera from patients treated with isotretinoin.

Sera of 20 patients treated with 20-40 mg isotretinoin/day were tested for embryotoxicity potential. For each patient, the first sample was taken before treatment (control sample) and the second was taken 2 months after the start of treatment (treated sample). Six embryos displaying six or seven pairs of somites were cultured for 26 hr in each serum sample, when sufficient serum was available. No deaths were observed in the control sample, whereas dead embryos (6%) were observed in the treated sample. The rates of malformed embryos were 13 and 81% in the control and in the treated sample, respectively. The most frequent abnormalities affected the cephalic neural tube, the branchial bars, the yolk sac circulation and the caudal neural tube. Growth and differentiation were significantly decreased in the treated sample. The concentrations of isotretinoin and of two metabolites (trans-retinoic acid and 4-oxo-isotretinoin) were measured in 12 sera. A correlation between embryotoxicity and concentration was established for two of the chemicals. Modulation of the embryotoxicity by drug-induced changes in the serum cannot be excluded.

Intravenous instrumentation alters the autonomic state in humans.

Intravascular instrumentation may induce syncope or presyncope. It is not known whether asymptomatic subjects also have autonomic reactions, albeit concealed. We addressed this issue by studying 44 healthy young male subjects of various levels of fitness, ranging from inactivity to athletic [mean maximal oxygen uptake was 49.1 (SD 10.7) ml*kg(-1)*min(-1), range 28.7-71.9 ml*kg(-1)*min(-1)]. The autonomic response to venous cannulation was quantified by measuring heart rate before cannulation (HR(1)), after cannulation (HR(2)), and after complete pharmacological autonomic blockade (HR(0) = the intrinsic heart rate). The sympathovagal balance before and after cannulation was computed as HR(1)/HR(0) and HR(2)/HR(0), respectively. The group means of heart rate and sympathovagal balance decreased significantly (paired Student's t-test P <0.01) from 62.5 to 59.9 beats*min(-1), and from 0.71 to 0.68, respectively. The maximal decrease in heart rate was 8.8 beats*min(-1), and in the sympathovagal balance was 0.11. Our study demonstrated that the asymptomatic subjects responded to intravenous instrumentation with a concealed autonomic reaction. Thus, from our findings it would seem that intravenous instrumentation interferes with measurements relating to autonomic nervous system activity.

Patch testing with preservatives at St John's from 1982 to 1993.

We have reviewed our patch test results for preservative allergy from 1982 to 1993. 8 preservatives were included: formaldehyde, 2-bromo-2-nitropropane-1,3-diol (Bronopol(TM)), quaternium-15 (Dowicil 200TM), imidazolidinyl urea (Germall 115TM), diazolidinyl urea (Germall IITM), parabens, 5-chloro-2methyl-isothiazolin-3-one (Kathon CG(TM)) and 1,2-dibromo-2,4-dicyanobutane (one of the constituents of Euxyl K 400TM). Whereas the allergy rate to formaldehyde is quite stable, there is a slight increase in the imidazolidinyl urea allergy rate. Quaternium-15's rate is decreasing and 5-chloro-2-methyl-isothiazolin-3-one plus 2-methyl-isothiazolin-3-one's rate, after a rapid rise, seems to have stabilized. Although very important constituents of cosmetics, preservatives not only induce allergies on the face but also on the hands, and, as expected, the allergy rate in men and women generally differs. Among the 5 formaldehyde-releasers, there are some favoured simultaneous reactions: quaternium-15 and formaldehyde, and diazolidinyl urea and imidazolidinyl urea. Concomitant reactions between 1-bromo-2-nitropropane-1,3-diol and formaldehyde are not common, and those between 2-bromo-2-nitropropane-1,3-diol and diazolidinyl urea, and formaldehyde are not very common. This supports the hypothesis that allergic reactions to the Germalls are directed toward the initial molecule rather than to formaldehyde.

Effect of chronic smoking on endothelium-dependent vascular relaxation in humans.

1. Cigarette smoking is one of the major risk factors for the development of atherosclerosis. It is not clear, however, whether chronic cigarette smoking impairs the normal physiological function of the endothelium before the development of morphological vascular lesions. To test this, we investigated endothelium-dependent vascular relaxation in young habitual smoking subjects. 2. In 11 non-smokers and 10 habitual smokers we measured the changes in bilateral forearm blood flow, arterial blood pressure and forearm vascular resistance (ratio between mean arterial blood pressure and forearm blood flow) during three interventions: post-occlusive forearm hyperaemia, intrabrachial infusion of methacholine which causes vasodilatation by stimulating the release of endothelium-dependent relaxing factor, and intrabrachial infusion of sodium nitroprusside which causes vasodilatation independently from the endothelium by a direct effect on the vascular smooth muscle wall. 3. During infusion of the highest dose of methacholine, forearm vascular resistance decreased by 91.7 +/- 1.4% in the smokers and by 89.9 +/- 1.8% in the non-smokers. During infusion of sodium nitroprusside, forearm vascular resistance decreased by 80.0 +/- 3.8% in the smokers as compared with 80.7 +/- 6.1% in the non-smokers. There was no difference in basal forearm vascular resistance or in post-ischaemic reactive hyperaemia between smokers and non-smokers. Thus, vasodilatation induced by both methacholine and sodium nitroprusside was not significantly different between smokers and non-smokers. 4. We conclude that in young habitual cigarette smokers the endothelium-dependent vasodilation in the forearm seems to be preserved, suggesting that habitual smoking does not result in permanent endothelial dysfunction in the human forearm.

Effects of acute and chronic angiotensin converting enzyme inhibition by spirapril on cardiovascular regulation in essential hypertensive patients. Assessment by spectral analysis and haemodynamic measurements.

1. The effects of a first dose and of chronic treatment with spirapril, a novel angiotensin converting enzyme (ACE) inhibitor, on short-term blood pressure and heart rate fluctuations were assessed by fast Fourier spectral analysis. The effects on systemic haemodynamics in supine and standing position were also studied. We treated 11 patients with 3 mg and 13 patients with 12 mg spirapril for 8 weeks. 2. Overall blood pressure variability was not changed by spirapril. By spectral analysis the changes in blood pressure and heart rate variability in various frequency bands can be assessed, which may be related to changes in activity of the autonomic nervous system. The relative power in the mid-frequency band (0.08-0.12 Hz) of supine systolic pressure was 23 +/- 10% during placebo and decreased during treatment with 12 mg to 11 +/- 4% (P < 0.01 vs placebo, first dose) and to 13 +/- 6% (P < 0.01, chronic treatment). Standing systolic mid-frequency power was 38 +/- 12% during placebo and decreased to 27 +/- 9% (P < 0.01 vs placebo) after the first dose of 12 mg, but it did not decrease after chronic treatment (29 +/- 13%). Treatment with 3 mg induced no changes in mid-frequency blood pressure variability. A decrease in power of the mid-frequency band may point to a decrease in sympathetic vascular drive. The power in the high-frequency band (0.15-0.40 Hz) of heart rate did not change after treatment, suggesting that there is no change in the vagal cardiac drive. 3. Supine blood pressure decreased by a decrease in vascular resistance by 16 +/- 23% (3 mg) and 14 +/- 19% (12 mg) after 8 weeks treatment. Heart rate, stroke volume and cardiac output did not change. No orthostatic hypotension occurred after the first dose. In the 12 mg group the orthostatic induced rise in heart rate (compared with supine) increased from + 9 +/- 5 beats min-1 (placebo) to + 14 +/- 4 beats min-1 (P < 0.05) after the first dose. No changes in the orthostatic heart rate increase occurred in the 3 mg group. The orthostatic changes in stroke volume, cardiac output and vascular resistance were not influenced by spirapril. 4. In conclusion, the decrease in mid-frequency blood pressure variability may suggest an inhibitory effect of acute and chronic ACE inhibition upon sympathetic vasomotor control. Vagal activity was not influenced as high-frequency heart rate variability did not change. Acute and chronic ACE inhibition did not blunt important cardiovascular reflexes, as the haemodynamic response to orthostasis remained intact.

Role of radiation therapy in the management of malignant chondroid syringoma.

BACKGROUND: Malignant sweat gland neoplasms are exceedingly rare tumors. Malignant chondroid syringoma (MCS) is one of the rarest subtypes, and as such, still poorly understood. It lacks distinctive clinical features, often delaying initial diagnosis and therapeutic management. OBJECTIVE: A current case and the available literature are reviewed to determine the overall clinical course of the MCS and the potential role of adjuvant therapy. METHODS: A case of MCS was studied by light microscope, immunohistochemistry, and electron microscopy. The clinical data of this case and of other reported cases are summarized and compared. RESULTS: This tumor recurred locally after initial local excision. Subsequent re-excision and radiation therapy rendered the patient without evidence of disease. This case study and the literature review of the 20 reported cases indicate that MCS is highly recurrent with tendency toward metastasis. CONCLUSION: MCS appears to behave in an aggressive manner. An initial treatment modality is aggressive surgery. Adjuvant radiation therapy with or without chemotherapy should be tried in future cases.

Long-term beta 1-adrenergic blockade restores adrenomedullary activity in primary hypertension.

In this study we examined the effects of long-term treatment of 19 patients with primary hypertension with the beta 1-adrenoceptor antagonist atenolol on norepinephrine and epinephrine kinetics, at rest and during sympathoadrenal stimulation by lower body negative pressure. Norepinephrine and epinephrine kinetics were measured by using the radioisotope-dilution technique by steady-state infusion of tritiated norepinephrine and epinephrine. The patients were studied before and at the end of 3 months of treatment with atenolol (50 or 100 mg daily). A control group of four normotensive subjects was studied before and after 3 months without any drug treatment. In this group, only arterial blood samples were collected without infusion of the tritiated catecholamines. Atenolol decreased blood pressure and heart rate, but forearm vascular resistance was not affected by atenolol. During atenolol, baseline arterial plasma epinephrine decreased from 0.23 +/- 0.02 to 0.17 +/- 0.01 nM (p < 0.05), and this was accompanied by a decrease in total body epinephrine spillover from 0.50 +/- 0.05 to 0.35 +/- 0.04 nmol/min (p < 0.05). In the control group, arterial plasma epinephrine had not decreased after 3 months. In addition, the increment of arterial plasma epinephrine during lower body negative pressure at -40 mm Hg was attenuated during atenolol. Atenolol had no effect on total body and forearm norepinephrine spillover rates, either at rest or during lower body negative pressure. Clearance rates of epinephrine and norepinephrine were not significantly affected by atenolol. These results suggest that treatment of patients with primary hypertension with the beta 1-adrenoceptor blocker atenolol inhibits the adrenomedullary secretion of epinephrine, but it does not affect the biochemical indices of sympathoneural activity. It remains speculative whether this selective effect of atenolol on epinephrine secretion contributes to its hypotensive action and to its cardioprotective effects in the long term.

Atrial natriuretic factor potentiates the human forearm vasoconstrictor response to sympathetic stimulation.

1. Atrial natriuretic factor has been suggested to affect human sympathetic nervous system activity. The interaction between atrial natriuretic factor and the sympathetic nervous system has not been fully elucidated yet, but may occur at different sites. We studied this modulator effect at the level of the forearm vascular bed: the forearm vasoconstrictor response was examined after alpha-adrenergic sympathetic stimulation in healthy subjects during the locoregional administration of atrial natriuretic factor, sodium nitroprusside and placebo. As a sympathetic stimulation test, the technique of the lower body negative pressure (-20 mmHg) was used. 2. Lower body negative pressure increased the forearm vascular resistance by +37 +/- 8% during concomitant intra-arterial infusion of placebo (n = 10). During a predilator state achieved by infusion of atrial natriuretic factor (10 ng min-1 100 ml-1 forearm volume) into the brachial artery, lower body negative pressure subsequently induced a forearm vasoconstrictor response of +153 +/- 22% (P < 0.05 versus placebo), whereas this was +64 +/- 14% when predilatation was achieved by infusion of an equipotent vasodilator dose of sodium nitroprusside (P > 0.1 versus placebo; P < 0.05 versus atrial natriuretic factor). The potentiation of the forearm vasoconstrictor response to lower body negative pressure by atrial natriuretic factor only occurred in the experimental and not in the contralateral arm. According to calculations on simultaneously sampled arterial and venous plasma catecholamine concentrations, the augmented forearm vasoconstrictor response seemed not to be caused by an increased release of noradrenaline.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential effects of low- and high-intensity lower body negative pressure on noradrenaline and adrenaline kinetics in humans.

1. Lower body negative pressure provides a means to examine neurocirculatory reflexive responses to decreases in venous return to the heart. We assessed whether the pattern of catecholaminergic responses to lower body negative pressure depends on the intensity of the stimulus (-15 versus -40 mmHg). 2. In 14 healthy subjects, responses of forearm blood flow and noradrenaline spillover and of total body noradrenaline and adrenaline spillover were assessed during infusion of [3H]noradrenaline and [3H]adrenaline during -15 and -40 mmHg of lower body negative pressure. 3. During lower body negative pressure at -15 mmHg, heart rate and pulse pressure did not change, but forearm vascular resistance increased by 25-50%. Forearm noradrenaline spillover increased by about 50%, from 0.63 +/- 0.16 to 0.94 +/- 0.23 pmol min-1 100 ml-1 (P < 0.05). Total body noradrenaline spillover did not change, and total body adrenaline spillover increased significantly by about 30%. Clearances of noradrenaline and adrenaline were unchanged. 4. During lower body negative pressure at -40 mmHg, heart rate increased and pulse pressure decreased. Forearm vascular resistance increased by about 100%, and forearm noradrenaline spillover increased by 80%, from 0.73 +/- 0.19 to 1.32 +/- 0.36 pmol min-1 100 ml-1 (P < 0.05). Total body noradrenaline spillover increased by 30%, and total body adrenaline spillover increased by about 50%. Clearances of both noradrenaline and adrenaline decreased. 5. The results are consistent with the view that selective deactivation of cardiopulmonary baroreceptors during low-intensity lower body negative pressure increases sympathoneural traffic to forearm skeletal muscle and increases adrenomedullary secretion without a concomitant generalized increase in sympathoneural outflows. Concurrent deactivation of cardiopulmonary and arterial baroreceptors during high-intensity lower body negative pressure evokes a more generalized increase in sympathoneural activity, accompanied by further increased adrenomedullary secretion and decreased plasma clearances of noradrenaline and adrenaline. The findings support differential increases in skeletal sympathoneural and adrenomedullary outflows during orthostasis, with more generalized sympathoneural responses to systemic hypotension.