Quality assurance of radiotherapy in the ongoing EORTC 1420 "Best of" trial for early stage oropharyngeal, supraglottic and hypopharyngeal carcinoma: results of the benchmark case procedure.

INTRODUCTION: The current phase III EORTC 1420 Best-of trial (NCT02984410) compares the swallowing function after transoral surgery versus intensity modulated radiotherapy (RT) in patients with early-stage carcinoma of the oropharynx, supraglottis and hypopharynx. We report the analysis of the Benchmark Case (BC) procedures before patient recruitment with special attention to dysphagia/aspiration related structures (DARS). MATERIALS AND METHODS: Submitted RT volumes and plans from participating centers were analyzed and compared against the gold-standard expert delineations and dose distributions. Descriptive analysis of protocol deviations was conducted. Mean Sorensen-Dice similarity index (mDSI) and Hausdorff distance (mHD) were applied to evaluate the inter-observer variability (IOV). RESULTS: 65% (23/35) of the institutions needed more than one submission to achieve Quality assurance (RTQA) clearance. OAR volume delineations were the cause for rejection in 53% (40/76) of cases. IOV could be improved in 5 out of 12 OARs by more than 10 mm after resubmission (mHD). Despite this, final IOV for critical OARs in delineation remained significant among DARS by choosing an aleatory threshold of 0.7 (mDSI) and 15 mm (mHD). CONCLUSIONS: This is to our knowledge the largest BC analysis among Head and neck RTQA programs performed in the framework of a prospective trial. Benchmarking identified non-common OARs and target delineations errors as the main source of deviations and IOV could be reduced in a significant number of cases after this process. Due to the substantial resources involved with benchmarking, future benchmark analyses should assess fully the impact on patients' clinical outcome.

High-dose re-irradiation of intracranial lesions - Efficacy and safety including dosimetric analysis based on accumulated EQD2Gy dose EQD calculation.

INTRODUCTION: The use of cranial re-irradiation is growing with improving overall survival and the advent of high-precision radiotherapy techniques. Still the value of re-irradiation needs careful evaluation regarding safety and efficacy. We analyzed dosimetric and clinical data of patients receiving cranial re-irradiation using EQD2 sum plans. METHODS AND MATERIAL: We retrospectively analyzed the data of 76 patients who received repeated cranial radiotherapy from 02/2013 to 09/2016. 34 patients suffered from recurrent primary brain tumors, 42 from brain metastases. Dosimetric analysis was performed accumulating EQD2 dose distributions based on rigid image registration. Clinical and radiological data was collected at follow-ups including toxicity, local control and overall survival. RESULTS: In total 76 patients had at least 2 courses of intracranial radiotherapy. The median accumulated prescription EQD2 dose was 96.5 Gy2 for all radiation courses combined. The median D(0.1 cc) of the brain for patients receiving more than 100 Gy2 was 114 Gy2 with a highest dose of 161.5 Gy2. 74% of patients suffered from low grade (G1-G2) acute toxicity, only two high grade (>G3) toxicities were recorded.Median overall survival from the time of first re-irradiation was 57 weeks (range 4-186 weeks). The median time to local failure for patients with a primary brain tumor was not reached and 24 weeks (range 1-77 weeks) for patients with brain metastases. CONCLUSION: Repeated radiotherapy appears both safe and efficient in patients with recurrent primary or secondary brain tumors with doses to the brain up to 120 Gy2 EQD2, doses below 100 Gy2 for brainstem and doses below 75 Gy2 EQD2 to chiasm and optic nerves.

Re-irradiation in the thorax - An analysis of efficacy and safety based on accumulated EQD2 doses.

INTRODUCTION: Thoracic re-irradiation remains a challenge regarding the balance of local efficacy and acceptable toxicities. In this retrospective analysis we analyzed dosimetrical and clinical data of patients treated with thoracic re-irradiation based on accumulated EQD2Gy doses. METHODS AND MATERIAL: We retrospectively analyzed the data of 42 consecutive single-institutional patients treated with repeated courses of thoracic radiotherapy from 12/2011 to 01/2017. Accumulated EQD2 dose distributions were calculated and dose parameters for organs at risk and target volumes were analysed. RESULTS: The median prescription dose was 42.2 Gy (10-70.6 Gy) for all RT courses. The median Dmean of both lungs was 10.1 Gy3 (range: 1.9 Gy3-17.9 Gy3) with a maximum D0.1 cc of 253.86 Gy3. The median D0.1 cc of the esophagus was 62.2 Gy3 with a maximum of 103.78 Gy3. The maximum D0.1 cc for the bronchial tree was 187.33 Gy3 (median 74.35 Gy3) and for the Aorta 216.1 Gy3 (median 70.9 Gy3). Median OS after first re-irradiation was 19 months (range 1-45 months). 12-month local control after a course of re-irradiation was 52.6%. 80% of patients suffered from a G1-G2 toxicity, most frequently coughing. One patient suffered from a G5 complication probably unrelated to re-irradiation. CONCLUSION: Even though several organs at risk received maximum accumulated doses of >100 Gy3, thoracic reirradiation resulted in an acceptable toxicity profile. Local tumor control and overall survival remained encouraging even after multiple courses of thoracic radiotherapy.

Interhemispheric coordination of premotor neural activity during singing in adult zebra finches.

The song system, a neural network that mediates the learning and production of song by oscine songbirds, is investigated extensively as a model system for understanding the neural basis of complex skill learning. Part of the complexity of birdsong arises from the coordinated recruitment of multiple groups of muscles on both sides of the body. Although the song system is bilaterally organized, little is known about how premotor activities on the two sides are coordinated during singing. We investigated this by unilaterally recording neural activity in the forebrain song nucleus HVc (also known as the high vocal center) during singing and by forcing the premotor activities in the two hemispheres out of synchrony by perturbing neural activity in the contralateral HVc with electrical stimulation. Perturbing the activity in one HVc at any time during a song led to a short-latency readjustment of activity in the contralateral HVc. This readjustment consisted of a true resetting of the temporal pattern of activity in the contralateral HVc rather than merely a transient activity suppression overlaid on an unaltered pattern of premotor activity. These results strongly suggest that the output of song premotor areas in the forebrain is continuously monitored and that an active mechanism exists for resynchronizing the outputs from the two hemispheres whenever their gross temporal patterns differ significantly. The possible anatomical substrates for these coordinating mechanisms and their potential roles in song learning are discussed.

Early and intermediate term clinical outcome after multiple coronary stenting.

OBJECTIVE: To examine the immediate and intermediate term clinical outcome of multiple coronary stenting. DESIGN: Consecutive patients were prospectively entered on a dedicated database. Follow up information was obtained from outpatient and telephone interviews with patients and family physicians. SETTING: A tertiary referral centre. PATIENTS: 140 consecutive patients underwent multiple coronary stenting between April 1994 and November 1996. Most patients had unstable coronary syndromes. MAIN OUTCOME MEASURES: Death, cerebrovascular accidents, myocardial infarction (MI), coronary artery bypass surgery (CABG), and repeat angioplasty (PTCA). RESULTS: The angiographic success rate was 100% and the clinical procedural success rate 93%. The mean (SD) follow up was 11.9 (7.2) months (range 2-32). The mean (SD) number of stents per patient was 2.4 (0.7). The mean (SD) number of lesions treated per patient was 1.4 (0.6). There were four in-hospital deaths (2.9%) and five patients (3.6%) had an MI before hospital discharge. All in-hospital deaths occurred in patients presenting with an acute MI and cardiogenic shock. Three patients (2.2%) had a late MI. One patient with stent thrombosis underwent emergency CABG. Three patients (2.2%) underwent late CABG. Eight patients (5.7%) had a repeat PTCA. Eighty three patients (61.5%) were asymptomatic at follow up and 121 (86.4%) were free from major clinical events. CONCLUSION: In an era of increased operator experience, high pressure stent deployment, and reduced anticoagulation with antiplatelet treatment alone, multiple coronary stenting may be performed with a high procedural success rate and good intermediate term outcome.

Multiple coronary stenting in unstable angina: early and late clinical outcomes.

We examined clinical outcomes in 110 consecutive patients with unstable angina who underwent multiple coronary stenting over a 32-mo period. The main outcome measures were death, stroke, myocardial infarction, bypass surgery, and repeat angioplasty. The angiographic success rate was 100%, and the procedural success rate was 96%. There were no in-hospital deaths and five (4.5%) patients had a myocardial infarction prior to discharge. There were four (3.6%) stent thromboses with one (0.9%) patient requiring urgent bypass surgery and two (1.8%) requiring repeat angioplasty. At late follow-up (11.9+/-7.1 mo), there was (0.9%) death and three patients (2.8%) suffered myocardial infarction. Three (2.8%) patients underwent late bypass surgery and five (4.6%) had a repeat angioplasty. At follow-up, 86% of patients were event free. We conclude that multiple coronary stenting in unstable angina may be performed with a high procedural success rate and good long-term outcome.

Bilateral feedback projections to the forebrain in the premotor network for singing in zebra finches.

A discrete neural circuit mediates the production of learned vocalizations in oscine songbirds. Although this circuit includes some bilateral pathways at midbrain and medullary levels, the forebrain components of the song control network are not directly connected across the midline. There have been no previous reports of bilateral projections from medullary and midbrain vocal control nuclei back to the forebrain song system, but the existence of such bilateral corollary discharge pathways was strongly suggested by the recent observation that unilateral stimulation of a forebrain song nucleus during singing leads to a rapid readjustment of premotor activity in the contralateral forebrain. In the present study, we used neuroanatomical tracers to demonstrate bilateral projections from (a) the rostral ventrolateral medulla (RVL), which may control respiratory aspects of vocalization, to nucleus uvaeformis (Uva), and (b) the dorsomedial intercollicular nucleus (DM), a midbrain vocal control region, to Uva. Both RVL and DM receive descending projections from the forebrain song nucleus robustus archistriatalis, and Uva projects directly to the forebrain song nuclei interfacialis and high vocal center. We suggest that the bilateral feedback projections from DM and RVL to Uva function to coordinate the two hemispheres during singing in adult songbirds and to convey internal feedback of premotor signals to the forebrain in young birds that are learning to sing.

Postexcitatory inhibition of the crayfish lateral giant neuron: a mechanism for sensory temporal filtering.

Crayfish escape from threats by either giant neuron-mediated "reflex" tail flexions that occur with very little delay but do not allow for much sensory guidance of trajectory or by "nongiant" tail flexion responses that allow for sensory guidance but occur much less promptly. Thus, when a stimulus occurs, the nervous system must make a rapid assessment of whether to use the faster reflex system or the slower nongiant one. It does this on the basis of the abruptness of stimulus onset; only stimuli of very abrupt onset trigger giant-mediated responses. We report here that stimuli which excite the lateral giant (LG) command neurons for one form of reflex escape also produce a slightly delayed postexcitatory inhibition (PEI) of the command neurons. As a result, only stimuli that become strong enough to excite the command neurons to firing threshold before the onset of PEI, within a few milliseconds of stimulus onset, can cause giant-mediated responses. This inhibition is directed to distal dendrites of the LG neurons, which allows for some location specificity of PEI within the sensory field of a single hemisegment.

A 12-lipoxygenase product, 12-hydroxyeicosatetraenoic acid, is increased in diabetics with incipient and early renal disease.

Earlier studies in diabetic animal models or ex vivo from diabetics suggest a deficiency in prostacyclin (PGI2) production and an increase in an alternate arachidonic acid metabolite, 12-hydroxyeicosatetraenoic acid (12-HETE), which stimulates angiogenesis, mitogenesis, and inhibits renin secretion. We studied the urinary excretion rate of 6-keto-PGF1 alpha (a stable metabolite of PGI2) and 12-HETE in controls and 42 noninsulin-dependent diabetes mellitus (NIDDM) patients with normal renal function and those with micro- or macroalbuminuria/hyporeninemic hypoaldosteronism (HH). The 2 eicosanoids were measured in urine using previously described high pressure liquid chromatography and RIA methods. Normal subjects and patients with NIDDM and microalbuminuria were infused with low dose calcium infusions that stimulate prostacyclin production in normal subjects. The PGI2 excretion rate of NIDDM patients with normal renal function was not different from that of controls (143 +/- 17 vs. 118 +/- 34 ng/g creatinine), but was reduced in those with microalbuminuria (75 +/- 10) and in macroalbuminuria patients (48 +/- 7; P < 0.01). In contrast, 12-HETE was increased in diabetics with normal renal function as well as in those with micro- or macroalbuminuria patients (69 +/- 18 vs. 250 +/- 62 vs. 226 +/- 60 and 404 +/- 131 ng/g creatinine; P < 0.01). Calcium did not stimulate PGI2, but increased 12-HETE in diabetics with microalbuminuria in contrast to levels in normal subjects. HH patients excreted less PGI2 (as previously reported), but had increased 12-HETE. HETE/PGI2 ratios further demonstrated these changes in the various groups. In a nondiabetic hypertensive microalbuminuria group, 12-HETE excretion was normal (73 +/- 28 ng/g creatinine). We conclude that the lipoxygenase product 12-HETE is increased early in the diabetic process, whereas PGI2 production is progressively impaired in NIDDM. These changes may play a role in the vascular disease of diabetes and partially explain the HH syndrome.

Renin response to 12-hydroxyeicosatetraenoic acid is increased in diabetic rats.

Eicosanoids (prostaglandins) can alter renin secretion and angiotensin (ANG) II action. We have studied the effects of both prostacyclin and a lipoxygenase (LO) product, 12-hydroxyeicosatetraenoic acid (12-HETE), on renin in normal and streptozotocin-induced diabetic rats. 12-HETE is not only a potent inhibitor of basal renin secretion but also a key mediator of ANG II-induced renin inhibition. We have also examined the effects of ANG II on 12-HETE formation in normal and diabetic animals. Both plasma (3.9 +/- 0.9 vs. 0.8 +/- 0.1 ng ANG I.ml-1.h-1, P < 0.01) and tissue (38 +/- 6 vs. 21 +/- 2 ng ANG I.mg tissue-1.h-1, P < 0.05) renin activity levels were markedly reduced in diabetic animals. Iloprost (10(-6) mol/l), a stable analog of prostacyclin, had similar stimulatory effects on renin secretion in both normal and diabetic tissues, but the response was enhanced by LO inhibition in diabetic tissue. 12-HETE (10(-7) mol/l) had an exaggerated effect on renin inhibition in diabetic tissue (78 +/- 2% normal vs. 65 +/- 4% diabetic, P < 0.05). Similarly, ANG II (10(-8) mol/l) inhibition of renin was significantly enhanced in diabetic rats (P < 0.001). However, ANG II did not produce an exaggerated increase in 12-HETE in diabetic renal tissue. Insulin reversed the inhibitory effects of ANG II on renin in normal rats, but it blunted the effect of ANG II in diabetic rats. These studies suggest that, while the capacity of renal cortical tissue to synthesize 12-HETE in response to ANG II is not altered, 12-HETE and ANG II actions are exaggerated in diabetes, and this may contribute to reduced renin production.

Identification of a forebrain motor programming network for the learned song of zebra finches.

The stereotyped delivery of sequences of vocalizations by singing zebra finches is thought to be mediated by a "central motor program." We hypothesized that electrically stimulating, and thus perturbing, the neural components of this motor program during singing should alter the subsequent singing pattern. In contrast, perturbing the activity of other neurons in the song motor pathway that do not participate directly in generating the song temporal pattern should not affect the singing pattern. We found that unilaterally stimulating the forebrain area RA of singing birds with chronically implanted electrodes distorted ongoing syllables without changing the order or timing of ensuing syllables. However, stimulating forebrain area HVc, which projects directly to RA, altered both ongoing syllables and the ensuing song pattern. These findings indicate that syllable sequencing during singing is organized in forebrain areas above RA (including HVc) and that the resulting pattern is imposed on lower structures of the motor pathway. Furthermore, the observation that unilateral forebrain perturbation was sufficient to alter the pattern of this bilaterally organized behavior suggests that (non-auditory) feedback pathways to the forebrain exist to coordinate the two hemispheres during singing. We suggest that the study of the motor control system for birdsong has provided the most direct evidence to date for localizing the programming of a skilled motor sequence to the telencephalon.

Effect of dopamine2 blockade on renal function under varied sodium intake.

This study explored the role of the dopamine-2 receptor (DA2) in the control of renal blood flow (RBF) and the influence of variations in sodium intake. These relationships have not been previously defined in man. Seven normotensive male subjects underwent a low dose dopamine (DA) infusion (1 microgram/kg.min) for 3 h, known to activate both DA1 and DA2 receptors. The effect of DA2 receptor on renal hemodynamics was studied using a relatively specific DA2 blocker [domperidone (DOM); 60 mg, orally] alone and with a DA infusion. Systemic and renal hemodynamics parameters were measured noninvasively. Urinary prostacyclin was measured in 3-h urine specimens, obtained during the DA infusion. The DA infusion increased RBF and prostacyclin during both normal and high salt diets, but this effect was attenuated on a low salt diet. DOM alone significantly reduced basal RBF during normal (1304 +/- 48 vs. 1175 +/- 45 mL/min.1.73 m2; P < 0.01) and low salt diets (1402 +/- 80 vs. 1220 +/- 101 mL/min.1.73 m2; P < 0.02), but was without effect during high sodium intake. DOM had no effect on prostacyclin excretion at any level of salt intake. These results suggest that both DA1 and DA2 are activated in renal vessels by DA, and that DA2 receptors play a role in the renal vasodilating action of DA. Changes in sodium balance alter the actions of the two receptors (DA1 and DA2) in a coordinated fashion in the regulation of RBF.

The mechanism of tonic inhibition of crayfish escape behavior: distal inhibition and its functional significance.

The excitability of crayfish escape behavior is seldom fully predictable. A major determinant of this fickleness is a form of descending inhibition that is reliably evoked during restraint or feeding and is called "tonic inhibition." Tonic inhibition was found to inhibit postsynaptically the lateral giant neurons, the command neurons for one form of escape. This inhibition is located on lateral giant dendrites that are electrotonically distant from the neuron's spike initiating zone. in contrast, the postsynaptic inhibition due to "recurrent inhibition," which prevents new escape responses from starting while a previously initiated one is in process, occurs proximally, near the spike initiating zone. The distalness of tonic inhibition could be an adaptation for selective suppression of parts of the lateral giant dendritic tree. Consistent with this, evidence was obtained that the tonic inhibitory system can suppress responses to specific sensory fields. An independent reason for targeting recurrent inhibition proximally and tonic inhibition distally was suggested by the functional requirements of each inhibitory process: recurrent inhibition needs to be "absolute" in the sense that the response should be absolutely prevented, whereas it must be possible to override tonic inhibition. Neuronal models demonstrated that proximal inhibition gives recurrent inhibition the required property of absoluteness while distal inhibition allows tonic inhibition to be overridden ("relativity"). It was shown that the relativity of distal inhibition arises from its interaction with the process of saturation of excitation and that tonic inhibition does indeed interact with excitatory saturation as predicted. It is suggested that the property of relativity of distal inhibition is exploited in other nervous systems as well.

Crayfish tonic inhibition: prolonged modulation of behavioral excitability by classical GABAergic inhibition.

Previous studies have indirectly implicated the two neurotransmitters 5-HT and GABA in mediating tonic inhibition of the crayfish lateral giant (LG) escape reaction. In this study, pharmacological agents were selectively delivered to restricted portions of the abdominal CNS (where LG escape circuitry resides) to assess directly the role of these two transmitters in tonic inhibition. Both 5-HT and GABA depressed monosynaptic, electrical transmission to the LG neurons, the command neurons for LG escape, and application of either transmitter resulted in a depolarizing conductance increase in the LG neuron. The effects of 5-HT persisted in preparations in which chemical transmission was effectively abolished, implying that there are 5-HT receptors on the LG neuron itself, along with the known GABA receptors. Restricted delivery of the GABA chloride channel blocker picrotoxin to only the abdominal CNS blocked the expression of tonic inhibition there (without interfering with the rostral generation of tonic inhibition). Therefore, if 5-HT mediated tonic inhibition, the effects of 5-HT on the abdomen should also be antagonized by picrotoxin. However, this was not the case, thus suggesting that 5-HT does not mediate tonic inhibition. The most likely neurotransmitter used for tonic inhibition is GABA acting via ligand-gated chloride channels. Thus, although this form of behavioral modulation can be tonically active for very long periods, it nevertheless appears to be mediated by a classical synaptic mechanism.

Cholinergic transmission at the first synapse of the circuit mediating the crayfish lateral giant escape reaction.

1. The chemical synapses between mechanoreceptor neurons and first-order interneurons in the lateral giant (LG) neuron escape circuit of the crayfish have plastic properties, some of which are believed to be the basis for behavioral habituation and sensitization. In this investigation pharmacological experiments were conducted to assess the role of cholinergic synaptic transmission in this pathway. 2. Arterial perfusion of the cholinergic agonist carbachol produced increased activity of many abdominal nerve cord units, including an identified first-order interneuron (interneuron A) in the LG circuit. A general increase in activity of interneurons in this circuit in the presence of certain cholinergic agonists was inferred from an increase in the frequency of occurrence of spontaneous excitatory postsynaptic potentials (EPSPs) recorded in the LG. 3. Cholinergic antagonists reduced the amplitude of spontaneous and evoked sensory neuron-to-interneuron A EPSPs and decreased the disynaptic (via 1st-order interneurons) component of evoked EPSPs in the LG. These effects indicate that postsynaptic cholinergic receptors are utilized in mechanosensory synaptic transmission to the first-order interneurons of this circuit. The relative potencies of the blockers tested (mecamylamine > picrotoxin >>> curare > atropine) suggest that the receptors on the interneurons belong to a previously characterized class of crustacean cholinergic receptors that resemble the ganglionic nicotinic subtype of vertebrates. 4. Nicotinic agonists (carbachol, tetramethylammonium hydroxide, 1,1-dimethyl-4-phenyl-piperazium iodide) produced depolarizing (decreased input resistance) responses on the LG neuron itself. These responses persisted during blockade of chemical transmission by cobalt. The presence of cholinergic receptors on the LG, a cell in which all known inputs mediating sensory excitation are electrical, is discussed. 5. Application of muscarinic agonists (pilocarpine, oxotremorine) resulted in a long-lasting reduction of the evoked sensory neuron-to-interneuron A EPSP and the disynaptic component of the evoked EPSP in the LG. No effects on the membrane potential or input resistance of the interneurons were detected. It is proposed that presynaptic receptors with a muscarinic profile are present on mechanosensory neurons and that these receptors mediate a reduction of transmitter release.

Altered regulation of renin secretion by insulinlike growth factors and angiotensin II in diabetic rats.

The etiology of the low renin state in DM is not clear. To assess the role of certain growth and regulatory factors in this process, we studied the effects of insulin, IGF-I, and IGF-II on the renin-angiotensin system in normal and 8-wk STZ-induced diabetic rats. Renin secretion was studied both in static incubations and by perifusion of rat renal cortical slices. In diabetic rats, both plasma renin activity (0.65 +/- 1.6 vs. 4.0 +/- 1.2 ng ANG I.ml-1.h-1) and tissue renin concentrations (27 +/- 5 vs. 51 +/- 8 ng ANG I.mg tissue-1.h-1) were reduced. Insulin (0.1-1.0 mu/ml) and IGF-I (10(-9) to 4 x 10(-9) M) stimulated renin secretion in normal tissue (control, 95 +/- 3%; insulin [0.5 mu/ml], 134 +/- 7%; IGF-I [4 x 10(-9) M], 149 +/- 7%). IGF-I stimulated renin secretion in perifusions as early as 30 min, whereas IGF-II had no effect. However, in diabetic renal tissue, neither insulin (0.1-1.0 mu/ml) nor IGF-I (10(-9) to 4 x 10(-9) M) had an effect on renin. This lack of effect was overcome by adding up to 100-fold higher concentrations of these growth factors. ANG II (10(-10) M-10(-8) M) had an exaggerated inhibitory effect on renin secretion in diabetic tissue. This study suggests that the low renin state in DM may be explained by the enhanced inhibitory effect of ANG II and the resistance to the secretogogue actions of insulin and IGF-I.

Evidence for a computational distinction between proximal and distal neuronal inhibition.

Most neurons have inhibitory synapses both "proximally" near the spike-initiating zone and "distally" on dendrites. Although distal inhibition is thought to be an adaptation for selective inhibition of particular dendritic branches, another important distinction exists between proximal and distal inhibition. Proximal inhibition can attenuate excitatory input absolutely so that no amount of excitation causes firing. Distal inhibition, however, inhibits relatively; any amount of it can be overcome by sufficient excitation. These properties are used as predicted in the circuit-mediating crayfish escape behavior. Many neuronal computations require relative inhibition. This could partly account for the ubiquity of distal inhibition.

Effect of dopamine on renal blood flow, prostaglandins, renin and electrolyte excretion in normal and hypertensive humans.

A low dose of dopamine (1 microgram/min/kg) infused for 3 h, which is without systemic hemodynamic effects in normal subjects, increased the renal blood flow and renal production of prostacyclin (PGI2). This action was blocked by metoclopramide as well as by either of two cyclooxygenase (CO) blockers, but effects were not altered by administration of the alpha 1 blocker prazosin. Much of the effect of dopamine (DA) is apparently via the DA1 receptor, since fenoldopam (0.1 microgram/min/kg) reproduced these actions. However, although fenoldopam increased glomerular filtration rate and urinary Na+, CO blockers were without effect. In contrast neither DA or fenoldopam infusions changed either renal blood flow or PGI2 in a group of patients with essential hypertension. Renin secretion was shown to be increased via DA1 receptor activation both in humans and rat renal tissue. The DA2 receptor may also play a role since domperidone can reduce renal blood flow.