Comparison of four-year toxicities and local control of ultra-hypofractionated vs moderate-hypofractionated image guided prostate radiation with HDR brachytherapy boost: A phase I-II single institution trial.

Purpose/Objectives: To analyze the long term efficacy and safety of an ultra-hypofractionated (UHF) radiation therapy prostate treatment regimen with HDR brachytherapy boost (BB) and compare it to moderate-hypofractionated regimens (MHF). Materials/Methods: In this single arm, prospective monocentric study, 28 patients with intermediate risk prostate cancer were recruited in an experimental treatment arm of 25 Gy in 5 fractions plus a 15 Gy HDR BB. They were then compared to two historical control groups, treated with either 36 Gy in 12 fractions or 37.5 Gy in 15 fractions with a similar HDR BB. The control groups included 151 and 311 patients respectively. Patient outcomes were reported using the International Prostate Symptom Score (IPSS) and Expanded Prostate Index Composite (EPIC-26) questionnaires at baseline and at each follow-up visit. Results: Median follow-up for the experimental arm was 48.5 months compared to 47 months and 60 months compared to the 36/12 and 37,5/15 groups respectively. The IPSS and EPIC scores did not demonstrate any significant differences in the gastrointestinal or genitourinary domains between the three groups over time. No biochemical recurrence occurred in the UHF arm as defined by the Phoenix criterion. Conclusion: The UHF treatment scheme with HDR BB seems equivalent to standard treatment arms in terms of toxicities and local control. Randomized control trials with larger cohorts are ongoing and needed to further confirm our findings.

Cognitive Digital Biomarkers from Automated Transcription of Spoken Language.

BACKGROUND: Although patients with Alzheimer's disease and other cognitive-related neurodegenerative disorders may benefit from early detection, development of a reliable diagnostic test has remained elusive. The penetration of digital voice-recording technologies and multiple cognitive processes deployed when constructing spoken responses might offer an opportunity to predict cognitive status. OBJECTIVE: To determine whether cognitive status might be predicted from voice recordings of neuropsychological testing. DESIGN: Comparison of acoustic and (para)linguistic variables from low-quality automated transcriptions of neuropsychological testing (n = 200) versus variables from high-quality manual transcriptions (n = 127). We trained a logistic regression classifier to predict cognitive status, which was tested against actual diagnoses. SETTING: Observational cohort study. PARTICIPANTS: 146 participants in the Framingham Heart Study. MEASUREMENTS: Acoustic and either paralinguistic variables (e.g., speaking time) from automated transcriptions or linguistic variables (e.g., phrase complexity) from manual transcriptions. RESULTS: Models based on demographic features alone were not robust (area under the receiver-operator characteristic curve [AUROC] 0.60). Addition of clinical and standard acoustic features boosted the AUROC to 0.81. Additional inclusion of transcription-related features yielded an AUROC of 0.90. CONCLUSIONS: The use of voice-based digital biomarkers derived from automated processing methods, combined with standard patient screening, might constitute a scalable way to enable early detection of dementia.

Evaluating the performance of temporal pattern discovery: new application using statins and rhabdomyolysis in OMOP databases.

BACKGROUND: Temporal pattern discovery (TPD) is a method of signal detection using electronic healthcare databases, serving as an alternative to spontaneous reporting of adverse drug events. Here, we aimed to replicate and optimise a TPD approach previously used to assess temporal signals of statins with rhabdomyolysis (in The Health Improvement Network (THIN) database) by using the OHDSI tools designed for OMOP data sources. METHODS: We used data from the Truven MarketScan US Commercial Claims and the Commercial Claims and Encounters (CCAE). Using an extension of the OHDSI ICTemporalPatternDiscovery package, we ran positive and negative controls through four analytical settings and calculated sensitivity, specificity, bias and AUC to assess performance. RESULTS: Similar to previous findings, we noted an increase in the Information Component (IC) for simvastatin and rhabdomyolysis following initial exposure and throughout the surveillance window. For example, the change in IC was 0.266 for the surveillance period of 1-30 days as compared to the control period of - 180 to - 1 days. Our modification of the existing OHDSI software allowed for faster queries and more efficient generation of chronographs. CONCLUSION: Our OMOP replication matched the we can account forwe can account for of the original THIN study, only simvastatin had a signal. The TPD method is a useful signal detection tool that provides a single statistic on temporal association and a graphical depiction of the temporal pattern of the drug outcome combination. It remains unclear if the method works well for rare adverse events, but it has been shown to be a useful risk identification tool for longitudinal observational databases. Future work should compare the performance of TPD with other pharmacoepidemiology methods and mining techniques of signal detection. In addition, it would be worth investigating the relative TPD performance characteristics using a variety of observational data sources.

The impact of bisphenol S on bovine granulosa and theca cells.

Bisphenol S (BPS) is an endocrine-disrupting chemical with multiple potential mechanisms of action, including as an oestrogen receptor agonist. BPS is increasingly used in plastics and thermal receipts as a substitute for bisphenol A, which has been phased out due to concerns about human health implications. The ability of BPS to alter female reproductive function in mammals has not been widely studied, despite the importance of normal hormone signalling for female reproduction. The aim of this study was to investigate how BPS (in a wide range of doses, including very low doses) affects granulosa cell and theca cell steroid hormone production and cell viability in the bovine. Granulosa cell oestradiol production was stimulated when cells were exposed to 100 µM BPS under basal conditions, but there was no effect of BPS when cells were stimulated with follicle-stimulating hormone (FSH). Additionally, there was no effect of BPS on granulosa cell progesterone production or cell viability under basal or FSH-stimulated conditions. BPS did not affect theca cell androstenedione or progesterone production, or theca cell viability under basal or luteinizing hormone-stimulated conditions. This study suggests for the first time that BPS may alter oestradiol production by bovine granulosa cells, albeit at a concentration that is unlikely to be physiologically relevant. Further studies are needed to determine the effects of BPS on the bovine oocyte and on other functions of follicular cells.

Poster - Thurs Eve-39: Full 3D dose calculation for total body irradiation: A comparison study between treatment planning systems in homogeneous and heterogeneous conditions.

PURPOSE: To perform full 3D heterogeneous dose calculations for total body irradiation (TBI) cases and compare different treatment planning softwares (TPS). METHOD: A retrospective study was performed on 7 patients. Dose distributions obtained with Pinnacle3 v.7.9u (Philips Medical Systems) were compared with the ones calculated using our actual TBI planning system Theraplan Plus (TPP) by MDS Nordion/Nucletron. Two different Pinnacle3 models were studied: standard beam commissioning (std_Pinnacle3 ) and TBI commissioning (TBI_Pinnacle3 ). For the later case, commissioning was adapted for the special TBI conditions (extended SSD of 190cm, large field, acrylic beam spoiler, and out of field dose (OFD)). RESULTS: Significant differences are found between the TPP, std_Pinnacle3 and TBI_Pinnacle3 dose distributions. For the relative mid-line doses, differences up to 12% were observed. Systematic overestimations of 5% were found in patients extremities between TPP and TBI_Pinnacle3 . Average dose underestimation of 3% was observed between std_Pinnacle3 and TBI_Pinnacle3 . Differences in patient extremities are attributed to the OFD contribution which is not correctly computed in TPP and std_Pinnacle3 . Dose comparison outside the patient's mid-line showed greater differences (up to 20%) between models. Accurate 3D heterogeneous dose calculations with TBI_Pinnacle3 model show major differences (homogeneous versus heterogeneous) in high and low density regions. Dose overestimation of 5% was observed in bony regions and dose underestimation of 5% to 10% was observed in lung regions. CONCLUSION: Those results are of major interest since they show a strong dependence of the dose calculation outcome on both TPS and commissioning used, potentially leading to significant dose misevaluation.

Can access to spirometry in asthma education centres influence the referral rate by primary physicians for education?

BACKGROUND AND OBJECTIVES: Asthma remains uncontrolled in a large number of asthmatic patients. Recent surveys have shown that a minority of asthmatic patients are referred to asthma educators. The objective of the present study was to assess the influence of increased access to spirometry in asthma education centres (AECs) on the rate of patient referrals to these centres by general practitioners. METHODS: A one-year, prospective, randomized, multicentric, parallel group study was conducted over two consecutive periods of six months each, with added spirometry being offered in the second six-month period to the experimental group. Ten AECs were enrolled in the project. An advertisement describing the AECs' services was sent by mail to a total of 303 general practitioners at the start of each period, inviting them to refer their patients. Measures of the frequency of medical referrals to the AECs were assessed for each period. RESULTS: The group of AECs randomly selected for spirometry in the second six-month period received 48 medical referrals during the first period and 32 during the second one, following proposed spirometry. AECs that had not offered spirometry received five referrals during the first period and seven during the second period. One AEC withdrew a few weeks after the study began and others encountered administrative problems, reducing their ability to provide interventions. CONCLUSIONS: Referral to AECs is not yet integrated into the primary care of asthma and offering more rapid access to spirometry in the AECs does not seem to be a significant incentive for such referrals.

Crosstalk between endothelin and nitric oxide in the control of vascular tone.

Several lines of evidence indicate that nitric oxide (NO) impairs endothelin (ET) production/action in vitro. Acute pressor responses caused by the blockade of NO formation with arginine analogues in vivo are blunted by selective ET(A) or dual ET(A)/ET(B) receptor blockade whereas blockade of NO formation magnifies ET-induced constriction of various vascular territories. Given that ET receptor blockade has normally limited effects on mean arterial pressure, the reversal of pressor responses caused by the blockade of NO formation with ET receptor blockade most likely reflects a significant crosstalk between NO and ET. Suppression of NO formation also leads to significant increases in ET production caused by agents targeting the endothelium, such as acetylcholine and thrombin. In addition, the inhibitory effect of shear stress on endothelial cells ET production also involves NO as an intermediate.Paradoxically, chronic exposure to organic nitrates which causes nitrate tolerance leads to an augmented vascular ET content. An increased angiotensin II (AII) production is apparently pivotal in this process. This article reviews observations pointing to the importance of NO/ET interactions as a fundamental and common regulatory mechanism shared across species. As a consequence of this crosstalk between NO and ET, experimental strategies designed to assess endothelial NO-dependent activity by the blockade of NO formation may be mitigated by magnified ET-dependent influences.

Influence of dual ET(A)/ET(B)-receptor blockade on coronary responses to treadmill exercise in dogs.

We hypothesized that endothelin (ET) release during exercise may be triggered by alpha-adrenergic-receptor activation and thereby influence coronary hemodynamics and O(2) metabolism in dogs. Exercise resulted in coronary blood flow increases (to 1.88+/-0.26 from 1.10+/- 0.12 ml x min(-1) x g(-1)) and in a fall (P<0.01) in coronary sinus O(2) saturation (17.4+/-1.5 to 9.6+/-0.7 vol%), whereas myocardial O(2) consumption (MVO(2)) increased (109+/-13% from 145+/-16 microl O(2) min(-1) x g(-1)). Tezosentan, a dual ET(A)/ET(B)-receptor blocker, slightly reduced mean arterial pressure (MAP) and increased heart rate throughout exercise. The relationship between coronary sinus O(2) saturation and MVO(2) was shifted upward (P<0.05) after tezosentan administration; i.e., as MVO(2) increased during exercise, coronary sinus O(2) saturation was disproportionately higher after ET-receptor blockade. After propranolol, tezosentan resulted in significant decreases (P<0.05) in left ventricular pressure, the first derivative of left ventricular pressure over time, and MAP during exercise. As MVO(2) increased during exercise, coronary sinus O(2) saturation levels after tezosentan became superimposable over those observed before ET-receptor blockade. Thus dual blockade of ET(A)/ET(B) receptors alters coronary hemodynamics and O(2) metabolism during exercise, but ET activity failed to increase beyond baseline levels.

Endothelin-dependent effects limit flow-induced dilation of conductance coronary vessels after blockade of nitric oxide formation in conscious dogs.

OBJECTIVE: To determine whether endothelin (ET)-dependent effects limit shear stress-induced dilation of large epicardial coronary arteries after blockade of nitric oxide (NO) formation. METHODS: In conscious dogs instrumented for measuring coronary blood flow (CBF) and external diameter (CD) of the circumflex coronary artery, flow-dependent CD dilation was elicited by intracoronary (i.c.) adenosine (500 ng kg-1 min-1). RESULTS: I.c. adenosine increased CBF by 28 +/- 4 from 38 +/- 5 ml min-1 and CD by 0.25 +/- 0.03 from 3.53 +/- 0.07 mm without other hemodynamic effects. After N omega-nitro-L-arginine methyl ester (L-NAME), baseline CD fell (P < 0.01) to 3.35 +/- 0.08 mm but CBF was not significantly altered (36 +/- 5 ml min-1). CBF increases caused by adenosine were smaller (17 +/- 2 ml min-1, P < 0.05) and CD responses were nearly abolished (0.02 +/- 0.01 mm, P < 0.01). I.c. Ro 61-1790, an ETA receptor blocker, given after L-NAME did not significantly influence baseline CBF (36 +/- 5 ml min-1) but increased (P < 0.01) CD to 3.45 +/- 0.09 mm. CBF responses to adenosine were not significantly altered by Ro 61-1790 but CD responses (0.10 +/- 0.01 mm) were partially restored (P < 0.01). In contrast, blockade of ETB receptors with Ro 46-8443 after L-NAME had no further effects on CD and CBF responses to adenosine. CONCLUSION: ETA receptor-mediated effects limit flow-dependent dilation of large epicardial coronary arteries in conscious dogs. Suppression of the L-arginine/NO-dependent pathway with L-NAME reveals significant ET-dependent effects.

Contribution of endogenous endothelin to large epicardial coronary artery tone in dogs and humans.

Nitric oxide (NO) may normally impair endothelin (ET) activity in epicardial coronary arteries. Lifting this inhibitory feedback could reveal ET-dependent effects involving ET(A)- and/or ET(B)-receptor activation. In conscious dogs, the blockade of ET(A) receptors (intracoronary Ro-61-1790) increased external circumflex coronary artery diameter (CD) (sonomicrometry) by 0.10 +/- 0.01 from 3.04 +/- 0.12 mm (P < 0.01) without altering coronary blood flow (Doppler). Similarly, CD increased (0.09 +/- 0.01 from 2.91 +/- 0.14 mm; P < 0. 01) when Ro-61-1790 was given after blockade of NO formation with intracoronary N(omega)-nitro-L-arginine methyl ester (L-NAME). In contrast, ET(B)-receptor blockade (intracoronary Ro-46-8443) did not influence baseline CD with and without L-NAME. In vitro, increases in tension caused by N(omega)-nitro-L-arginine (L-NNA) or PGF(2alpha) in arterial rings were reduced by ET(A)- but not ET(B)-receptor blockade. ET(A)-receptor blockade also reduced the increase in tension caused by L-NNA in human coronary arterial rings. Thus ET(A) receptors, but not ET(B) receptors, account for ET-dependent constriction in canine epicardial coronary arteries in vivo. ET-dependent effects were independent of the level of NO formation in vitro and in vivo. In human epicardial coronary arterial rings, ET(A)-receptor blockade also caused significant relaxation.

[Validation of a questionnaire of physical sensations in a French-Canadian population]. / Validation du questionnaire des sensations physiques auprès de la population canadienne-française.

The objectives of this study are three-fold. The first objective is to present the aspects of reliability and validity of a self-reported questionnaire that evaluates a specific facet of Panic Disorder with Agoraphobia (PDA) for the francophone population of Quebec, mainly the fear of fear. The Body Sensations Questionnaire (17), translated as the Questionnaire des Sensations Physiques (QSP) evaluates the degree to which individuals fear somatic symptoms commonly associated with panic. A second objective is to determine the factorial validity of the QSP and to investigate the dimensionality of the construct as assessed by the questionnaire. The third objective is to establish a reference database for the agoraphobic (N = 141 and N = 70) and the non-clinical population (N = 223). Results suggest that both questionnaires have similar internal consistency, temporal stability, construct validity, and discriminative validity. While the factorial solution of the present study uncovered a three-factor model (somatic, cardiac, and psychosensorial), which points to the multidimensional nature of the construct evaluated by the QSP, it greatly differs from the one obtained by Arrindel's study (5). Nevertheless, the extraction of the three principal components is supported by the results of the screen test and by two different implementations of parallel analysis, i.e., the computation of random eigen values and the use of an interpolation table of eigen values. Finally, it can be concluded that the psychometric properties of the French-Canadian translation of the BSQ are indications that it is an appropriate instrument to use in clinical research and in clinical practice to assess the fear of bodily sensations associated with the fear of fear.

Endothelin-dependent tone limits acetylcholine-induced dilation of resistance coronary vessels after blockade of NO formation in conscious dogs.

Nitric oxide (NO) impairs endothelin (ET) formation and/or action in isolated vessels. We hypothesized that ET may magnify the consequences of NO formation blockade on receptor-operated dilation of resistance coronary vessels in conscious dogs. In conscious instrumented dogs, graded intracoronary (IC) doses of acetylcholine (ACh) were delivered before IC administration of Nomega-nitro-L-arginine methyl ester (L-NAME), after L-NAME, and after L-NAME plus IC bosentan, an ETA/ETB receptor blocker. Before L-NAME, ACh (100 ng. kg-1. min-1) increased coronary blood flow (CBF) by 43+/-4% from 47+/-6 mL. min-1. After L-NAME, ACh failed to increase CBF (-3+/-2% from 50+/-7 mL. min-1). CBF responses to ACh were partially restored (+10+/-2% from 50+/-7 mL. min-1, P<0.01) after the addition of bosentan. Bosentan alone (without L-NAME) did not alter CBF responses to ACh. Blockade of ETA (Ro 61-1790) but not ETB (Ro 46-8443) receptors partially restored CBF responses to ACh after L-NAME. Myocardial immunoreactive ET levels in the perfusion territories of the circumflex and left anterior descending coronary arteries did not differ. ETA-dependent tone magnified the inhibitory effects of blockade of NO formation on receptor-operated dilation to ACh in resistance coronary vessels. Presumably, stimulated NO release has an inhibitory action on endogenous ET production and/or action at the level of resistance coronary vessels.

Experience of aboriginal health interpreters in mediation of conflicting values in end-of-life decision making.

This paper examines the experience of Aboriginal medical interpreters working with terminally ill patients, family members, and care providers, and serving as mediators when cultural values and decision frameworks are in conflict. The discussion is based on a qualitative analysis of interaction in 12 patient encounters which were observed and for which transcripts were made of the discourse and interaction. Each case involved intervention by a professional interpreter. Interaction involved the signing of advance directives or other consent agreements in situations in which Aboriginal patients were terminally ill. Analysis will focus on the cultural dimension of value conflict situations, particularly in relation to issues of individual autonomy and biomedical emphasis on truth-telling in the communication of terminal prognosis.

Nitric oxide-independent dilation of conductance coronary arteries to acetylcholine in conscious dogs.

NO and prostacyclin formation cannot entirely account for receptor-operated endothelium-dependent dilation of coronary vessels, since vasodilator responses are not completely suppressed by inhibitors of these agents. Therefore, we considered that another factor, such as an endothelium-derived hyperpolarizing factor described in vitro, may participate in NO- and prostacyclin-independent coronary dilator responses. In conscious instrumented dogs, intracoronary acetylcholine (ACh, 30.0 ng.kg-1.min-1) increased the external epicardial coronary diameter (CD) by 0.18 +/- 0.03 mm (from 3.44 +/- 0.11 mm) when increases in coronary blood flow (CBF) were prevented and increased the CD by 0.20 +/- 0.05 when CBF was allowed to increase. After the administration of intracoronary N omega-nitro-L-arginine methyl ester (L-NAME), CBF responses to ACh were abolished, but CD responses (0.23 +/- 0.05 from 3.22 +/- 0.09 mm) were maintained. Blockade of NO formation was confirmed by reduced CD baselines and blunted flow-dependent CD responses caused by adenosine and transient coronary artery occlusions after L-NAME administration. ACh-induced CD increases resistant to L-NAME and indomethacin were reduced after the administration of intracoronary quinacrine, an inhibitor of phospholipase A2, or proadifen, an inhibitor of cytochrome P-450. Quinacrine or proadifen alone (without L-NAME) did not alter CD responses to ACh, but L-NAME given after proadifen blunted ACh-induced increases in CD. The increases in CD caused by arachidonic acid given after L-NAME + indomethacin were antagonized by proadifen but not altered by quinacrine. Thus, a cytochrome P-450 metabolite of arachidonic acid accounts for L-NAME-resistant and indomethacin-resistant dilation of large epicardial coronary arteries to ACh. Conversely, NO formation is the dominant mechanism of ACh-induced dilation after blockade of the cytochrome P-450 pathway.

Influence on asthma morbidity of asthma education programs based on self-management plans following treatment optimization.

The objective of this study was to evaluate the effectiveness of an asthma education program on morbidity, knowledge, and compliance with inhaled corticosteroid treatment using a prospective, randomized, controlled, one-year-before/one-year-after protocol. After rigorous optimization of asthma therapy under the care of respirologists, patients were assigned to one of three groups: Group C (control group: no formal education), Group P (education and action plan based on peak-flow monitoring), and Group S (education with action plan based on monitoring of asthma symptoms). A total of 188 subjects with moderate to severe asthma were enrolled and 149 completed the study. Asthma morbidity decreased significantly in all groups (p = 0.001). Mean values one-year-before/one-year-after in Groups C, P, and S were: unscheduled medical visits, 2.4/0.8, 2.3/0.7, and 1.9/ 0.7; hospitalizations, 0.21/0.04, 0.24/0.04, and 0.40/0.09; oral steroid treatments; 1.3/0.5, 1.2/0.7, and 1.3/0.9; absenteeism from work/school, 9.6/5.2, 8.8/2.2, and 6.3/2.9. Between-group differences did not reach statistical significance (p > 0.05). Asthma knowledge increased in both educated groups compared with the control group (p < 0.001) as did short-term compliance with inhaled corticosteroids. These results confirm that treatment optimization coupled with sustained high quality care in motivated patients can lead to a significant decrease in asthma morbidity. In such clinical settings, structured asthma education significantly improved short-term compliance with treatment and knowledge about asthma, although it could not add extra benefit with regard to morbidity. Nevertheless, this study does not refute the potential benefit of educational interventions aimed at improving asthma-related morbidity over a longer time period or in patients with less optimal care or with high-risk factors.

Beta 2-adrenergic dilation of resistance coronary vessels involves KATP channels and nitric oxide in conscious dogs.

BACKGROUND: We considered that beta 2-adrenergic stimulation may dilate resistance coronary vessels by opening ATP-sensitive potassium (KATP) channels, thereby triggering NO formation. METHODS AND RESULTS: In conscious instrumented dogs after beta 1-adrenergic blockade, intracoronary (IC) injections of acetylcholine (ACh), nitroglycerin (NTG), and pirbuterol (PIR), a selective beta 2-adrenergic agonist, were performed before and after blockade of NO formation with IC N omega-nitro-L-arginine methyl ester (L-NAME, 50 micrograms.kg-1.min-1 x 12 minutes) or blockade of KATP channels with IC glibenclamide (25 micrograms.kg-1.min-1 x 12 minutes followed by 2 micrograms.kg-1.min-1). PIR (50.0 ng/kg) increased coronary blood flow (CBF) by 32 +/- 6 from 43 +/- 7 mL/min and by only 11 +/- 2 (P < .01) from 40 +/- 7 mL/min after L-NAME. Increases in CBF to ACh were also reduced by L-NAME, but NTG responses were not. Before glibenclamide, PIR increased CBF by 33 +/- 5 from 45 +/- 7 mL/min and by only 14 +/- 3 (P < .01) from 36 +/- 5 mL/min thereafter. CBF responses to ACh and NTG were maintained after glibenclamide. Lemakalim, a selective opener of KATP channels, caused dose-dependent increases in CBF that were partially inhibited by L-NAME. In experiments in which CBF was controlled, the fall in distal coronary pressure caused by PIR was less after L-NAME or glibenclamide than before. CONCLUSIONS: beta 2-Adrenergic dilation of resistance coronary vessels involves both the opening of KATP channels and NO formation. L-NAME antagonized lemakalim responses consistent with a link between the opening of KATP channels and NO formation in canine resistance coronary vessels.

Beta 2-adrenergic dilation of conductance coronary arteries involves flow-dependent NO formation in conscious dogs.

The contribution of nitric oxide (NO) formation to the dilation of large epicardial coronary arteries to beta 1- and beta 2-adrenergic receptor stimulation was investigated in conscious dogs. After beta 1-adrenergic blockade (atenolol, 1.0 mg/kg iv), selective beta 2-adrenergic receptor activation with intracoronary bolus injections of pirbuterol (50 ng/kg) increased coronary blood flow (CBF) by 95 +/- 19% from 48.5 +/- 8.4 ml/min and external epicardial coronary diameter (CD) by 0.14 +/- 0.03 from 3.23 +/- 0.31 mm. After intracoronary N omega-nitro-L-arginine methyl ester (L-NAME, 50 micrograms.kg-1.min-1 x 12 min) was administered, baseline CD decreased but CBF was not altered. After L-NAME, bolus injections of pirbuterol resulted in smaller (P < 0.01) CBF responses (40 +/- 12%), and increases in CD were abolished. When pirbuterol (500 ng.kg-1.min-1) was given as a continuous infusion, CBF increased by 36 +/- 5% from 55.4 +/- 5.8 ml/min and CD by 0.16 +/- 0.03 mm from 3.44 +/- 0.16 mm. L-NAME abolished CD increases and limited (P < 0.01) CBF responses to 9 +/- 3%. When increases in CBF caused by pirbuterol before L-NAME were prevented by arterial constriction, CD increases were suppressed. In contrast, CBF and CD responses to beta 1-adrenergic stimulation were maintained after L-NAME. Thus beta 2-adrenergic dilation of epicardial conductance arteries is primarily a flow-dependent process involving NO formation. In contrast, beta 1-adrenergic activation produces epicardial coronary dilation independent of an L-NAME-sensitive mechanism.

Contrasting effects of blockade of nitric oxide formation on resistance and conductance coronary vessels in conscious dogs.

OBJECTIVES: To determine the differential effects of blockade of nitric oxide (NO) formation by an arginine analogue on basal and stimulated NO release in conductance and resistance coronary vessels. METHODS: In conscious dogs, instrumented for measuring coronary blood flow (CBF) and external epicardial coronary artery diameter (CD), intracoronary (ic) acetylcholine (ACH, 3.0 ng/kg), adenosine (ADENO 100.0 ng/kg) and nitroglycerin (NTG, 10.0 ng/kg) were injected before and after ic N omega-nitro-L-arginine methyl ester (L-NAME, 50.0 micrograms.kg-1 min-1 for 12 min) to block NO synthesis. RESULTS: Before L-NAME, ACH increased CBF by 65.3 +/- 9.0 from 42.4 +/- 2.9 ml/min and CD by 0.199 +/- 0.035 from 3.374 +/- 0.193 mm. L-NAME failed to alter baseline CBF but reduced (P < 0.01) CD to 3.220 +/- 0.199 mm. CBF responses to ACH were smaller (P < 0.01) (32.8 +/- 5.3 ml/min) after L-NAME. In contrast, ACH-induced increases in CD (0.184 +/- 0.053 mm) were not altered. L-NAME did not change CBF responses to NTG but increased CD responses (0.345 +/- 0.062 vs 0.217 +/- 0.043 mm, P < 0.01). ADENO-induced increases in CBF were smaller after L-NAME (46.5 +/- 5.6 vs 79.8 +/- 10.9 ml/min, P < 0.01). Increases in CD created by ADENO, a flow-dependent phenomenon, were nearly abolished after L-NAME (0.043 +/- 0.018 vs 0.195 +/- 0.026 mm, P < 0.01) and partially restored by ic L-arginine. The effects of L-NAME on CBF and CD responses to ACH and ADENO continuously delivered into the coronary artery were similar to those of boluses. CONCLUSIONS: L-NAME selectively reduced ACH-induced dilation in resistance coronary vessels but failed to prevent responses of conductance coronary vessels in spite of reducing baseline CD and blocking flow-dependent effects of ADENO. Therefore, blockade of NO formation resulted in disparate effects on receptor-operated dilation of resistance and conductance coronary vessels.

Nitric oxide formation contributes to beta-adrenergic dilation of resistance coronary vessels in conscious dogs.

The contribution of the L-arginine/nitric oxide pathway to beta-adrenergic dilation of resistance coronary vessels was examined in conscious dogs instrumented for measuring coronary blood flow (CBF), left ventricular (LV) wall thickening, and LV and aortic pressures and for intracoronary injections of acetylcholine (0.003 micrograms/kg), nitroglycerin (0.175 micrograms/kg), and graded doses of isoproterenol (0.0005 to 0.004 micrograms/kg). Peak increases in CBF with intracoronary isoproterenol (0.001 micrograms/kg) averaged 105 +/- 10% from baseline. With acetylcholine, CBF increased by 158 +/- 11%, and with nitroglycerin, CBF increased by 139 +/- 10%. After the administration of intracoronary N omega-nitro-L-arginine methyl ester (L-NAME, 10 micrograms/kg per minute for 12 minutes) to block nitric oxide synthesis from L-arginine, baseline CBF was not altered, and CBF increased by 49 +/- 7% with isoproterenol and by 94 +/- 6% with acetylcholine; both values were smaller (P < .01) than those before the arginine analogue. With nitroglycerin, CBF was increased by 145 +/- 11%, not significantly different from the value before L-NAME. Intracoronary L-arginine (1.0 mg/kg per minute for 12 minutes), the precursor of nitric oxide synthesis, partially reversed the inhibition of L-NAME on CBF responses to acetylcholine and isoproterenol. After beta 1-adrenergic blockade, CBF responses to isoproterenol and acetylcholine were also reduced (P < .05) by the arginine analogue. When increases in CBF were prevented, peak changes in coronary vascular conductance with intracoronary bolus doses of acetylcholine and isoproterenol were attenuated (P < .01) by L-NAME. Thus, nitric oxide formation is an important intermediate in beta-adrenergic dilation of resistance coronary vessels in conscious dogs.