The effect of endovascular irradiation on platelet recruitment at sites of balloon angioplasty in pig coronary arteries.

BACKGROUND: Endovascular irradiation (EI) inhibits balloon-induced neointima formation in animals and is now in clinical trials for restenosis prevention. However, little is known of the effect of EI on vessel thrombogenicity due to delayed arterial healing. We investigated EI effects on platelet recruitment in pig coronary arteries. METHODS AND RESULTS: EI was performed using (90)Sr/Y at 0 Gray (Gy), 15Gy, or 30Gy at 2 mm after balloon overstretch injury. At 1 day, 1 week, and 1 month, platelet recruitment and thrombus formation were assessed using autologous (111)In-oxine-platelet labeling and light and scanning electron microscopy. In balloon-injured nonirradiated vessels, there was complete reendothelialization at 1 month, and platelet recruitment was similar to normal uninjured arteries. In irradiated vessels, scanning electron microscopy showed incomplete reendothelialization at 1 month, and these areas demonstrated attachment of activated platelets. Light microscopy of irradiated coronaries showed adherent partially organized thrombi and incomplete resolution of intramural hemorrhages. There was a significant increase in platelet recruitment at 1 month in arteries receiving EI at 15Gy (5.1+/-2. 8x10(6), P=0.02) or 30Gy (12.5+/-9.9x10(6), P=0.005) compared with nonirradiated controls (2.7+/-1.5x10(6)); 30Gy was also higher than 15Gy (P=0.05). Platelet recruitment was also increased for 30Gy compared with control at 1 day. CONCLUSIONS: Endovascular irradiation at 15Gy or 30Gy after balloon angioplasty results in incomplete endothelial recovery, impaired resolution of intramural hemorrhage, and a dose-dependent increase in platelet recruitment at 1 month.

Intracoronary beta-radiation exacerbates long-term neointima formation in balloon-injured pig coronary arteries.

BACKGROUND: Long-term biological effects of ionizing radiation on coronary arteries remain poorly defined. We examined late arterial responses 6 months after balloon angioplasty and beta-radiation in normal pig coronary arteries. METHODS AND RESULTS: Coronary arteries of 25 adult pigs were randomized to receive 20 Gy (n=8) or 30 Gy (n=9) of (186)Re beta-radiation or sham radiation (n=8) immediately after balloon angioplasty. Aspirin was given daily during follow-up. The study vessels were analyzed histopathologically at 6 months. beta-Radiation decreased lumen area (20 Gy, 1.55+/-0.99 mm(2); 30 Gy, 1.03+/-0.82 mm(2); and 0 Gy, 2.05+/-0.80 mm(2); P<0.05) but not overall vessel area. The neointimal area was significantly larger within the injured segment with beta-radiation (20 Gy, 1.92+/-1.23 mm(2); 30 Gy, 1.51+/-0.97 mm(2); and 0 Gy, 0.89+/-0.31 mm(2); 0 Gy versus 20 Gy, P<0.05), and a significant increase of edge stenosis was observed with beta-radiation. Irradiated vessels also had larger thrombus areas within the neointima (30 Gy, 0.24+/-0.61 mm(2); 20 Gy, 0.98+/-1.57 mm2; and 0 Gy, 0.00+/-0.01 mm(2); P<0.05) and larger adventitial areas (20 Gy, 2.25+/-0.75 mm(2); 30 Gy, 2.38+/-0.98 mm(2); and 0 Gy, 1.23+/-0.29 mm(2); 0 Gy versus 20 or 30 Gy, P<0.05) that showed substantial collagen accumulation. CONCLUSIONS: Intracoronary beta-radiation did not inhibit neointima formation in balloon-injured normal pig coronary arteries 6 months after the interventional procedure. Unresorbed thrombus contributed to, but was not the sole component of, augmented neointima formation. Irradiated vessels demonstrated more adventitial thickening and fibrosis. These observations may have relevance for long-term clinical outcomes after intracoronary beta-radiation.

Clinical trials in coronary angiogenesis: issues, problems, consensus: An expert panel summary.

The rapid development of angiogenic growth factor therapy for patients with advanced ischemic heart disease over the last 5 years offers hope of a new treatment strategy based on generation of new blood supply in the diseased heart. However, as the field of therapeutic coronary angiogenesis is maturing from basic and preclinical investigations to clinical trials, many new and presently unresolved issues are coming into focus. These include in-depth understanding of the biology of angiogenesis, selection of appropriate patient populations for clinical trials, choice of therapeutic end points and means of their assessment, choice of therapeutic strategy (gene versus protein delivery), route of administration, and the side effect profile. The present article presents a summary statement of a panel of experts actively working in the field, convened by the Angiogenesis Foundation and the Angiogenesis Research Center during the 72nd meeting of the American Heart Association to define and achieve a consensus on the challenges facing development of therapeutic angiogenesis for coronary disease.

Intracoronary basic fibroblast growth factor (FGF-2) in patients with severe ischemic heart disease: results of a phase I open-label dose escalation study.

OBJECTIVES: Evaluate the safety, tolerability and preliminary efficacy of intracoronary (IC) basic fibroblast growth factor (bFGF, FGF-2). BACKGROUND: FGF-2 is a heparin-binding growth factor capable of inducing functionally significant angiogenesis in animal models of myocardial ischemia. METHODS: Phase I, open-label dose-escalation study of FGF-2 administered as a single 20-min infusion in patients with ischemic heart disease not amenable to treatment with CABG or PTCA. RESULTS: Fifty-two patients enrolled in this study received IC FGF-2 (0.33 to 48 microg/kg). Hypotension was dose-dependent and dose-limiting, with 36 microg/kg being the maximally tolerated dose. Four patients died and four patients had non-Q-wave myocardial infarctions. Laboratory parameters and retinal examinations showed mild and mainly transient changes during the 6-month follow-up. There was an improvement in quality of life as assessed by Seattle Angina Questionnaire and improvement in exercise tolerance as assessed by treadmill exercise testing (510+/-24 s at baseline, 561+/-26 s at day 29 [p = 0.023], 609+/-26 s at day 57 (p < 0.001), and 633+/-24 s at day 180 (p < 0.001), overall p < 0.001). Magnetic resonance (MR) imaging showed increased regional wall thickening (baseline: 34+/-1.7%, day 29: 38.7+/-1.9% [p = 0.006], day 57: 41.4+/-1.9% [p < 0.001], and day 180: 42.0+/-2.3% [p < 0.001], overall p = 0.001) and a reduction in the extent of the ischemic area at all time points compared with baseline. CONCLUSIONS: Intracoronary administration of rFGF-2 appears safe and is well tolerated over a 100-fold dose range (0.33 to 0.36 microk/kg). Preliminary evidence of efficacy is tempered by the open-label uncontrolled design of the study.

Inhibition of neointima formation by tranilast in pig coronary arteries after balloon angioplasty and stent implantation.

OBJECTIVES: We evaluated the effect of orally administered tranilast, N-(3,4-dimethoxycinnamoyl) anthranilic acid, on histologic and histomorphometric changes after angioplasty or stent implantation in pig coronary arteries. BACKGROUND: Tranilast, which has antikeloid and antiallergic properties and therefore may modulate the fibrotic and inflammatory tissue responses to angioplasty and stenting, has been shown to inhibit angiographic restenosis in small clinical trials. However, its effect on histomorphometric changes in coronary arteries after angioplasty and stenting is unknown. METHODS: Following initial pharmacokinetic studies in two pigs to determine desirable plasma levels of orally administered tranilast, 36 crossbred juvenile pigs were randomized to placebo or tranilast before undergoing balloon angioplasty in both the left anterior descending and left circumflex plus stent implantation in the right coronary artery. Oral tranilast was administered at 3 g/day starting 3 days before coronary injury and continued for 28 days until euthanasia. Injured vessels were harvested and sections analyzed by computer-assisted microscopic planimetry. RESULTS: In balloon-injured vessels, tranilast was associated with a 37% reduction in neointimal area normalized to fracture length (0.47 +/- 0.01 vs. 0.74 +/- 0.03 mm; p < 0.001) and a 23% reduction in adventitial area normalized to vessel size (0.43 +/- 0.02 vs. 0.56 +/- 0.03; p = 0.003). In stented arteries, neointimal area normalized to injury score was 32% lower in the tranilast-treated group compared to control (1.94 +/- 0.17 vs. 2.86 +/- 0.29; p = 0.01). CONCLUSIONS: In pig coronary arteries, tranilast was associated with a reduction in neointima formation and adventitial reaction after balloon injury. In stented vessels, tranilast was associated with a reduction in neointima formation normalized to injury score.

High-dose external beam irradiation inhibits neointima formation in stented pig coronary arteries.

PURPOSE: To evaluate high-dose external beam irradiation (EBRT) in a pig coronary stent preparation because low and intermediate-dose EBRT failed to show inhibition of neointima formation in stented animal models. METHODS AND MATERIALS: Thirty-five stents were implanted in the coronary arteries of 17 pigs. Seven pigs were exposed to a single dose of 21 Gy EBRT immediately after stenting. Ten stented, nonirradiated pigs served as controls. After 4 weeks, the study arteries and myocardium were examined by light and scanning electron microscopy. RESULTS: Compared with controls, 21 Gy EBRT resulted in a larger lumen area (7.57 +/- 1.67 mm2 vs. 4.00 +/- 1.63 mm2, p <0.001), a smaller neointima area (0.47 +/- 0.43 mm2 vs. 3.36 +/- 2.26 mm2, p <0.001) and a smaller maximal intimal thickness (0.16 +/- 0.09 mm vs. 0.68 +/- 0.31 mm, p <0.001). Unresorbed intramural hemorrhages and adherent mural thrombi were present in the irradiated vessels, which also showed incomplete re-endothelialization. The irradiated hearts demonstrated diffuse interstitial and perivascular inflammation and fibrosis. CONCLUSIONS: EBRT at 21 Gy to the entire heart significantly inhibited neointima formation in stented pig coronary arteries but also resulted in incomplete re-endothelialization, myocardial inflammation, and fibrosis. Improvements in localization and delivery techniques are required to allow clinical implementation of this technique.

Antithrombotic effects of ionic and non-ionic contrast media in nonhuman primates.

Thromboembolic complications have been attributed to the use of radiographic contrast media (CM) during interventional procedures for arterial revascularization. However, due to the low frequency of adverse events, comparisons between different CM have been difficult to perform, although it has been suggested that ionic (vs. non-ionic) CM may be associated with fewer thrombotic events. The present study was undertaken using well-characterized baboon thrombosis models in order to compare different CM under physiologically relevant and controlled conditions of blood flow, exposure time, and CM concentration. Three CM were studied: ioxaglate, iohexol, and iodixanol. CM were locally infused into the proximal segment of femoral arteriovenous shunts. Palmaz-Schatz stents (4 mm i.d.) and expanded tubular segments (9 mm i.d.), which exhibited venous-type flow recirculation and stasis, were deployed into the shunts distally. Saline was infused in identical control studies. Blood flow was maintained at 100 ml/min. Thrombosis was measured over a blood exposure period of 2 hours by gamma camera imaging of 111In-platelets and by gamma counting of deposited 125I-fibrin. CM concentrations within the flowfield were predicted using computational fluid dynamics. At infusion rates of 0.1 and 0.3 ml/min, the low-osmolar ionic CM ioxaglate reduced both platelet and fibrin deposition on the stents by 75-80% (p <0.005), while both iohexol and iodixanol reduced platelet deposition by 30-50% (p <0.05). In the regions of low shear flow, ioxaglate (0.3 ml/min) also reduced platelet deposition significantly (by 52% vs. control results; p <0.05). Thus the three agents evaluated--ioxaglate, iohexol, and iodixanol--all produced anticoagulant and antiplatelet effects and were inherently antithrombotic in vivo. The most striking effects were seen with the low osmolarity, ionic contrast agent ioxaglate.

Enprostil inhibits post-prandial gastrin release: a dose-response study.

In a double-blind placebo-controlled study in nine healthy volunteers, the effects of single doses of oral enprostil (8.75, 17.5, 35 and 70 micrograms), taken before a standard breakfast, were assessed on the post-prandial release of gastrin into the plasma. All doses of enprostil caused a significant dose-related decrease in median post-prandial plasma gastrin concentration (range from -29 to -44%). In the same subjects, two doses of 25 mg indomethacin caused a significant (38%) increase in median post-prandial plasma gastrin concentration.

Twenty-four-hour intragastric acidity and plasma gastrin concentration in healthy subjects and patients with duodenal or gastric ulcer, or pernicious anaemia.

Twenty-four-hour intragastric acidity and plasma gastrin concentration were measured in healthy subjects (n = 16), and patients with duodenal (n = 12) or gastric (n = 10) ulceration, or pernicious anaemia (n = 8). Median integrated 24-hour intragastric acidity was highest in duodenal ulcer patients and lowest in pernicious anaemia patients (1148 and 0 mmol.hour litre-1, respectively). Median integrated 24-hour plasma gastrin was highest in pernicious anaemia and lowest in the healthy subjects (9886 and 238 pmol.hour litre-1, respectively). Pernicious anaemia patients have unremitting hypergastrinaemia throughout the 24 hours. The results of this study not only provide a reference range of acidity and plasma gastrin in health and disease, but also will act as a baseline for future studies using antisecretory drugs.

Twenty-four-hour intragastric acidity and plasma gastrin concentration before and during treatment with either ranitidine or omeprazole.

Simultaneous 24-hour intragastric acidity and plasma gastrin concentrations were measured in 12 duodenal ulcer patients before and on the twenty-eighth day of treatment with either ranitidine 150 mg b.d. or omeprazole 20 mg o.m. Median integrated 24-hour intragastric acidity was decreased significantly from 1148 to 490 and 36 mmol.hour litre-1 during treatment with ranitidine and omeprazole, respectively, whilst median intragastric 24-hour plasma gastrin was raised significantly from 328 to 799 and 1519 pmol.hour litre-1 respectively. When the results of all 48 experiments were considered together, there was a significant inverse correlation between the 24-hour integrated values for intragastric acidity and plasma gastrin concentration. Both drugs caused a significant elevation of plasma gastrin throughout the 24 hours, although ranitidine had no effect on intragastric acidity from 1900 to 2200 hours. When compared with similar profiles of acidity and gastrin in pernicious-anaemia patients, the modest elevations of plasma gastrin observed in this study suggest that neither drug will be associated with clinically relevant enterochromaffin-like cell proliferation in duodenal ulcer patients.

Pharmacokinetics and pharmacodynamics of recombinant FGF-2 in a phase I trial in coronary artery disease.

Fibroblast growth factor-2 (FGF-2) is a heparin-binding protein capable of inducing angiogenesis in multiple animal models of chronic ischemia. The pharmacokinetics and pharmacodynamics of a single dose of recombinant FGF-2 (rFGF-2) administered by intracoronary or intravenous infusion were evaluated in a Phase I trial in 66 patients with severe coronary artery disease. rFGF-2 displayed biphasic elimination with a mean studywide distribution t1/2 of 21 minutes and a mean apparent terminal elimination t1/2 of 7.6 hours. Systemic exposure to rFGF-2 was comparable following intracoronary or intravenous administration. Peak plasma concentration and area under the concentration-time curve increased proportionally with dose, indicating linear pharmacokinetics over the dose range examined (0.33 to 48.0 micrograms/kg). Greater systemic exposure was observed when heparin was administered closer to rFGF-2 infusion, consistent with slower clearance of heparin/rFGF-2 complexes. Infusion of rFGF-2 was associated with changes in acute hemodynamics. While a clear PK/PD dose-response relationship was not established, a trend toward hypotension and tachycardia with higher rFGF-2 doses was observed.

The progression of thrombus in an ex-vivo shunt model evaluated by intravascular ultrasound radiofrequency analysis.

We tested the ability of ultrasound radiofrequency (RF) signal analysis to characterize thrombus accumulation in a Dacron graft incorporated into the exteriorized arteriovenous shunt in 3 baboons with constant blood flow for 60 min. Thrombus formation was quantified by sequential measurements of 111Indium-labeled platelet deposition. RF signals were acquired every 15 min at 2 sites in the graft, using a 2.9 Fr intravascular ultrasound catheter-based transducer (30 MHz) and digitized at 250 MHz in 8-bit resolution. Regions of interest were placed within a 0.5-mm perimeter adjacent to the graft wall. Integrated backscatter increased significantly (p < 0.001) with increasing platelet deposition. However, mean-to-standard deviation ratio of the RF envelope showed no significant change and the distribution pattern of the RF probability function remained constant and consistent with a Rayleigh scattering process. These results provide a basis for using RF analysis to monitor the time-course of thrombus formation.

New technologies in interventional cardiology.

This review confines itself to the new technologies that are widely used and that are being tested in formal trials. To date there have been few well-performed trials to compare the technologies, a fact that may have opened the way for the inappropriate use of some of these new technologies. This has allowed enthusiasts to perform procedures with as yet unproven tools no better and possibly worse than balloon angioplasty. New technologies can be broadly divided into three categories depending on their intended role: 1) mechanical removal, such as directional atherectomy, extractional atherectomy, and rotational atherectomy, that is designed to debulk lesions and remove atheromatous material, 2) high-energy removal by laser technologies designed to disobliterate lesions without producing the theoretically damaging lateral stretching of normal balloon angioplasty, 3) intraluminal scaffolding through the use of stents designed to give intravascular support, eg, balloon expandable, self-expanding, and temporary removable devices.

Epinephrine sensitizes human platelets in vivo and in vitro as studied by fibrinogen binding and P-selectin expression.

Epinephrine (Epi) infusion influences platelet activation markers in vivo, but in vitro studies have mainly examined supraphysiological Epi concentrations and have yielded conflicting results. In this study whole-blood flow-cytometric measurements of platelet fibrinogen binding and P-selectin expression were used to compare enhancement of ADP (0.1 to 10 mumol/L)-induced platelet activation by Epi infusion in vivo (0.1 and 0.4 nmol.kg-1.min-1) and by Epi in vitro (10 and 50 nmol/L) in nine healthy volunteers. ADP caused concentration-dependent increases in the percentage of platelets that bound fibrinogen (from 4.4 +/- 0.9% to 69.9 +/- 4.2%) and that expressed P-selectin (from 4.5 +/- 0.5% to 44.2 +/- 3.8%). Fibrinogen and P-selectin binding indices (FgBI and PSBI; calculated from mean fluorescence intensity and percentage of positive cells) also increased from 0.18 +/- 0.03 to 11.70 +/- 1.99 for FgBI and from 0.22 +/- 0.03 to 2.34 +/- 0.29 for PSBI. Epi concentration-dependently enhanced fibrinogen binding and P-selectin expression in vitro (by approximately 30% at the midportion of the ADP curve at 10 nmol/L Epi; P < .001 for both by ANOVAs). High-dose Epi infusion enhanced FgBI similarly and increased maximal P-selectin expression by 38%. Epi (50 nmol/L in vitro) enhanced platelet activation further, whether samples were taken with or without prior Epi infusion. Total expression of glycoprotein IIb/IIIa was unaffected by Epi infusion, but glycoprotein Ib expression per platelet was reduced (P < .05). These in vivo and in vitro effects of Epi on platelet responses to agonist stimulation indicate a prothrombotic potential for sympathoadrenal activation in humans.

Profound platelet degranulation is an important side effect of some types of contrast media used in interventional cardiology.

BACKGROUND: Thrombotic complications occurring during coronary angiography and percutaneous transluminal coronary angioplasty (PTCA) are relatively frequent and can be influenced by the type of radiographic contrast media used. Low osmolar contrast media (LOCM), both ionic and nonionic, have been considered to be safer than the older high osmolar contrast media (HOCM), causing less haemodynamic and symptomatic side effects. Recently, however, nonionic LOCM have been associated with an increased incidence of thrombotic events, including coronary occlusion and stroke. METHODS AND RESULTS: The effects of commonly used contrast media on platelets in native blood were investigated using immunolabeling and flow cytometry to detect platelet activation in vitro. A nonionic LOCM (Omnipaque) caused profound platelet degranulation in nearly 80% of platelets compared with 2 to 3% of platelets in the control. Conversely, an ionic HOCM (Urografin) caused only 25% degranulation, whereas an ionic LOCM (Hexabrix) caused no platelet activation and, furthermore, it inhibited the effects of thrombin on platelets. Platelet degranulation, quantified by immunolabeling, was paralleled by release of beta-thromboglobulin and platelet factor 4 from platelet alpha-granules. Blood from patients anticoagulated with heparin and pretreated with standard-dose aspirin in preparation for PTCA showed the same pattern of contrast media-induced platelet activation as normal subjects. CONCLUSIONS: These results suggest that the type of contrast media used during invasive imaging of the vasculature could have a significant effect on platelets. Platelet degranulation within a PTCA-damaged vessel would be increased by a nonionic contrast medium, releasing procoagulant molecules and platelet-derived growth factors into the damaged vessel lumen, which might contribute to acute thrombosis and the initiation of the restenosis process.

Aspirin does not affect the flow cytometric detection of fibrinogen binding to, or release of alpha-granules or lysosomes from, human platelets.

1. Aspirin inhibits the conversion of arachidonic acid to thromboxane A2 which reinforces the effects of weak agonists such as ADP in platelets. 2. In this study the effect of aspirin (300 mg/day) on platelet agonist response was measured by whole blood flow cytometry of unfixed blood samples from normal subjects (n = 10), an assay that investigates aggregation-independent changes in the platelet. 3. Fibrinogen binding to unstimulated platelets or to platelets stimulated with ADP or thrombin was unaffected by aspirin. 4. Under the conditions of this assay, platelets undergo a partial degranulation of alpha-granules and lysosomes (evidenced by expression of P-selectin and CD63, respectively) in response to ADP, and full degranulation in response to thrombin. P-selectin expression was paralleled by release of beta-thromboglobulin. None of these events was affected by aspirin. 5. Thromboxane formation was totally prevented by the aspirin treatment, as shown by Born aggregometry in which the platelet aggregatory response to arachidonic acid was abolished and secondary aggregation by ADP was inhibited. 6. The flow cytometric assay can therefore be used to investigate platelets in patients, regardless of aspirin therapy. 7. These findings suggest that platelet fibrinogen binding and the release of platelet alpha-granule and lysosomal contents, in response to stimulation with physiological agonists, can continue in patients despite aspirin therapy. This may help to explain why aspirin is only partially effective in preventing thrombotic events.

Slow pathway catheter ablation of atrioventricular nodal re-entrant tachycardia guided by electroanatomical mapping: a randomized comparison to the conventional approach.

BACKGROUND: Electroanatomical mapping may be expected to improve safety, efficiency and efficacy of selective slow pathway ablation for atrioventricular nodal re-entrant tachycardia (AVNRT). The goal of this prospective randomized study was to compare the efficiency of conventional fluoroscopic and electroanatomical mapping in guiding catheter ablation of AVNRT. METHODS AND RESULTS: Following induction of typical AVNRT, 20 consecutive patients were randomized to either conventional fluoroscopic or electroanatomical (CARTO) mapping to guide slow pathway ablation using a 4mm electrode. Endpoints for ablation were non-inducibility and no more than a single AV nodal echo on aggressive retesting. Acute procedural success was 100% in both groups, with no complications. Although there were no differences in time taken for pre- and post-ablation electrophysiological evaluations, in the electroanatomical group the ablation portion of the procedure showed a substantial reduction in duration (12.6+/-6.8 vs 35.9+/-18.3 min; P< 0.001) and fluoroscopic exposure (0.7+/-0.5 vs 9.6+/-5.0 min; P< 0.001) compared with the fluoroscopic group, reflected in reduced total procedure time (83.6+/-23.6 vs 114+/-19.3 min; P=0.008) and total fluoroscopic exposure (4.2+/-1.4 vs 15.9+/-6.4 min; P< 0.001). Electroanatomical mapping was associated with a lower number (2.7+/-1.6 vs 5+/-2.8; P=0.018), duration (165.3+/-181.6 vs 341+/-177.7s; P=0.013), and total energy delivery (24.3+/-3.1 vs 28.7+/-4.5 watts; P=0.042) of RF applications. There were no acute or long-term (8.9+/-2.2 month) complications or arrhythmia recurrence in either group. CONCLUSIONS: While both conventional and non-fluoroscopic electroanatomical mapping are associated with excellent results in guiding ablation of typical AVNRT, the latter offers significantly shorter procedure and fluoroscopy times, improving the efficiency of the procedure and reducing X-ray exposure.

Twenty four hour intragastric acidity and plasma gastrin concentration in healthy volunteers taking nizatidine 150 mg, nizatidine 300 mg, ranitidine 300 mg, or placebo at 21:00 h.

Nine healthy volunteers were studied on the seventh day of dosing at 21:00 h with nizatidine 150 mg (N 150), nizatidine 300 mg (N 300), ranitidine 300 mg (R 300), or placebo, given in a predetermined random order. The double-blind 24 hour studies, using the Royal Free Hospital standard protocol, simultaneously measured intragastric acidity and plasma gastrin concentration. Compared with placebo, subjects responded to dosing with each H2-antagonist by a significant decrease of 24 hour intragastric acidity (N 150-45%; N 300-49% R 300-56%; p less than 0.01) and a significant rise of plasma gastrin concentration (N 150 + 20%; N 300 + 27%; R 300 + 58%; p less than 0.01). All three drug regimens caused similar significant decreases of nocturnal acidity (N 150-72%; N 300-79%; R 300-85%; p less than 0.01) and increases of nocturnal plasma gastrin concentration (N 150 + 41%; N300 + 52%; R 300 + 80%; p less than 0.01). Dosing with ranitidine 300 mg at 21:00 h also caused a simultaneous significant decrease of morning acidity (-32%; p less than 0.05) with a significant increase of plasma gastrin concentration (+36%; p less than 0.05), but the antisecretory effects of nizatidine 150 or 300 mg at 21:00 h were only observed during the night, with no effect during the morning. No drug regimen had any effect on acidity or plasma gastrin in the afternoon or early evening.