Role of invading leukocytes in enhanced atrial eicosanoid production following rabbit left ventricular myocardial infarction.

The isolated perfused hearts of rabbits previously subjected to in vivo left ventricular myocardial infarction (LVMI) show a 5-10-fold increase in f-Met-Leu-Phe (FMLP) and bradykinin (BK)-stimulated eicosanoid metabolite production relative to noninfarcted hearts. This exaggerated arachidonate metabolism has been shown to occur primarily in the cardiac atria, a site remote from the zone of injury and to be associated with a 10-15-fold increase in atrial FMLP receptor number in the absence of atrial inflammation. All of these changes were temporally related to leukocyte infiltration into the infarct zone. To determine whether invading leukocytes mediate these responses, acute inflammatory cell influx was suppressed either by inducing leukopenia with nitrogen mustard or by administration of BW-755C, a mixed cyclooxygenase-lipoxygenase inhibitor. Both pharmacological manipulations resulted in a decrease in inflammatory cells in the infarct zone and a marked suppression (50-70%) of ex vivo agonist-stimulated eicosanoid metabolite production from perfused hearts and isolated atria. These manipulations also resulted in reversal of ex vivo FMLP-induced coronary vasoconstriction as well as augmentation of BK-induced coronary vasodilation. Further studies in nitrogen mustard-treated animals revealed a suppression of the LVMI-stimulated increase in atrial FMLP receptor number. These data show that suppression of leukocyte invasion after LVMI attenuates enhanced cardiac and atrial eicosanoid metabolite production, and results in marked changes in coronary vascular reactivity. An additional finding was that basal and stimulated LTB4 production was markedly increased in infarcted hearts. In vivo suppression of the increase in LTB4 production by BW-755C was associated with inhibition of inflammatory cell influx into the infarct zone. It therefore appears that LTB4 may be an important proinflammatory mediator of leukocyte invasion after LVMI.

Parallel cone bipolar pathways to a ganglion cell use different rates and amplitudes of quantal excitation.

The cone signal reaches the cat's On-beta (X) ganglion cell via several parallel circuits (bipolar cell types b1, b2, and b3). These circuits might convey different regions of the cone's temporal bandwidth. To test this, I presented a step of light that elicited a transient depolarization followed by a sustained depolarization. The contribution of bipolar cells to these response components was isolated by blocking action potentials with tetrodotoxin and by blocking inhibitory synaptic potentials with bicuculline and strychnine. Stationary fluctuation analysis of the sustained depolarization gave the rate of quantal bombardment: approximately 5100 quanta sec(-1) for small central cells and approximately 45,000 quanta sec(-1) for large peripheral cells. Normalizing these rates for the vastly different numbers of bipolar synapses (150-370 per small cell vs 2000 per large cell), quantal rate was constant across the retina, approximately 22 quanta synapse(-1) sec(-1). Nonstationary fluctuation analysis gave the mean quantal EPSP amplitude: approximately 240 microV for the transient depolarization and 30 microV for the sustained depolarization. The b1 bipolar cell is known from noise analysis of the On-alpha ganglion cell to have a near-maximal sustained release of only approximately two quanta synapse(-1) sec(-1). This implies that the other bipolar types (b2 and b3) contribute many more quanta to the sustained depolarization (>/=46 synapse(-1) sec(-1)). Type b1 probably contributes large quanta to the transient depolarization. Thus, bipolar cell types b1 and b2/b3 apparently constitute parallel circuits that convey, respectively, high and low frequencies.

Functional circuitry of the retinal ganglion cell's nonlinear receptive field.

A retinal ganglion cell commonly expresses two spatially overlapping receptive field mechanisms. One is the familiar "center/surround," which sums excitation and inhibition across a region somewhat broader than the ganglion cell's dendritic field. This mechanism responds to a drifting grating by modulating firing at the drift frequency (linear response). Less familiar is the "nonlinear" mechanism, which sums the rectified output of many small subunits that extend for millimeters beyond the dendritic field. This mechanism responds to a contrast-reversing grating by modulating firing at twice the reversal frequency (nonlinear response). We investigated this nonlinear mechanism by presenting visual stimuli to the intact guinea pig retina in vitro while recording intracellularly from large brisk and sluggish ganglion cells. A contrast-reversing grating modulated the membrane potential (in addition to the firing rate) at twice the reversal frequency. This response was initially hyperpolarizing for some cells (either ON or OFF center) and initially depolarizing for others. Experiments in which responses to bars were summed in-phase or out-of-phase suggested that the single class of bipolar cells (either ON or OFF) that drives the center/surround response also drives the nonlinear response. Consistent with this, nonlinear responses persisted in OFF ganglion cells when ON bipolar cell responses were blocked by L-AP-4. Nonlinear responses evoked from millimeters beyond the ganglion cell were eliminated by tetrodotoxin. Thus, to relay the response from distant regions of the receptive field requires a spiking interneuron. Nonlinear responses from different regions of the receptive field added linearly.

Is routine preoperative cardiac catheterization necessary before repair of secundum and sinus venosus atrial septal defects?

Between January 1976 and July 1983, 217 patients with atrial septal defect underwent surgical repair at Children's Hospital. Thirty with a primum atrial septal defect and 26 who underwent cardiac catheterization elsewhere before being seen were excluded from analysis. Of the 161 remaining patients, 52 (31%) underwent preoperative cardiac catheterization, 38 because the physical examination was considered atypical for a secundum atrial septal defect and 14 because of a preexisting routine indication. One hundred nine (69%) underwent surgery without catheterization, with the attending cardiologist relying on clinical examination alone in 5, additional technetium radionuclide angiocardiography in 5, M-mode echocardiography in 13 and two-dimensional echocardiography in 43; both M-mode echocardiography and radionuclide angiography were performed in 24 and two-dimensional echocardiography and radionuclide angiography in 19. Since 1976, there has been a trend toward a reduction in the use of catheterization and use of one rather than two noninvasive or semiinvasive techniques for the detection of atrial defects. Of the 52 patients who underwent catheterization, the correct anatomic diagnosis was made before catheterization in 47 (90%). Two patients with a sinus venosus defect and one each with a sinus venosus defect plus partial anomalous pulmonary venous connection, partial anomalous pulmonary venous connection without an atrial septal defect and a sinoseptal defect were missed. Of 109 patients without catheterization, a correct morphologic diagnosis was made before surgery in 92 (84%). Nine patients with a sinus venosus defect, three with sinus venous defect and partial anomolous pulmonary venous connection, four with partial anomalous pulmonary venous return without an atrial septal defect and one with a secundum defect were incorrectly diagnosed.(ABSTRACT TRUNCATED AT 250 WORDS)

Task Force 1: The underserved.

The ACC has affirmed its commitment to universal access to health care. Underserved populations exist in urban and rural centers. Common to each is a paucity of personnel trained in cardiovascular care and a lack of access to preventive and highly technologic services. These factors contribute to a poor health outcome (75). Part of the rural problem can be corrected by the transfer of information to local providers by the use of new information systems. Included would be real-time electronic consultation, on-site subspecialty visits and the appropriate use of nonphysician providers (15). The urban problem requires changes in priorities and responsibilities of the academic health centers toward the communities they serve. Curricula changes of cardiovascular specialists, internists, generalists and nonphysician health care personnel must include diversity in training, physician training of ethnically matched providers in addition to technical excellence and research into methods of patient education and motivation for a healthier life-style (51). Reimbursement must appropriately reward those caring for underserved patients and those providing evaluation and management services (43,52).

Valve replacement in children less than 5 years of age.

Between 1966 and 1984, there were 63 children less than 5 years of age who underwent 70 valve replacements (49 mitral [5 repeat], 6 aortic, 11 tricuspid [systemic ventricle; 2 repeat]), 2 tricuspid [pulmonary ventricle] and 1 multiple [mitral-aortic]) at Children's Hospital. Tissue valves were used in 20%. Since 1980, only Björk-Shiley and St. Jude valves have been used. The most common indication for valve replacement was mitral regurgitation after repair of atrioventricular (AV) canal (34%). Mortality dropped considerably over time: 76% before 1979, 33% from 1979 to 1982 and 22% since 1982. More than two-thirds of fatalities were operative deaths, usually within 3 days of surgery. Actuarial survival curves for those operated on since 1980 predict 1 and 5 year survival of 73 and 51%, respectively. For the 46 operative survivors 1 and 5 year valve survival was 97 and 70%, respectively. Postoperative hemodynamics were significantly improved on elective postoperative catheterizations. All but one patient with non-tissue valves received anticoagulant therapy. Postoperative complications included thromboembolism (1.6/100 patients-years) and hemorrhage (0.8/100 patient-years). The frequency of intravascular hemolysis and endocarditis was 1.6%, comparable with adult experience. Complete heart block requiring a pacemaker developed in nine patients (14.1%), in all after AV valve replacement. Valve replacement in young children generally results in considerable hemodynamic improvement. The mortality rate remains above that observed in adults but has declined considerably for those operated on after 1980.

Primary surgical closure of ventricular septal defect in the first year of life: results in 128 infants.

Between January 1973 and July 1981, 128 patients less than 1 year of age with failure to thrive, congestive heart failure or pulmonary artery hypertension underwent primary repair of a ventricular septal defect. The hospital mortality rate was 7.8% (10 of 128), and the late mortality rate was 2.3% (3 of 128). Mortality was highest among younger infants with preexisting respiratory problems or a hemodynamically significant residual lesion postoperatively. Complications included a large residual shunt in eight (6.2%), transient neurologic problems in five (3.9%) and persistent complete heart block in three (2.3%). Lung biopsy specimens obtained from 49 patients showed pulmonary vascular abnormalities in all. Complete right bundle branch block developed in 74 (64%) and bifascicular block appeared in 11 (9%). Recatheterization in 70 patients (55%) showed normal pulmonary artery pressures in all but 2 patients with a large residual shunt. Complete closure of the defect had been achieved in 49 (70%), and a hemodynamically insignificant shunt remained in 19 (27%). Patients without significant hemodynamic residua were asymptomatic and tended to accelerate in growth after surgery.

Are residual stenoses after excimer laser angioplasty and coronary atherectomy due to inefficient or small devices? Comparison with balloon angioplasty.

OBJECTIVES: The purpose of this study was to determine whether residual stenoses after excimer laser angioplasty and atherectomy were due to inefficient tissue ablation/removal or to undersized devices. BACKGROUND: Significant residual stenoses are commonly observed after use of laser and atherectomy devices. It is not known whether these residual stenoses are due to inefficient or undersized devices. METHODS: To determine the relative contribution of these factors, the minimal lumen diameter, percent diameter stenosis and normal reference diameter were measured immediately before and after coronary interventions in 696 lesions, including transluminal extraction atherectomy, high speed mechanical rotational atherectomy, excimer laser angioplasty and conventional balloon angioplasty. The ratio of the diameter of the device to the normal reference diameter (D/A, a measure of device sizing) and the ratio of the residual lumen diameter after use of the device to the device diameter (RLD/D, a measure of the efficiency of lumen enlargement) were calculated. RESULTS: Baseline diameter stenoses were similar for all interventions. The percent diameter stenoses were greater immediately after extraction atherectomy (60 +/- 21%), rotational atherectomy (54 +/- 23%) and excimer laser angioplasty (61 +/- 18%) compared with balloon angioplasty (26 +/- 12%, p < 0.001). The D/A ratio was smaller after extraction atherectomy (0.63 +/- 0.14), rotational atherectomy (0.59 +/- 0.17) and excimer laser angioplasty (0.51 +/- 0.11) compared with balloon angioplasty (1.05 +/- 0.13, p < 0.001). The RLD/D ratio was similar after extraction atherectomy (0.73 +/- 0.24) and balloon angioplasty (0.71 +/- 0.11) but was greater after rotational atherectomy (0.92 +/- 0.16, p < 0.001) and excimer laser angioplasty (0.85 +/- 0.30, p < 0.01) compared with balloon angioplasty. CONCLUSIONS: Residual stenoses after extraction atherectomy, rotational atherectomy and excimer laser angioplasty were more severe than after balloon angioplasty but were due to undersized devices (low D/A ratio), not to inefficient devices (low RLD/D ratio). Rotational atherectomy and excimer laser angioplasty were more efficient (higher RLD/D) than balloon angioplasty, whereas extraction atherectomy and balloon angioplasty were similar.

Do excimer laser angioplasty and rotational atherectomy facilitate balloon angioplasty? Implications for lesion-specific coronary intervention.

OBJECTIVES: This study sought to determine whether adjunctive balloon angioplasty after rotational atherectomy and excimer laser angioplasty provides better lumen enlargement ("facilitated angioplasty") than angioplasty alone. BACKGROUND: Adjunctive angioplasty is often used immediately after atherectomy and laser angioplasty to further enlarge lumen dimensions, but it is not known whether this practice is superior to angioplasty alone. METHODS: Balloon angioplasty was performed in 1,266 native coronary lesions alone (n = 541) or after extraction atherectomy (n = 277), rotational atherectomy (Rotablator) (n = 211) or excimer laser angioplasty (n = 237). Quantitative angiographic analysis included final lumen diameter, final diameter stenosis and efficiency of balloon-mediated lumen enlargement. RESULTS: Compared with angioplasty alone (33 +/- 12% [mean +/- SD]), final diameter stenosis was higher for adjunctive angioplasty after extraction atherectomy (37 +/- 16%, p < 0.001) and excimer laser angioplasty (37 +/- 16%, p < 0.001) and lower after rotational atherectomy (27 +/- 15%, p < 0.001). However, there was significant undersizing of balloons after all three devices. To correct for differences in balloon size, the efficiency index (final lumen diameter/balloon diameter ratio) was calculated and was higher for adjunctive angioplasty after the Rotablator (0.78 +/- 0.14, p < 0.001) than after angioplasty alone (0.69 +/- 0.12). The efficiency indexes suggested facilitated angioplasty after rotational atherectomy for ostial, eccentric, ulcerated and calcified lesions and lesions > 20 mm long. Facilitated angioplasty was also observed after extraction atherectomy and excimer laser angioplasty for ostial lesions, but not for any other lesion subsets. CONCLUSIONS: Rotational atherectomy, extraction atherectomy and excimer laser angioplasty can facilitate the results of balloon angioplasty. However, the extent of facilitated angioplasty is dependent on the device and baseline lesion morphology, consistent with the need for lesion-specific coronary intervention.

Ventricular tachycardia in acute rheumatic fever.

A 19-year-old man presented with fever, migratory polyarthritis, and palpitations; a diagnosis of acute rheumatic fever was made. Twenty-four-hour ambulatory cardiac monitoring (Holter) performed during the patient's hospitalization revealed ventricular tachycardia. Although disturbances in cardiac conduction and rhythm are common during the acute phase of rheumatic fever, malignant ventricular arrhythmias, to our knowledge, have not been described. Recognition of this occurrence emphasizes the need for continuous cardiac monitoring in selected patients.

A randomized trial of rosiglitazone therapy in patients with inadequately controlled insulin-treated type 2 diabetes.

OBJECTIVE: To determine the efficacy and safety of rosiglitazone (RSG) when added to insulin in the treatment of type 2 diabetic patients who are inadequately controlled on insulin monotherapy. RESEARCH DESIGN AND METHODS: After 8 weeks of insulin standardization and placebo (PBO) run-in, 319 type 2 diabetic patients with mean baseline HbA(1c) > or = 7.5% (8.9 +/- 1.1 to 9.1 +/- 1.3) on twice-daily insulin therapy (total daily dose > or = 30 U) were randomized to 26 weeks of additional treatment with RSG (4 or 8 mg daily) or PBO. Insulin dose could be down- titrated only for safety reasons. The primary end point was reduction of HbA(1c) from baseline. RESULTS: RSG 4 and 8 mg daily significantly improved glycemic control, which was unchanged on PBO. By intent-to-treat analysis, treatment with RSG 8 mg plus insulin resulted in a mean reduction from baseline in HbA(1c) of 1.2% (P < 0.0001), despite a 12% mean reduction of insulin dosage. Over 50% of subjects treated daily with RSG 8 mg plus insulin had a reduction of HbA(1c) > or = 1.0%. Neither total:HDL cholesterol nor LDL:HDL cholesterol ratios significantly changed with RSG treatment. Serious adverse events did not differ among groups. CONCLUSIONS: The addition of RSG to insulin treatment results in significant improvement in glycemic control and is generally well tolerated.

Rosiglitazone monotherapy is effective in patients with type 2 diabetes.

This study evaluated the efficacy and safety of rosiglitazone monotherapy in patients with type 2 diabetes. After a 4-week placebo run-in period, 493 patients with type 2 diabetes were randomized to receive rosiglitazone [2 or 4 mg twice daily (bd)] or placebo for 26 weeks. The primary end point was change in hemoglobin A(1c); other variables assessed included fasting plasma glucose, fructosamine, endogenous insulin secretion, urinary albumin excretion, serum lipids, and adverse events. Rosiglitazone (2 and 4 mg bd) decreased mean hemoglobin A(1c) relative to placebo by 1.2 and 1.5 percentage points, respectively, and reduced fasting plasma glucose concentrations relative to placebo by 3.22 and 4.22 mmol/L, respectively. Fasting plasma insulin and insulin precursor molecules decreased significantly. Homeostasis model assessment estimates indicate that rosiglitazone (2 and 4 mg bd) reduced insulin resistance by 16.0% and 24.6%, respectively, and improved ss-cell function over baseline by 49.5% and 60.0%, respectively. Urinary albumin excretion decreased significantly in the rosiglitazone (4 mg bd) group. There was no increase in adverse events with rosiglitazone. In the short-term, rosiglitazone is an insulin sensitizer that is effective and safe as monotherapy in patients with type 2 diabetes who are inadequately controlled by lifestyle interventions.

Pharmacokinetics of famciclovir in subjects with varying degrees of renal impairment.

OBJECTIVE: To characterize the pharmacokinetics of a single 500 mg oral dose of famciclovir in subjects with varying degrees of renal impairment. METHODS: Twenty-seven subjects were enrolled in an open-label parallel-group study. Eighteen patients had renal impairment (average age [ +/- SD], 49 +/- 12 years), and nine subjects were healthy volunteers (average age, 28 +/- 7 years). Patients with renal impairment were stratified into groups based on estimated creatinine clearance (CLCR): mild impairment (CLCR, 60 to 80 ml/min/1.73 m2), moderate impairment (CLCR, 30 to 59 ml/min/1.73 m2) and severe impairment (CLCR, 5 to 29 ml/min/1.73 m2). Plasma and urine specimens were analyzed for concentrations of penciclovir, the antivirally active metabolite of famciclovir, by reverse-phase HPLC. Plasma data were analyzed with use of model-independent methods. RESULTS: In subjects with normal renal function (CLCR > 80), the mean maximum plasma concentrations of penciclovir was 2.83 micrograms/ml (range, 1.30 to 3.82 micrograms/ml) and the mean time to reach maximum concentration was 0.89 hours (range, 1/2 to 1 1/2 hours). The mean apparent terminal elimination half-life was 2.15 hours (range, 1.56 to 2.87 hours). A linear relationship was observed between the plasma elimination rate constant and CLCR and between renal clearance and CLCR. Mean area under the plasma concentration-time curve from zero to infinity was approximately tenfold higher and the plasma elimination rate constant was approximately fourfold lower in patients with severe renal impairment than in subjects with normal renal function. CONCLUSION: Consideration should be given to modification of the dosing schedule of famciclovir from the usual 8-hour interval to a 12-hour interval for patients with moderate renal impairment (CLCR 30 to 59 ml/min/1.73 m2) or a 24-hour interval for patients with severe renal impairment (CLCR < 30 ml/min/1.73 m2).

Pharmacokinetics and pharmacodynamics of SB 209670, an endothelin receptor antagonist: effects on the regulation of renal vascular tone.

OBJECTIVE: To evaluate the pharmacokinetics and pharmacodynamics of an infusion of SB 209670, a non-peptide endothelin-A/endothelin-B receptor antagonist. METHODS: The study was conducted in 2 parts. Part 1 was a placebo-controlled, single-blind, rising-dose crossover evaluation of the pharmacokinetics and safety of SB 209670 infused at doses that ranged from 0.2 to 1.5 mirog kg(-1) for approximately 8 hours in 17 healthy male volunteers. In part 2, renal hemodynamic effects of a 4-hour infusion of SB 209670 were assessed in 10 healthy male volunteers in a 2-period, period-balanced, single-blind, randomized, placebo-controlled crossover study. RESULTS: SB 209670 appeared to display linear kinetics over the dose range from 0.2 to 1.5 microg kg(-1) min(-1). The half-life was approximately 4 to 5 hours. Plasma immunoreactive endothelin-1 increased in an apparent dose-dependent manner. Mean renal hemodynamic responses (para-aminohippurate clearance) increased by approximately 15% relative to placebo (P = .007). Renal sodium excretion was similar during SB 209670 and placebo infusion. CONCLUSION: The pharmacokinetics of intravenous SB 209670 appeared to be linear, and infusion resulted in dose-related increases in immunoreactive endothelin-1. The lack of anti-natriuretic effect and the renal vasodilator response observed in this study indicate that SB 209670 does not possess any partial agonist activity. Further, the renal hemodynamic response supported a potential physiologic role for endogenous endothelin in the maintenance of renal vascular tone in humans.

A dose-response study to assess the renal hemodynamic, vascular, and hormonal effects of eprosartan, an angiotensin II AT1-receptor antagonist, in sodium-replete healthy men.

STUDY DESIGN: The effects of orally administered eprosartan on changes induced by angiotensin II in blood pressure, renal hemodynamics, and aldosterone secretion were evaluated in healthy men in this double-blind, randomized, single-dose, placebo-controlled crossover study, which was conducted in three parts. Part 1 (n = 12) assessed the onset and duration of the effect of eprosartan 350 mg or placebo; part 2 (n = 14) assessed the dose-response profile of placebo or 10, 30, 50, 70, 100 or 200 mg eprosartan; and part 3 (n = 5) assessed the duration of the effect of 50, 100, or 350 mg eprosartan. RESULTS: In part 1 of the study; 350 mg eprosartan caused complete inhibition of angiotensin II-induced pressor and renal blood flow hemodynamic effects (effects on effective renal plasma flow [ERPF]) and inhibited angiotensin II-induced stimulation of aldosterone secretion from 1 to 3 hours after administration. Eprosartan, 350 mg, inhibited the effects of exogenous angiotensin II by approximately 50% to 70% from 12 to 15 hours after dosing. Eprosartan had no angiotensin II agonistic activity and produced an increase in ERPF starting at 1 to 4 hours after dosing. In study part 2, at 3 hours after single doses of 10, 30, 50, 70, 100, and 200 mg, eprosartan inhibited angiotensin 11-induced decreases in ERPF by 39.1%, 49.9%, 33.0%, 56.0%, 71.0%, and 85.7%, respectively, compared with placebo. In study part 3, 50, 100, and 350 mg eprosartan produced measurable Inhibition of angiotensin II-induced decreases in ERPF from 12 to 15 hours after administration. In parts 2 and 3, the eprosartan angiotensin II antagonism on blood pressure response and aldosterone secretion mirrored the angiotensin II antagonism on ERPF.

Rod bipolar array in the cat retina: pattern of input from rods and GABA-accumulating amacrine cells.

The potential and actual connections between rod and rod bipolar arrays in the area centralis of the cat retina were studied by electron microscopy of serial ultrathin sections. In the region studied there were about 378,000 rods/mm2 and 36,000-47,000 rod bipolars/mm2. The tangential spread of rod bipolar dendrites was 11.2 microns in diameter, and the "coverage factor" for the rod bipolar cell was 3.5-4.6. We estimate that about 37 rods potentially converge on a rod bipolar cell and that one rod potentially diverges to about four rod bipolar cells. The actual connections, however, are less than this by about half: 16-20 rods actually converge on a bipolar cell and one rod actually diverges to slightly less than two rod bipolar cells. The degree of convergence appears to reflect a compromise between the need to signal graded stimulus intensities (requiring wide convergence) and the need to maintain a good signal/noise ratio (requiring narrow convergence). Amacrine varicosities that provide reciprocal contact at the rod bipolar dyad were studied in serial electron microscopic autoradiograms following intraocular administration of 3H-GABA or 3H-glycine. More that 90% of the reciprocal amacrine processes accumulated GABA in a specific fashion. This information, in conjunction with Nelson's recordings from the rod bipolar and amacrine cells postsynaptic at the dyad (Nelson et al: Invest. Ophthalmol. 15:946-953, '76; Kolb and Nelson: Vision Res. 23:301-312, '83), suggests that feedback at the rod bipolar output might be positive.

Four types of amacrine in the cat retina that accumulate GABA.

Roughly one-quarter of neurons in the amacrine cell layer accumulate exogenous gamma-aminobutyric acid (GABA). Some of these (8%) are interplexiform cells; the remainder are true amacrine cells. We partially reconstructed, from serial electron microscopy autoradiograms, 25 GABA-accumulating amacrines and distinguished four types based on cytoplasmic appearance, soma size and shape, and the form of primary and secondary processes. Type 1 had a large (609 +/- 60 microns3), dark soma, and multiple, medium-diameter (0.6 microns) processes splayed from the soma margins like the appendages from a crab. Type 2 had a medium (360 +/- 40 microns3), helmet-shaped, pale soma, and medium-diameter (0.8 microns) processes that branched in sublamina alpha. Type 3 had a small (267 +/- 44 microns3), dark, pyriform soma. The latter formed a single stout (3.0 microns) process that bifurcated in the middle of sublamina alpha. Type 4 had a very large, pale soma (860 microns3). This was pyriform, tapering into a stout (2.0 microns) process that descended into the middle of sublamina alpha where it emitted smaller tangential processes. It is to be expected that each of these amacrine cell types will have distinct functions in neurotransmitter retinal circuitry.

OFF-alpha and OFF-beta ganglion cells in cat retina. I: Intracellular electrophysiology and HRP stains.

Six OFF-alpha ganglion cells and a single OFF-beta ganglion cell were penetrated with intracellular microelectrodes and marked with horseradish peroxidase (HRP) in a perfused cat eyecup. Gaussian center radii (Rc) ranging from 40 to 217 microns were measured for receptive fields mapped with slits, values in agreement with previous extracellular reports. ON and OFF response components revealed nearly identical Rc's and center locations. Although Gaussian diameters (2Rc) were about 80% of dendritic field diameters overall, in this sample dendritic and receptive fields were not well correlated. Spatial tuning of ganglion cells was evidenced in peaked amplitude-vs.-width functions, fit by difference-of-Gaussians models. Such plots yielded Rc values about 40% less than position-vs amplitude plots. Rs values for surrounds ranged from 200 to 1,700 microns. Rod and cone signals were investigated with flicker. Rod flicker signals in OFF-alpha cells were larger and of shorter latency than in either horizontal or AII amacrine cells. Cone flicker signals were also short in latency, with an ON response time constant of 9 msec, and an OFF response time constant of 3 msec. The OFF-alpha rod-cone transition involved a latency increase of 20-30 msec. The spontaneous and light-evoked impulse rates of OFF-alpha responses varied linearly with extrinsic current, but the amplitude of ON hyperpolarization was little affected. After injection of staining current, the OFF-beta cell transiently depolarized at ON, suggestive of ON inhibition with reversed chloride gradient, a result not seen in OFF-alpha responses. Events (peaked, depolarizing voltage fluctuations) of high, low, and intermediate amplitudes were studied in OFF-alpha responses. High amplitude events (impulses), were OFF-correlated with the stimulus, and exhibited mean rise times (transit time from 25 to 75% of peak amplitude) from 255 to 392 microseconds. Intermediate level events (presumed synaptic origin) were also OFF correlated and had longer rise times (325 microseconds to 1.56 microseconds). Low level events (234-685 microseconds) revealed either ON, ON/OFF, or not stimulus correlation.

ON-OFF amacrine cells in cat retina.

We studied the morphology, photic responses, and synaptic connections of ON-OFF amacrine cells in the cat retina by penetrating them with intracellular electrodes, staining them with horseradish peroxidase, and examining them with the electron microscope. In a sample of seven cells, we found two different morphological types: the A19, which ramifies narrowly in stratum 2 (sublamina a) of the inner plexiform layer, and the A22, which ramifies mostly in stratum 4 (sublamina b) but extends some dendrites to sublamina a. Both of these cell types have axon-like processes that extend > 800 microns from the conventional dendritic arbor. ON-OFF amacrine cells in our sample had receptive fields (1.7 +/- 0.3 mm diameter) that were broader than their dendritic arbors (425 +/- 35 microns diameter) and that extended over the region of axon-like processes. In addition, we found many features in common with ON-OFF amacrine cells in poikilotherm vertebrates: a broad receptive field without surround antagonism, two sizes of spike-like events, narrow dynamic range (1 log unit intensity), and excitatory postsynaptic potentials at light on and light off. Two A19 amacrine cells were examined in the electron microscope: most synaptic inputs (93 and 76%, respectively) to either cell were from amacrine cells, with minor inputs from cone bipolar cells. Synaptic outputs were to bipolar, amacrine, and ganglion cells, including the OFF-alpha cell.