Immunohistochemical characterization of reparative tissue present in human osteoarthritic tissue.

Studies involving disease progression in osteoarthritis (OA) have typically focused on the deterioration of native articular cartilage (AC) rather than the de novo cartilage which is frequently present. In general, there are two categories of de novo tissue observed in OA: (1) a pannus-like fibrocartilage that overlays native AC and (2) osteophytes. In this study, 30 AC samples representing a range of disease stages consistent with early to intermediate OA were examined for the occurrence of pannus-like tissue. All AC samples were examined immunohistochemically and compared with cartilage from three mature-looking osteophytes. To accomplish this, serial cartilage sections, derived from total knee arthroplasty specimens, were stained with hematoxylin and eosin and probed with antibodies raised against collagen type I, collagen type II, and aggrecan. Pannus-like tissue ranging from fibrous tissue to fibrocartilage was observed in 3 out of 30 AC samples. The appearance of this tissue was restricted to cartilage displaying signs of intermediate deterioration consistent with Outerbridge grade 2. Collagen type I, collagen type II, and aggrecan were abundant in both pannus-like tissue and osteophyte cartilage. In OA, the intrinsic repair process can yield a range of tissue types between fibrous tissue and fibrocartilage that is well integrated with the underlying, eroded AC. The absence of repair tissue from osteoarthritic samples representing the early stages of AC deterioration indicated that a relationship exists between macroscopic damage and a localized cellular repair response. Several histological and immunohistochemical similarities were also observed between the pannus-like tissue and osteophyte-derived cartilage, suggesting a common developmental process.

A longitudinal subspecialty experience for internal medicine residents.

OBJECTIVE: Market and technology innovations have greatly changed the teaching and practice of medicine in the past 10 years. This report describes an innovation in the ambulatory education of internal medicine residents: a subspecialty continuity clinic. METHODS: A subspecialty continuity clinic was developed to improve the training of internal medicine residents in caring for complex ambulatory patients. The clinic structure is discussed from the perspective of patients, residents, and subspecialists. Logistical challenges and solutions are described. RESULTS: Two and one-half years into the program, feedback from residents and subspecialists has been positive. In-training examination scores are relatively higher in the involved specialties, and residents are managing illnesses they rarely saw in an outpatient setting before this program. CONCLUSION: This experience suggests that a subspecialty continuity clinic is worthwhile and practical in educating primary care residents.

Sympathetic control of BP and BP variability in borderline hypertensive rats on high- vs. low-salt diet.

This experiment tested the effect of a high-salt diet on the interaction between arterial blood pressure (BP) and sympathetic nerve activity (SNA) at rest and during a controlled behavioral stress at an early stage in the development of hypertension in borderline hypertensive rats (BHR). Ten rats were maintained on a high-salt diet (8% NaCl) while 14 were fed a low-salt diet (0.8% NaCl) for 8 wk. They were trained in a Pavlovian paradigm by following a conditional stimulus tone (CS+) with a 0.5-s shock. SNA and BP were measured by implanted electrodes around the left renal nerve and a catheter in the femoral artery, respectively. There were no detectable between-group differences in BP or in BP variability in the resting animal at the end of the 8-wk dietary treatment. Moreover, there were no significant between-group differences in the changes in SNA evoked by the CS+ tone. Conversely, the amplitude of the initial conditional increase in BP was significantly (P < 0.05) larger in the high-salt (6 +/- 0.6 mmHg; mean +/- SEM) compared with the low-salt (4 +/- 0.4 mmHg) group. In addition, the BP excursion (peak/trough) during CS+ was larger in the high (18.2 +/- 6.1 mmHg)- vs. low-salt (5.8 +/- 0.4 mmHg) diet-fed subjects. The ratio of the average percent change in mean BP to the average percent change in SNA at the beginning of CS+ was 0.029 +/- 0.004 for the low-salt group and 0.041 +/- 0.006 for the high-salt group. We find that, before the development of overt hypertension, the enhanced conditional BP response in the high-salt BHR appears to reside at the interface between changes in SNA and the effector response and not within the central nervous system. These observations help explain the increasing BP variability typically observed with the development of hypertension in humans.

Low-frequency renal sympathetic nerve activity, arterial BP, stationary "1/f noise," and the baroreflex.

The object of this study is to quantify the very low frequency (i.e., <0.1 Hz) interactions between renal sympathetic nerve activity (SNA) and arterial blood pressure (ABP). Six rats were instrumented for chronic recordings of SNA and ABP. Data were collected 24 h after surgery at 10 kHz for 2-5 h and subsequently compressed to a 1-kHz signal. The power spectra and ordinary coherence were calculated from data epochs up to 1 h in length. The very low frequency spectra for both variables were fitted to a constant times f (-beta). The peak magnitude squared of the coherence near 0.4 Hz was 0.82 +/- 0.08, but the apparent linear coherence fell off quickly at lower frequencies so that it was close to zero for frequencies <0.1 Hz. Moreover, at these low frequencies beta, as computed by a coarse grain spectral analysis, was significantly (P < 0.01) different for SNA (0.66 +/- 0.12) and ABP (1.12 +/- 0.14). Assuming that SNA and ABP are stationary time series, the results of our classical spectral analysis would indicate that SNA and ABP are not linearly correlated at frequencies with a period more than approximately 10 s. Accordingly, we tested for stationarity by computing the spectral coherence and found that SNA and ABP are not stationary "1/f noise" within the frequency range from 0.02 to 2.0 Hz. Rather the SNA exerts control over the cardiovascular system through intermittent bursts of activity. Such intermittent behavior can be modeled by nonlinear dynamics.

Ablation of posterior atrial ganglionated plexus potentiates sympathetic tachycardia to behavioral stress.

The role of the posterior atrial ganglionated plexus (PAGP) in heart rate (HR) control was tested in unanesthetized dogs (n = 8). Resting HR was unchanged before (85 +/- 20 beats/min, mean +/- SD) versus after (87 +/- 18 beats/min) surgical ablation of these intrinsic cardiac ganglia (PAGPX). However, the peak tachycardia to a 30-s stressful stimulus was significantly increased (P < 0.05) from +53 +/- 22 beats/min before the denervation to +77 +/- 13 beats/min after PAGPX. Conversely, the peak HR increase during the stress after beta-adrenergic blockade was the same before (36 +/- 24 beats/min) versus after (38 +/- 14 beats/min) PAGPX. Moreover, the HR response to a neutral behavioral stimulus, which is mediated primarily by withdrawal of parasympathetic inhibition of the sinoatrial (SA) node, was unaltered by PAGPX. Thus the augmented tachycardia subsequent to PAGPX was attributable primarily to increased sympathetic action at the SA node. These findings indicate that a major role of PAGP parasympathetic neurons is to inhibit sympathoexcitatory effects on HR, probably either via interactions between neurons comprising the intrinsic plexus(es) or perhaps via presynaptic inhibition of sympathetic neurotransmitter release. This organization would allow parasympathetic ganglia within the PAGP to selectively modify sympathetic input to the SA node independent of direct vagal inhibition of pacemaker activity.

Laboratories which produce veterinary vaccines.

Borders, continents and oceans no longer provide a significant barrier to the movement of goods and services. Under the regulations of the General Agreement on Tariffs and Trade and the World Trade Organisation, governments may no longer prevent the importation of veterinary vaccines without scientific proof that the product would pose a threat to the health and safety of the nation. The origins of production laboratories for veterinary vaccines and the management of those laboratories are as diverse as the government programmes by which they are regulated. Both processed-based and performance-based approaches can be equally effective in the quality assurance of products. Seven international and regulatory initiatives have been developed to review these regulatory systems and, where possible, to harmonise standards and/or recognise equivalents to ease the movement of products. Continued exchange of information on a regional and world-wide basis can ensure the quality and availability of veterinary vaccines for animal health programmes around the world.

Roles of cardiac output and peripheral resistance in mediating blood pressure response to stress in rats.

The change in arterial blood pressure (BP) in response to presentation of an acute behavioral stress (i.e., classical conditioning) in rat includes an initial rapid rise (C1) followed by a delayed, but more sustained, pressor response (C2). The purpose of this experiment is to determine the patterns of change in cardiac output (CO) and total peripheral vascular resistance (TPR) that are associated with the behaviorally induced pressor response. A blood flow probe was implanted around the ascending aorta, and a catheter was implanted in a femoral artery in 10 male Sprague-Dawley rats. The rats were trained by a 15-s tone (CS+) followed by a 0.5-s tail shock; another tone (CS-), never followed by shock, served as a behavioral control. BP responded to the stressful stimulus (CS+) by a rapid C1 increase (8 +/- 1 mmHg; mean +/- SE) followed by the delayed C2 response (2 +/- 0.3 mmHg); the unconditioned response to shock was a 9 +/- 2 mmHg increase in BP. The C1 BP increase produced a significant increase in TPR (10 +/- 1 dyn.s/cm5); CO was not significantly changed. TPR decreased during C2 (-4 +/- 2 dyn.s/cm5), whereas CO was significantly increased (2 +/- 1 ml/min). These data contribute to our understanding of how the autonomic nervous system organizes the cardiovascular response to a suddenly perceived behavioral stress.

Multifiber renal SNA recordings predict mean arterial blood pressure in unanesthetized rat.

The goal of this analysis was to quantify the relationship between renal sympathetic nerve activity (SNA) and mean arterial blood pressure (MAP). We previously recorded renal SNA and MAP in conscious rats during a stressful behavioral stimulus and during a nonstressful stimulus. We then formulated a set of two linear, first-order differential equations that uses our SNA recordings after a time delay (the input) to predict fluctuations in MAP (the output). Our model has four parameters: 1) the cardiovascular time constant T that characterizes the frequency response function between the effector elements controlled by the sympathetic nerves and the cardiovascular system (1-5 s); 2) the effector time constant Te determined by the coupling between the sympathetic nervous system and the effectors (0.0-0.6 s); 3) the efferent time delay tau e between a change in SNA and a change in MAP (0.4-0.6 s); and 4) a proportionality constant C between fluctuations in SNA and fluctuations in MAP (0.3-3.4 mmHg/nV). The parameters of the model were determined that minimize the residual error between the simulated time series and the actual data time series for a stressful stimulus. Then we tested the ability of the transfer function to predict the MAP response to a nonstressful stimulus. In five of seven rats tested, the model's predictions were good, with mean cross-correlation coefficients for the predicted trials between 0.62 and 0.83. We show that multifiber renal SNA recordings can reliably predict changes in MAP in the unanesthetized rat. Thus the overall sympathetic drive to the cardiovascular system is indexed by renal SNA, although the vasomotor effectors driven by renal SNA control only approximately 20% of the blood cow.

Eliminating unnecessary lactate dehydrogenase testing. A utilization review study and national survey.

BACKGROUND: Consensus recommendations call for the elimination of lactate dehydrogenase (LDH) tests from routine rule out myocardial infarction (ROMI) protocols. METHODS: We conducted a utilization review project in which we evaluated the institutional impact of removing LDH and LDH isoenzyme tests from our hospital diagnostic panel. We then conducted a scripted telephone survey of 100 US hospitals to assess the generalizability of this project. RESULTS: All our cardiology staff members supported this intervention. Lactate dehydrogenase isoenzyme test results did not add clinically useful data for any of 200 consecutive patients discharged with a diagnosis of acute myocardial infarction, and selective use of LDH isoenzyme testing in cases where it was clinically believed to be indicated cut costs 99% during the year after our intervention. Furthermore, our telephone survey demonstrated that 66% of US hospitals polled continue to test for LDH isoenzymes in every patient with possible myocardial infarction. CONCLUSIONS: Our results corroborate prior recommendations for the removal of LDH testing from the routine ROMI protocol. Such an intervention may be accomplished easily, with excellent staff acceptance and considerable savings. Most US hospitals continue to include LDH testing in their ROMI panels despite national guidelines recommending otherwise.

Autonomic nervous control of heart rate orienting and alpha responses in dog.

The object of this experiment is to study the autonomic nervous control of alpha responses elicited in classical conditioning. Twenty-two mongrel dogs were trained in classical discriminative conditioning. Typical two-phase tachycardic responses were observed in positive (CS+) trials while only the earliest, phase 1, response was observed in negative (CS-) trials. The phase 1 response, which was identical in CS+ and CS-trials, was compared in dogs before and after selective SA-nodal parasympathectomy (N = 7) and beta-adrenergic blockade (N = 11). The phase 1 tachycardic response was eliminated by selective SA-nodal parasympathectomy but not by beta-adrenergic blockade. We conclude that the phase 1 response observed in both CS+ and CS-trials with similar time sequence and magnitude is an alpha response. The heart rate orienting response results from a withdrawal of parasympathetic activity with little or no change in sympathetic tone.

Sympathetic nervous activity and arterial pressure responses during rest and acute behavioral stress in SHR versus WKY rats.

The object of this experiment is to compare changes in renal sympathetic nerve activity (SNA), mean arterial blood pressure (MAP) and heart rate (HR) during rest and behavioral stress in 12-14 week old spontaneously hypertensive rats (SHR; N = 12) and normotensive Wistar-Kyoto (WKY; N = 12) controls. Animals were behaviorally trained by following a 15 s auditory conditional stimulus (CS+) with a 1/2 s tail shock. Resting MAP was higher (p < 0.001) in SHR (154 +/- 3 mmHg, mean +/- SEM) compared to WKY (116 +/- 3 mmHg); conversely, there was no difference in the average resting HR. The pattern of the SNA and MAP changes during the CS+ was similar across groups, but the amplitude was larger in the SHR. The CS+ stress stimulus evoked an initial transient MAP increase averaging 14 +/- 2 mmHg in the SHR compared to 4 +/- 1 mmHg in the WKY. This pressor response was preceded by a sudden burst of SNA averaging 177 +/- 22% over baseline in SHR versus 105 +/- 13% for the WKY. HR decreased in SHR only during the second component of the CS+ trial despite the large increase in SNA. We conclude that (1) SHR have higher reactivity than WKY to stress in SNA and MAP; (2) both SHR and WKY have greater SNA and MAP responses to CS+ than CS-(i.e., the discriminative paradigm was effective); (3) control of sympathetic and parasympathetic nervous activity during sustained stress differs remarkably in hypertensive and normotensive subjects; and (4) SHR blood pressure effector mechanisms may have a higher responsiveness to sympathetic nervous activity as compared to WKY.

First-order differential-delay equation for the baroreflex predicts the 0.4-Hz blood pressure rhythm in rats.

We have described a 0.4-Hz rhythm in renal sympathetic nerve activity (SNA) that is tightly coupled to 0.4-Hz oscillations in blood pressure in the unanesthetized rat. In previous work, the relationship between SNA and fluctuations in mean arterial blood pressure (MAP) was described by a set of two first-order differential equations. We have now modified our earlier model to test the feasibility that the 0.4-Hz rhythm can be explained by the baroreflex without requiring a neural oscillator. In this baroreflex model, a linear feedback term replaces the sympathetic drive to the cardiovascular system. The time delay in the feedback loop is set equal to the time delay on the efferent side, approximately 0.5 s (as determined in the initial model), plus a time delay of 0.2 s on the afferent side for a total time delay of approximately 0.7 s. A stability analysis of this new model yields feedback resonant frequencies close to 0.4 Hz. Because of the time delay in the feedback loop, the proportional gain may not exceed a value on the order of 10 to maintain stability. The addition of a derivative feedback term increases the system's stability for a positive range of derivative gains. We conclude that the known physiological time delay for the sympathetic portion of the baroreflex can account for the observed 0.4-Hz rhythm in rat MAP and that the sensitivity of the baroreceptors to the rate of change in blood pressure, as well as average blood pressure, would enhance the natural stability of the baroreflex.

The Unites States Department of Agriculture Regulation of Veterinary Biological Products. The use of prelicensing evaluation and postlicensing monitoring to achieve regulatory compliance.

The United Stated Department of Agriculture is responsible for regulating veterinary biological products in the United States, and the regulatory authority is provided in the Animal Virus-serum-Toxin Act of 1913. The act authorizes the Secretary of Agriculture to promulgate regulations for the production, testing, and marketing of veterinary biological products into, within, or from the United States. The current regulatory program consists of extensive prelicensing review of products, labeling, facilities, and personnel and a postlicensing monitoring system of unannounced in-depth inspections, premarketing control of product batches (serials), random check testing of finished product, and postmarketing epidemiological surveillance. This combination of regulatory oversight before and after licensure assures that pure, safe, potent, and effective veterinary biologics are available for use in the United States.

Sympathetic nervous activity and arterial blood pressure control in conscious rat during rest and behavioral stress.

The object of this experiment is to analyze the neural control of arterial blood pressure (BP) during rest and a sudden behavioral stress. Sprague-Dawley rats were classically conditioned by following a 15-s tone (CS+) with a 0.5-s tail shock. Bipolar renal nerve electrodes and a caudal artery catheter were implanted. Two days later BP and sympathetic nervous activity (SNA) were recorded in the behaviorally trained animals. The CS+ evoked a large initial increase in BP (peak, 14 +/- 5 mmHg, mean +/- SD; n = 12) that lasted 3.9 +/- 0.8 s. An abrupt (latency = 0.16 +/- 0.03 s), short (duration = 0.58 +/- 0.12 s), and intense (4.09 +/- 1.02 times average control) burst in sympathetic activity preceded this first component (C1) of the BP conditional response. The size of C1 was related to the magnitude of the SNA burst. SNA then fell below control; this quiet period preceded a fall in BP after the C1 peak. Pressure rose again (C2; peak = 6 +/- 3 mmHg, average increase = 3 +/- 3 mmHg) for the remainder of the CS+. SNA increased to 1.24 +/- 0.14 of control during this second component of the BP conditional response. Ganglionic blockade eliminated the BP and SNA conditional response (n = 3). The C1 pressure increase appears to result from an "open-loop" process in which a brief barrage of nerve activity governs BP changes lasting several seconds. The quite period probably results from a negative feedback (i.e., baroreflex) relationship between SNA and BP.(ABSTRACT TRUNCATED AT 250 WORDS)

Sympathetic activity and blood pressure are tightly coupled at 0.4 Hz in conscious rats.

Interactions of sympathetic nerve activity (SNA) with blood pressure (BP) and heart rate (HR) were assessed in conscious rats while they rested quietly in a cloth sock (n = 7), roamed freely in their home cage (n = 6), and then after anesthesia with pentobarbital (30 mg/kg; n = 7). The power and coherence spectra below 3 Hz were calculated from data collected for 9.56 min. In the conscious rat, SNA spectral power peaked at 0.4 Hz, whereas the majority of spectral power for both BP and HR occurred at frequencies lower than 0.4 Hz. However, there was an inconspicuous peak in the BP power spectra at 0.4 Hz that was not seen in the HR spectra. Coherence between SNA and BP peaked at a frequency of approximately 0.4 Hz, the same frequency at which the SNA spectral peaks occurred. In contrast, at frequencies below 0.4 Hz where maximum BP power occurred, the coherence was considerably lower. Anesthesia with pentobarbital lowered spectral power for BP, SNA, and HR but essentially did not change the coherence between SNA and BP. Interactions between respiration and each of the other variables were weak in the conscious rat. However, prominent respiratory interactions at approximately 1.2 Hz were evident after anesthesia. These data indicate a close coupling between SNA and BP at 0.4 Hz, raising the possibility that the BP spectral power at 0.4 Hz reliably reflects sympathetic activity.

Protein accumulation in cerebrospinal fluid during -90 degrees head-down tilt in rabbit.

Plasma proteins are only somewhat larger than the intercellular spaces of the cerebral microvessels that constitute the blood-brain barrier or of the choroid plexus villi that elaborate cerebrospinal fluid (CSF). We hypothesized that the integrity of these barriers in anesthetized rabbits might be compromised during head-down tilt (HDT). Plasma protein and osmolality, hematocrit, and CSF protein concentration were compared in rabbits exposed to 1 h of HDT (n = 20) and prone rabbits (n = 10). In addition, the concentration of trypan blue dye, injected intravenously at the end of HDT or the prone position, was measured in brain homogenate. Finally, arterial blood pressure was measured via a catheterized carotid artery. HDT disrupted the barrier between blood and CSF, as indicated by a significantly (P < 0.01) greater brain trypan blue concentration in the HDT rabbits [172.2 +/- 14.4 (SD) micrograms/g dry wt] than in the prone rabbits (29.8 +/- 4.4 micrograms/g dry wt). Moreover CSF protein 5 min after HDT onset was significantly increased compared with control in HDT rabbits (54.6 +/- 1.9 vs. 81.4 +/- 5.2 mg/dl; n = 8) but not in prone rabbits (55.6 +/- 2.7 vs. 57.2 +/- 5.0 mg/dl; n = 6). Changes in the plasma protein-to-hematocrit ratio in the HDT animals, but not in the prone animals, were also compatible with a loss of fluid from the vascular compartment.(ABSTRACT TRUNCATED AT 250 WORDS)

Stability of visceral behavior in the awake rat during rest.

Brady and colleagues have championed the importance of careful delineation and control of a subject's behavioral state. In this paper we develop the concept of visceral behavior from a physiological perspective. Sprague-Dawley rats were instrumented to record arterial blood pressure, renal sympathetic nerve activity, and respiration. The rats were restrained in a conical cloth sock. Rats that were well adapted to the sock restraint showed a regular respiratory pattern and consistent pressure recordings; they rested quietly in the sock and moved only occasionally to adjust their position. Fourier analysis of blood pressure and nerve activity showed a concentration of power below 1 Hz. The coherence between the two signals was strong (0.83 +/- 0.03) at 0.42 Hz. Conversely, during their initial adjustment to the sock restraint, the rats tended to show large fluctuations in blood pressure associated with episodic apneic breathing; 1 animal displayed this pattern of visceral behavior throughout most of the experiment. Despite this instability in pressure, the rats' overt behavior was stable: They rested quietly in the sock with only occasional position shifts. Spectral analysis and coherence computations showed large shifts in the distribution of power and frequency range over which arterial pressure and sympathetic activity were tightly coupled. These data are consistent with the view that an animal's circulatory adjustments, as well as adjustments in other aspects of its physiological state, constitute an important aspect of behavior, and that this behavior can influence the interpretation of biobehavioral data.

Two-component arterial blood pressure conditional response in rat.

The objective of these experiments was to quantify the pattern of change in arterial blood pressure (BP) during a discriminative aversive classical conditioning paradigm in rat using a new "high resolution" computer analysis. Sprague-Dawley rats (n = 5) were restrained in a soft, conical cloth pouch and conditioned using a 6 sec. pulsed tone (CS+) followed by a 0.5 sec. tail shock; a steady tone, never followed by shock, served as a CS-. BP peaked at 16.4 +/- 6.5 mm Hg (mean +/- SD) above control at 1.5 +/- 0.1 sec. after onset of CS+. This "first component" ("C1") also occurred during CS- (12.1 +/- 3.8 mm Hg), although the magnitudes of the two were significantly (p < 0.05) different. Another group of rats (n = 8) was treated identically except the tones were 15 seconds long. The conditional BP response consisted of two components. C1 was reminiscent of that seen using the short tone: for CS+ a peak of 13.6 +/- 5.6 mm Hg at 1.5 sec. or, for CS-, of 10.0 +/- 4.3 at 1.3 sec. (p < 0.05). In CS+ trials BP peaked again ("C2," 7.4 +/- 2.5 mm Hg) at 8.3 +/- 1.2 sec. There was no statistically significant C2 for CS- trials, clearly demonstrating discrimination between tones. The unconditional BP response in both groups consisted of two large, closely spaced peaks in BP. Respiration was recorded in 3 additional rats. After shock delivery these subjects often showed a sudden shift between (1) a regular respiratory pattern with moderate chest excursion and (2) apneic episodes interspersed with single, deep breaths. This latter pattern was associated with large, low frequency fluctuations in BP. Continued development of the rat conditioning paradigm is especially warranted because of the ability to record sympathetic nerve activity in intact, awake subjects and the large number of readily available genetic strains, which model human pathological states.

Potentiation of the pressor response to stress by tolbutamide in dogs.

Tolbutamide has previously been shown to amplify the pressor effects of "exogenous" catecholamines in conscious dogs, possibly due to sensitization of the alpha 1-adrenoreceptor-mediated vasoconstriction. The objective of this study was to examine if tolbutamide also amplifies the pressor effects of "endogenous" catecholamines released during psychological stress (classical Pavlovian aversive conditioning). Experiments were conducted in beta-adrenoreceptor-blocked (propranolol, 1 mg/kg, i.v.) conscious dogs (n = 4) trained in classical aversive conditioning. Conditioning was accomplished by following a tone (CS+) with a 1/2 second shock; another tone (CS-) was not followed by any shock and served as control. With saline pretreatment, aversive conditioning (i.e., CS+) increased mean arterial pressure (MAP) only by approximately 4.7% when compared to CS-, whereas with tolbutamide (45 mg/kg, i.v.) pretreatment, the increase in MAP induced by CS+ beyond what was induced by the CS- (approximately 6.2%) was significantly (p < 0.05) larger than that with saline pretreatment. In isolated canine femoral arterial segments (n = 4), the vasoconstrictor effect of phenylephrine (an alpha 1-agonist) at 5 x 10(-6) M (which was the EC50 value) was amplified by 2 x 10(-2) M of tolbutamide from 54.0 +/- 2.0% to 66.9 +/- 2.1%. In conclusion, tolbutamide amplifies the pressor effects of "endogenous" catecholamines in conscious dogs, possibly by sensitization of the alpha 1-adrenoreceptor-mediated vasoconstriction. This mechanism of action is novel and has not been reported with other agents.