Oxime carbamate--discovery of a series of novel FAAH inhibitors.

A series of novel oxime carbamates have been identified as potent inhibitors of the key regulatory enzyme of the endocannabinoid signaling system, fatty acid amide hydrolase (FAAH). In this Letter, the rationale behind the discovery and the biological evaluations of this novel class of FAAH inhibitors are presented. Both in vitro and in vivo results of selected targets are discussed, along with inhibition kinetics and molecular modeling studies.(1).

The Penumbra System: a mechanical device for the treatment of acute stroke due to thromboembolism.

BACKGROUND AND PURPOSE: Data from recent reports have indicated that mechanical thrombectomy may have potential as a treatment for acute ischemic stroke. The purpose of this study was to assess the safety and performance of the Penumbra System (PS): a novel mechanical device designed to reduce clot burden in acute stroke due to large-vessel occlusive disease. MATERIALS AND METHODS: A prospective, single arm, independently monitored and core laboratory adjudicated trial enrolled subjects with an acute neurologic deficit consistent with acute stroke, presenting within 8 hours of symptom onset and an angiographically verified occlusion (Thrombolysis in Myocardial Infarction [TIMI] grade 0 or 1) of a treatable intracranial vessel. The primary end point was revascularization of the target vessel to TIMI grade 2 or 3. Secondary end points were the proportion of subjects who achieved a modified Rankin Scale (mRS) score of 2 or less or a 4-point improvement on the National Institutes of Health Stroke Scale (NIHSS) score at 30-day follow-up, as well as all-cause mortality. RESULTS: Twenty-three subjects were enrolled, and 21 target vessels were treated in 20 subjects by the PS. At baseline, mean age was 60 years, mean mRS score was 4.6, and mean NIHSS score was 21. Postprocedure, all 21 of the treated vessels (100%) were successfully revascularized by the PS to TIMI 2 or 3. At 30-day follow-up, 9 subjects (45%) had a 4-point or more NIHSS improvement or an mRS of 2 or less. The all-cause mortality rate was 45% (9 of 20), which is lower than expected in this severe stroke cohort, where 70% of the subjects at baseline had either an NIHSS score of more than 20 or a basilar occlusion. CONCLUSION: Thus, early clinical experience suggests that the PS allows revascularization in certain subjects experiencing acute ischemic stroke.

Novel inhibitors of fatty acid amide hydrolase.

A class of bisarylimidazole derivatives are identified as potent inhibitors of the enzyme fatty acid amide hydrolase (FAAH). Compound 17 (IC(50)=2 nM) dose-dependently (0.1-10mg/kg, iv) potentiates the effects of exogenous anandamide (1 mg/kg, iv) in a rat thermal escape test (Hargreaves test), and shows robust antinociceptive activity in animal models of persistent (formalin test) and neuropathic (Chung model) pain. Compound 17 (20 mg/kg, iv) demonstrates activity in the formalin test that is comparable to morphine (3mg/kg, iv), and is dose-dependently inhibited by the CB1 antagonist SR141716A. In the Chung model, compound 17 shows antineuropathic effects similar to high-dose (100 mg/kg) gabapentin. FAAH inhibition shows potential utility for the clinical treatment of persistent and neuropathic pain.

Age-dependent fatigue behaviour of human cortical bone.

Despite a general understanding that bone quality contributes to skeletal fragility, very little information exits on the age-dependent fatigue behavior of human bone. In this study four-point bending fatigue tests were conducted on aging bone in conjunction with the analysis of stiffness loss and preliminary investigation of nanoindentation based measurements of local tissue stiffness and histological evaluation of resultant tensile and compressive damage to identify the damage mechanism responsible for the increase in age-related bone fragility. The results obtained show that there is an exponential decrease in fatigue life with age, and old bone exhibits different modulus degradation profiles than young bone. In addition, this study provides preliminary evidence indicating that during fatigue loading, younger bone formed diffuse damage, lost local tissue stiffness on the tensile side. Older bone, in contrast, formed linear microcracks lost local tissue stiffness on the compressive side. Thus, the propensity of aging human bone to form more linear microcracks than diffuse damage may be a significant contributor to bone quality, and age related fragility in bone.

Dihydropyridine neuropeptide Y Y1 receptor antagonists 2. bioisosteric urea replacements.

Structure-activity studies around the urea linkage in BMS-193885 (4a) identified the cyanoguanidine moiety as an effective urea replacement in a series of dihydropyridine NPY Y(1) receptor antagonists. In comparison to urea 4a (K(i)=3.3 nM), cyanoguanidine 20 (BMS-205749) displayed similar binding potency at the Y(1) receptor (K(i)=5.1 nM) and full functional antagonism (K(b)=2.6 nM) in SK-N-MC cells. Cyanoguanidine 20 also demonstrated improved permeability properties in Caco-2 cells in comparison to urea 4a (43 vs 19 nm/s).

Dinapsoline: characterization of a D1 dopamine receptor agonist in a rat model of Parkinson's disease.

Dinapsoline is a new potent, full agonist at D1 dopamine receptors with limited selectivity relative to D2 receptors. The efficacy of this compound was assessed in rats with unilateral 6-hydroxydopamine lesions of the medial forebrain bundle, a standard rat model of Parkinson's disease. Dinapsoline produced robust contralateral rotation after either subcutaneous or oral administration. This rotational behavior was attenuated markedly by the D1 receptor antagonist SCH-23390, but not by the D2 receptor antagonist raclopride. During a chronic 14-day treatment period in which rats received dinapsoline either once or twice a day, dinapsoline did not produce tolerance (in fact, some sensitization of the rotational response was observed in one experiment). Because dinapsoline shows less D1:D2 selectivity in vitro than other D1 agonists, the contribution of D2 activity to tolerance was assessed. Chronic daily cotreatment with dinapsoline and raclopride did not enable the development of tolerance to chronic dinapsoline treatment. In contrast, when dinapsoline was administered by osmotic minipump, rapid tolerance was observed. To explore further the contribution of D1 and D2 receptors to tolerance, experiments were performed with the selective D1 agonist A-77636. Daily dosing with A-77636 rapidly produced complete tolerance, as previously observed, whereas coadministration of the D2 agonist quinpirole plus A-77636 failed to either delay or prevent tolerance. Taken together, these results indicate that the development of tolerance to D1 receptor agonists is influenced by the pattern of drug exposure but not by the D1:D2 selectivity of the agonist.

Dopamine agonists in the treatment of Parkinson s disease past, present and future.

An attempt is made by the author to highlight the important events that laid the foundation of dopamine agonists as a treatment strategy for Parkinson s disease. This debilitating neurodegenerative disorder is long recognized as a result of progressive cell loss in the substantia nigra of the midbrain. The destruction of dopaminergic neurons with projections to the striatum results in the diminishing striatal dopamine levels. Anticholinergic drugs were once widely used to counteract the relative overactivity of cholinergic output from the basal ganglia and the strategy was only met with limited success. The discovery of dopamine depletion and the use of levodopa - a dopamine metabolic precursor, led the way to dopamine replacement therapy . The initial success with levodopa was soon overshadowed by the long-term side effects associated with levodopa. Many new drugs were developed with the hope to replace or strengthen the usefulness of levodopa. Apomorphine and ergot alkaloids have been around for some time; they are recently joined by newer dopamine agonists such as ropinirole and pramipexole. Each of these has its own characteristics and has occupied a place in the pharmacotherapy of Parkinson s disease. In this review older aporphines and ergot alkaloids are discussed first. More emphasis is directed to the side-effect profiles, metabolism and pharmacokinetics in terms of their unique chemical structures. The most recent agonists will be briefly discussed before we move on to the future - the future of emerging novel classes of promising dopaminergic agonists.

Pharmacology of bepridil.

Bepridil is an antianginal agent with multiple therapeutic actions. It decreases calcium influx through potential-dependent and receptor-operated sarcolemmic calcium channels and acts intracellularly as a calmodulin antagonist and calcium sensitizer. Thus, in cardiac muscle it enhances the sensitivity of troponin C to calcium, stimulates myofibrillar adenosine triphosphatase activity, removes calmodulin's inhibitory effect on sarcoplasmic reticulum calcium release, and inhibits sodium-calcium exchange--actions that tend to offset the effects of calcium influx blockade on cardiac contractile force. However, in vascular smooth muscle where the calcium-calmodulin complex promotes muscle contraction by activating myosin light-chain kinase phosphorylation of contractile proteins, calmodulin antagonism, coupled with bepridil's blockade of calcium influx, leads to vasorelaxation. In animal models of ischemia, bepridil and other calmodulin inhibitors show antiarrhythmic efficacy following reperfusion. Additionally, interfering with calmodulin's role in sympathetic nerve terminal function may help to limit the ischemia-induced catecholamine release that contributes to arrhythmogenesis. Bepridil shows a lidocaine-like fast kinetic block of inward sodium current (as distinct from the slow or intermediate kinetic inhibition expressed by encainide or quinidine, respectively). This inhibition is pH-dependent; activity is expressed to a greater degree at lower pH levels. This, this potentially antiarrhythmic mechanism is activated by conditions of ischemia. Bepridil's blockade of outward potassium currents and its inhibition of sodium-calcium exchange increase action potential duration and ventricular refractoriness, prolong the QT interval, and form the basis for a class III antiarrhythmic mechanism. Because hypokalemia also prolongs the QT interval, the addition of bepridil in the presence of hypokalemia can lead to excessive prolongation. Bepridil both increases myocardial oxygen supply through coronary vasodilation and decreases myocardial oxygen demand through mild heart rate and afterload reduction, and shows potential antiarrhythmic activity through class IB, III, and IV mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of calcium channel blocker overdose-induced toxicity in the conscious dog.

STUDY OBJECTIVE: To evaluate the effects of nifedipine, diltiazem, and verapamil overdose on systemic hemodynamics and blood flows to the coronary, superior mesenteric, renal, and iliac arteries in the unanesthetized dog. DESIGN: Nonblinded, controlled animal study. SETTING: Research laboratory of a large pharmaceutical company. TYPE OF PARTICIPANTS: Nineteen healthy mongrel dogs obtained from a commercial supplier. INTERVENTIONS: Under general anesthesia, flow probes were placed about the ascending aorta, circumflex coronary, superior mesenteric, renal, and iliac arteries; a micromanometer was implanted into the tip of the left ventricle; and a catheter was inserted into the descending aorta. Experiments were performed after a recovery period of at least two weeks. MEASUREMENTS AND MAIN RESULTS: Arterial blood pressure, heart rate, cardiac output, left ventricular pressure, and regional blood flows were measured prior to drug administration, and after 0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg IV administration of the study drugs. Dogs receiving diltiazem or verapamil also received a dose of 10.0 mg/kg. When the blood pressure had been reduced from baseline by 30%, 1.43 mg/kg nifedipine IV (six dogs) decreased total peripheral resistance by 51%, increased cardiac output by 35%, and increased heart rate by 132%. Coronary blood flow and iliac blood flow increased 93% and 45%, respectively, but mesenteric blood flow and renal blood flow were not significantly altered. Diltiazem (eight) and verapamil (seven) at equivasodepressor doses (1.43 to 4.43 mg/kg) caused less peripheral vasodilation and reflex tachycardia. At severely toxic levels when arterial blood pressure fell by 50%, all three drugs decreased cardiac output. Nifedipine still increased heart rate. Diltiazem and verapamil caused high-grade atrioventricular block, resulting in bradycardia. All three drugs caused a redistribution of cardiac output favoring the coronary bed over the other beds. CONCLUSIONS: In the conscious dog, calcium channel blocker-induced hypotension at the moderate level is associated with disparate effects on systemic hemodynamics, probably resulting from differential reflex sympathetic activation. However, at a more severe level, their toxic effects are similar and manifested predominantly by their actions on the slow calcium channel.

Synthesis, biological profile, and quantitative structure-activity relationship of a series of novel 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.

A series of 9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(alkyltetrazol-5-yl)- 6,8-nonadienoic acid derivatives 1 were synthesized and found to inhibit competitively the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. The analogues having 1N-methyltetrazol-5-yl attached to the C8-position (3a, 4a, R1 = R2 = F) are the most active in suppressing cholesterol biosynthesis in both in vitro and in vivo models: the IC50 for the chiral form of 3a is 19 nM, Ki = 4.3 x 10(-9)M when Km for HMG-CoA is 28 x 10(-6) M;1 the ED50 (oral) value corresponding to the lactone derivative (4a, BMY 22089) is approximately 0.1 mg/kg. Further, BMY 21950 is nearly 2 orders of magnitude more active in parenchymal heptaocytes, from which most of the serum cholesterol originates, than in other cell preparations (such as spleen, testes, ileum, adrenal, and ocular lens epithelial cells; Table III). This apparent tissue specificity may be highly beneficial since the blocking of cholesterol biosynthesis in other vital organs could eventually lead to undesirable side effects. In addition to the chemical synthesis and biological evaluation, a theoretical study aimed at relating the HMG-CoA reductase inhibitory potency to the three-dimensional structure of the inhibitors was undertaken. With a combination of molecular mapping and 3D-QSAR techniques, it was possible to determine a logical candidate for the conformation of the bound inhibitor and to quantitatively relate inhibitory potency to the shape and size of both the binding site and the C8-substituent.

Selective inhibition of cholesterol synthesis in liver versus extrahepatic tissues by HMG-CoA reductase inhibitors.

Hepatic specificity of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase may be achieved by efficient first-pass liver extraction resulting in low circulating drug levels, as with lovastatin, or by lower cellular uptake in peripheral tissues, seen with pravastatin. BMY-21950 and its lactone form BMY-22089, new synthetic inhibitors of HMG-CoA reductase, were compared with the major reference agent lovastatin and with the synthetic inhibitor fluindostatin in several in vitro and in vivo models of potency and tissue selectivity. The kinetic mechanism and the potency of BMY-21950 as a competitive inhibitor of isolated HMG-CoA reductase were comparable to the reference agents. The inhibitory potency (cholesterol synthesis assayed by 3H2O or [14C]acetate incorporation) of BMY-21950 in rat hepatocytes (IC50 = 21 nM) and dog liver slices (IC50 = 23 nM) equalled or exceeded the potencies of the reference agents. Hepatic cholesterol synthesis in vivo in rats was effectively inhibited by BMY-21950 and its lactone form BMY-22089 (ED50 = 0.1 mg/kg p.o.), but oral doses (20 mg/kg) that suppressed liver synthesis by 83-95% inhibited sterol synthesis by only 17-24% in the ileum. In contrast, equivalent doses of lovastatin markedly inhibited cholesterol synthesis in both organs. In tissue slices from rat ileum, cell dispersions from testes, adrenal, and spleen, and in bovine ocular lens epithelial cells, BMY-21950 inhibited sterol synthesis weakly in vitro with IC50 values 76- and 188-times higher than in hepatocytes; similar effects were seen for BMY-22089. However, the IC50 ratios (tissue/hepatocyte) for lovastatin and fluindostatin were near unity in these models. Thus, BMY-21950 and BMY-22089 are the first potent synthetic HMG-CoA reductase inhibitors that possess a very high degree of liver selectivity based upon differential inhibition sensitivities in tissues. This cellular uptake-based property of hepatic specificity of BMY-21950 and BMY-22089, also manifest in pravastatin, is biochemically distinct from the pharmacodynamic-based disposition of lovastatin, which along with fluindostatin exhibited potent inhibition in all tissues that were exposed to it.

Antiarrhythmic and antifibrillatory properties of McN-4130 in several animal models.

McN-4130 is an experimental compound having antiarrhythmic and antifibrillatory activity in several animal models. In anesthetized, open-chest pigs subjected to total occlusion and subsequent reperfusion of the left anterior descending coronary artery, McN-4130 dose-dependently (2.5-10.0 mg/kg i.v.) protected against fibrillation and death. Mean arterial pressure was not significantly affected, but heart rate was dose-dependently reduced. In anesthetized normal dogs, McN-4130 increased ventricular fibrillation threshold for up to 45 min. This increase in fibrillation threshold was associated with concurrent increases in ventricular conduction time and ventricular effective refractory period. In conscious dogs subjected to occlusion of the left anterior descending coronary artery 24 h previously, McN-4130, 2.5 and 5.0 mg/kg i.v., significantly reduced the rate of ventricular arrhythmias for up to 45 min. McN-4130 was more effective and had a longer duration of action than comparable doses of lidocaine and disopyramide. McN-4130 was orally effective in this model at 10 mg/kg. These results indicate that McN-4130, a structurally unique experimental antiarrhythmic compound, may be useful as a ventricular antiarrhythmic agent with antifibrillatory properties.

Regulation of jejunal blood flow and oxygenation during glucose and oleic acid absorption.

To differentiate the mechanisms whereby actively absorbed glucose and passively absorbed oleic acid increase blood flow and oxygen uptake during their absorption, the effects of these two nutrients on jejunal blood flow, arteriovenous oxygen difference [(a-v)O2], O2 uptake, absorption, rubidium extraction, and capillary permeability-surface area product (PS) were compared in anesthetized dogs. Oleic acid (37 mM) produced significantly greater hyperemia (+28.2%) than glucose (270 mM) did (+12.5%). As estimated by (a-v)O2, tissue oxygen extraction was decreased by oleic acid (-12%) but increased by glucose (+6.5%); the increases in O2 uptake by these two nutrients did not differ significantly. Glucose absorption was accompanied by an increase in rubidium extraction and capillary PS (+11.3%), whereas oleic acid absorption was not. Unlike glucose, intra-arterial infusion of oleic acid decreased vascular resistance and increased blood flow equally to the mucosa and muscularis layers. A significant relation existed between oleic acid absorption and blood flow but not between glucose absorption and blood flow. The enhancement of glucose-induced hyperemia by bile was not related to glucose absorption. Unmasking of oleic acid-induced hyperemia by bile is unrelated to oleic acid absorption but is related to solubility of oleic acid in aqueous solution. The above findings suggest that glucose absorption affects both resistance and exchange vessels, whereas oleic acid absorption affects primarily resistance vessels.

Time course of jejunal blood flow, O2 uptake, and O2 extraction during nutrient absorption.

Experiments were performed on anesthetized dogs to determine whether responses of jejunal blood flow, arteriovenous O2 difference, O2 uptake (VO2), and glucose absorption to luminal placement of predigested food or glucose would change with time during 30- and 60-min placement periods and to determine whether bile alters the responses. During the initial 15 min, food, glucose, food plus bile, and glucose plus bile produced a 13, 10, 51, and 30% increase in flow, respectively. During the next 15 min, flow returned to control levels, while arteriovenous O2 difference significantly increased with food or glucose; with glucose plus bile, flow decreased to 28% above control. In the case of food plus bile, flow decreased to 26% above control at 30 min and returned to control 50 min after placement. Despite the fluctuation in flow, the increase in VO2, and glucose absorption stayed at a steady level throughout the entire placement period. Bile significantly enhanced the increases in both flow and VO2 produced by food or glucose, prolonged the hypermia, delayed the significant rise in arteriovenous O2 difference, and had no effect on glucose absorption. In conclusion, the relative contributions of blood flow and O2 extraction to the enhanced VO2 produced by luminal food and glucose change with time, and bile significantly alters the magnitude or time course of changes in the above three variables.

Effects of pressure overload, left ventricular hypertrophy on beta-adrenergic receptors, and responsiveness to catecholamines.

Pressure overload left ventricular (LV) hypertrophy was produced by banding the ascending aorta of puppies and allowing them to grow to adulthood. LV free wall weight per body weight increased by 87% from a normal value of 3.23 +/- 0.19 g/kg. Hemodynamic studies of conscious dogs with LV hypertrophy and of normal, conscious dogs without LV hypertrophy showed similar base-line values for mean arterial pressure, heart rate, and LV end-diastolic pressure and diameter. LV systolic pressure was significantly greater, P less than 0.01, and LV stroke shortening was significantly lss, P less than 0.01, in the LV hypertrophy group. In both normal and LV hypertrophy groups, increasing bolus doses of norepinephrine or isoproterenol produced equivalent changes in LV dP/dt. beta-adrenergic receptor binding studies with [3H]-dihydroalprenolol ( [3H]DHA) indicated that the density of binding sites was significantly elevated, P less than 0.01, in the hypertrophied LV plasma membranes (111 +/- 8.8, n = 8), as compared with normal LV (61 +/- 5.6 fmol/mg protein, n = 11). The receptor affinity decreased, i.e., disassociation constant (KD) increased, selectively in the LV of the hypertrophy group; the KD in the normal LV was 6.8 +/- 0.7 nM compared with 10.7 +/- 1.8 nM in the hypertrophied LV. These effects were observed only in the LV of the LV hypertrophy group and not in the right ventricles from the same dogs. The plasma membrane marker, 5' -nucleotidase activity, was slightly lower per milligram protein in the LV hypertrophy group, indicating that the differences in beta-adrenergic receptor binding and affinity were not due to an increase in plasma membrane protein in the LV hypertrophy group. The EC50 for isoproterenol-stimulated adenylate cyclase activity was similar in both the right and left ventricles and in the two groups. However, maximal-stimulated adenylate cyclase was lower in the hypertrophied left ventricle. Plasma catecholamines were similar in the normal and hypertrophied groups, but myocardial norepinephrine was depressed in the dogs with LV hypertrophy (163 +/- 48 pg/mg) compared with normal dogs (835 +/- 166 pg/mg). Thus, severe, but compensated LV hypertrophy, induced by aortic banding in puppies, is characterized by essentially normal hemodynamics in adult dogs studied at rest and in response to catecholamines in the conscious state. At the cellular level, reduced affinity and increased beta-adrenergic receptor number characterized the LV hypertrophy group, while the EC50 for isoproterenol-stimulated adenylate cyclase activity was normal. By these mechanisms, adequate responsiveness to catecholamines is retained in conscious dogs with severe LV hypertrophy.

Responses of renal hemodynamics and function to acute volume expansion in the conscious dog.

The renal vascular and functional responses to acute volume expansion were determined in conscious dogs with all reflexes intact, sinoaortic arterial baroreceptor denervation, arterial baroreceptor denervation plus bilateral stellectomy, and arterial baroreceptor denervation plus bilateral vagotomy. In the intact dogs, when an isotonic saline infusion increased right atrial pressure by 6 mm Hg, arterial pressure increased by 15 +/- 3 from 95 +/- 3 mm Hg (P less than 0.01) and heart rate rose from 87 +/- 4 to 135 +/- 6 beats/min (P less than 0.01), while renal blood flow rose only slightly (4 +/- 2%), and calculated renal resistance was not altered significantly. After arterial baroreceptor denervation, volume expansion with saline induced a greater rise in blood flow (16 +/- 2%), but did not alter arterial pressure, and calculated resistance fell by 19 +/- 3% from 0.72 +/- 0.05 mm Hg/ml per min (P less than 0.01), while heart rate still increased. After arterial baroreceptor denervation and either bilateral stellectomy or vagotomy, volume expansion reduced renal vascular resistance by similar amounts. When intact animals were volume expanded by 20% of estimated blood volume with isooncotic, isotonic 3% dextran in saline solution, and with renal perfusion pressure held constant, central venous pressure increased by 4.5 +/- 0.6 from 1.8 +/- 0.4 mm Hg (P less than 0.01), renal blood flow increased significantly by 16 +/- 5 ml/min (P less than 0.05) from 191 +/- 30 ml/min, while calculated renal vascular resistance decreased significantly by 0.08 +/- 0.02 from 0.62 +/- 0.09 mm Hg/ml per min (P less than 0.05). Average urine flow rate and sodium excretion 10-60 minutes after expansion increased markedly by 1.85 +/- 0.27 ml/min and 9.84 +/- 1.13 muEq/min per kg, respectively (P less than 0.01). After arterial baroreceptor denervation, volume expansion induced a similar rise in central venous pressure and renal blood flow. The diuretic and natriuretic responses were not attenuated by arterial baroreceptor denervation. After arterial baroreceptor denervation plus bilateral vagotomy, there was a significant and similar rise in renal blood flow, whereas diuretic (urine flow rate rose by only 0.50 +/- 0.10 from 0.35 +/- 0.08 ml/min) and natriuretic (sodium excretion rose by only 4.83 +/- 0.95 from 1.50 +/- 0.48 muEq/min per kg) responses were significantly attenuated (P less than 0.01).(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of anesthesia on the canine carotid chemoreceptor reflex.

We studied the effects of alpha-chloralose (100 mg/kg, iv), Na pentobarbital (25 mg/kg, iv) and halothane (1 vol% and 2 vol%) on the response to carotid chemoreceptor stimulation (CCRS) in eight chronically instrumented dogs. CCRS was accomplished by means of intracarotid injections of nicotine while ventilation was held constant in the unanesthetized state and following administration of one of three different anesthetics. In the conscious state, CCRS elicited intense bradycardia and peripheral vasoconstriction as reflected by a 173 +/- 14% increase in initial cardiac cycle length and a 216 /+- 22% increase in mean iliac vascular resistance. Each anaesthetic, studied on separate days, attenuated these responses to CCRS strikingly (P less than 0.01). For instance, after alpha-chloralose, CCRS increased iliac resistance by only 55 +/- 14% and cardiac cycle length by only 27 +/- 13%. After Na pentobarbital, CCRS increased iliac resistance by 12 +/- 4% and cardiac cycle length by 8 +/- 5%. After inhalation of halothane (1 vol%), CCRS increased iliac resistance by 28 +/- 7% and cardiac cycle length by 11 +/- 5%, whereas halothane (2 vol%) abolished these responses to CCRS. Thus, general anesthesia interferes severely with carotid chemoreceptor control of the circulation. Whereas halothane and Na pentobarbital altered responses to CCRS the most, we found that even alpha-chloralose, which has been thought to maintain or augment reflex responses, was able to depress the response to CCRS strikingly.