Effects of practolol on exercise tolerance and cardiac haemodynamics and metabolism in patients with coronary artery disease.

Sixteen male patients with typical angina pectoris secondary to coronary atherosclerosis performed two daily standardized exercise tests during two consecutive days. Three hours before each exercise they received placebo or 400 mg practolol administered orally in double-blind fashion in order to complete a cross-over design. Practolol significantly prolonged the exercise duration by 30.6% and delayed the appearance time of ischaemic electrocardiographic changes by 67.7%. Maximal heart rate, systolic pressure, and pressure-rate product were also reduced after medication. In order to investigate further the effects of this beta blocking agent, myocardial function and metabolism at rest and during supine exercise were assessed in 12 male patients with coronary artery disease before and after practolol 30 mg, iv. At rest, practolol produced a decrease in tension-time index (18%), cardiac index (17%), heart rate (10%), and stroke index (7%). A significant reduction was also observed in resting stroke work index (14%) and systolic and mean aortic pressure (6%). Left ventricular end-diastolic pressure remained unchanged. During supine exercise, only time-tension index (12%), heart rate (12%), and cardiac index (10%) were significantly reduced after the beta blocking agent. Practolol did not significantly change the arterial glucose, lactate, inorganic phosphate, potassium, calcium, magnesium, pH, PCO2, or PO2. The beta blocking agent did not modify the myocardial extraction of any of these substrates at rest or during exercise. In the dosage used in both studies, practolol significantly improved the exercise tolerance and reduced the ischaemic manifestations. The efficacy of practolol in angina pectoris may result mostly from its ability to decrease heart rate and systolic pressure during exercise.

Endogenous angiotensin II as a determinant of sodium-modulated changes in tissue responsiveness to angiotensin II in normal man.

Dietary sodium restriction reduces vascular smooth muscle, particularly renovascular, responsiveness to infused angiotensin II (AII), while the responsiveness of the adrenal and the AII-renin short feedback loop to AII is enhanced. To determine whether circulating AII mediates these changes in responsiveness, we studied 11 sodium-restricted and 9 sodium-replete normal subjects before and after 75 h of converting enzyme inhibitor pretreatment with MK421. All subjects received infusions of paraaminohippurate (PAH) to assess renal plasma flow during graded AII infusion (0.3-10 ng/kg X min) before and after MK421 administration. Plasma aldosterone, cortisol, PRA, AII, sodium, potassium, and PAH clearance were measured at the onset and end of each AII dose. In sodium-restricted subjects, preinfusion AII and aldosterone levels were significantly reduced, (P less than 0.001) to the range found in sodium-replete subjects, after 75 h of MK421 administration, whereas blood pressure and PAH responses to infused AII were significantly enhanced (P less than 0.01). Blood pressure and PAH responses to infused AII in sodium-replete subjects were not significantly modified by MK421 treatment, confirming that the drug effect was specific. In contrast, the plasma aldosterone increment and PRA decrement after AII infusion were similar before and after MK421 on both diets. Thus, sodium-modulated changes in PAH and blood pressure responsiveness to infused AII depend on circulating AII levels. However, circulating AII does not mediate sodium modulation of adrenal or PRA short-feedback loop responsiveness to infused AII. Two different mechanisms determine sodium modulation of tissue responsiveness to AII; in one, circulating AII via a receptor mechanism is the mediator, and in the other, some other factor(s) also linked to sodium intake must be responsible.

Biotransformation of sulindac in end-stage renal disease.

In normal humans sulindac, a prodrug, undergoes two major biotransformations: irreversible oxidation to the inactive sulfone metabolite and reversible reduction to the pharmacologically active sulfide metabolite. To assess any effect of end-stage renal failure on sulindac biotransformation, six patients were given 200 mg sulindac orally. Plasma was sampled over 24 hours. Protein binding of sulindac and metabolites was determined by equilibrium dialysis. Results were compared with historic controls. AUC(0-12) for sulindac and the sulfone were similar to controls. AUC(0-12) for the sulfide was significantly reduced to 4.85 micrograms X hr/ml from 13.1 micrograms X hr/ml (P less than 0.02). Protein binding of all three compounds was significantly reduced by renal failure. When corrected for protein binding, the AUC(0-12) for sulindac and the sulfone was twice that of controls whereas that of the sulfide was 42 ng X hr/ml compared with 83 ng X hr/ml in normal individuals (P less than 0.001). This suggests that end-stage renal failure impairs the reduction of sulindac to the active sulfide whereas oxidation to the sulfone is intact.

Nonsteroidal anti-inflammatory effect of sulindac sulfoxide and sulfide on gastric mucosa.

Gastric injury resulting from nonsteroidal anti-inflammatory drugs is thought to require direct contact of the drug with the gastric mucosa. An inactive form of a drug (as a prodrug) should protect against mucosal damage. Because sulindac sulfoxide has little effect on prostaglandin synthesis until it is reduced to sulindac sulfide after absorption, we performed a double-blind, crossover endoscopic study in 15 normal subjects to compare the prodrug sulindac sulfoxide (200 mg b.i.d.), the active sulfide metabolite sulindac sulfide (100 mg b.i.d., which yields similar sulfide blood concentrations), a positive control (aspirin, 650 mg q.i.d.), and a negative control (placebo). Each drug was taken for 1 week and gastric mucosa were endoscopically assessed before and after 2, 5, and 7 days of dosing. Aspirin predictably damaged the gastric mucosa, whereas the effects of sulindac sulfoxide and sulindac sulfide could not be distinguished from those of the placebo. We conclude that sulindac sulfoxide as a prodrug is not directly responsible for the reduced severity of gastric mucosal lesions. Both sulindac sulfoxide and sulindac sulfide are poorly soluble in acid gastric contents and the reduced damage may relate to the inability of high concentrations of the drug to enter gastric mucosal cells.

Effects of diflunisal on platelet function and fecal blood loss.

The effects of diflunisal, a nonacetylated difluorinated salicylate, on platelet function were compared with those of aspirin and placebo. In a randomized, double-blind trial, normal subjects were given diflunisal, 250, 500, or 1,000 mg twice daily; aspirin, 650 or 1,300 mg twice daily; or placebo for 8-day periods. Difunisal, 250 mg, had no effect on platelet function, whereas 500 mg induced minimal inhibition of colagen-induced release of platelet serotonin, and 1,000 mg inhibited platelet malondialdehyde production, moderately prolonged template bleeding times (P = NS), and increased fecal blood loss (P less than 0.05). In contrast, aspirin, 650 mg, markedly inhibited collagen-induced platelet aggregation and serotonin release, and 1,300 mg prolonged bleeding time (P less than 0.01) and increased fecal blood loss (P less than 0.01). The effects of aspirin lasted for up to 5 days, whereas changes induced by diflunisal had returned to baseline 24 hr after the drug was discontinued. We conclude that in doses in the same range as those of aspirin diflunisal inhibits platelet function less.

Kinetics of osmotically controlled indomethacin delivery systems after repeated dosing.

Two osmotically driven, controlled-release dosage forms of indomethacin were evaluated in a multiple-dose crossover study in 12 healthy subjects. Following equivalent daily doses, less frequent dosing of both controlled-release forms resulted in plasma concentration profiles that are more uniform than those following capsule regimens. After the first day, morning predose plasma levels wer significantly higher for the controlled-release treatments. Renal clearances were similar between days and among treatments. Total urinary recoveries were comparable for all regimens.

Timolol and propranolol: bioavailability, plasma concentrations, and beta blockade.

Timolol, like propranolol, is a nonselective beta-adrenergic blocker, but it is much less lipid soluble and is formulated as a single enantiomer rather than a racemic mixture. We examined the effects of such differences on bioavailability, systemic clearance, and pharmacologic response. Ten healthy subjects received placebo, 0.2 mg/kg IV propranolol, 3.2 mg/kg oral propranolol, 0.025 mg/kg IV timolol, and 0.4 mg/kg oral timolol in double-blind, randomized crossover fashion. Plasma concentrations of total drug were monitored up to 8 hr, while responses to submaximal exercise were measured at 0, 2, and 6 hr. Timolol had greater bioavailability (F = 0.61 +/- 0.06(SEM) and 0.32 +/- 0.04) and lower systemic clearance (463 +/- 74 ml kg-1 hr-1 and 1040 +/- 120 ml kg-1 hr-1) than propranolol. Half-lifes were of the same order (2.7 and 2.9 hr). There was a marginal correlation between areas under the intravenous and oral plasma concentration-time curves for timolol (r = 0.66, P = 0.054), but none for propranolol (r = 0.48, P NS). There were also correlations of the response (percent reduction in heart rate) to oral and intravenous timolol at 2 hr (r = 0.72, P less than 0.05) and 6 hr (r = 0.84, P less than 0.01) hr, but none between responses to oral and intravenous propranolol. Finally, the response to oral timolol was related to the area under its plasma concentration-time curve, whereas that to propranolol was not. We conclude that the physicochemical properties of timolol lead to greater bioavailability. Pharmacologic response to an oral dose of timolol, unlike that to propranolol, can be predicted from the response to an intravenous dose and reflects its plasma concentration.

Comparison of oral indacrinone with furosemide.

The oral dose response and time course of action of indacrinone was compared with that of furosemide in six healthy men on a sodium and potassium-controlled diet. The single doses were 5, 10, 20, 40, and 80 mg indacrinone and 20, 40, and 80 mg furosemide. Diuretic, natriuretic, and kaliuretic effects revealed that indacrinone was more potent, had a longer duration of action, and induced a greater sodium for equivalent potassium loss during its period of peak activity than furosemide. During the 8 hr after drug, all doses of indacrinone decreased serum uric acid levels and increased uric acid clearance while furosemide generally increased serum uric acid and decreased uric acid clearance. After 24 hr, serum uric acid and uric acid clearance were the same for the two drugs. A rise in plasma renin activity was observed 2 hr after an 80-mg dose of furosemide but not after indacrinone.

Enterohepatic circulation of sulindac and metabolites.

Four subjects were studied by continuous intraduodenal sampling to establish the existence and determine the extent of enterohepatic recirculation of sulindac and its sulfide and sulfone metabolites. Sulindac, 200 mg by mouth, was given every 12 hr for 7 days. After the last dose was given intraduodenally, constant duodenal infusion of a nutrient mixture and sampling of duodenal contents were performed through a triple-lumen intraduodenal tube for 12 hr. Calculation of nonabsorbed drug in the samples and quantitation of drug and metabolite levels in the biliary secretions were made possible by nonabsorbable markers in the drug solution and in the infusate. Interindividual variations in the absolute values for each of the chemical species were over a 200% range, but for each subject relative clearances were in a remarkably constant ratio, averaging 1:12:12 for sulfide:sulindac:sulfone. Total biliary excretions of the prodrug (sulindac) and active pharmacophore (sulfide) calculated from these biliary clearances and historic mean plasma AUCs were 136% and 22% of dose. Thus, there is a correlation between data in man and those in five other species and the data established that, after sulindac, the contribution of enterohepatic circulation to conservation of the active pharmacophore is achieved predominantly at the level of inactive prodrug.

Pharmacology of enantiomers and (-) p-OH metabolite of indacrinone.

Indacrinone, a racemic mixture, is a loop-blocking diuretic with effects on uric acid elimination that differ from those of furosemide. A series of studies in healthy men was undertaken to characterize the pharmacologic activity of the positive (+) and negative (-) enantiomers (E) of indacrinone and its (-) p-OH metabolite, (-) MET. All subjects were on sodium- and potassium-controlled diet; each experiment was similar in design and included placebo and positive controls. Oral (-)E and (-)MET exerted dose-related natriuretic and diuretic effects; intravenous doses of (-)E were more effective than (-)MET. The effects of (-)E and (-)MET on serum uric acid were the same as those reported with indacrinone. After (-)E, both (-)E and generated (-)MET appeared to contribute to the natriuresis. (+)E induced dose-related decreases in serum uric acid up to 24 hr after dosage; at the higher doses of (+)E, the hypouricemic effects were of the order of those after 500 mg of probenecid. Thus, indacrinone is a novel loop diuretic with enantiomers and a (-)MET, each of which has a different pharmacologic profile.

Enalapril worldwide experience.

Overall, the worldwide experience on enalapril to date is very encouraging. The drug produces good to excellent responses in 54 to 66 percent of patients with essential hypertension and is at least as effective as either diuretics or beta blockers. The effects of enalapril compared with those of diuretics confirm that patients more dependent upon the renin-angiotensin system respond better. When hydrochlorothiazide is administered concomitantly with enalapril, almost all patients respond, with good long-term maintenance. In patients with severe hypertension, Blocadren or Aldomet may be added in addition to hydrochlorothiazide and will produce additional benefit. Enalapril attenuates the adverse metabolic effects of hydrochlorothiazide, particularly hypokalemia. Overall, although the efficacy of enalapril and that of captopril are similar, enalapril is better tolerated and does not appear to be associated with any significant occurrence of captopril-type side effects, particularly the skin rash and loss of taste. As expected, enalapril and other converting inhibitors may be associated with azotemia in patients with bilateral renovascular hypertension.

Differential sensitivity of laryngeal and pharyngeal motoneurons to iontophoretic application of serotonin.

Serotonergic neurons decrease their activity during sleep, especially rapid eye movement sleep, thereby reducing their facilitatory effect on upper airway motoneurons. The magnitude of teh sleep-related loss of tone varies among upper airway muscles (e.g., pharyngeal dilator motoneurons are more suppressed than laryngeal motoneurons). We hypothesized that these differences may be related to the sensitivity of different groups of upper airway motoneurons to serotonin. Experiments were done on decerebrate, vagotomized, paralysed and artificially-ventilated cats. Hypoglossal and laryngeal motoneurons were recorded extracellularly using five-barrel pipettes filled with: serotonin, glutamate and methysergide (serotonergic antagonist) for iontophoresis, and NaCl for recording and current balancing. All but two of the 65 hypoglossal motoneurons (45 inspiratory, 10 expiratory, 10 tonic) and 27 out of 32 laryngeal motoneurons (14 inspiratory, 18 expiratory) were excited by serotonin, and the excitation was abolished by methysergide. To compare the magnitude of the excitatory effect among distinct motoneuronal groups, we applied small ejection currents in a standardized manner (+15 nA for 3 min; 10 mM serotonin in 150 NaCl) onto spontaneously active motoneurons (13 inspiratory hypoglossal, 11 inspiratory laryngeal and 11 expiratory laryngeal). Serotonin increased the number of spikes per respiratory burst of inspiratory hypoglossal motoneurons from 19 +/- 4.0 (S.E.M.) to 35 +/- 4.8, of inspiratory laryngeal motoneurons from 44 +/- 8.3 to 55 +/- 8.8, and of expiratory laryngeal motoneurons from 23 +/- 4.8 to 33 +/- 6.2. The relative increases in activity (to 220% +/- 24, 147% +/- 23 and 148% +/- 9 of control, respectively) were significantly higher in hypoglossal than in laryngeal motoneurons. In addition, the excitatory effect developed significantly faster in hypoglossal than in laryngeal motoneurons. Methysergide reduced the spontaneous activity of about half the hypoglossal and laryngeal motoneurons to 66% +/- 5 of control. Thus, the sensitivity to the excitatory effects of serotonin varies among different pools of upper airway motoneurons. These differences correlate with the pattern of airway muscle hypotonia seen during sleep.

Clinical safety profile of sotalol in the treatment of arrhythmias.

The safety of sotalol was evaluated in 3,257 patients treated for cardiac arrhythmias in double-blind and open-label clinical trials that support United States registration of the drug. In this composite population, 80% of patients had structural heart disease and 42% had life-threatening ventricular arrhythmias, i.e., ventricular tachycardia (VT) or fibrillation (VF). Proarrhythmia was reported in 141 patients (4.3%). Of these, 78 (2.4%) had torsades de pointes and 26 (0.8%) had sustained VT or VF. The overall incidence was higher in patients treated for sustained VT or VF (6.5%). In these patients, serious proarrhythmia was predominantly torsades de pointes (4.1%) and was more prevalent in patients with congestive heart failure and low ejection fraction. Torsades de pointes was observed early in the course of treatment, and its occurrence was related to dose. The overall mortality in patients treated with sotalol was 4.3% (139 patients); in patients with life-threatening arrhythmias, cardiac mortality was 4.8%. In only 27 patients (0.8%) was the death thought to be potentially drug-related. The deaths were not related to dose. Data from a previously reported placebo-controlled postmyocardial infarction trial indicated no significant difference in mortality between sotalol and placebo. Heart failure was reported in 3.3% of patients and was most prevalent in those with a previous history of congestive heart failure, cardiomyopathy, or structural heart disease. The occurrence of heart failure was unrelated to dose or time on drug; in more than half of the patients, sotalol treatment was continued. On average, there was no decrease in ejection fraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Enalapril in hypertension and congestive heart failure. Overall review of efficacy and safety.

Multiclinic controlled studies have shown that enalapril alone 10 to 40 mg/day orally is effective in lowering blood pressure in patients with essential hypertension. Enalapril has been compared with thiazides and beta-blockers (propranolol, metoprolol and atenolol). The effect on systolic blood pressure has been greater with enalapril than with beta-blockers. The proportion of patients who respond to enalapril alone with a decrease in diastolic blood pressure (greater than or equal to 10mm Hg) is around 70%. When a thiazide is added to the treatment, the proportion is above 90%. Enalapril improves the signs and symptoms associated with congestive heart failure. Patients increased their exercise tolerance by an average of 148 sec and improved in their NYHA cardiac status and prognosis classification. The overall incidence of side effects is similar to that seen in the placebo control groups. Side effects such as agranulocytosis, taste loss, rash, proteinuria were not characteristic of enalapril. This supports the hypothesis that the improved safety profile of enalapril is the result of being a nonsulphydryl angiotensin-converting enzyme (ACE) inhibitor. The most common side effects reported were dizziness, headache and asthenia. Abnormalities in electrolytes, uric acid, glucose or in lipids have generally not been associated with enalapril.

Spontaneous ventilation and respiratory motor output during carbachol-induced atonia of REM sleep in the decerebrate cat.

Microinjections of carbachol into the pons induce a state that resembles rapid eye movement (REM) sleep in intact cats and, in decerebrate, artificially ventilated cats, produce postural atonia accompanied by a powerful depression of the respiratory motor output. In this study, pontine carbachol was used in decerebrate, spontaneously breathing cats to assess the effects of mechanical and chemical respiratory reflexes on the magnitude and pattern of the carbachol-induced depression of breathing, and to determine whether the depression is altered in those animals in which rapid eye movements are present. Phrenic nerve activity and tidal volume were only transiently depressed at the onset of the carbachol-induced postural atonia, whereas the decrease in respiratory rate and the depressions of hypoglossal and intercostal activities persisted until the response was reversed by a pontine microinjection of atropine 15-101 minutes after the onset of carbachol response. Ventilation was reduced to 70% of control during the steady-state conditions. The irregularity of breathing, characterized by the inter-quartile ranges of the distributions of the peak phrenic nerve activity and respiratory timing, did not increase following pontine carbachol. Neither vagotomy nor vigorous eye movements were associated with increased breathing irregularity. This contrasts with the irregular breathing (with minor average changes in ventilation) typical of natural REM sleep. We propose that the carbachol-injected decerebrate cat provides a useful model of the depressant effects that neural events associated with REM sleep may have on breathing.

Interaction of serotonergic excitatory drive to hypoglossal motoneurons with carbachol-induced, REM sleep-like atonia.

The facilitatory effect of serotonin (5HT) on hypoglossal (XII) motoneurons is likely to be reduced during rapid eye movement (REM) sleep, when the activity of the brainstem serotonergic system reaches its nadir. Therefore, we assessed the hypothesis that application of exogenous 5HT will attenuate the REM sleep-like suppression of XII motoneurons produced in decerebrate cats by pontine microinjections of a cholinergic agonist, carbachol. Microinjections of 5HT or 5-carboxamidotryptamine into the XII nucleus increased XII nerve activity to 182 +/- 53% (standard deviation; SD) of control. Subsequent pontine microinjections of carbachol reduced XII nerve activity by 55 +/- 21% of the pre-5HT level (n = 12). Microinjections of methysergide (a 5HT antagonist) into the XII nucleus reduced XII nerve activity to 54 +/- 17% of the pre-methysergide control (n = 6). Pontine carbachol injections after methysergide further reduced XII nerve activity by 49 +/- 20% of the pre-methysergide level. Treatments with both agonists and the antagonist attenuated the carbachol-induced decrease when compared to two previous studies using the same model: 1) In experiments with no injections of serotonergic agents, pontine carbachol injections decreased XII nerve activity by 90 +/- 6% of control. 2) After enhancement of XII nerve activity by inhibitory amino acid antagonists (to 135 +/- 60%), the subsequent carbachol-induced decrease was even larger, 112 +/- 62% of control. We propose that serotonergic excitation can significantly attenuate the REM sleep-like suppression of XII nerve activity, and that this is achieved, in part, by substituting for the decreased endogenous 5HT in the XII nucleus. The study also demonstrates that other, non-serotonergic, mechanisms also contribute to the carbachol-induced suppression.

Bilateral convergence of pulmonary stretch receptor inputs on I beta-neurons in the cat.

Extracellular recordings were made from inspiratory beta- (I beta) neurons in the nucleus of the tractus solitarius in decerebrate cats. A reversible direct current block of myelinated fibers in the ipsilateral vagus nerve was used to evaluate the input from pulmonary stretch receptor afferents (PSR) of the contralateral vagus to individual I beta-neurons. This block served to remove all ipsilateral (which includes all monosynaptic) inputs from PSR to I beta-cells. The effect of withholding inflation on the firing rate and the time of onset of firing of I beta-neurons was determined before, during and after application of the direct current block. There was considerable variation in the strengths of the inputs from the ipsilateral and contralateral nerves; some cells received PSR inputs from only the ipsilateral vagus, but the majority were excited with varying magnitude from both vagi. Several neurons had powerful excitatory inputs from PSR of the contralateral vagus, with the ipsilateral (monosynaptic) contribution being of minor importance.

Cholinergic stimulation of the pons depresses respiration in decerebrate cats.

The injection of carbachol into the pontine tegmentum of decerebrate cats evokes a postural motor atonia that has many of the characteristics of the atonia of natural rapid-eye-movement (REM) sleep (Morales et al. J. Neurophysiol. 57: 1118-1129, 1987). We have used the carbachol-injected decerebrate cat to study the changes in respiratory neuronal activity that accompany the atonia. The activities of representative respiratory motor nerves--phrenic, intercostal, and hypoglossal--and that of a motor branch of C4 were recorded in decerebrate, vagotomized, paralyzed, and artificially ventilated cats. After the microinjection of carbachol, there was a profound suppression of activity in all the nerves and a decrease in respiratory rate. This was a consistent stereotyped response in which the magnitude of the suppression of respiratory-related activity was phrenic (to approximately 65% of control) less than inspiratory intercostal (approximately 50%) less than hypoglossal (approximately 10%) less than expiratory intercostal (approximately 5%). The decrease in respiratory rate (to approximately 70% of control) was caused by a prolongation of both inspiratory and expiratory durations. Complete reversal of the carbachol effect was elicited by the microinjection of atropine into the same site as the carbachol injection. This allowed us to produce a second episode of atonia by the injection of carbachol into the contralateral pons. Thus we have demonstrated the existence of neural pathways originating in the cholinoceptive cells of the pons that have the potential to powerfully and differentially depress various respiratory motoneuronal pools and to reduce the respiratory rate. These pathways are likely to be activated along with the atonia of REM sleep.

Control of activity of the diaphragm in rapid-eye-movement sleep.

Respiration in rapid-eye-movement sleep (REMS) is known to be highly variable. The purpose of this study was to investigate the source of this variability and to determine which ordering principles remained operative in REM sleep. In unrestrained, naturally sleeping cats we recorded the electroencephalogram, electrooculogram, neck electromyogram, and diaphragmatic electromyogram (EMG) and computed its moving average (MAdi). As a reference, we first examined MAdi during "tonic" REMS, since breathing is fairly regular in this state. "Control" ranges for peak amplitude (PEMG), inspiratory time (TI), duration of postinspiratory inspiratory activity, expiratory time, and the calculated inspiratory slope (PEMG/TI) were determined by overlaying individual breath traces of the time course of MAdi during tonic REMS to form a composite tracing. Next, the time course of the EMG during individual breaths in slow-wave sleep (SWS) and a complete period of consecutive breaths in REMS (both tonic and phasic) were compared with this tonic REMS composite. The number of eye movements per breath was tabulated as an index of phasic activity. The inspiratory slopes during SWS and tonic REMS were similar. However, during phasic REMS, many breaths displayed either increases (excitation) or decreases (inhibition) in slope compared with the "typical" breaths seen in tonic REMS. The occurrence of these altered slopes increased with the frequency of phasic events. TI was inversely related to the slope of the EMG, which tended to minimize changes in PEMG.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of dorsolateral pontine lesions on diaphragmatic activity during REMS.

Muscle atonia is a feature of normal rapid-eye-movement sleep (REMS). The suppression of accessory respiratory muscle activity has been investigated and a role for sleep-disordered breathing hypothesized, but the suppression of diaphragmatic activity has rarely been considered. We hypothesized that the activity of the diaphragm was suppressed by an area of the dorsolateral pons during REMS. Lesions in this region have previously been shown to abolish the atonia of REMS. The diaphragmatic electromyogram (EMG) activity was analyzed in five naturally sleeping cats before and after pontine lesions leading to REMS without atonia. Although respiratory timing parameters were not altered by the lesion, the inspiratory rate of rise was significantly increased in all cats, and the brief pauses (40-100 ms) in the diaphragmatic EMG normally seen in REMS were virtually abolished. We conclude that the dorsolateral pons has a role in suppressing diaphragmatic activation during REMS. This suppression affects the average rate of rise of diaphragmatic activity and also leads to brief intermittent complete cessation of ongoing muscle activity. These decrements in diaphragm activity could jeopardize ventilation during REMS.