Unanesthetized Dogs Research Articles

Acute sodium bicarbonate administration improves ventilatory efficiency in experimental respiratory acidosis: clinical implications.

Administering sodium bicarbonate (NaHCO3) to patients with respiratory acidosis breathing spontaneously is contraindicated because it increases carbon dioxide load and depresses pulmonary ventilation. Nonetheless, several studies have reported salutary effects of NaHCO3 in patients with respiratory acidosis but the underlying mechanism remains uncertain. Considering that such reports have been ignored, we examined the ventilatory response of unanesthetized dogs with respiratory acidosis to hypertonic NaHCO3 infusion (1 N, 5 mmol/kg) and compared it with that of animals with normal acid-base status or one of the remaining acid-base disorders. Ventilatory response to NaHCO3 infusion was evaluated by examining the ensuing change in PaCO2 and the linear regression of the PaCO2 vs. pH relationship. Strikingly, PaCO2 failed to increase and the ΔPaCO2 vs. ΔpH slope was negative in respiratory acidosis, whereas PaCO2 increased consistently and the ΔPaCO2 vs. ΔpH slope was positive in the remaining study groups. These results cannot be explained by differences in buffering-induced decomposition of infused bicarbonate or baseline levels of blood pH, PaCO2, and pulmonary ventilation. We propose that NaHCO3 infusion improved the ventilatory efficiency of animals with respiratory acidosis, i.e., it decreased their ratio of total pulmonary ventilation to carbon dioxide excretion (VE/VCO2). Such exclusive effect of NaHCO3 infusion in animals with respiratory acidosis might emanate from baseline increased VD/VT (dead space/tidal volume) caused by bronchoconstriction and likely reduced pulmonary blood flow, defects that are reversed by alkali infusion. Our observations might explain the beneficial effects of NaHCO3 reported in patients with acute respiratory acidosis.

Determinants of hypokalemia following hypertonic sodium bicarbonate infusion.

The hypokalemic response to alkali infusion has been attributed to the resulting extracellular fluid (ECF) expansion, urinary potassium excretion, and internal potassium shifts, but the dominant mechanism remains uncertain. Hypertonic NaHCO3 infusion (1 N, 5 mmol/kg) to unanesthetized dogs with normal acid-base status or one of the four chronic acid-base disorders decreased plasma potassium concentration ([K+]p) at 30 min in all study groups (Δ[K+]p, - 0.16 to - 0.73 mmol/L), which remained essentially unaltered up to 90-min postinfusion. ECF expansion accounted for only a small fraction of the decrease in ECF potassium content, (K+)e. Urinary potassium losses were large in normals and chronic respiratory acid-base disorders, limited in chronic metabolic alkalosis, and minimal in chronic metabolic acidosis, yet, ongoing kaliuresis did not impact the stability of [K+]p. All five groups experienced a reduction in (K+)e at 30-min postinfusion, Δ(K+)e remaining unchanged thereafter. Intracellular fluid (ICF) potassium content, (K+)i, decreased progressively postinfusion in all groups excluding chronic metabolic acidosis, in which a reduction in (K+)e was accompanied by an increase in (K+)i. We demonstrate that hypokalemia following hypertonic NaHCO3 infusion in intact animals with acidemia, alkalemia, or normal acid-base status and intact or depleted potassium stores is critically dependent on mechanisms of internal potassium balance and not ECF volume expansion or kaliuresis. We envision that the acute NaHCO3 infusion elicits immediate ionic shifts between ECF and ICF leading to hypokalemia. Thereafter, maintenance of a relatively stable, although depressed, [K+]e requires that cells release potassium to counterbalance ongoing urinary potassium losses.

Snakes and Hypertension.

Inhibition of Angiotensin Conversion in Experimental Renovascular Hypertension. By Miller ED Jr, Samuels A, Haber E, and Barger AC. Science 1972; 177:1108-9. Reprinted with permission from AAAS.Constriction of the renal artery and controlled reduction of renal perfusion pressure is followed by a prompt increase in systemic renin activity and a concomitant rise in blood pressure in trained, unanesthetized dogs. The elevated blood pressure induced by the renal artery stenosis can be prevented by prior treatment with the nonapeptide Pyr-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro, which blocks conversion of angiotensin I to angiotensin II. Further, the nonapeptide can restore systemic pressure to normal in the early phase of renovascular hypertension. These results offer strong evidence that the renin- angiotensin system is responsible for the initiation of hypertension in the unilaterally nephrectomized dog with renal artery constriction.

Pulmonary vasodilation by acetazolamide during hypoxia: impact of methyl-group substitutions and administration route in conscious, spontaneously breathing dogs

Acetazolamide (ACZ) prevents hypoxic pulmonary vasoconstriction (HPV) in isolated lungs, animals, and humans, but not by carbonic anhydrase (CA) inhibition. We studied administration routes in, and certain structural aspects of, ACZ critical to HPV inhibition. Analogs of ACZ during acute hypoxia were tested in unanesthetized dogs. Dogs breathed normoxic gas for 1 h (inspired O2 fraction = 0.21), followed by 10% O2 for 2 h (hypoxia) in these protocols: 1) controls; 2) ACZ intravenously (2 mg · kg(-1) · h(-1)); 3) ACZ orally (5 mg/kg, 12 and 1 h before the experiment); 4) inhaled ACZ (750 mg); 5) methazolamide (MTZ) intravenously (3 mg · kg(-1) · h(-1)); and 6) N-methyl-acetazolamide (NMA) intravenously (10 mg · kg(-1) · h(-1)). In controls, mean pulmonary arterial pressure (MPAP) increased 7 mmHg, and pulmonary vascular resistance (PVR) 224 dyn · s · cm(-5) with hypoxia (P < 0.05). With intravenous and inhaled ACZ, MPAP and PVR did not change during hypoxia. With oral ACZ, HPV was only slightly suppressed; MPAP increased 5 mmHg and PVR by 178 dyn · s · cm(-5) during hypoxia. With MTZ and NMA, the MPAP rise (4 ± 2 mmHg) was reduced, and PVR did not increase during hypoxia compared with normoxia (MTZ intravenous: 81 ± 77 and 68 ± 82 dyn · s · cm(-5) with NMA intravenous). Inhaled ACZ prevents HPV, but not without causing systemic CA inhibition. NMA, a compound lacking CA inhibiting effects by methylation at the sulfonamide moiety, and MTZ, a CA-inhibiting analog methylated at the thiadiazole ring, are only slightly less effective than ACZ in reducing HPV.

Amrinone, Forerunner of Novel Cardiotonic Agents, Caused Paradigm Shift of Heart Failure Pharmacotherapy

Amrinone has been a great forerunner of noncatechol and nonglycoside novel cardiotonic agents and given an extraordinary strong impact in the development of novel cardiotonic agents. Unexpectedly, amrinone failed to rescue the patients with chronic heart failure, thereby produced a prominent paradigm shift from inotropic to cardioprotective therapy, and contributed to advances in the current pharmacotherapy of chronic heart failure. In this study, Alousi et al showed that amrinone is a potent, long-acting positive inotropic agent when given orally or intravenously to either anesthetized or unanesthetized dogs. Amrinone was orally active with a rapid onset of action and duration of >5 hours and showed a wide separation between the positive inotropic and chronotropic effect. Amrinone increased contractile force and the rate of force development without changes in duration of the contractile cycle or time-to-peak tension, and in action potential or excitability even when it was given in relatively high concentrations. The toxicological studies attested to a low toxicity of amrinone ≤10 mg/kg, with less serious side effects such as lowering in blood pressure and an increase in heart rate compared with cardiac glycosides and catecholamines. The therapeutic index of amrinone was wide in contrast to that of cardiac glycosides that have a therapeutic index of ≈2 to 3, with life-threatening arrhythmias. Of greater interest was that amrinone did not increase cardiac output of the normal (nonfailing), but increased that of the failing heart model. The mechanism of action of amrinone, however, was shown only by exclusion criteria. Amrinone did not seem to act via a catecholamine mechanism because its inotropic effect was not blocked by the β-receptor blocking agent propranolol or by depletion of cardiac norepinephrine with reserpine. It was reported that there were no significant changes in the level of cardiac cAMP or phosphodiesterase (PDE) that could be responsible …

COMPUTED TOMOGRAPHIC IMAGING OF DOGS WITH PRIMARY LARYNGEAL OR TRACHEAL AIRWAY OBSTRUCTION

Seventeen dogs with clinical signs attributable to nonneoplastic obstruction of the larynx, trachea, or large bronchi underwent computed tomography (CT) imaging. In 16 of the 17 dogs, CT was performed without general anesthesia using a positioning device. Fifteen of these 16 dogs were imaged without sedation or general anesthesia. Three-dimensional (3D) internal rendering was performed on each image set based on lesion localization determined by routine image planes. Visual laryngeal examination, endoscopy, video fluoroscopy, and necropsy were used for achieving the cause of the upper airway obstruction. The CT and 3D internal rendering accurately indicated the presence and cause of upper airway obstruction in all dogs. CT findings indicative of laryngeal paralysis included failure to abduct the arytenoid cartilages, narrowed rima glottis, and air-filled laryngeal ventricles. Laryngeal collapse findings depended on the grade of collapse and included everted laryngeal saccules, collapse of the cuneiform processes and corniculate processes, and narrowed rima glottis. Trachea abnormalities included hypoplasia, stenosis, or collapse syndrome. The CT findings in tracheal hypoplasia consisted of a severely narrowed lumen throughout the entire length. Tracheal stenosis was represented by a circumferential decrease in tracheal lumen size limited to one region. Tracheal collapse syndrome was diagnosed by severe asymmetric narrowing. Lobar bronchi collapse appeared in CT images as a narrowed asymmetric lumen diameter. CT imaging of unanesthetized dogs with upper airway obstruction compares favorably with traditional definitive diagnostic methods.

Central/Peripheral Chemoreceptor Interaction in the Unanesthetized Dog: Evidence for Hyperaddition

We assessed the contribution of carotid body chemoreceptors (CB) to the ventilatory response to specific CNS hypercapnia in the unanesthetized awake dog. We used extracorporeal blood perfusion of the reversibly isolated carotid sinus to maintain normal blood gases (normoxic, normocapnic perfusate) at the CB, to inhibit the CB (hyperoxic, hypocapnic perfusate), or to stimulate the CB (hypoxic, normocapnic perfusate) while the systemic circulation, and therefore the central nervous system (CNS), was exposed to normocapnia and 4 progressive levels of hypercapnia for 7 minutes at each level. Relative to control (normoxic and normocapnic perfusion), we found that CB inhibition decreased the slope of the ventilatory response to CNS hypercapnia in all dogs by 80% on average (N=6) whereas CB stimulation increased the slope of the ventilatory response to CNS hypercapnia in all dogs by 123% on average (N=4). We conclude that the gain of the CNS CO2/H+ chemoreceptors is critically dependent on CB afferent activity and the CNS/CB interaction results in hyperadditive ventilatory responses. Supported by NIH/NHLBI &amp; American Heart Association.

Contribution of the carotid body chemoreceptors to eupneic ventilation in the intact, unanesthetized dog

We used extracorporeal perfusion of the reversibly isolated carotid sinus region to determine the effects of specific carotid body (CB) chemoreceptor inhibition on eupneic ventilation (Vi) in the resting, awake, intact dog. Four female spayed dogs were studied during wakefulness when CB was perfused with 1) normoxic, normocapnic blood; and 2) hyperoxic (>500 mmHg), hypocapnic ( approximately 20 mmHg) blood to maximally inhibit the CB tonic activity. We found that CB perfusion per se (normoxic-normocapnic) had no effect on Vi. CB inhibition caused marked reductions in Vi (-60%, range 49-80%) and inspiratory flow rate (-58%, range 44-87%) 24-41 s following the onset of CB perfusion. Thereafter, a partial compensatory response was observed, and a steady state in Vi was reached after 50-76 s following the onset of CB perfusion. This steady-state tidal volume-mediated hypoventilation ( approximately 31%) coincided with a significant reduction in mean diaphragm electromyogram (-24%) and increase in mean arterial pressure (+12 mmHg), which persisted for 7-25 min until CB perfusion was stopped, despite a substantial increase in CO(2) retention (+9 Torr, arterial Pco(2)) and systemic respiratory acidosis. We interpret these data to mean that CB chemoreceptors contribute more than one-half to the total eupneic drive to breathe in the normoxic, intact, awake animal. We speculate that this CB contribution consists of both the normal tonic sensory input from the CB chemoreceptors to medullary respiratory controllers, as well as a strong modulatory effect on central chemoreceptor responsiveness to CO(2).

The effect of surgically created gastroesophageal reflux on intrapleural pressures in dogs

The causal relationship between gastroesophageal reflux (GER) and respiratory disorders is not well understood. Previous experimental studies that investigated this relationship were performed in anesthetized animals and used artificial acidification of esophagus for simulation of GER. In this study, we investigated the impact of GER on intrapleural pressures (IPP) in conscious, unanesthetized dogs. After the induction of appropriate anesthesia, 5 purpose-bred mongrel dogs underwent reflux-creating surgery (partial cardiomyectomy). The presence of GER was confirmed by determining the reflux index (RI) and the duration of longest reflux episode (DLRE) after 24-h intraesophageal pH-metry. IP was monitored before and after cardiomyectomy using a subcutaneously placed telemetric implant with its pressure-sensor catheter tip inserted into the pleural space. Partial cardiomyectomy resulted in a significant increase in RI from a preoperative mean value of 0.38 +/- 0.21 to 7.52 +/- 2.56%, and DLRE from 1.22 +/- 1.12 to 36.80 +/- 12.71 min, as recorded by the proximal sensor of the pH probe. A similar trend was observed at the distal sensor. After cardiomyectomy, the negative inspiratory IPP significantly increased from 17.2 +/- 7.9 to 28.4 +/- 9.7 mm Hg. A similar effect was observed in the negative expiratory IPP. The negative inspiratory IPP had a significant correlation with both RI (R = 0.932) and DLRE (R = 0.899). Cardiomyectomy causes GER, the severity of which correlates with negative inspiratory IPP in a dog model. The suggested model allows for the investigation of the pathologic association of GER with respiratory disorders in conscious animals.

The apneic threshold during non-REM sleep in dogs: sensitivity of carotid body vs. central chemoreceptors

The relative importance of peripheral vs. central chemoreceptors in causing apnea/unstable breathing during sleep is unresolved. This has never been tested in an unanesthetized preparation with intact carotid bodies. We studied three unanesthetized dogs during normal sleep in a preparation in which intact carotid body chemoreceptors could be reversibly isolated from the systemic circulation and perfused. Apneic thresholds and the CO(2) reserve (end-tidal Pco(2) eupneic - end-tidal Pco(2) apneic threshold) were determined using a pressure support ventilation technique. Dogs were studied when both central and peripheral chemoreceptors sensed transient hypocapnia induced by the pressure support ventilation and again with carotid body isolation such that only the central chemoreceptors sensed the hypocapnia. We observed that the CO(2) reserve was congruent with4.5 Torr when the carotid chemoreceptors sensed the transient hypocapnia but more than doubled (>9 Torr) when only the central chemoreceptors sensed hypocapnia. Furthermore, the expiratory time prolongations observed when only central chemoreceptors were exposed to hypocapnia differed from those obtained when both the central and peripheral chemoreceptors sensed the hypocapnia in that they 1) were substantially shorter for a given reduction in end-tidal Pco(2), 2) showed no stimulus: response relationship with increasing hypocapnia, and 3) often occurred at a time (>45 s) beyond the latency expected for the central chemoreceptors. These findings agree with those previously obtained using an identical pressure support ventilation protocol in carotid body-denervated sleeping dogs (Nakayama H, Smith CA, Rodman JR, Skatrud JB, Dempsey JA. J Appl Physiol 94: 155-164, 2003). We conclude that hypocapnia sensed at the carotid body chemoreceptor is required for the initiation of apnea following a transient ventilatory overshoot in non-rapid eye movement sleep.

Patterns of Small Intestinal Motor Activity During Intraluminal Infusion of Elementary Diets in Dogs

During continuous intraintestinal infusion of elementary diets, periodic fluctuation of the frequency of contractions has been observed. This study sought to characterize the temporospatial organization of this pattern and the influence of cholinergic input. Studies were performed on unanesthetized dogs with a duodenal cannula. Motor activity was recorded by means of infused catheters and external transducers. Nutrients were infused continuously at the duodenum and jejunal levels. Studies were repeated after administration of atropine. Six to 14 periodic variations of frequency of contractions during 10 basal infusion experiments were observed in random order. During duodenal infusion, atropine significantly increased the number of these events, associated with a synchronous pattern. Frequency and amplitude of contractions during jejunal infusion were significantly lower compared to duodenal infusion. Cyclic pattern elicited by nutrient infusion is related to a cholinergic mechanism; changes depend on the level of infusion.

Prevention of acute mountain sickness by acetazolamide: as yet an unfinished story

since the 1970s, over 200 studies with acetazolamide have shown it safe and 60–80% effective in acute mountain sickness (AMS). Despite much investigation, our understanding of its action in AMS remains incomplete and more complicated than generally taught. This should come as no surprise

Pulmonary vasodilation by acetazolamide during hypoxia is unrelated to carbonic anhydrase inhibition

Acute hypoxic pulmonary vasoconstriction can be inhibited by high doses of the carbonic anhydrase inhibitor acetazolamide. This study aimed to determine whether acetazolamide is effective at dosing relevant to human use at high altitude and to investigate whether its efficacy against hypoxic pulmonary vasoconstriction is dependent on carbonic anhydrase inhibition by testing other potent heterocyclic sulfonamide carbonic anhydrase inhibitors. Six conscious dogs were studied in five protocols: 1) controls, 2) low-dose intravenous acetazolamide (2 mg.kg(-1).h(-1)), 3) oral acetazolamide (5 mg/kg), 4) benzolamide, a membrane-impermeant inhibitor, and 5) ethoxzolamide, a membrane-permeant inhibitor. In all protocols, unanesthetized dogs breathed spontaneously during the first hour (normoxia) and then breathed 9-10% O(2) for the next 2 h. Arterial oxygen tension ranged between 35 and 39 mmHg during hypoxia in all protocols. In controls, mean pulmonary artery pressure increased by 8 mmHg and pulmonary vascular resistance by 200 dyn.s.cm(-5) (P <0.05). With intravenous acetazolamide, mean pulmonary artery pressure and pulmonary vascular resistance remained unchanged during hypoxia. With oral acetazolamide, mean pulmonary artery pressure increased by 5 mmHg (P < 0.05), but pulmonary vascular resistance did not change during hypoxia. With benzolamide and ethoxzolamide, mean pulmonary artery pressure increased by 6-7 mmHg and pulmonary vascular resistance by 150-200 dyn.s.cm(-5) during hypoxia (P < 0.05). Low-dose acetazolamide is effective against acute hypoxic pulmonary vasoconstriction in vivo. The lack of effect with two other potent carbonic anhydrase inhibitors suggests that carbonic anhydrase is not involved in the mediation of hypoxic pulmonary vasoconstriction and that acetazolamide acts on a different receptor or channel.

Increased propensity for apnea in response to acute elevations in left atrial pressure during sleep in the dog

Periodic breathing is commonly observed in chronic heart failure (CHF) when pulmonary capillary wedge pressure is abnormally high and there is usually concomitant tachypneic hyperventilation. We hypothesized that acute pulmonary hypertension at pressures encountered in CHF and involving all of the lungs and pulmonary vessels would predispose to apnea/unstable breathing during sleep. We tested this in a chronically instrumented, unanesthetized dog model during non-rapid eye movement (NREM) sleep. Pulmonary hypertension was created by partial occlusion of the left atrium by means of an implanted balloon catheter in the atrial lumen. Raising mean left atrial pressure by 5.7 +/- 1.1 Torr resulted immediately in tachypneic hyperventilation [breathing frequency increased significantly from 13.8 to 19.9 breaths/min; end-tidal P(CO2) (P(ET(CO2))) fell significantly from 38.5 to 35.9 Torr]. This tachypneic hyperventilation was present during wakefulness, NREM sleep, and rapid eye movement sleep. In NREM sleep, this increase in left atrial pressure increased the gain of the ventilatory response to CO2 below eupnea (1.3 to 2.2 l.min(-1).Torr(-1)) and thereby narrowed the CO2 reserve [P(ET(CO2)) (apneic threshold) - P(ET(CO2)) (eupnea)], despite the decreased plant gain resulting from the hyperventilation. We conclude that acute pulmonary hypertension during sleep results in a narrowed CO2 reserve and thus predisposes toward apnea/unstable breathing and may, therefore, contribute to the breathing instability observed in CHF.

Response time and sensitivity of the ventilatory response to CO2 in unanesthetized intact dogs: central vs. peripheral chemoreceptors

We assessed the speed of the ventilatory response to square-wave changes in alveolar P(CO2) and the relative gains of the steady-state ventilatory response to CO2 of the central chemoreceptors vs. the carotid body chemoreceptors in intact, unanesthetized dogs. We used extracorporeal perfusion of the reversibly isolated carotid sinus to maintain normal tonic activity of the carotid body chemoreceptor while preventing it from sensing systemic changes in CO2, thereby allowing us to determine the response of the central chemoreceptors alone. We found the following. 1) The ventilatory response of the central chemoreceptors alone is 11.2 (SD = 3.6) s slower than when carotid bodies are allowed to sense CO2 changes. 2) On average, the central chemoreceptors contribute approximately 63% of the gain to steady-state increases in CO2. There was wide dog-to-dog variability in the relative contributions of central vs. carotid body chemoreceptors; the central exceeded the carotid body gain in four of six dogs, but in two dogs carotid body gain exceeded central CO2 gain. If humans respond similarly to dogs, we propose that the slower response of the central chemoreceptors vs. the carotid chemoreceptors prevents the central chemoreceptors from contributing significantly to ventilatory responses to rapid, transient changes in arterial P(CO2) such as those after periods of hypoventilation or hyperventilation ("ventilatory undershoots or overshoots") observed during sleep-disordered breathing. However, the greater average responsiveness of the central chemoreceptors to brain hypercapnia in the steady-state suggests that these receptors may contribute significantly to ventilatory overshoots once unstable/periodic breathing is fully established.

Hypothalamic control of body temperature: insights from the past.

This essay looks at the historical significance of three APS classic papers that are freely available online: Hammel HT, Hardy JD, and Fusco MM. Thermoregulatory responses to hypothalamic cooling in unanesthetized dogs. Am J Physiol 198: 481—486, 1960 ( http://ajplegacy.physiology.org/cgi/reprint/198/3/481 ). Hammel HT, Jackson DC, Stolwijk JAJ, Hardy JD, and Strømme SB. Temperature regulation by hypothalamic proportional control with an adjustable set point. J Appl Physiol 18: 1146—1154, 1963 ( http://jap.physiology.org/cgi/reprint/18/6/1146 ). Hellstrøm B and Hammel HT. Some characteristics of temperature regulation in the unanesthetized dog. Am J Physiol 213: 547—556, 1967 ( http://ajplegacy.physiology.org/cgi/reprint/213/2/547 ).

Different endogenous opioid effects on delta- and mu-receptor subtypes in antral and duodenal motility of conscious dogs.

To evaluate the role of endogenous opioids in regulation of upper gastrointestinal motility in unanesthetized dogs and to differentiate the actions on mu- and delta-opioid receptors, seven strain gauges and five platinum electrodes were chronically implanted at the serosa along the antrum and duodenum and connected to a plug in the neck of the dog. Signals were processed by a Hellige AC amplifier, a rectilinear recorder, and a data aquisition system. A motility index (MI) was calculated and together with the electrical data a contractile activity percentage (CAP) was determined for consecutive 30 min periods. The delta-opioid antagonist ICI 741 864 and the mu-receptor blocker naloxone were injected intraarterially through a chronic Groshong catheter placed in the pyloric region and connected to a subcutaneous port. After a meal of solid food, ICI 174 864 increased motility relative to controls in the antrum averaged over 5 hr by 144.4%+/-26 for the MI and 73%+/-26 for CAP; after naloxone MI increased by 222%+/-60 and CAP 121%+/-76. In the duodenum, ICI 174 864 decreased MI over a range of 57% to 22% (P < 0.05). Naloxone increased MI and CAP significantly after 2.5 hr. We interpreted the results of ICI 174 864 in the duodenum to reflect suppression of a tonic opioid influence at the delta-receptor mainly at the prevertebral ganglion. In the interdigestive state in 56% of the dogs, naloxone delayed the occurrence of phase III of the migrating myoelectric complex (MMC) for up to 370 min, while under ICI 174 864, normal interdigestive cycles were present. Disturbance of the timing of the interdigestive cycles at central mu-opioid receptors may by involved in the effect.

Differential effects of hypoxia and hypercapnia on respiratory sinus arrhythmia in conscious dogs.

To test the hypothesis that hypoxia and hypercapnia have different effects on the genesis of respiratory sinus arrhythmia (RSA), the magnitude of RSA to these stimuli was compared in 3 unanesthetized dogs. Respiration was continuously monitored through a permanent tracheostomy, and the electrocardiogram and blood pressure were also monitored. The magnitude of RSA was assessed as an instantaneous amplitude of the R-R interval oscillation in the high-frequency band of 0.15-0.80Hz by means of complex demodulation. In a total of 47 runs with hypoxia, heart rate, mean arterial pressure, respiratory rate and tidal volume increased, but RSA magnitude decreased even after adjusting for the effects of respiratory rate and tidal volume. In a total of 39 runs with hypercapnia, heart rate and mean arterial pressure did not change, despite the increased respiratory rate and tidal volume. In contrast to hypoxia, RSA magnitude increased even after adjusting for the effects of respiratory rate and tidal volume. The different effects of the two respiratory stimuli on RSA magnitude were noted at any level of ventilation and support the original hypothesis.

Pavlov and integrative physiology.

Ivan Petrovich Pavlov was the first physiologist to win the Nobel Prize. The Prize was given in 1904 for his research on the neural control of salivary, gastric, and pancreatic secretion. A major reason for the success and novelty of his research was the use of unanesthetized dogs surgically prepared with chronic fistulas or gastric pouches that permitted repeated experiments in the same animal for months. Pavlov invented this chronic method because of the limitations he perceived in the use of acute anesthetized animals for investigating physiological systems. By introducing the chronic method and by showing its experimental advantages, Pavlov founded modern integrative physiology. This paper reviews Pavlov's journey from his birthplace in a provincial village in Russia to Stockholm to receive the Prize. It begins with childhood influences, describes his training and mentors, summarizes the major points of his research by reviewing his book Lectures on the Work of the Digestive Glands, and discusses his views on the relationship between physiology and medicine.

Hemodynamic effects of pressures applied to the upper airway during sleep.

The increase in systemic blood pressure after an obstructive apnea is due, in part, to sympathetically mediated vasoconstriction. We questioned whether upper airway (UA) receptors could contribute reflexly to this vasoconstriction. Four unanesthetized dogs were studied during wakefulness and non-rapid-eye-movement (NREM) sleep. The dogs breathed via a fenestrated tracheostomy tube sealed around the tracheal stoma. The snout was sealed with an airtight mask, thereby isolating the UA when the fenestration was closed and exposing the UA to negative inspiratory intrathoracic pressure when it was open. The blood pressure response to three UA perturbations was studied: 1) square-wave negative pressures sufficient to cause UA collapse with the fenestration closed during a mechanical hyperventilation-induced central apnea; 2) tracheal occlusion with the fenestration open vs. closed; and 3) high-frequency pressure oscillations (HFPO) with the fenestration closed. During NREM sleep, 1) blood pressure response to tracheal occlusion was similar with the fenestration open or closed; 2) collapsing the UA with negative pressures failed to alter blood pressure during a central apnea; and 3) application of HFPO to the UA during eupnea and resistive-loaded breaths increased heart rate and blood pressure. However, these changes were likely to be secondary to the effects of HFPO-induced reflex changes on prolonging expiratory time. These findings suggest that activation of UA pressure-sensitive receptors does not contribute directly to the pressor response associated with sleep-disordered breathing events.