Acute effects of hypercapnia and hypoxia on minute ventilation in unrestrained Weddell seals

We studied the ventilatory response to hypoxia and hypercapnia in five freely diving juvenile Weddell seals (age = 2 years) at McMurdo Station, Antarctica. The ventilatory response to CO2 was brisk, with minute ventilation increasing as a linear function of end tidal CO2 with an average slope of 3.1 L X (min X mm Hg)-1. The ventilatory response to hypoxia was small and variable. End tidal PO2 values as low as 28 mm Hg provoked at most a doubling of minute ventilation. These results were supported by the observation that elevated end tidal CO2 always inhibited voluntary diving whereas low PO2 values did not. Comparison of the Weddell seals' CO2 responsiveness to that of other mammals reveals similar CO2 sensitivity. We conclude that CO2 is the major determinant of ventilatory drive in wild Weddell seals.     

Effects of hypercapnia and hypoxia on laryngeal resistance to airflow.

Ventilation, laryngeal resistance and electromyograms of the diaphragm, posterior cricoarytenoid (PCA) and thyroarytenoid (TA) muscles were recorded in anesthetized, spontaneously breathing cats during 100% O2 administration and during steady state inhalation of hypercapnic and hypoxic gas mixtures. As shown previously, hyperoxic hypercapnia lowered expiratory laryngeal resistance (RlarE). Isocapnic hypoxia also lowered RlarE, and hypercapnia superimposed on hypoxia decreased it further. Hypocapnia raised RlarE. Changes in inspiratory laryngeal resistance (RlarI) were similar to those in RlarE, but smaller. When ventilation was stimulated to the same extent by hypoxia and by hypercapnia, RlarE was lower under hypoxic than hypercapnic conditions in most animals. The electromyograms showed that the respiratory oscillations in laryngeal resistance and the laryngeal responses to hypercapnia and hypoxia were determined chiefly by the activity of the PCA muscle, the abductor of the vocal cords. The TA-a representative adductor muscle-was silent under all conditions studied. The results, considered with previous work, indicate that the larynx plays a part in determining the breathing pattern under resting conditions and during respiratory stimulation by hypercapnia and hypoxia.     

Effects of hypoxia and hypercapnia on cricothyroid muscle response to airway pressure.

We studied the effects of hypercapnia (FICO2 = 0.07) and hypoxia (FIO2 = 0.13) on the cricothyroid muscle response (peak integrated CT EMG) to graded inspiratory resistance (RI). Five anesthetized dogs spontaneously breathed through the upper airway (UAB) or a side arm of a tracheotomy cannula bypassing the larynx (TB). With room air UAB, graded increases in RI increased CT EMG, upper airway pressure change (Paw) and esophageal pressure change (Pes, indicating increased inspiratory drive), but decreased VT. For room air TB, the effects of RI were much less but still significant. Hypercapnia increased VT, fR, Pes, Paw and CT EMG for any given RI during UAB more than during TB. Hypoxia increased fR but did not increase VT, Pes, Paw, or CT EMG. The results are consistent with a model predicting CT activity as additive functions of inspiratory drive and laryngeal receptor stimulation by Paw and no direct effects of chemoreceptor stimulation on the CT, independent of those resulting from changes in inspiratory drive and upper airway pressure.     

Breathing frequencies of northern elephant seals at sea and on land revealed by heart rate spectral analysis

Elephant seals breathe episodically at sea and on land and surprisingly long apnoeas occur in both situations. An important difference is that recovery from apnoeic periods is much quicker at sea, which might be due, in part, to differences in the ventilatory response. Respiratory frequencies of juvenile northern elephant seals diving at sea and resting on land were estimated from time-frequency maps of the Wigner distribution of heart rate variability. Simultaneous direct measurement of respiration and estimation of respiratory frequency (fR) in the laboratory demonstrated that the error of estimation was small (mean +/- S.D.= 1.05+/-1.23%) and was independent of the magnitude of fR. Eupnoeic fR at sea was 2.4 times higher than on land (22.0+/-2.0 vs. 9.2+/-1.3 breaths min(-1), respectively), facilitating quick recovery from the preceding dive and allowing a 34% increase in time spent apnoeic at sea versus on land. The overall fR (no. of breaths in a eupnoea divided by the total time of the apnoea+eupnoea cycle) of 2.3+/-0.6 breaths min(-1) at sea was no different from the rate on land and was inversely related to the preceding dive duration, suggesting that metabolism on longer dives may be reduced.     

Effects of hypoxia and hypercapnia on the force-velocity relation of rabbit myocardium

The separate effects of hypoxia and hypercapnia on the force-velocity relation of rabbit myocardium were compared in 10 papillary or trabecular muscles superfused using control (95% O2-5% CO2), hypoxic (18% O2), and hypercapnic (20% CO2) physiological salt solutions. This level of hypoxia did not irreversibly damage the muscles and reduced peak isometric force by 53 +/- 11%. The level of hypercapnia was chosen to match the force depression (50 +/- 12%) produced by hypoxia. Multiple force-velocity points were measured by applying critically damped isotonic force steps at 90% of the time to peak isometric force and at the time to 50% peak isometric force. These points defined the force-velocity relation and maximum velocity of shortening, the extrapolated isometric force, and the maximum power of nonpotentiated and postextrasytolic potentiated contractions. Hypoxia and hypercapnia reduced maximum force and maximum power nearly equally. Maximum velocity of shortening decreased more during hypoxia (21 +/- 12%) than during hypercapnia (12 +/- 9%) (p less than 0.01). Postextrasystolic potentiation completely reversed the reduction of maximum velocity of shortening during hypercapnia but not during hypoxia. A 6% internal load could account for the reduction in maximum velocity of shortening during hypercapnia and all but 9% of the reduction in maximum velocity of shortening during hypoxia. The relative time course of the force-velocity relation was not altered by either hypoxia or hypercapnia. We conclude that hypercapnia reduces the effect of activation because increased activation (by postextrasystolic potentiation) restored the force-velocity relation and maximum velocity of shortening to control values.(ABSTRACT TRUNCATED AT 250 WORDS)     

Histamine and phenyldiguanide induced tachypnea in hypercapnia and hypoxia.

The rapid shallow breathing of pulmonary vagal origin following administration of histamine (H) and phenyldiguanide (PDG) was studied at different levels of hypercapnic and hypoxic stimulation. At all levels of chemical drive H and PDG caused an excitatory effect on timing of breathing and an inhibitory effect on the respiratory output. The latter was evaluated from the mean inspiratory flow rate and the mean rate of change of pressure developed in the lungs during an inspiratory effort against closed airways. The timing effect was greater at low than at high PaCO2 while the opposite was true for the output effect. At all PaCO2, H and PDG decreased the volume-threshold for termination of inspiration (leftward displacement of the VT vs TI relationship) of the VT Vs TI relationship). Hypoxia increased the respiratory output in control as much as with drug stimulation. Moreover, hypoxia did not affect the volume-threshold curve both in control and with H and PDG. We concluded that vagal afferents stimulated by H and PDG (irritant and/or J receptors) interfere with the timing and output response to central chemoreceptors stimulation (CO2 sensitivity) without affecting the response to peripheral chemoreceptors stimulation (mainly hypoxic chemosensitivity).     

Thyroid function testing in elephant seals in health and disease

Northern Elephant Seal Skin Disease (NESSD) is a severe, ulcerative, skin condition of unknown cause affecting primarily yearling northern elephant seals (Mirounga angustirostris); it has been associated with decreased levels of circulating thyroxine (T4) and triiodothyronine (T3). Abnormalities of the thyroid gland that result in decreased hormone levels (hypothyroidism) can result in hair loss, scaling and secondary skin infections. However, concurrent illness (including skin ailments) can suppress basal levels of thyroid hormones and mimic hypothyroidism; when this occurs in animals with normal thyroid glands it is called "sick euthyroid syndrome". The two conditions (true hypothyroidism vs. "sick euthyroid") can be distinguished in dogs by testing the response of the thyroid gland to exogenous thyrotropin (Thyroid Stimulating Hormone, TSH). To determine whether hypothyroidism is involved in the etiology of NESSD, we tested thyroid function of stranded yearling elephant seals in the following categories: healthy seals (rehabilitated and ready for release; N=9), seals suffering from NESSD (N=16) and seals with other illnesses (e.g., lungworm pneumonia; N=10). Levels of T4 increased significantly for all three categories of elephant seals following TSH stimulation, suggesting that seals with NESSD are "sick euthyroid" and that the disease is not associated with abnormal thyroid gland function.     

Ventilatory responses to hypercapnia and hypoxia following chronic hypercapnia in the rat

This study investigated the effects of an 18 week exposure to 10% CO(2) in air on minute ventilation (V(E)), breathing pattern and the chemoresponiveness of rats to hypoxic and hyperoxic stimuli. We found that V(E) remained elevated over the 18 weeks. Nonetheless, the breathing pattern changed significantly. Tidal volume increased and the durations of inspiration and the total cycle decreased. After the sustained hypercapnia the mean Pa(CO(2)) was 72.0+/-5.1 (S. D.) mmHg. Every 6 weeks the chemoresponiveness of the CO(2)-exposed rats was tested by an acute exposure sequentially to room air, then a 6% O(2), 10% CO(2) and 84% N(2) gas mixture, and finally a 90% O(2) in 10% CO(2) mixture. On either room air or the hyperoxic-hypercapnic mixture V(E) fell to its pre-hypercapnic level. On the hypoxic-hypercapnic mixture V(E) increased significantly. These results demonstrate that the initial stimulating effect of 10% CO(2) on V(E) persisted for the entire 18 weeks without altering hypoxic or hyperoxic ventilatory responses.     

Hormonal changes associated with the transition between nursing and natural fasting in northern elephant seals (Mirounga angustirostris)

To better interpret previously described hormonal changes observed during the natural postweaning fast (2-3 months) endured by pups of the northern elephant seal (Mirounga angustirostris), we compared plasma cortisol, thyroid hormones, and leptin in pups (n=5) measured during nursing and fasting periods. Blood samples were taken at four times; early (9 days postpartum) and late (18-22 days postpartum) nursing, and early (second week postweaning) and late (eighth week postweaning) fasting. Plasma cortisol increased 39% between early and late nursing and almost 4-fold by late fasting. After the early nursing period, cortisol and body mass were negatively correlated (y=28.3-0.19 x; R=0.569; p=0.027). Total thyroxine (tT(4)), free T(4) (fT(4)), total triiodothyronine (tT3) and reverse T(3) (rT(3)) were greatest at early nursing and reduced by late nursing and remained so throughout the fast, with the exception of tT(4), which increased between late nursing (17.7+/-2.1 ng mL(-1)) and late fasting (30.1+/-2.8 ng mL(-1)) periods. Leptin remained unaltered among the four sampling periods and was not correlated with body mass. Pups appear to exhibit a shift in the relationship between cortisol and body mass suggesting a potential role for cortisol in the regulation of body fat. The higher concentrations of tT(3) and tT(4) during early nursing may reflect enhanced growth and development during this period, however the increase late in fasting is likely physiologically insignificant and an artifact of reduced metabolic clearance of these hormones. Transition of the pups from nursing to fasting states is characterized by a striking lack of change in cortisol, thyroid hormones, and leptin suggesting that any metabolic alterations associated with this transition may occur independent of these hormones.     

Chronotropic effects of progressive hypoxia and hypercapnia

The effects of acute, progressive isocapnic hypoxia and hyperoxic hypercapnia on heart rate (HR) were determined in 13 normal individuals. In all subjects there was an inverse linear relationship between hemoglobin oxygen saturation and HR. For the group, the HR (mean +/- SE) increased from 72 +/- 2 to 89.5 +/- 3 beats/min representing a 25% increase. During progressive hypercapnia, the HR increased from 72 +/- 2 to 75 +/- 2 beats/min, representing only a 4% increase. In contrast to the HR response to hypoxia, there was a heterogeneous HR response to hypercapnia, with most subjects having a mild increase in HR, but some showing no response and a few exhibiting a decrease in HR. We conclude that although there is a significant tachycardic response to isocapnic hypoxia, the tachycardic response to hyperoxic hypercapnia is small and clinically insignificant. In addition, while there is uniformly a tachycardic response to isocapnic hypoxia, there is a considerable interindividual variability of the HR response to hyperoxic hypercapnia.     

Renal compensation of hypercapnia in prolonged hypoxia

We previously showed that rats made hypoxic for three weeks were able to regulate their plasma pH better than normoxic rats during acute hypercapnia. This improved pH regulation was abolished by nephrectomy, suggesting that it was due, at least in part, to a more effective renal compensation of hypercapnia in hypoxic rats. To test this possibility renal acid excretion was measured in conscious rats that had been kept at PB 370-380 Torr for three weeks. The rats were studied in a chamber where PIO2 was kept at 68-70 Torr at ambient PB (740-750 Torr). Controls were pair-fed normoxic rats. After a 2 h control period, inspired PCO2 was increased for 4 h. The apparent non-bicarbonate buffer value of arterial blood plasma was twice as high in the hypoxic than in the normoxic rats. Renal excretion of ammonium increased to a similar extent during hypercapnia in both normoxic and hypoxic rats. Titratable acid excretion of normoxic rats did not change significantly during hypercapnia. In the hypoxic rats, on the other hand, total excretion of titratable acid in the 2 h control period was 90.9 +/- 16.4 mumol/rat; and increased to 150.0 +/- 13.4 mumol/rat in the first 2 h and to 232.9 +/- 26.0 mumol/rat in the last 2 h of hypercapnia. In spite of this large increase in acid excretion, urine pH of hypoxic rats did not change significantly, indicating a higher buffer value of the urine of hypoxic rats. These results confirm our previous observations and support the idea that the improved pH regulation of hypoxic rats is due in part to a more effective renal compensation of hypercapnia.     

Effects of forced diving on the spleen and hepatic sinus in northern elephant seal pups

In phocid seals, an increase in hematocrit (Hct) accompanies diving and periods of apnea. The variability of phocid Hct suggests that the total red cell mass is not always in circulation, leading researchers to speculate on the means of blood volume partitioning. The histology and disproportionate size of the phocid spleen implicates it as the likely site for RBC storage. We used magnetic resonance imaging on Northern elephant seals to demonstrate a rapid contraction of the spleen and a simultaneous filling of the hepatic sinus during forced dives (P < 0.0001, R(2) = 0.97). The resulting images are clear evidence demonstrating a functional relationship between the spleen and hepatic sinus. The transfer of blood from the spleen to the sinus provides an explanation for the disparity between the timing of diving-induced splenic contraction ( approximately 1-3 min) and the occurrence of peak Hct (15-25 min). Facial immersion was accompanied by an immediate and profound splenic contraction, with no further significant decrease in splenic volume after min 2 (Tukey-Kramer HSD, P = 0.05). At the conclusion of the dive, the spleen had contracted to 16% of its predive volume (mean resting splenic volume = 3,141 ml +/- 68.01 ml; 3.54% of body mass). In the postdive period, the spleen required 18-22 min to achieve resting volume, indicating that this species may not have sufficient time to refill the spleen when routinely diving at sea, which is virtually continuous with interdive surface intervals between 1 and 3 min.     

Effect of inspiratory resistance of occlusion pressure in hypoxia and hypercapnia.

The authors measured ventilation and the mouth pressure developed during the first 0.1 sec of inspiratory effort against a closed airway (P 0.1) in response to normoxic hypercapnia and normocapnic hypoxia, with and without added inspiratory resistance. Hypercapneic responses were elicited by a steady-state technique, hypoxic responses by a non-steady-state technique. External resistance depressed the ventilatory response to CO2 but in general augmented the P 0.1 response. The degree of change of response was not predictable on the basis of the response in the absence of resistance. Hypoxic ventilatory response was also diminished by resistance and P 0.1 increased. The authors concluded that in normal subjects added inspiratory resistance increased inspiratory drive as assessed by P 0.1.     

Effects of regional ischemia on metabolic function in adjacent aerobic myocardium

Increased mechanical demands are placed on aerobic heart muscle during restrictions in coronary flow to myocardium adjacent to and contiguous with normally perfused tissue. In a preparation of regional ischemia (ten intact working swine hearts), changes in substrate preference and utilization were detailed in separate beds of perfused myocardium before and during regional disruptions in coronary flow. Mild-to-moderate levels of ischemia (?52Δ% reduction in flow to the anterior left heart) caused significant declines in both regional and global estimates of mechanical function (?39 and ?31Δ% in regional and global work indices, P < 0.05 and P < 0.025, respectively). Oxygen consumption and fatty acid oxidation were reduced in ischemic muscle. Conversely, in normally perfused myocardium and presumably in response to increased mechanical burdens, oxygen consumption and fatty acid uptake were increased (+29 and +80Δ%, respectively). There was no commensurate increase in ¹⁴CO₂ production from labeled palmitate, however, and certain fatty acid intermediates (long chain acyl CoA and carnitine) appeared increased. To compensate metabolically, a greater preference for glucose utilization (two-fold increase in uptake) was documented in non-ischemic myocardium and energy production was maintained. Thus, although glucose has long been argued to treat acute and chronically ischemic myocytes (with mixed results), an alternate source of benefit may derive from its effects on preserving cell viability and function in adjacent aerobic heart muscle.     

Differing responses to hypercapnia and hypoxia following pneumotaxic center ablation.

The respiratory responses of 21 cats were examined upon exposure to hypercapnia and isocapnic hypoxia. Animals having bilateral electrolytic lesions localized in the pontile pneumotaxic center exhibited hypercapnia-induced minute volumes which were significantly less than those of unlesioned control cats. The hypoxia-induced minute volumes of pneumotaxic lesioned animals, examined at isocapnic alveolar gas partial pressures, were likewise significantly less than control animals at end-expired oxygen partial pressures (PAO2) in excess of 65.0 mm Hg. At PAO2 levels below 65.0 mmHg. the minute volume of experimental animals rose sharply and became statistically indistinguishable from that of the unlesioned cats. The placement of control brain stem lesions typically produced no significant alterations in the respiratory responses to hypoxia or hypercapnia. It was concluded that the pneumotaxic center constitutes an integral component of the central chemoreceptor CO1-H+ CONTROLLING SUBSYSTEM. The concept of differing anatomical sites within the brain stem serving integrative functions for central chemoreceptor and peripheral chemoreceptor afferent stimuli is also supported.