To elucidate the role of serotonin in the maintenance of normal breathing and upper airway (UA) patency in obesity, we studied the effects of systemic administration of ritanserin, a serotonin (5-HT) 2A and 2C receptor antagonist, on ventilation (V E) during room air breathing and during hypoxic (10% O2) and hypercapnic (4% CO2) ventilatory challenges in awake young (6-8 wk) and older (7-8 mo) obese and lean Zucker (Z) rats. Older obese Z rats adopted a more rapid shallow breathing pattern compared with older lean rats. The administration of ritanserin (1 mg/kg intraperitoneally) to older obese rats resulted in a reduction in V E (439 +/- 35 [SD] to 386 +/- 41 ml/kg/min, p < 0.01), a decrease in respiratory rate, a prolongation of inspiratory time, and an increase in V O2 (16.4 +/- 1.7 to 18.2 +/- 1.9 ml/kg(0.75)/min, p < 0.05) during room air breathing. By comparison, it had little effect on ventilation in young lean and obese Z or older lean Z rats. Ritanserin also had no effect on ventilatory responses to either hypoxia or hypercapnia in young or older lean and obese Z rats. The collapsibility of the isolated UA was examined in older Z rats. The pharyngeal critical pressure (Pcrit) of older obese rats was significantly greater than that of lean rats (p < 0.05), indicating that obese rats have more collapsible UA than lean rats. The administration of ritanserin significantly increased Pcrit in older obese rats (-1.6 +/- 0.3 to -0.8 +/- 0.2 cm H2O, p < 0.01) and in lean rats (-3.1 +/- 1.0 to -2.4 +/- 0.6 cm H2O, p < 0.05). We suggest that the 5-HT(2A/2C) receptor subtype plays an important role in the maintenance of UA stability and normal breathing in obesity, and we speculate that older obese Z rats may have augmented serotonergic control of UA dilator muscles as a mechanism to prevent pharyngeal collapse.

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Exercise and inflammatory lung disorders such as asthma and acute lung injury increase exhaled nitric oxide (NO). This finding is interpreted as a rise in production of NO by the lungs (VNO) but fails to take into account the diffusing capacity for NO (DNO) that carries NO into the pulmonary capillary blood. We have derived equations to measure VNO from the following rates, which determine NO tension in the lungs (PL) at any moment from 1) production (VNO); 2) diffusion, where DNO(PL) = rate of removal by lung capillary blood; and 3) ventilation, where V A(PL)/(PB - 47) = the rate of NO removal by alveolar ventilation (V A) and PB is barometric pressure. During open-circuit breathing when PL is not in equilibrium, d/dt PL[V(L)/ (PB - 47)] (where V(L) is volume of NO in the lower airways) = VNO - DNO(PL) - V A(PL)/(PB - 47). When PL reaches a steady state so that d/dt = 0 and V A is eliminated by rebreathing or breath holding, then PL = VNO/DNO. PL can be interpreted as NO production per unit of DNO. This equation predicts that diseases that diminish DNO but do not alter VNO will increase expired NO levels. These equations permit precise measurements of VNO that can be applied to determining factors controlling NO production by the lungs.

The modulating effect of CO2 on the circulatory response to hypoxia in chronically instrumented conscious dogs was examined over a wide range of arterial partial pressure of O2 [PaO2 (from 80 to 25 Torr)] during a 41-min rebreathing period at three CO2 levels: hypocapnia (from PaCO2 of 32 to 18 Torr), eucapnia (32 Torr), and mild hypercapnia (40 Torr). Eucapnic and hypercapnic hypoxic responses were also measured after sinoaortic denervation (SAD) to assess the arterial chemoreceptor and baroreceptor reflex contributions. Elevating PaCO2 attenuated the tachycardia during hypoxia and produced progressively greater systemic, renal, and splanchnic vasoconstriction before but not after SAD. Vagal block converted the rises in renal and splanchnic flows observed during hypocapnic hypoxia to declines. The increase in left ventricular dP/dtmax was not affected by varying PaCO2 either before or after SAD. Coronary flow increased an additional onefold during hypoxia when PaCO2 was elevated both before and after SAD, but the tension-time indices did not differ significantly. These results indicate that: a) cardiopulmonary vagal afferents effectively counteract chemoreflex-induced vasoconstriction during hypocapnic hypoxia; b) chemoreflex vasoconstriction predominates in the renal and splanchnic beds when PaCO2 is elevated; c) the sinoaortic reflexes restrain the heart rate, but not the contractility response to hypoxia when PaCO2 is increased; and d) the augmented coronary vasodilation produced by CO2 is probably mediated by local CO2-hypoxic interactions.

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Summary: This investigation determined the effects of sustained hypercapnia on cerebral blood flow (CBF; ra diolabeled microspheres), cerebral metabolic rates for O2 and glucose (CMR02 and CMRg1c), and brain water con tent in conscious sheep instrumented with aortic, left ven tricular, vena cava, and brain sagittal sinus catheters. PaC02 was elevated from 38 ± 3 to 53 ± 3 (mean ± SD) mm Hg and Pa02 from 109 ± 7 to 131 ± 4 mm Hg for 96 h in an environmental chamber. Hypercapnia did not alter sheep behavior, food and water intake, arterial pressures, core temperature, or brain lactate release. Total and re gional CBF and CBF/CMR02 reached peak values at 1 h and then readjusted, to stabilize at lower, but still ele vated levels at 24 h and thereafter. CMR02 and CMRglc CO2 retention is commonly observed in patients with chronic pulmonary disease and this can be as sociated with impairment of integrated brain func tion (Sieker and Hickam, 1956; Woodbury and Received September \, 1993; final revision received Novem ber 18, 1993; accepted December 13, 1993. Abbreviations used: bpm, beats per minute; Ca g le and CV gle , cerebral arterial and venous blood glucose content, respectively; CaOZ and CvOz, cerebral arterial and venous blood oxygen con tent, respectively; CMRlaco cerebral metabolic rate for lactate; CPP, cerebral perfusion pressure; CVR, cerebral vascular resis tance; FE g i c and FEOz, cerebral glucose and oxygen extraction fraction, respectively; F\COz, inspired fraction of carbon diox ide; GD, cerebral glucose delivery; GOI, glucose-oxygen index; Hba and Hbv, arterial and venous hemoglobin, respectively; Hcta and Hctv, arterial and venous hematocrit, respectively; HR, heart rate; 10, inner diameter; OD ' cerebral oxygen delivery; 00, outer diameter; Pa and P s a s' arterial and sagittal sinus pres sure, respectively; pHa' arterial pH; PRU, peripheral resistance units; rCBF, regional CBF; SaOZ% and SvOz%, arterial and ve nous oxygen saturation, respectively. 115increased at 6 h and thereafter during hypercapnia. PaC02, CBF, CMR02, and CMRglc remained elevated at 3 h after restoration to room air, while CBF/CMR02 re turned to the control value. Frontal and occipital lobe wet-to-dry weight ratios increased modestly but signifi cantly after hypercapnic exposure. It is concluded that sustained hypercapnia induces stable and nonadapting in creases in both CBF and brain metabolism that persist for at least 3 h after restoration to room air in association with hypoventilization and modest elevations of brain wa ter. Key Words: Brain bicarbonate-Brain edema-Brain glucose metabolism-Brain lactate-Brain O2 uptake Cerebral fluid shifts-C02 retention-Hyperventilation. Karler, 1960; Krnjevic et aI. , 1965). Most studies have attributed the increase in cerebral blood flow (CBF) during hypercapnia to an increase in the [H+] in brain interstitial fluid (Kontos et aI. , 1977). More recently, evidence indicates that nitric oxide related mechanisms may contribute to hypercapnic brain vasodilation also (ladecola, 1992; Wang ...

The hypothermic response of rats to only brief ( approximately 2 h) hypoxia has been described previously. The present study analyzes the hypothermic response in rats, as well as level of activity (L(a)), to prolonged (63 h) hypoxia at rat thermoneutral temperature (29 degrees C). Mini Mitter transmitters were implanted in the abdomens of 10 adult Sprague-Dawley rats to continuously record body temperature (T(b)) and L(a). After habituation for 7 days to 29 degrees C and 12:12-h dark-light cycles, 48 h of baseline data were acquired from six control and four experimental rats. The mean T(b) for the group oscillated from a nocturnal peak of 38.4 +/- 0.18 degrees C (SD) to a diurnal nadir of 36.7 +/- 0.15 degrees C. Then the experimental group was switched to 10% O(2) in N(2). The immediate T(b) response, phase I, was a disappearance of circadian rhythm and a fall in T(b) to 36.3 +/- 0.52 degrees C. In phase II, T(b) increased to a peak of 38.7 +/- 0.64 degrees C. In phase III, T(b) gradually decreased. At reoxygenation at the end of the hypoxic period, phase IV, T(b) increased 1.1 +/- 0.25 degrees C. Before hypoxia, L(a) decreased 70% from its nocturnal peak to its diurnal nadir and was entrained with T(b). With hypoxia L(a) decreased in phase I to essential quiescence by phase II. L(a) had returned, but only to a low level in phase III, and was devoid of any circadian rhythm. L(a) resumed its circadian rhythm on reoxygenation. We conclude that 63 h of sustained hypoxia 1) completely disrupts the circadian rhythms of both T(b) and L(a) throughout the hypoxic exposure, 2) the hypoxia-induced changes in T(b) and L(a) are independent of each other and of the circadian clock, and 3) the T(b) response to hypoxia at thermoneutrality has several phases and includes both hypothermic and hyperthermic components.

Levels of endogenous opioids are increased in morbidly obese humans and obese rats. Endogenous opioids are important neuromodulators, and are involved in a wide range of functions including ventilatory control. We studied eight lean and eight obese Zucker (Z) rats at 6 and 16 wk of age. We assessed minute ventilation (V E) at rest and during hypercapnic challenges, as well as peak oxygen consumption (V O(2peak)) after the administration of saline (control), naloxone hydrochloride (N(HCl)), and naloxone methiodide (N(M)). Administration of N(HCl) and N(M) to lean animals had no effect on V E and V O(2peak). Similarly, N(M) failed to alter V E and V O(2peak) in obese rats studied at 6 or 16 wk of age. In young obese rats, N(HCl) significantly (p < 0.05) increased resting V E (721 +/- 154 [mean +/- SD] ml/kg/min versus 937 +/- 207 ml/kg/min, saline versus N(HCl), respectively); VE in response to 4% CO(2) (924 +/- 110 ml/kg/min versus 1,212 +/- 172 ml/ kg/min); V E in response to 8% CO(2) (1,233 +/- 172 ml/kg/min versus 1,565 +/- 327 ml/kg/min); and V O(2peak) (90.8 +/- 9.6 ml/kg(0.75)/min versus 98.3 +/- 5.9 ml/kg(0.75)/min). However, N(HCl) administration had no effect on V E or V O(2peak) in obese rats retested at 16 wk of age. Thus, endogenous opioids modulate resting ventilation, ventilatory responsiveness to CO(2), and V O(2peak) in young obese rats by acting specifically on receptors located within the central nervous system. This modulation disappears once the animals reach 16 wk of age.