Normal chemoreceptor function in obesity before and after ileal bypass surgery to force weight reduction.

Ventilatory responses to progressive isocapnic hypoxia and rebreathing of carbon dioxide in oxygen were determined in four obese women before and approximately 1 year after ileal bypass surgery to force weight reduction. None of the patients was hypoventilating and all had normal pulmonary function tests. The ventilatory responses to hypoxia were normal before surgery and were not effected by weight reduction. The ventilatory responses to hypercapnia did not change in slope but a shift of the carbon dioxide response line toward a lower arterial carbon dioxide tension occurred in two subjects after weight reduction. We conclude that obesity per se does not necessarily cause loss of hypoxic ventilatory drive.

In vivo pharmacology of a novel AT1 selective angiotensin II receptor antagonist, MK-996.

MK-996, N-(4'-(5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl- methyl)1,1'-biphenyl-2-yl)-sulfonylbenzamide, is a potent, orally active, highly selective, nonpeptide angiotensin II (AII) receptor antagonist. MK-996 prevents the pressor response to intravenous AII in the conscious rat, dog, and rhesus monkey (ED50, mg/kg; oral/intravenous = 0.067/0.014, 0.035/0.017, and 0.1/0.036, respectively). In the anesthetized chimpanzee, MK-996 (1 mg/kg, iv) produces 100% (peak) inhibition of the AII pressor response and is still active (52%) at 24 h. To our knowledge this pharmacologic profile in the rat, dog, rhesus monkey, and chimpanzee presents the least species variability of any AII receptor antagonist yet described. Responses to methoxamine and arginine vasopressin are not affected by MK-996. In aortic coarcted (high renin) rats, MK-996 (3 mg/kg, by mouth) reduces blood pressure to normotensive (< 120 mm Hg) levels without reflex tachycardia. This dose of MK-996 reduces blood pressure to approximately the same level as both losartan (3 mg/kg, by mouth) and enalapril (3 mg/kg, by mouth) in this model. The duration of antihypertensive activity of MK-996 is similar to enalapril and shorter than losartan at the doses tested. Additionally, in the rat MK-996 does not potentiate the vasodepressor response to bradykinin and completely prevents the ability of AII to stimulate an increase in plasma levels of aldosterone. Therefore, MK-996 is a potent, orally active, nonpeptide AII receptor antagonist with a long duration of action, little species variability, and anti-hypertensive activity.

Hydrochloric acid in the correction of metabolic alkalosis.

Intravenous infusion of hydrochloric acid was used as a safe, effective, and quantitative method for correction of metabolic alkalosis in two patients. The first shows the risks of intravenously administered ammonium chloride, the currently available alternative to hydrochloric acid therapy. The second shows the efficacy of intravenously administered hydrochloric acid. While breathing spontaneously throughout the period of severe alkalosis, this patient showed compensatory hypoventilation with conspicuous increase in arterial carbon dioxide pressure. Normal spontaneous ventilation returned with correction of the metabolic alkalosis.

In vivo pharmacology of an angiotensin AT1 receptor antagonist with balanced affinity for AT2 receptors.

L-163,017 (6-[benzoylamino]-7-methyl-2-propyl-3-[[2'-(N-(3-methyl-1-butoxy) carbonylaminosulfonyl)[1,1']-biphenyl-4-yl]methyl]-3H-imidazo[4,5- b]pyridine) is a potent, orally active, nonpeptide angiotensin II receptor antagonist. Conscious rats and dogs were dosed p.o. and i.v.; in both species the plasma bioequivalents are similar at the angiotensin AT1 and AT2 receptor sites indicating balanced activity is maintained in vivo. L-163,017 prevents the pressor response to intravenous (i.v.) angiotensin II in the conscious rat, dog, and rhesus monkey. L-163,017 also significantly reduces blood pressure in a renin-dependent model of hypertension, similar to an angiotensin converting enzyme inhibitor (Enalapril) and an angiotensin AT1 receptor-selective antagonist (L-159,282). These studies indicate that neither the angiotensin AT2 receptor nor bradykinin is important in the acute antihypertensive activity of angiotensin converting enzyme inhibitors or angiotensin II receptor antagonists.

A new method of measuring renal function in conscious rats without the use of radioisotopes.

The purpose of the current experiment was to develop fast and accurate assays for measuring glomerular filtration rate (GFR) and effective renal plasma flow (ERPF). An enzymatic method was developed for the determination of inulin, and a colorimetric method was developed for determination of p-aminohippurate (PAH) in the plasma and urine of rats. These assays are easily automated and do not require the use of radioisotopes or corrosive chemicals. Glomerular filtration rate was measured by the clearance of inulin, and effective renal plasma flow was measured by the clearance of PAH. Blood pressure, heart rate, and renal function (urine volume, electrolytes, GFR, and ERPF) were measured in conscious rats for 1.5 h prior to drug treatment and for 3 h after treatment. Baseline renal function was compared to historical data. Acute changes in GFR and ERPF following administration of the vasoconstrictor peptide endothelin-1 (ET-1) were accurately measured with results similar to those obtained with older methodologies. These new methods offer many advantages over previously described methods by eliminating the use of radioisotopes and harsh chemicals. In addition, these methods can be used with an automated instrument with high accuracy and precision. Therefore, these new methods can be used to accurately determine GFR and ERPF and are sensitive enough to detect acute changes in GFR and ERPF in conscious animals.

Effect of platelet activating factor (PAF) on blood flow distribution in the spontaneously hypertensive rat.

A dose-dependent decrease in mean arterial blood pressure was produced in spontaneously hypertensive rats by intravenous PAF infusion. Heart rate was monitored, while cardiac index and regional blood flow were quantitated during maintenance of the PAF-induced hypotension using the radioactive microsphere method. Our results suggest that PAF administration is associated with specific changes in vascular resistance, since estimated blood flow was decreased to certain organs or tissues, but remained unchanged in others. Therefore, the hypotension observed during PAF infusion is dose-dependent, and is contributed to by decreases in vascular resistance in specific organs.

Endogenous opioids and ventilatory adaptation to prolonged hypoxia in goats.

To investigate whether endogenous opioid peptides mediate time-dependent changes in ventilatory control during prolonged hypoxia, we studied four adult goats at rest during 14 days at simulated high altitude in a hypobaric chamber (PB approximately 450 Torr). Arterial PCO2 fell during the first several hours of hypoxia, remained stable over the next 7 days, and then rose slightly (but without statistical significance) by day 14. Ventilatory responsiveness to CO2 increased during the first week of hypoxia. By day 14, while still greater than control, the ventilatory response to CO2 was less than that observed on day 7. Immunoactive beta-endorphin levels in plasma and CSF did not change during the 14-day period. Administration of naloxone on day 14 did not restore the ventilatory response to CO2 to the level observed during the first week of acclimatization. We conclude that in adult goats, time-dependent changes in ventilatory response to CO2 during acclimatization to prolonged hypoxia are not primarily attributable to alterations in endogenous opioid peptide activity.

Naloxone does not affect ventilatory responses to hypoxia and hypercapnia in rats.

Ventilatory responses (tidal volume, respiratory frequency, and minute ventilation) to steady-state hypoxia and steady-state hypercapnia were measured plethysmographically in awake unrestrained adult rats, before and after subcutaneous injection of placebo (saline) naloxone in doses up to 5.0 mg/kg. Naloxone did not alter the ventilatory responses to hypoxia or hypercapnia.

Dental complications during and after tracheal intubation.

Surveyed were 133 directors of training programs in anesthesiology. The directors reported an average incidence of 1:1,000 dental injuries during or after 1,135,212 tracheal intubations in 1 year. A well-documented dental evaluation before delivery of anesthetics and appropriate precautions and protective devices during intubation will prevent most dental trauma related to the delivery of general anesthetics. Also, early use of dental and risk management services often will ensure timely resolution of such problems.

Reconstruction errors in computer generated binary holograms: a comparative study.

The image degradation encountered in reconstructing computer-generated binary holograms is compared for the Lohmann-Paris, Lee, and Burckhardt-type hologram plots. The results reported here assist one in properly choosing the hologram plotting parameters and predicting resulting image quality for each type of hologram plot. The analytic results are supported by simulation.

Algorithms for calculating and correcting blood-gas and acid-base variables.

This is a review of the origins, derivations, and 'fidelity' of available equations for correcting PO2, PCO2, and pH for temperature, and for estimating blood-gas and acid-base variables from measured values: 1. Oxygen saturation (SO2) from PO2, PCO2, pH, and body temperature (T). 2. Oxygen concentration (CO2) from SO2, PO2, and hemoglobin concentration (Hb). 3. Base excess (BE) from pH, PCO2, and Hb. 4. 'In vivo BE' (BE3) from pH and PCO2. 5. 'Compensated BE3' (BEC) from PCO2. 6. Bicarbonate ([HCO3-]) and carbon dioxide concentrations (CCO2) from pH and PCO2. PHysiologic considerations are emphasized, with mathematical background when it contributes to understanding. Algorithms are variously compared with their graphic counterparts, with the data from which they were derived, and with each other.

Quality assurance/peer review for recredentialing/relicensure in New York State.

In consultation with the State Health Department, the New York State Society of Anesthesiologists has developed a Model Program of Quality Assurance/Peer Review for Recredentialing/Relicensure. The Model Program was developed to provide a standardized peer review process through which anesthesiologists practicing in New York State can be recredentialed and relicensed when recredentialing becomes a requirement for relicensure of New York State physicians. The program of recredentialing and relicensure is part of the agenda of the Governor's office, the State Health Department, and the State Education Department to improve the quality of healthcare in New York State through (1) identifying physicians whose quality of care is below reasonable thresholds, (2) assuring that these physicians receive appropriate remedial education or training, and (3) generally raising the quality of healthcare provided by all physicians practicing in New York State.

Depression of ventilation hypoxia in man.

In five normal male subjects, ventilation, PaO2, and PaCO2 were measured during the rapid progressive isocapnic production of hypoxia (5 min) and during the equally rapid isocapnic reversal of hypoxia. At similar PaO2, PaCO2, and pH, ventilation was less at a time when alveolar PO2 was increasing than when alveolar PO2 was decreasing. We interpret these results as showing that human ventilation is depressed by mild-to-moderate hypoxia (40-60 Torr), that such depression is probably central, and that it is ordinarily masked by peripheral chemoreceptor stimulation. We are not able to distinguish whether the ventilatory depression is caused by decreased central chemoreceptor PCO2 due to an increase in cerebral flow, direct hypoxic depressing of the central respiratory mechanism, or both.

Minimization of reconstruction errors with computer generated binary holograms.

Generation of holograms by computer allows the possibility of better controlling the hologram formation process and of displaying a synthesized image in the case where the object does not exist physically. However, limitations of equipment used to plot the hologram can cause degradation of the reconstructed image. We examine these degradations for the binary Fourier transform hologram and present a method by which the plotting procedure may be designed so as to yield a most faithful reconstructed image. Experimental results which support the analysis are included.

Prediction of PO2 from SO2 using the standard oxygen hemoglobin equilibrium curve.

We have fitted polynomial equations to three major segments of the standard oxygen hemoglobin equilibrium curve (OHEC) using oxygen saturation (SO2) rather than oxygen tension (PO2) as the independent variable. Hill's transformation contributes substantially to the very small residual errors of PO2, less than 0.21 Torr for all points. This characterization of the OHEC is more precise, and for certain applications more conveniently used than other available equations.

Ventilatory interaction between hypoxia and [H+] at chemoreceptors of man.

By measuring ventilation during isocapnic progressive hypoxia, peripheral chemoreceptor sensitivity to acute hypoxia (deltaV40) was measured in five normal young men under four sets of conditions: 1) at sea level at the subject's resting PCO2, 2) at sea level with PCO2 5 Torr above resting PCO2, 3) after 24 h at a simulated altitude of 4,267 m (PB = 447 Torr) at the subject's resting PCO2 measured during acute hyperoxia, and 4) after 24 h at high altitude, with PCO2 elevated to the subject's sea-level resting PCO2. With this experimental design, we were able to systematically vary the PCO2 and [H+] at the peripheral and central chemoreceptors of man. When mean pHa was decreased from 7.424 to 7.377 without significant change in PACO2, the mean deltaV40 increased from 18.0 to 55.9 1/min. Conversely, when mean PACO2 was altered between 33.8 and 41.6 Torr with pHa held relatively constant, the mean deltaV40 did not change. This suggests that it is the H+ and not CO2 which interacts with hypoxia in stimulating the ventilation of man. An additional finding was that the intrinsic sensitivity of the peripheral chemoreceptors to acute hypoxia did not change during 24 h of acclimatization to high altitude.

Composition of cerebral fluids in goats adapted to high altitude.

We explored the ionic composition of cerebral interstitial fluid (cISF) in six unanesthetized goats at sea level (SL) and again after 5 days at a simulated high altitude (HA) of 4,300 m. By measuring net transependymal fluxes of HCO3-, Cl-, and lactate during ventriculocisternal perfusions with lactate-free artificial cerebrospinal fluid (CSF) with various [HCO3-] and [Cl-], we determined [HCO3-] and [Cl-] in the inflowing perfusate that produced zero flux, which are estimates of the concentrations of these ions in cISF. Ventilatory acclimatization to HA was established in the goats with alkaline shift in cisternal CSF pH. At SL zero flux of HCO3- and of Cl- occurred when [HCO3-] and [Cl-] in the perfusate were equal to those in CSF. At HA Cl- flux again was zero when [Cl-] in perfusate and in the goat's own CSF were equal; however, for HCO3-, zero flux occurred at HA when [HCO3-] in perfusate was significantly lower than in CSF. Mean transependymal washout of lactate was 16 times larger at HA than at SL. We conclude that at SL [HCO3-] and [Cl-] in CSF were the same as in cISF. In goats adapted to HA [Cl-] in cISF and in CSF were again equal, whereas [HCO3-] in cISF was lower and [lactate] presumably higher than in CSF. The fluid surrounding the central chemoreceptors appears to be more acidic in goats acclimatized to HA than at SL despite the alkalosis in cisternal CSF. This may contribute to ventilatory acclimatization to HA.

Effects of BQ-123 on renal function and acute cyclosporine-induced renal dysfunction.

Cyclosporin A (CsA) is widely used to suppress graft rejection following transplantation and in the treatment of a variety of autoimmune diseases. Therapy with CsA is often accompanied by adverse effects which include hepatotoxicity, hypertension, and nephrotoxicity. The role of endothelin (Et) in CsA-induced nephrotoxicity has been the subject of recent investigations. BQ-123 is a recently discovered Et receptor antagonist which is selective for the EtA receptor. In the present study, BQ-123 was used to further characterize the role of Et in CsA-induced nephrotoxicity. All experiments were performed in Inactin (100 mg/kg, i.p.) anesthetized male Munich-Wistar rats (250 to 350 g). Animals were prepared for the recording of blood pressure (MAP) and heart rate (HR) as well as the measurement of urine volume (UV), UNaV, UKV, GFR and effective renal plasma flow (ERPF). GFR and ERPF were estimated from the clearance of 14C-inulin and 3H-PAH, respectively. On the day of the experiment, animals were randomly assigned to one of three groups and treated according to the following protocols: Group 1, pretreatment with BQ-123 (1 mg/kg, i.v. bolus with 0.1 mg/kg/hr i.v. infusion) followed by treatment with vehicle (cremophor; 0.15 ml, i.v.); Group 2, pretreatment with normal saline (1.0 ml/kg; plus 25 microliters/min infusion) followed by treatment with CsA (20 mg/kg, i.v.); and Group 3, pretreatment with BQ-123 (same as group 1) followed by CsA (20 mg/kg, i.v.). BQ-123 administration alone produced transient changes in several of the measured parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaline shift in lumbar and intracranial CSF in man after 5 days at high altitude.

In six healthy male volunteers at sea level (PB 747-759 Torr), we measured pH and PCO2 in cerebrospinal fluid (CSF), and in arterial and jugular bulb blood; from these data we estimated PCO2 (12) and pH for the intracranial portion of CSF. The measurements were repeated after 5 days in a hypobaric chamber (PB 447 Torr). Both lumbar and intracranial CSF were significantly more alkaline at simulated altitude than at sea level. Decrease in [HCO3-] IN lumbar CSF at altitude was similar to that in blood plasma. Both at sea level and at high altitude, PCO2 measured in the lumbar CSF was higher than that estimated for the intracranial CSF. At altitude, hyperoxia, in comparison with breathing room air, resulted in an increase in intracranial PCO2, and a decrease in the estimated pH in intracranial CSF. With hyperoxia at altitude, alveolar ventilation was significantly higher than during sea-level hyperoxia or normoxia, confirming that a degree of acclimatization had occurred. Changes in cerebral arteriovenous differences in CO2, measured in three subjects, suggest that cerebral blood flow may have been elevated after 5 days at altitude.