Biomedical subjects

D W Sheehan

Publications and source records attributed to D W Sheehan.

6 recordsLinked to original sources

PubMed1998

Effects of hypoxia on energy state and pH in resting pulmonary and femoral arterial smooth muscles.

To determine the effects of hypoxia on energy state and intracellular pH (pHi) in resting pulmonary and systemic arterial smooth muscles, we used 31P nuclear magnetic resonance spectroscopy and colorimetric and enzymatic assays to measure pHi; intracellular concentrations of ATP, phosphocreatine, creatine, and Pi; and phosphorylation potential in superfused tissue segments from porcine proximal intrapulmonary and superficial femoral arteries. Under baseline conditions (PO2 467 +/- 12.1 mmHg), energy state and total creatine (phosphocreatine + creatine) concentration were lower and pHi was higher in pulmonary arteries. During hypoxia (PO2 23 +/- 2.4 mmHg), energy state deteriorated more in femoral arteries than in pulmonary arteries. pHi fell in both tissues but was always more alkaline in pulmonary arteries. Reoxygenation reversed the changes induced by hypoxia. These results suggest that production and/or elimination of ATP and H+ was different in resting pulmonary and systemic arterial smooth muscles under baseline and hypoxic conditions. Because energy state and pHi affect a wide variety of cellular processes, including signal transduction, contractile protein interaction, and activities of ion pumps and channels, further investigation is indicated to determine whether these differences have functional significance.

Adenosine Triphosphate↗

PubMed1993

Local pulmonary blood flow: control and gas exchange.

We studied the local response of the pulmonary vasculature to combined changes in alveolar PO2 and PCO2 in the right apical lobe (RAL) of six conscious sheep. That lobe inspired an O2-CO2-N2 mixture adjusted to produce one of 12 alveolar gas compositions: end-tidal PCO2 (PETCO2) of 40, 50, and 60 Torr, each coupled with end-tidal PO2 (PETO2) of 100, 75, 50, and 25 Torr. In addition, at each of the four PETO2, the inspired CO2 was set to 0 and PETCO2 was allowed to vary as RAL perfusion changed. The remainder of the lung, which served as control (CL) inspired air. Fraction of the total pulmonary blood flow going to the RAL (%QRAL) was obtained by comparing the methane elimination from the RAL to that of the whole lung, and expressed as a percentage of that fraction at PETCO2 = 40, PETO2 = 100. Cardiac output, pulmonary vascular pressures, and CL gas tensions were unaffected or only minimally affected by changes in RAL gas composition. A drop in PO2 from 100 to 50 Torr decreased local blood flow by 60% in normocapnia and by 66% at a PCO2 of 60. At all levels of oxygenation, an increase in PCO2 from 40 to 60 reduced QRAL by nearly 50%. With these stimulus-response data, we developed a model of gas exchange, which takes into account the effects of test segment size on blood flow diversion. This model predicts that: (1) when the ventilation to one compartment of a two compartment lung is progressively decreased, PAO2 remains above 60 Torr for up to 60% reductions in alveolar ventilation, irrespective of compartment size; (2) the decrease in PAO2 that occurs at altitude is accompanied by a drop in PACO2 that limits the decrease in conductance and minimizes the pulmonary hypertension; and (3) as we stand, local blood flow control by the alveolar gas tensions halves the alveolar-arterial PO2 and PCO2 differences imposed by gravity.

Analysis of Variance↗

PubMed1993

Characterization and mechanisms of H2O2-induced contractions of pulmonary arteries.

We studied H2O2-induced contractions of isolated rabbit intrapulmonary arteries mounted in standard tissue baths. All vessels were pretreated with a thromboxane A2/prostaglandin H2 receptor antagonist, SQ 29,548, to block immediate transient contractions to H2O2 and to isolate slowly developing sustained contractions. When exposed to H2O2 (0.1, 0.2, 0.3, 0.6, and 1.0 mM) for 30 min, vessels contracted in (0.1, 0.2, 0.3, 0.6, and 1.0 mM) for 30 min, vessels contracted in a concentration-dependent fashion between 0.1 and 0.3 mM H2O2; contractions at 0.6 and 1.0 mM H2O2 were not significantly different from those at 0.3 mM H2O2. During recovery (90 min) from H2O2 exposures, baseline tension was significantly greater, but active tension (10 microM phenylephrine) was significantly less for vessels previously exposed to 0.6 and 1.0 mM H2O2. Contractions to 0.3 mM H2O2 were not blunted by the following interventions: 1) endothelium rubbing, 2) incubation in Ca(2+)-free 100 microM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) Krebs-Ringer solution, 3) incubation in the Ca(2+)-free solution and depletion of ryanodine (20 microM)-sensitive Ca(2+) stores, or 4) pretreatment with the protein kinase C inhibitor 1-(5-isoquinolinylsulfonyl)-3-methyl-piperazine (20 microM). However, contractions were depressed by approximately 50% when vessels were pretreated with the phospholipase C/serine esterase inhibitor 2-nitro-4-carboxy-phenyl-N,N-diphenylcarbamate (50 microM). These results suggest that slow-developing contractions to H2O2 are concentration dependent and may result, in part, from activation of a serine esterase(s) and/or phospholipase C.

Animals↗

PubMed1992

Pulmonary hypoxic vasoconstriction: how strong? How fast?

We have developed a minimally invasive technique for studying regional blood flow in conscious sheep, bypassing the complications of open-chest surgery, flow probes and tracer infusion. We quantitate regional perfusion continuously on the basis of regional clearance of methane (methane is produced in the sheep rumen, enters the circulation and is eliminated nearly completely (greater than 95%) in the lung). Tracheal intubation with a dual-lumen catheter isolates the gas exchange of the right apical lobe (RAL; less than 15% of the lung) from that of the remainder of the lung, which serves as a control (CL). We measure RAL and CL methane elimination by entraining expirates in constant flows, sampled continuously for methane. Results obtained with this technique and from regional oxygen uptake are in excellent agreement. We have found that hypoxic vasoconstriction is far more potent and stable during eucapnic hypoxia than during hypocapnic hypoxia. The time course of the vasoconstriction suggests that many of the data in the literature may have been obtained prior to steady state.

Analysis of Variance↗

PubMed1992

Prolonged lobar hypoxia in vivo enhances the responsivity of isolated pulmonary veins to hypoxia.

The hypoxic response of pulmonary vessels isolated from eight sheep whose right apical lobes (RAL) had inspired 100% N2 for 20 h was studied. The RAL of these conscious sheep inspired hypoxic gas and the remainder of the lung inspired air. During hypoxia, RAL perfusion was 33 +/- 3% of its air value, carotid arterial PO2 averaged 86 +/- 3 mm Hg and pulmonary perfusion pressure was not significantly different from the initial control period when the RAL inspired air. At the end of the hypoxic exposure, the sheep were killed, and pulmonary artery and vein rings (0.5 to 2 mm inner diameter) were isolated from both the RAL and the right cardiac lobe, which served as the control lobe (CL). Arteries from the RAL and CL did not contract in response to 6% O2/6% CO2/88% N2 (hypoxia). In contrast, RAL veins did contract vigorously in response to hypoxia, whereas CL veins did not contract or contracted only minimally. Rubbing of the endothelium or prior incubation of RAL veins with catalase (1,200 units/ml), indomethacin (10(-5) M), or the thromboxane A2/prostaglandin H2 (TxA2/PGH2) receptor antagonist, SQ 29,548 (3 X 10(-6) M) each significantly reduced the response to hypoxia. RAL veins were also found to be more reactive than CL veins to the prostaglandin endoperoxide analogue U46619. We conclude that prolonged lobar hypoxia in vivo increases the responsivity of isolated pulmonary veins to hypoxia. These contractions may result from an increase in reactive O2 species, which in turn modify production of, metabolism of, and/or tissue responsivity to TxA2/PGH2.

Animals↗

PubMed1990

Pulmonary circulation and systemic circulation: similar problems, different solutions.

Both the systemic and the pulmonary circulations respond to local hypoxia in the appropriate manner, the former by vasodilating, thereby providing more oxygen, and the latter by constricting and rerouting blood flow to areas where more O2 is available. In either case, changes in local conductance affect total conductance, and through that variable, the perfusing pressure; as a result, the effects of local vasomotion should be reduced. In the systemic circulation, arterial pressure can be prevented from falling by two important mechanisms: vasoconstriction of other vascular beds, and an increase in cardiac output. There are no similar means for protecting pulmonary arterial pressure against a rise when vessels in hypoxic areas contract; the only defense is provided by passive expansion of the vascular bed. Thus, in the lung regional circulatory readjustments conflict with the need to maintain a reasonably low pulmonary arterial pressure and local regulation (and maintenance of arterial oxygenation) may be subordinate to prevention of pulmonary hypertension.

Animals↗