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Biomedical subjects

L J Rubin

Publications and source records attributed to L J Rubin.

At least 109 records · Page 6Linked to original sources
PubMed1991

Pulmonary vascular distensibility of arterial, middle, and venous regions in newborn lambs.

The pulmonary circulation in the adult is characterized by being relatively distensible, but whether the newborn lung shares this feature is less certain. We perfused isolated lungs treated with indomethacin from lambs of four ages (less than 1, 2-4, 12-14, and 30-32 days) to determine the effects of increasing left atrial pressure on the pulmonary vascular pressures measured by vascular inflow and outflow occlusion. An index of pulmonary vascular distensibility was assessed by comparing the slope of the pulmonary vascular pressure at the upstream end of a region as a function of the pressure at the downstream end of the region. A vascular distensibility index (VDI) of 1 indicates a rigid nondistensible system, whereas a VDI less than 1 indicates some degree of distensibility. During normoxia, lungs from all age groups were relatively indistensible as determined by VDI for the total vasculature (VDItotal) as well as for the different regions based on occlusion pressures (VDIarterial, VDImiddle, and VDIvenous). There were significant effects of age on the VDItotal, with decreases in the normoxic values occurring over the first 12-14 days of age, indicating an increase in pulmonary vascular distensibility. Only the VDIvenous was similarly affected by increasing neonatal age. Hypoxia significantly reduced the VDItotal in these same age groups. In addition, hypoxia, which increased the pressure gradients of the arterial and middle regions, significantly increased the VDIarterial in the youngest and oldest age groups but significantly decreased the VDImiddle at all ages by approximately 50%. In summary, we observed age-related changes in the vascular distensibility of the pulmonary circulation, with the VDItotal decreasing with increasing postnatal age.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Indomethacin prevents ventilation-induced decreases in pulmonary vascular resistance of the middle region in fetal lambs.

Previously, we report that the major site of pulmonary vascular resistance in fetal lambs occurred in the middle region defined by vascular occlusion, and that this region exhibited the greatest decrease upon ventilation with O2. To assess the relative individual contributions of ventilation and oxygenation to this decrease, we determined the distribution of pressures across the pulmonary circulation in isolated perfused lungs from 20 fetal lambs (131 - 137 d gestation) by inflow and outflow vascular occlusions. A membrane oxygenator was included in the extracorporeal circuit to control the PO2 at 4 kPa (30 torr) in the unventilated fetal lungs. Half of the fetal lungs were ventilated first without changing the initial gas tensions, and the others were oxygenated first by changing the initial gas tension to a hyperoxic mixture [PO2 = 26.6 kPa (200 torr)] without ventilation. Finally, both groups of lungs were ventilated and oxygenated. In addition, indomethacin was added to the perfusate (0.112 mM, or 40 micrograms/mL) in half of the preparations in each group to determine the effect of prostaglandins on the distribution of pressures during these conditions. The decrease in the total pulmonary vascular resistance with ventilation and/or oxygenation was primarily due to changes in the middle pressure gradient (delta Pm). In fetal lungs without indomethacin, ventilation without oxygenation reduced delta Pm from 6.1 +/- 0.8 to 2.5 +/- 1.0 kPa, or 74% of the total ventilation- and oxygenation-induced decrease in delta Pm (final value = 1.2 +/- 0.6 kPa).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol). Results of a randomized trial.

STUDY OBJECTIVE: To determine the efficacy of continuous intravenous infusion of prostacyclin (epoprostenol) in primary pulmonary hypertension. DESIGN: Randomized trial with 8-week treatment periods and nonrandomized treatment for up to 18 months. SETTING: Four referral centers. PATIENTS: Sequential sample of 24 patients with primary pulmonary hypertension. Nineteen patients completed the study. Four patients died and one left the study because of adverse effects (pulmonary edema). INTERVENTIONS: Continuous intravenous prostacyclin administered by portable infusion pump at doses determined by acute responses during baseline catheterization in ten patients. Nine patients were treated with anticoagulants, oral vasodilators, and diuretics. MEASUREMENTS AND MAIN RESULTS: Starting with a baseline value for total pulmonary resistance of 21.6 units, there was a decrease of 7.9 units (95% CI, -13.1 to -2.2; P = 0.022) in the prostacyclin-treated group after 8 weeks; there was virtually no change in the conventional therapy group (from 20.6 to 20.4 units, not significant). Six of ten prostacyclin-treated patients who completed the 8-week study period had reductions in mean pulmonary artery pressure of greater than 10 mm Hg, whereas only one of nine in the conventional treatment group had a similar response (P = 0.057). Nine patients receiving prostacyclin for up to 18 months have persistent hemodynamic effects, although dose requirements have increased with time. Complications have been attributable to the drug delivery system. CONCLUSIONS: Prostacyclin produces substantial and sustained hemodynamic and symptomatic responses in severe primary pulmonary hypertension and may be useful in the management of some patients with this disease.

Adolescent↗
PubMed1990

Contrasting effects of hypoxia on tension in rat pulmonary and mesenteric arteries.

The effects of hypoxia on resting and K-stimulated tension were tested on small rings of rat pulmonary and mesenteric resistance arteries (SPA and SMA, respectively) and on the large branches of the main pulmonary artery (LPA). Reduction of PO2 from approximately 135 Torr to less than 40 Torr slowly increased SPA and LPA resting tension but did not affect SMA tension. The increases in SPA and LPA tension during hypoxia were reversible and were dependent on external Ca2+. Verapamil, 10(-6) M, inhibited the hypoxic pulmonary vasoconstriction by 53-78%. The hypoxia-contracted SPA and LPA were relaxed by 2-4 microM cromakalim; these relaxations were reversed by 2 microM glibenclamide. Hypoxia attenuated the K-stimulated tension (delta TK) in both SPA and SMA at all external K+ concentrations ([K+]o = 10-100 mM) without affecting the shapes of the respective [K+]o-tension curves. However, the SPA curve was located much farther to the left on the [K+]o axis than the SMA curve. [K+]o congruent to 13 mM evoked a half-maximal increase in SPA tension; maximal delta TK was observed at [K+]o greater than or equal to 30 mM. In contrast, [K+]o less than 20 mM induced a negligible increase in SMA tension, whereas 35-40 mM K+ activated about one-half of the increase in tension elicited by 100 mM K+. The LPA [K+]o-tension curve in normoxia was intermediate between the SMA and SPA curves, but hypoxia shifted the LPA curve to the left: delta TK was augmented at [K+]o less than 20 mM and attenuated at high [K+]o.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Effects of nitrendipine and hypoxia on pulmonary vascular resistance in experimental emphysema.

We evaluated the hemodynamic effects of nitrendipine, a dihydropyridine Ca2+ channel blocker, and hypoxia in intact dogs with emphysema produced by treatments with aerosolized papain. We also determined the effects of emphysema, chronic Ca2+ channel blocker treatment, and acute hypoxia on the distribution of vascular resistance in isolated left lower lobes. Pulmonary vascular resistance was increased (4 +/- 1 mm Hg/L/min) in the animals studied 6 months after receiving 4 weekly treatments with papain compared with control animals (2.6 +/- 0.6 mm Hg/L/min, p less than 0.05), and this effect of emphysema was blunted with chronic nitrendipine, 3 mg/kg twice a day (3.1 +/- 0.9 mm Hg/L/min). Both at baseline and at 6 months, hypoxia-induced increases in pulmonary vascular resistance were abolished by nitrendipine. The total pulmonary pressure gradient (delta Pt) was partitioned into pressure gradients across arterial (delta Pa), middle (delta Pm), and venous (delta Pv) vessels by occlusions performed during normoxia (PIO2 = 200 mm Hg) and hypoxia (PIO2 = 30 mm Hg). Papain-treated animals had elevated delta Pt compared with that in control animals because of an increased delta Pv (9.7 +/- 1.1 mm Hg versus 5.2 +/- 0.4 mm Hg in control animals, p less than 0.05). In contrast, only delta Pm was increased with papain + nitrendipine (2.6 +/- 1.0 mm Hg versus 0.2 +/- 0.3 mm Hg in control animals, p less than 0.05). An increase in the downstream pressure gradient was also observed when lobes from animals with emphysema were studied under conditions of reverse perfusion. Hypoxic responses were similar in the control and papain groups, with increases in delta Pa and delta Pm.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Anion exchange chromatographic separation of inositol phosphates and their quantification by gas chromatography.

The direct measurement of mass of inositol trisphosphate from biologic samples is described. Separation of inositol monophosphate, bisphosphate, trisphosphate, and inositol tetrakisphosphate was achieved using anion exchange chromatography with a sodium sulfate gradient. In addition, separation of the isomers of each inositol phosphate was performed using HPLC procedures. The individual inositol phosphate fractions were subsequently dephosphorylated and desalted. The myo-inositol from each fraction was then derivatized to the hexatrimethylsilyl derivative and the myo-inositol derivatives were quantified by a novel gas chromatographic analysis using the hexatrimethylsilyl derivative of chiro-inositol as an internal concentration reference. This method is a reproducible and relatively rapid procedure for the direct quantification of inositol phosphate mass which overcomes many of the problems associated with the use of radiolabeled precursors. The method is a significant improvement over existing procedures for the quantitative determination of the mass of inositol phosphate by virtue of improved recovery, sensitivity, and technical simplicity. The applicability of this method is illustrated by the quantitative determination of inositol trisphosphate in response to norepinephrine stimulation of adult canine myocytes and cerebral cortical brain slices and by measurement of the isomers of inositol trisphosphate in isolated myocytes.

Chromatography, Gas↗
PubMed1989

Accessibility of colloidal gold and horseradish peroxidase to cytosolic spaces in Limulus ventral photoreceptors.

Physiological studies of intracellular messengers frequently employ intracellular injections of large molecules that either monitor or modulate the metabolism of the messenger cascade. Injected molecules have unknown mobility in the cytosol and unknown accessibility to various cytosolic compartments, including those postuiated to be traversed by intracellular messenger molecules. In order to determine whether injected molecules have access to the confined spaces through which messenger molecules must diffuse, we injected 5-nm colloidal gold or horseradish peroxidase, or both, into Limulus ventral photoreceptors. Injections were made by applying pressure pulses to the back of an intracellular micropipette that also monitored membrane voltage. The tissue was fixed at varying times after injection and processed for electron microscopy by conventional techniques. Cells fixed 1-3 min after injection contained HRP reaction product only in the cell body. HRP reaction product was found at varying distances down axons in direct relation to the interval between injection and fixation. Colloidal gold particles were found throughout the cell body but not in axons of tissue fixed 1-3 min after injection. Both HRP reaction product and 5-nm colloidal gold particles were observed within the microvillar projections of internal and external rhabdomere, as well as within the extracisternal spaces of endoplasmic reticulum. We conclude that large molecules injected from an intracellular micropipette into an arbitary locus of ventral photoreceptor cells have access to all of the presumed sites of the phototranduction cascade.

Animals↗
PubMed1989

Role of venoconstriction in thromboxane-induced pulmonary hypertension and edema in lambs.

We evaluated the dose response to a stable thromboxane (Tx) A2 analogue (sTxA2; 0.3-30 micrograms) in the pulmonary circulation and its effect on the distribution of pressure gradients determined by the occlusion technique in isolated nonblood perfused newborn lamb lungs. The total pulmonary pressure gradient (delta Pt) was partitioned into pressure drops across the relatively indistensible arteries and veins (delta Pv) and relatively compliant vessels. We also evaluated the effects of prostacyclin (PGI2) and a Tx receptor antagonist (ONO 3708) on the sTxA2-induced pulmonary responses. Injection of sTxA2 caused a dose-related increase in the pulmonary arterial pressure, with the primary component of the increase in delta Pt (4.1 +/- 0.8 to 13.9 +/- 0.4 Torr) at 30 micrograms derived from the prominent rise in delta Pv (1.8 +/- 0.3 to 9.8 +/- 0.9 Torr). Infusion of PGI2 (0.4 microgram.kg-1.min-1) reduced the response to sTxA2 mainly by attenuating the delta Pv elevation. Infusion of ONO 3708 (100 micrograms.kg-1.min-1) completely abolished the sTxA2-induced pulmonary hypertension. Injection of sTxA2 resulted in pulmonary edema characterized by a significant increase in wet-to-dry lung weight ratio (9.13 +/- 0.35 vs. 7.15 +/- 0.41 in control lungs). The sTxA2-induced pulmonary edema was increased by PGI2 and inhibited by ONO 3708. We conclude that thromboxane-induced pulmonary hypertension is primarily produced by venoconstriction and prostacyclin may worsen the edema induced by thromboxane.

Animals↗
PubMed1989

Effects of a thromboxane A2 analogue and prostacyclin on lung fluid balance in newborn lambs.

We have previously shown that the pulmonary venoconstriction produced by a stable thromboxane A2 analogue (STA2) is attenuated by prostacyclin (PGI2), but PGI2 increases the STA2-induced edema. The present study was designed to determine the effects of STA2 and PGI2 on the fluid balance in isolated blood-perfused newborn lamb lungs. Vascular permeability was evaluated by use of the fluid filtration coefficient (Kf) and the osmotic reflection coefficient for total proteins (sigma, hematocrit-protein double indicator technique), and pulmonary capillary pressure (Pc) was estimated by the double occlusion technique. All lungs had a period of hydrostatic stress induced by elevation of the left atrial pressure from 5 to 20 mm Hg to promote fluid filtration, and the rate of lung weight gain (delta W/delta T) during this period was determined. Studies were made in four groups; before the hydrostatic stress, lungs were given 1) STA2 (50 micrograms, n = 6), 2) PGI2 (0.4 micrograms/kg/min, n = 6), 3) both PGI2 and STA2 (n = 6), or 4) vehicles (control, n = 5). Measurements of Kf were made at the baseline period and after the hydrostatic stress. Kf was significantly increased by 76% with STA2, by 121% with PGI2, and by 157% with both PGI2 and STA2, but remained constant in controls. In comparison with control lungs, a similar delta W/delta T was observed with less of an increase in Pc during the hydrostatic stress in the STA2 group, and greater values of delta W/delta T were obtained with smaller elevations in Pc in the groups receiving PGI2 or both PGI2 and STA2.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

The influence of the transmembrane sodium gradient on the responses of pulmonary arteries to decreases in oxygen tension.

A Na/Ca exchange system has been demonstrated in systemic vascular smooth muscle and has been suggested as a mechanism for the entry and extrusion of Ca2+. Using isolated rings of bovine intrapulmonary arteries, we sought to determine whether a Na/Ca exchange mechanism is present in pulmonary vascular smooth muscle, and if so, whether it contributes to the modulation of vascular tone during hypoxia. Under both normoxic (PO2 greater than or equal to 120 mm Hg) and hypoxic (PO2 less than or equal to 40 mm Hg) conditions, the amplitude of the 40 mM K+ contraction was significantly (p less than 0.005) enhanced when most of the external Na+ was replaced with N-methylglucamine (NMG) (Na+ = 1.2 mM). The rate of contraction was also increased by replacing Na+ with NMG during normoxia (1.02 +/- 0.24 to 2.52 +/- 0.57 mg/mg weight/s, p less than 0.005) and hypoxia (1.72 +/- 0.74 to 4.08 +/- 1.63 mg/mg weight/s, p less than 0.05). Although the relaxation rate was slowed in the low Na+ media during normoxia (3.48 +/- 1.07 with Na+ versus 2.58 +/- 0.81 mg/mg weight/s with NMG, p less than 0.02), it was unaltered during hypoxia (3.15 +/- 0.90 with Na+ versus 2.95 +/- 0.83 mg/mg weight/s with NMG, p = 0.3). The ratio of relaxation rates in the normal and low Na+ media correlated with the perfusate PO2 (r = 0.76, p less than 0.001). During normoxia and hypoxia, inhibition of the Na+,K+ pump by strophanthidin, which increases intracellular [Na+], reversibly enhanced the amplitude of the K+ contraction, even when the voltage-gated channels were blocked with verapamil.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

The acute administration of vasodilators in primary pulmonary hypertension. Experience from the National Institutes of Health Registry on Primary Pulmonary Hypertension.

The hemodynamic responses to acute vasodilator administration were evaluated in 163 patients who were entered into the National Institutes of Health Registry on Primary Pulmonary Hypertension (PPH) between 1981 and 1985. Of a total of 491 drug administrations in these patients, 135 administrations in 104 patients were performed in a manner acceptable to the Registry. A single vasodilator was tried in 79 patients and more than one vasodilator in 25 patients. Two-thirds of the patients were in New York Heart Association Functional Classes III or IV. When the effects of all vasodilators were grouped together, there were significant decreases from baseline in mean pulmonary artery pressure (60 +/- 2 to 57 +/- 2 mm Hg, p less than 0.05) and total pulmonary resistance index (32.5 +/- 1.7 to 25.1 +/- 1.4 mm Hg/L/min/m2, p less than 0.0001), and increases in cardiac index (2.1 +/- 0.1 to 2.7 +/- 0.1 L/min/m2, p less than 0.0001). Mean systemic blood pressure fell (88 +/- 1 to 79 +/- 1 mm Hg, p less than 0.0001), whereas PaO2 was unchanged (70 +/- 3 to 71 +/- 3 mm Hg, p = NS). A fall in total pulmonary resistance greater than 20% was observed in 55% of the adequate drug trials. Adverse effects occurred in 32 of the total 491 patient-drug trials and were generally minor. Hypotension requiring treatment developed in six patients. There were two deaths attributable to vasodilator administration. Patients who died or had hypotension requiring treatment had higher right atrial pressures than did other treated patients (15 +/- 2 versus 9 +/- 1 mm Hg, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1988

Transient accumulation of inositol (1,3,4,5)-tetrakisphosphate in response to alpha 1-adrenergic stimulation in adult cardiac myocytes.

To investigate the response to catecholamine stimulation of adult cardiac myocytes and the metabolism of inositol (1,4,5)-trisphosphate (1,4,5-IP3) and inositol (1,3,4,5)-tetrakisphosphate (IP4), we have employed a procedure developed in our laboratory to directly measure the mass of inositol phosphates after separation of individual isomers of inositol phosphates by high performance liquid chromatography. Control, unstimulated myocytes, contained low levels of inositol (1,4)-bisphosphate (1,4-IP2), inositol (1,3)-bisphosphate (1,3-IP2), inositol (3,4)-bisphosphate (3,4-IP2), inositol (1,3,4)-trisphosphate (1,3,4-IP3), 1,4,5-IP3 and IP4. Stimulation with norepinephrine for 30 seconds produced peak 1,4,5-IP3 and IP4 levels which rapidly returned to basal values by 60 seconds of norepinephrine stimulation. 1,4-IP2, 1,3-IP2 and 1,3,4-IP3 were increased markedly but only after stimulation with norepinephrine for 60 seconds. These results indicate a rapid yet transient increase in 1,4,5-IP3 and IP4 in response to norepinephrine stimulation and are the first quantitative measurements of the isomers of inositol phosphates in cardiac tissue.

Animals↗
PubMed1988

[ATP]i in Limulus photoreceptors: no correlation with responsiveness or discrete event rate.

Firefly luciferin-luciferase was microinjected into single, intact photoreceptor cells of Limulus ventral eyes. In addition, total ATP content of whole end organs was measured. An attempt was made to correlate intracellular ATP levels with either the frequency of discrete events or responsiveness to light. Luciferin-luciferase luminescence emitted from a single photoreceptor cell increased after an injection of ATP or P[NH]P and decreased after injection of apyrase. We conclude that the luciferin-luciferase luminescence is monitoring increases as well as decreases in intracellular ATP concentration (ATPi). The ATPi was between 10(-3) and 10(-4) M. Bathing ventral eyes in vanadate or fluoride increased ATP content of whole end organs, increased ATPi in single photoreceptors, and increased the frequency of discrete events. However, apyrase decreased ATPi but did not affect the frequency of discrete events or responsiveness to light until ATPi was dramatically reduced. We conclude that changes in ATP levels are not strictly correlated with changes in responsiveness to light or to changes in the frequency of discrete events.

Adenosine Triphosphate↗