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C N Gillis

Publications and source records attributed to C N Gillis.

At least 19 recordsLinked to original sources
PubMed1992

Rapid reversal of angiotensin converting enzyme inhibition by lisinopril in the perfused rabbit lung.

Lisinopril is a potent competitive inhibitor of purified rabbit lung ACE (dissociation t1/2 = 105 min). To examine reversibility of binding and ACE functional activity in situ, the single-pass extraction (E) of an 125I-lisinopril analogue (351A) and the hydrolysis of an ACE substrate, benz-phe-ala-pro (BPAP) were studied. Lungs were perfused at 50 ml/min with a Krebs-albumin (3%) solution. A bolus containing [14C]dextran, [3H]BPAP, and 351A was injected and (E)351A measured by multiple indicator dilution technique. BPAP metabolism (M) was reflected by the appearance of its hydrolysis product [3H]benz-phe in lung effluent. Control (E)351A was 66 +/- 5% (mean +/- SD, n = 6) and (M)BPAP was 69 +/- 9% (n = 6). Unlabeled lisinopril (30 nmol) in the bolus significantly reduced E(351A) and M(BPAP) to 16 +/- 16% and 3 +/- 3%, respectively. Ten minutes later E(351A) and M(BPAP) had returned to control values. Reduction of E(351A) was partially reversible and M(BPAP) completely reversible after 1 min. After recirculation with 0.25 mM lisinopril for 30 min, however, significant depression of E(351A) was evident for 60 min after exposure to lisinopril was discontinued. Thus, rapid as well as slowly reversible components of inhibition of ACE inhibitor binding can be demonstrated in the perfused rabbit lung.

Albumins↗
PubMed1992

Lisinopril and ramiprilat protection of the vascular endothelium against free radical-induced functional injury.

We reported earlier that the vasodilator response to acetylcholine (ACh) in lungs exposed to indomethacin and preconstricted with an analog of thromboxane (U46619) is converted to vasoconstriction by brief electrolysis of inflowing perfusion medium and suggested that this effect reflected endothelial injury. The purpose of our present study was 2-fold. First, because captopril, a sulfhydryl-containing inhibitor of angiotensin-converting enzyme inhibitor, prevented this effect (we assumed by scavenging electrolysis generated free radicals of oxygen), we determined whether two angiotensin-converting enzyme inhibitors lacking this moiety, namely lisinopril and ramiprilat, provided similar protection. Second, we studied whether electrolysis, like other forms of experimental lung injury, impaired uptake of serotonin (5-HT) by the endothelium. Our study confirmed that within 5 min of electrolytic injury, the ACh response is converted to vasoconstriction. This effect was completely prevented by lisinopril (18 microM) or ramiprilat (30 microM), neither of which affected ACh vasodilatation in control lungs. Lower concentrations of either drug exerted lesser degrees of protection. Five or 20 min after electrolysis, single-pass uptake of [14C]5-HT was significantly (P less than .01; N = 11) lower than control (82.4 +/- 3.4% vs. 71 +/- 3.2 and 46.5 +/- 6%, respectively). In contrast, 5-HT uptake was unaltered by electrolysis in the presence of 18 microM lisinopril. We conclude that loss of ACh vasodilation is an early reflection of lung endothelial injury that is accompanied by reduced [14C]5-HT uptake. Also, the protective property of nonsulfhydryl-containing angiotensin-converting enzyme inhibitors may be related to unexpected antioxidant actions.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1979

Indicator dilution measurement of 5-hydroxytryptamine clearance by human lung.

A double indicator dilution method to measure 5-hydroxytryptamine (5-HT) clearance by lungs of anesthetized patients is described. Immediately after a bolus injection of [3H]dextran and [14C]5-HT into the right atrial port of a Swan-Ganz catheter, blood from the radial artery is fractionated and the tritium and carbon-14 of each fraction is measured. The difference between the normalized curves of dextran and 5-HT vs. time reflect the extent to which 5-HT is extracted by the lung. This method gave a mean value of 61 +/- 3% (n = 10) for extraction of 5-HT, compared to 59 +/- 4% measured simultaneously by means of the pulmonary artery-left atrial gradient of 5-HT. Variations among three successive determinations in each patient made postoperatively were not statistically significant. This technique is applicable whenever Swan-Ganz and radial or brachial artery catheters are placed for routine clinical management and, therefore, may have wide application for measurement of pulmonary amine (or kinin) extraction in conscious human subjects or experimental animals. Because pulmonay clearance may be compromised by endothelial damage, 5-HT extraction measured in this manner could reflect early damage to human pulmonary endothelium--perhaps before clinical evidence of damage, such as interstitial edema and respiratory distress, is evident.

Carbon Radioisotopes↗
PubMed1978

Effects of monocrotaline pretreatment of rats on removal of 5-hydroxytryptamine and noradrenaline by perfused lung.

1 The alkaloid, monocrotaline, causes significant pulmonary damage in many species, including the rat. We, therefore, determined whether the inactivation of biogenic amines by perfused lungs of rats was modified by prior treatment of the animals with monocrotaline.2 Young rats (45 to 50 g) treated for 21 days with monocrotaline (22 mug/ml) in their drinking water developed right ventricular hypertrophy. Treated animals gained weight more slowly and consumed less food and water than control rats that drank tap water. Lungs from monocrotaline-treated animals were heavier and had a higher protein content than control lungs.3 Isolated lungs from treated animals removed and metabolized 50% less perfused 5-hydroxytryptamine than did controls.4 The diminished 5-hydroxytryptamine metabolism was probably due to impaired delivery of substrate to intrapulmonary monoamine oxidase (MAO) since MAO activity in 600 g supernatant fractions of homogenates of lungs from monocrotaline-treated rats was not different from control values.5 Pulmonary removal of perfused noradrenaline was decreased about 60% by the 21-day treatment, suggesting that the effects of monocrotaline were somewhat nonspecific.6 These effects were not caused by monocrotaline directly, since perfusion of lungs from untreated animals with this drug did not alter removal of co-perfused 5-hydroxytryptamine.7 Reduced pulmonary removal of circulating biogenic amines following pretreatment with monocrotaline may reflect damage to capillary endothelium, which could also affect other metabolic functions of lung.

Animals↗
PubMed1977

The fate of biogenic monoamines in perfused rabbit lung.

1. Inactivation of beta-phenylethylamine and several of its derivatives was studied in a preparation of rabbit lung perfused with Krebs physiological medium at 37 degrees C. Inactivation or removal of these compounds was calculated as the difference between the concentration of each amine in the perfusion medium and the effluent, collected separately from each lung. The extent of amine metabolic degradation was also measured, by column chromatography, in lung effluent. 2. With this technique the magnitude of amine removal as a function of concentration was determined and an apparent Km and Vmax of removal were calculated for each amine. 3. Percentage removal was highest with phenylethylamine (95%), and decreased, apparently in relation to increasing phenyl- and side chain-hydroxylation (and therefore likely increased hydrophilicity), and 5-hydroxytryptamine (64%), tyramine (53%), octopamine (35%), dopamine (32%) and noradrenaline (23%). 4. Inactivation of each amine could be accounted for by metabolic degradation to deaminated products, which appeared in lung effluent within 90 s of beginning amine perfusion. 5. When intrapulmonary metabolism of phenylethylamine was inhibited by simultaneous perfusion with semicarbazide (10 mM) and pargyline (10 micronM), the removal rate was unaltered, establishing that uptake of the amine from the vascular space is not dependent on metabolism at least for 4 min infusions.

Animals↗
PubMed1977

Disposition of 14C-mescaline by rabbit lung.

Metabolism of mescaline by several rabbit tissues was examined in vitro. Mescaline-oxidizing activity (micromoles per milligram of protein/15 min) of lung homogenates was 4 times greater than that of either liver or kidney. Brain and plasma each had comparatively little capacity to metabolize mescaline. Mescaline metabolism in vitro was sensitive to inhibition by semicarbazide. Removal of mescaline from the medium perfusing the isolated rabbit lung was explained by intrapulmonary metabolism. Semicarbazide (10(-3) M pargyline. Semicarbazide-treated lungs accumulated more mescaline than did untreated lungs. Mescaline efflux from lung was slower than that of its metabolite. These results indicate that the intact lung removes perfused mescaline and may be important in the disposition of circulating mescaline in vivo.

Animals↗
PubMed1977

Fate of prostaglandins E(1) and A(1) in the human pulmonary circulation.

It is recognized that the lung extracts norepinephrine and 5-hydroxytryptamine from the pulmonary circulation and that this process is affected by cardiopulmonary bypass. Since alterations in the lung's processing of vasoactive substances may be a mechanism of pulmonary injury sustained during operation, we investigated the lung's ability to extract or metabolize prostaglandin A1 (ga1) and prostaglandin E1 (PGE 1). Sixteen patients undergoing cardiac surgery were studied. In five patients, just before going on bypass, a 10 ml of blood was withdrawn at a constant rate, simultaneously from the pulmonary artery and left atrium. In 11 patients, 3H-PGE1 was injected just prior to bypass and, in five of these, again after coming off bypass. Extraction was calculated from tritium activity in the samples. Metabolites were quantitated by thin-layer chromatography after being identified by marker compounds run simultaneously in each chromatogram. The pulmonary extraction of PGA1 was 11.3 +/- 2.3% and there were no detectable metabolites in left atrial blood. Before bypass the extraction of PGE1 was 42.3 +/- 14.3% and after bypass 24.8 +/- 10.0% (P less than 0.005; Student's paired t test). PGE1 was extensively metabolized with 79.7 +/- 7.1% of total radioactivity appearing in the left atrium as metabolites before bypass and 89.1 +/- 2.0% appearing after bypass. This study indicates that PGA(1) is not metabolized by the lung and is only slightly extracted. On the other hand, PGE(1) is extensively extracted and metabolized. While the rate of metabolism is not significantly affected by cardiopulmonary bypass, the extractiom before bypass was significantly greater than after bypass.

Adult↗