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Biomedical subjects

J J Smolich

Publications and source records attributed to J J Smolich.

At least 37 records · Page 2Linked to original sources
PubMed1999

Contribution of lungs to desipramine-induced changes in whole body catecholamine kinetics in newborn lambs.

To characterize pulmonary and total body norepinephrine and epinephrine kinetics in the immediate newborn period, the effects of desipramine were studied in six fetal lambs chronically instrumented at 133-134 days gestation (term 147 days) and delivered 1 wk later by cesarean section under spinal anesthesia. Norepinephrine and epinephrine kinetics were determined with isotope dilution methodology 4 h after birth and repeated 30 min after desipramine (2 mg/kg iv). At baseline, the lungs accounted for 35 +/- 10 and 47 +/- 13% of whole body norepinephrine clearance (93 +/- 8 ml. min-1. kg-1) and spillover (188 +/- 29 ng. min-1. kg-1) and 15 +/- 2 and 19 +/- 7% of whole body epinephrine clearance (82 +/- 4 ml. min -1. kg -1) and release (22.7 +/- 2.7 ng. min-1. kg-1), respectively. Desipramine decreased pulmonary norepinephrine and epinephrine clearance and spillover to near-zero levels, whereas whole body norepinephrine clearance fell by 51 +/- 3% (P < 0.001), norepinephrine spillover by 54 +/- 6% (P < 0.005), epinephrine clearance by 30 +/- 6% (P < 0.01), and epinephrine spillover by 34 +/- 11% (P < 0.05). These results indicate that, in the immediate newborn period, pulmonary removal and release of norepinephrine and epinephrine is mediated by a desipramine-sensitive process that accounts for a major portion of associated reductions in whole body norepinephrine and epinephrine clearance and release.

Animals↗
PubMed1999

Total body catecholamine kinetics before and after birth in spontaneously hypoxemic fetal lambs.

To study the effect of fetal hypoxemia on perinatal norepinephrine and epinephrine total body kinetics, 13 near-term fetal lambs were instrumented with vascular catheters under general anesthesia. One week later, norepinephrine and epinephrine kinetics were measured in normoxemic (n = 7) or spontaneously hypoxemic fetuses (n = 6) with isotope dilution methodology. Hypoxemic fetuses had lower body (P < 0.02) and placental (P = 0.01) weights and a threefold elevation in plasma norepinephrine (P < 0.005) and epinephrine (P < 0.025) associated with correspondingly higher total body norepinephrine (P < 0.005) and epinephrine (P < 0.05) spillovers. After birth, total body norepinephrine and epinephrine spillover increased 45% and 3.2-fold, respectively, in normoxemic animals (both P < 0.001). However, in the hypoxemic group, norepinephrine total body spillover was unchanged between fetal and 1-h lambs and then fell in 4-h lambs (P < 0.005). In addition, total body epinephrine release rose postnatally (P < 0.05) but less than in the normoxemic group (P < 0.02). No differences in norepinephrine or epinephrine total body clearance occurred between normoxemic and hypoxemic groups in either fetal or newborn lambs. These findings indicate that in hypoxemic and growth-restricted fetuses 1) elevated circulating norepinephrine and epinephrine levels are related to increased sympathoadrenal activity and 2) birth is associated with an initial maintenance and subsequent decline in global sympathetic activity but a blunting of adrenal medullary activation.

Animals↗
PubMed1998

Massive decline in lung liquid before vaginal delivery at term in the fetal lamb.

OBJECTIVE: Our aim was to determine the volume of liquid remaining in the lungs of the fetal lamb just before a normal vaginal delivery at term to assess the extent to which an excess of liquid in the airspaces might contribute to the respiratory morbidity that accompanies elective cesarean delivery. STUDY DESIGN: The volume of liquid in the future airspace of the lungs was determined at the end of labor in eight fetal lambs at term from the dilution of an impermeable tracer (125I-labeled human serum albumin) mixed into the liquid. This volume was compared with that measured in a second group of 10 fetal lambs studied 7 days before the expected date of delivery (term = 147 days). RESULTS: The volume of lung liquid present at the end of labor was 6.8 +/- 1.0 ml x kg(-1) (n = 8) compared with 28.2 +/- 1.8 ml x kg(-1) (n = 10) in the second group of lambs studied before the onset of labor at 140 days of gestation. CONCLUSION: Our results indicate that the bulk (>75%) of the liquid that fills the lungs of the fetal lamb at 140 days of gestation is cleared at some time before normal term birth, suggesting that the adverse respiratory impact of elective cesarean delivery may be largely explained by denying the fetus this important adaptive mechanism.

Animals↗
PubMed1998

Increased aortic blood pressure contributes to potentiated dobutamine inotropic responses after systemic NO synthase inhibition in sheep.

OBJECTIVE: To determine whether inotropic responses to the beta-adrenergic agonist dobutamine are potentiated by systemic inhibition of nitric oxide synthase (NOS) with the L-arginine analogue N omega-nitro-L-arginine (L-NNA), and to establish to what extent any observed responses are related to the increase in aortic blood pressure accompanying systemic NOS inhibition. METHODS: Dobutamine was infused incrementally at rates of 1, 2.5, 5 and 10 micrograms/kg/min in 15 open-chest, anaesthetised ewes before and after inhibition of NO synthesis with i.v. L-NNA (n = 8), or elevation of mean aortic blood pressure to the same extent as attained with NOS inhibition using proximal arterial occlusion (n = 7). RESULTS: By the peak infusion rate, dobutamine increased the maximal rate of rise of left ventricular pressure (LV dP/dtMAX) by 100% (p < 0.001) and reduced LV stroke work by 18% (p < 0.01). L-NNA and arterial occlusion increased resting mean aortic blood pressure by 55 +/- 4 and 51 +/- 3 mmHg respectively. Compared to dobutamine alone, subsequent peak dobutamine-related increases in LV dP/dtMAX were augmented by 76% after L-NNA and by 88% after arterial occlusion (both p < 0.001). Moreover, dobutamine increased LV stroke work by 23% at infusion rates of 1-5 micrograms/kg/min (p < 0.001) after L-NNA, and by 17% at an infusion rate of 1 microgram/kg/min (p < 0.01) after arterial occlusion. CONCLUSIONS: Systemic NOS inhibition potentiates the effects of dobutamine on LV isovolumic and pumping performance in the intact circulation, but this potentiation is in large part related to the increase in arterial blood pressure accompanying NOS inhibition.

Adrenergic beta-Agonists↗
PubMed1998

NO modulates fetoplacental blood flow distribution and whole body oxygen extraction in fetal sheep.

It is unknown if nitric oxide (NO) influences the relative level of the left (LV) and right ventricular (RV) outputs, the blood flow distribution between the body and placenta, or whole body O2 extraction and O2 consumption in the fetus. To address these questions eight fetal lambs were chronically instrumented at 128-134 days gestation (term 147 days), and blood flows were measured with radioactive microspheres 3-4 days later at baseline and after inhibition of NO synthesis with N omega-nitro-L-arginine (L-NNA, 10 and 25 mg/kg i.v.). L-NNA progressively reduced the combined ventricular output (P < 0.005) but did not alter the relative levels of the LV and RV outputs. Fetal body blood flow fell by 31% after 10 mg/kg L-NNA (P < 0.005), but a reduction in placental blood flow (P < 0.005) was smaller (20%) and not observed until 25 mg/kg L-NNA. Whole body O2 extraction increased by 71% after 10 mg/kg L-NNA (P < 0.005) and did change further at 25 mg/kg L-NNA, whereas whole body O2 consumption rose by 15% at 10 mg/kg L-NNA (P < 0.05) and returned to baseline at 25 mg/kg L-NNA. These results suggest that, as well as reducing the combined ventricular output, inhibition of fetal NO synthesis redistributes systemic blood flow toward the placenta and increases fetal body O2 extraction. The latter initially increases whole body O2 consumption and then maintains it at near baseline levels after a fall in placental perfusion.

Animals↗
PubMed1998

Major vasodilator role for nitric oxide in the gastrointestinal circulation of the mid-gestation fetal lamb.

As nitric oxide (NO) may be a particularly important vasodilator in early life, we investigated its role in the regulation of the gastrointestinal (GI) circulation at mid-gestation. Cardiac output and GI blood flow were measured by the radioactive microsphere technique in eight chronically instrumented and unanesthetized mid-gestation fetal sheep. Mean arterial pressure (MAP), heart rate, blood flow, oxygen delivery, and vascular resistance were determined before and after infusion of the specific NO synthase inhibitor, Nomega-nitro-L-arginine (L-NNA) at doses of 10 and 25 mg/kg. In response to L-NNA infusion, MAP increased (p < 0.01) and combined ventricular output decreased (p < 0.001). GI blood flow and oxygen delivery decreased and vascular resistance increased in the stomach and all segments of the small and large intestine (all p < 0.001). The greatest reduction in blood flow was in the small intestine (p < 0.01) and the basal differential pattern of small intestinal blood flow exceeding large intestinal flow was completely abolished. These changes were much greater than those previously described in late-gestation fetuses. Our results suggest that, at mid-gestation, NO plays a major role in the regulation of blood flow and vascular tone across all segments of the fetal GI tract, with its effects being more pronounced than later in development.

Animals↗
PubMed1997

Effect of warfarin on regional left atrial coagulation activity in mitral stenosis.

Increased regional left atrial (LA) coagulation activity has recently been implicated in the pathophysiology of LA thrombus and systemic embolism in mitral stenosis (MS). Anticoagulation with warfarin reduces the risk of such thromboembolism, but the effect of warfarin on LA coagulation activity is unknown. We have addressed this question in MS patients with normal or prolonged clotting times. Peripheral venous and LA coagulation activities were measured in MS patients on long-term oral anticoagulation, who were predisposed to increased LA coagulation activity because of the presence of LA spontaneous echo contrast. Patients ceased warfarin 4 days before percutaneous balloon mitral valvuloplasty, and had either a normal (n = 15) or prolonged (n = 8) International Normalized Ratio (INR) at valvuloplasty. Coagulation activity was assessed during the valvuloplasty procedure, but before valve dilation, by measuring levels of prothrombin fragment 1 + 2 (F1 + 2), a marker of thrombin generation. The LA F1 + 2 level exceeded the peripheral venous level in patients with a normal INR (p <0.001), but these levels were similar in patients with a prolonged INR (p = 0.16). Moreover, the LA (p <0.005) and peripheral venous (p <0.03) F1 + 2 levels, as well as the LA-peripheral venous F1 + 2 difference (p <0.03) were lower in patients with a prolonged INR. These results suggest that anticoagulation with warfarin in MS not only reduces systemic coagulation activity but is associated with a greater reduction in LA coagulation activity. The latter may contribute to the reduced risk of LA thrombus formation that accompanies warfarin therapy in MS.

Aged↗
PubMed1997

Evidence for specific regional patterns of responses to different vasoconstrictors and vasodilators in sheep isolated pulmonary arteries and veins.

1. Responses of large (5-7 mm in diameter) and medium sized (3-4 mm in diameter) branches of sheep isolated intrapulmonary arteries and veins and three groups of small pulmonary arteries (200, 500 and 1000 microns diameter) to the vasoconstrictors endothelin-1, 5-hydroxytryptamine (5-HT), noradrenaline and the thromboxane A2 mimetic, U46619, were examined. Also, relaxation responses to the endothelium-dependent vasodilators, acetylcholine (ACh), bradykinin and ionomycin and the endothelium-independent vasodilator, sodium nitroprusside (SNP), were studied to determine their predominant site of action within the pulmonary vasculature. 2. Endothelin-1 was the most potent vasoconstrictor tested in all vessels. The maximum response to endothelin-1, expressed as a percentage of the maximum contraction to KC1 depolarization, did not differ significantly between the different vessels. By contrast, pulmonary arteries greater than 200 microns in diameter failed to contract to U46619, whereas U46619 was a potent constrictor of large and medium-sized veins. 3. 5-HT caused similar contractions in all arteries > 200 microns in diameter, but the maximum response was significantly diminished in smaller arteries. By contrast, the maximum response to noradrenaline was progressively attenuated with decreasing arterial diameter. Both 5-HT and noradrenaline caused poor contractions in veins. Pulmonary veins were less sensitive to 5-HT than arteries and at low concentrations 5-HT caused relaxation. No change in sensitivity to noradrenaline was noted between the arteries and veins. 4. Relaxation responses to bradykinin and ionomycin decreased progressively along the pulmonary vascular tree and were nearly absent in large veins. Also, ACh was a poor relaxing agent of large and medium-sized arteries and failed to mediate any relaxation response in other vessel segments. Surprisingly the smallest arteries examined (approximately 200 microns in diameter) failed to relax to ionomycin, bradykinin and SNP. However, both the sensitivity and maximum relaxation to SNP were similar in all other arterial and venous segments. 5. In conclusion, marked regional differences in reactivity to both vasoconstrictors and vasodilators occur in arterial and venous segments of the sheep isolated pulmonary vasculature. Such specialization may have important implications for the regulation of resistance in this low tone vascular bed.

Animals↗
PubMed1997

Pulmonary clearance and release of norepinephrine and epinephrine in newborn lambs.

To examine the pulmonary kinetics of the catecholamines norepinephrine and epinephrine immediately after birth, eight fetal lambs were instrumented with vascular catheters under general anesthesia at 133-134 days gestation (term = 147 days) and were delivered by cesarean section 1 wk later. Pulmonary norepinephrine and epinephrine kinetics were then studied 1 and 4 h after birth using radiotracer dilution methodology. The pulmonary fractional extraction of norepinephrine was similar in 1-h (0.111 +/- 0.021) and 4-h (0.117 +/- 0.023) lambs and constituted 24 +/- 5 and 32 +/- 9% of total body norepinephrine clearance, respectively. Pulmonary removal of epinephrine was less pronounced with a fractional extraction of 0.035 +/- 0.017 in 1-h and 0.036 +/- 0.013 in 4-h lambs, which corresponded to 8 +/- 4 and 9 +/- 3% of total body epinephrine clearance, respectively. Pulmonary spillover of norepinephrine into the circulation was similar in 1-h (79 +/- 26 ng.min-1.kg-1) and 4-h (82 +/- 18 ng.min-1.kg-1) lambs, and this comprised 27 +/- 8 and 42 +/- 8% of total body norepinephrine spillover, respectively. Pulmonary epinephrine spillover was not detectable at 1 h, but it occurred in all 4-h lambs, averaging 4.7 +/- 0.8 ng.min-1.kg-1 or 20 +/- 6% of epinephrine total body spillover. These findings indicate that the lungs of newborn lambs 1) are a major site for removal of norepinephrine and epinephrine from the circulation; 2) release a substantial quantity of norepinephrine into the circulation, consistent with the presence of tonic pulmonary sympathetic nerve activity; and 3) constitute a significant extra-adrenal source of plasma epinephrine.

Animals↗
PubMed1997

Left ventricular norepinephrine and epinephrine kinetics at birth in lambs.

Little is known about the changes in the left ventricular (LV) kinetics of the catecholamines norepinephrine and epinephrine occurring at birth and their relationship to perinatal alterations in LV function and whole-body catecholamine kinetics. To address this issue, whole-body and LV catecholamine kinetics (radiotracer dilution methodology) and fetal LV output and myocardial blood flow (radioactive microspheres) were measured in chronically instrumented near-term fetuses and in the same animals 1 and 4 hours after birth. Between fetal and 1-hour lambs, LV external work increased 115% (P<.005); carotid arterial plasma norepinephrine concentration, 148% (P<.01); carotid arterial plasma epinephrine concentration, 546% (P<.005); LV norepinephrine spillover, a measure of LV sympathetic activity, 4.1-fold (P<.005); LV epinephrine spillover, 3-fold (P<.05); total-body spillover of norepinephrine, 52% (P<.025); and total-body spillover of epinephrine, 460% (P<.005). Arterial catecholamine concentrations and total-body catecholamine spillovers were unchanged between 1- and 4-hour lambs, but LV external work fell (P<.05) to a level still 77% greater than in fetal lambs (P<.005); LV norepinephrine spillover returned to near-fetal levels, and LV epinephrine spillover became undetectable. These results suggest that (1) a transient increase in LV sympathetic activity occurs at birth and may contribute to the immediate postnatal augmentation of LV performance, (2) organ differences in the pattern of sympathetic activation occur at birth, and (3) birth-related increases in LV sympathetic activity are accompanied by release of epinephrine from the heart.

Animals↗
PubMed1996

Determinants of increased regional left atrial coagulation activity in patients with mitral stenosis.

BACKGROUND: Recent evidence suggests that regional left atrial coagulation activity may be increased in mitral stenosis and perhaps contribute to the pathophysiology of left atrial thrombus. However, the relation of left atrial coagulation activity to factors that predispose to left atrial thrombus formation is unknown, and the relation between left atrial and systemic coagulation activities is unresolved. METHODS AND RESULTS: Left atrial and peripheral venous levels of the coagulation marker prothrombin fragment 1 + 2 (F1 + 2) were measured in 32 patients with mitral stenosis with normal clotting times and no left atrial thrombus who were undergoing percutaneous balloon mitral valvuloplasty. Baseline peripheral venous F1 + 2 levels, measured at the beginning of the valvuloplasty procedure, did not differ from those of 30 age-matched control patients. Prevalvuloplasty left atrial F1 + 2 levels, obtained immediately after transseptal puncture, were similar to femoral venous levels in patients without left atrial spontaneous echo contrast (LASEC) (0.81 +/- 0.32 versus 0.81 +/- 0.27 nmol/L, n = 7) but greater than femoral venous levels in patients with LASEC and either sinus rhythm (1.57 +/- 0.86 versus 0.99 +/- 0.38 nmol/L, n = 16, P < .001) or atrial fibrillation (1.52 +/- 0.69 versus 0.85 +/- 0.33 nmol/L, n = 9, P < .003). Furthermore, LASEC emerged as the only significant predictor of increased regional left atrial coagulation activity (P = .005) on stepwise multivariate logistic regression analysis. CONCLUSIONS: Increased regional left atrial coagulation activity in mitral stenosis occurs in the presence of LASEC, is evident in either sinus rhythm or atrial fibrillation, and is associated with normal systemic coagulation activity.

Adult↗
PubMed1996

Effect of lung liquid volume on respiratory performance after caesarean delivery in the lamb.

1. The volume of liquid in the lungs of the fetal lamb is reported to fall in the final days of gestation and during labour itself. We aimed to test the hypothesis that this fall in liquid volume adapts the lungs for air breathing and pulmonary gas exchange. 2. In twelve chronically catheterized fetal lambs we measured lung liquid volume at 140 days gestation (term is 147 days) and then delivered the fetuses by Caesarean section under maternal spinal anaesthesia. In five fetuses we removed approximately half the liquid contained in the lungs just before delivery (experimental group) while the remaining seven fetuses were delivered without change to their lung liquid (control group). 3. Lambs born with reduced lung liquid volume improved their arterial blood gas and acid-base status more quickly than lambs born without alteration to lung liquid. 4. Carotid arterial blood gas values in the first 60 min of postnatal life were significantly related to the volume of liquid present in the lungs at birth, with higher arterial partial pressure of oxygen (Pa,02) and arterial oxygen saturation (Sa,02) and lower arterial partial pressure of carbon dioxide (Pa,CO2) levels being associated with lower lung liquid volumes. 5. We conclude that postnatal gas exchange is enhanced by a reduction in the volume of liquid remaining in the lungs when breathing starts.

Animals↗
PubMed1996

Depressed function in remote myocardium after myocardial infarction: influence of orotic acid.

BACKGROUND: We have previously shown that infarction impairs recovery of global function after subsequent cardioplegic arrest and that therapy with orotic acid improves recovery. The aim of this study was to measure the effect of infarction on regional and global left ventricular function and to determine whether orotic acid exerts a beneficial effect exclusive of the effects of cardioplegia. METHODS: Acute myocardial infarction was produced in dogs. They then received either orotic acid or placebo (control) orally (n = 12 per group). Fractional radial shortening and systolic wall thickening were measured by two-dimensional echocardiography before and 1 and 3 days after infarction with and without beta-adrenergic blockade, and in 6 dogs up to 9 days after infarction. Global function was measured under anesthesia 4 days after infarction. RESULTS: In control animals, fractional radial shortening in the infarct decreased from 20.6% +/- 5.1% before infarction to 3.0% +/- 2.2% at day 1 and to 1.9% at day 3 (p < 0.01). In the border zone radial shortening declined from 21.9% +/- 3.7% to 11.0% +/- 2.3% at day 1 and 9.3% +/- 2.8% at day 3 (p < 0.05). In the noninfarcted myocardium radial shortening also declined from 27.1% +/- 1.9% before infarction to 18.3% +/- 2.3% on day 1 (p < 0.05) and to 16.0% +/- 2.8% on day 3 after infarction (p < 0.05) with recovery to preinfarct levels by 9 days after infarction. These findings were confirmed by measurements of systolic thickening. Before infarction beta-receptor blockade decreased fractional shortening in all regions of the left ventricle, but this effect was absent on day 3 after infarction, implying that the myocardium had become less responsive to beta-adrenergic stimulation. Measurements of global function 4 days after infarction showed marked depression of stroke work. There was no effect of orotic acid treatment on regional or global function. CONCLUSIONS: Myocardial infarction causes reversible depression of resting function and beta-adrenergic responsiveness in the remote and border zone areas, which is not prevented by metabolic therapy with orotic acid. This finding may explain the adverse response of the infarcted heart to cardioplegic arrest.

Adrenergic beta-Antagonists↗
PubMed1996

Nitric oxide modulates regional blood flow differences in the fetal gastrointestinal tract.

We studied the role of endogenous nitric oxide (NO) in the regulation of gastrointestinal (GI) circulation in 11 chronically instrumented and unanesthetized late-gestation fetal sheep. Systemic and GI blood flows were measured by the radiolabeled microsphere technique. Mean arterial pressure (MAP), heart rate, blood flows, oxygen delivery, and vascular resistance were determined before and after infusion of the specific NO synthase inhibitor, N omega-nitro-L-arginine (L-NNA), to cumulative doses of 10 and 25 mg/kg. At both L-NNA doses, MAP increased, and combined ventricular output and heart rate decreased. GI blood flow and oxygen delivery decreased and vascular resistance increased for the stomach, all segments of the small intestine, and proximal colon and cecum but were unchanged in the middle and distal colon and rectum. Because blood flow reduction in the small intestine was pronounced (from 176 to 107 ml.min-1.100 g-1, P < 0.001) and blood flow in the large intestine was unchanged, distribution of intestinal blood flow became more uniform. Overall, blood flow reduction was proportionally greater in GI circulation than in the remainder of fetal circulation. In three additional animals we established that L-NNA reduced blood flow to the mucosal-submucosal layer (P < 0.02) but not to the muscularis serosa of the small intestine. In the same animals, L-arginine (250 mg/kg) restored systemic hemodynamics and partially restored small intestinal blood flow. Our results suggest that NO is an important differential regulator of vascular tone in the developing GI circulation.

Animals↗