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Biomedical subjects

S Gasic

Publications and source records attributed to S Gasic.

At least 55 records · Page 3Linked to original sources
PubMed1991

Contribution of leg vascular tissues to the overall metabolic clearance of human atrial natriuretic factor (hANF) in man.

From experimental studies it has been suggested that considerable peripheral clearance of human atrial natriuretic factor (hANF) might occur. In healthy men (n = 7) the peripheral fractional extraction of hANF was about 35% under basal conditions resulting in hANF-uptake across the leg vascular bed of 2.1 +/- 2.4 pMol/min and regional leg clearance rate of 102.6 +/- 88.2 ml/min, which is approximately 2.5% of the total metabolic clearance rate. During a primed constant i.v. infusion of hANF (bolus 100 micrograms; infusion 100 micrograms/h, t = 1h) arterial and venous plasma concentrations of hANF increased about 10-fold (p less than 0.05), however, estimated leg blood flow as well as leg fractional extraction, leg uptake and clearance rates of hANF did not significantly change as compared to baseline. Total metabolic clearance rates and apparent production rates of hANF were 4.05 +/- 1.93 l/min and 84.1 +/- 29.9 pMol/min, respectively. We conclude that in healthy man the leg vascular bed does not play a major regulatory role in the metabolism of exogenously infused hANF. However, our results suggest that the peripheral vasculature is, to a certain extent, involved in the metabolic clearance of endogenous hANF and thus, contributes to the peptide's overall disposal.

Adult↗
PubMed1990

Quantitative evidence of peripheral conversion of angiotensin within the human leg: effects of local angiotensin-I administration and angiotensin-converting enzyme inhibition on regional blood flow and angiotensin-II balance across the leg.

The renin-angiotensin system relevantly contributes to the maintenance of systemic vascular tone and there is experimental evidence that large amounts of angiotensin-converting enzyme (ACE) are present in peripheral vascular tissues, including resistance vessels. To determine and quantify peripheral vascular conversion of angiotensin-I (ANG-I) to angiotensin-II (ANG-II) across the human leg, the response of regional blood flow to local regional intra-arterial infusion of ANG-I and change in associated ANG-II balance were evaluated during ANG-I infusion and following additional ACE inhibition. Ten sodium-loaded healthy men were enrolled in the study. Following cannulation of both femoral arteries and the right femoral vein, leg blood flow was determined (indocyanine-green dye-dilution method) at baseline conditions and during constant intra-arterial infusion of haemodynamically ineffective doses of ANG-I as well as following concomitant intra-arterial administration of low doses of the non-sulfhydril ACE inhibitor cilazapril. From the transfemoral arterio-venous differences in ANG-II plasma concentrations and the corresponding regional blood (plasma) flow, the ANG-II balance across the leg was calculated. Systemic blood pressure did not change throughout the trial, indicating that no major systemic effects were present during ANG-I infusion or concomitant ACE inhibition. Moreover, arterial ANG-II plasma concentrations were not significantly changed by ANG-I infusion. Leg blood flow decreased to below baseline values following ANG-I infusion, increasing again then in a dose-dependent manner during concomitant cilazapril administration. The calculated baseline ANG-II balance across the leg revealed a net extraction in 6 out of 10 subjects and a net ANG-II formation in 4.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Splanchnic, renal, and muscle clearance of alanylglutamine in man and organ fluxes of alanine and glutamine when infused in free and peptide forms.

The present study was designed to investigate organ metabolism of intravenously (IV) infused (100 mumol.h-1.kg-1) alanylglutamine and its amino acid constituents in a group of healthy subjects. The dipeptide clearance (mumol/min) by kidney (51 +/- 3) was significantly (P less than .01) greater than the clearance by either splanchnic organs (19 +/- 6) or skeletal muscle (21 +/- 8). Infusion of alanylglutamine significantly (P less than .01) increased arterial plasma concentrations of free alanine (260 +/- 31 v 330 +/- 38 mumol/L) and free glutamine (620 +/- 66 v 764 +/- 65 mumol/L) when compared with the baseline period. Concurrently, splanchnic uptake of alanine and glutamine increased and muscle release of alanine ceased. However, muscle release of glutamine remained unaffected. Renal balances of alanine and glutamine changed from neutral to negative (net release) and from positive (net uptake) to neutral, respectively. Infusion of a corresponding mixture of alanine and glutamine had similar effects on arterial plasma concentrations and splanchnic and muscle balances of alanine and glutamine, but had no effect on renal balances of these amino acids. From these studies in man, we conclude that kidney predominates over other organs in clearance of alanylglutamine from plasma and that this may account for the different effect of infusion of alanine and glutamine in free and peptide forms on renal fluxes of these amino acids.

Adult↗
PubMed1990

Renal disposal of human atrial natriuretic peptide in man.

In healthy men (n = 7) the renal fractional extraction of human atrial natriuretic factor (hANP) as determined by the renal venous catheter technique was approximately 50% both under basal conditions and during the administration of exogenous hANP. When arterial and venous plasma concentrations of hANP were maintained about tenfold above basal concentrations by a bolus- (100 micrograms) primed intravenous (IV) infusion (100 micrograms/h for 1 hour) of hANP, renal uptake of hANP increased from, basal, 11.2 +/- 6.7 pmol/min to 126.5 +/- 64.8 pmol/min (P less than .05), while estimated renal plasma flow (ERPF) decreased by about 25% (P less than .05). Total metabolic clearance rates (MCRs) of hANP, renal clearance rates, and production rates of hANP were 3.89 +/- 1.21 L/min, 0.42 +/- 0.18 L/min, and 76.1 +/- 52.7 pmol/min, respectively. In healthy men, one kidney accounts for about 10% of total hANP clearance.

Adult↗
PubMed1990

ACE inhibition with cilazapril improves myocardial perfusion to the ischemic regions during exercise: a pilot study.

This study was performed to examine whether cilazapril, a novel nonsulfhydril angiotensin-converting enzyme (ACE) inhibitor, may improve regional myocardial perfusion at exercise in patients with coronary heart disease (CHD). In a single-blind, nonrandomized trial, 5 mg cilazapril or placebo was administered to eight patients with documented CHD and stable exertional angina. Multistage bicycle exercise tests were performed and each patient served as his own control. At peak exercise, as well as at rest, [99mTc]hexakis-2-methoxy-2-isobutylisonitrile myocardial images were obtained. Percent myocardial activity differences (%AD) between exercise and resting images were compared (cilazapril versus placebo). Heart rate and blood pressure were not significantly different between trials. However, after cilazapril administration, %AD was higher than after placebo, with relative differences between trials of greater than 30%, along with alleviation of clinical symptoms in seven of eight patients. These data suggest that in patients with stable-effort angina, ACE inhibition with cilazapril is able to redistribute myocardial blood flow and to improve regional oxygen supply to the ischemic myocardium.

Angina Pectoris↗
PubMed1990

Interaction studies with moclobemide.

Drug interactions with moclobemide given to healthy subjects and depressed patients are reviewed. The drugs investigated for safety were antihypertensives, digoxin, oral contraceptives, anticoagulants and benzodiazepines. Cimetidine was studied for the pharmacokinetic effect, and possible interactions with alcohol (stimulation and/or sedation) were included. Finally, since inhibition of monoamine oxidase (MAO) can increase noradrenergic transmission, possible interaction with neuronal reuptake inhibitors such as tricyclic antidepressants (TCAs) was investigated. Whereas replacement of the older, irreversible MAO inhibitors by a TCA was held to be dangerous and to require a therapy-free interval, the studies reviewed here provide evidence that amitriptyline can replace or be added to moclobemide without any sign of impaired tolerance, need for dose reduction or a therapy-free interval. Combined administration of moclobemide and desipramine was also tolerated well. Moclobemide did not interact with the direct-interacting sympathomimetics norepinephrine and isoproterenol and only to a negligible extent with phenylephrine. The combination of moclobemide with antihypertensive agents did not cause postural hypotension or an increase in other side effects. No clinically relevant interaction was observed between moclobemide and phenprocoumon, glibenclamide, oral contraceptives, digoxin or benzodiazepines. Cimetidine increased the concentration of moclobemide in plasma after a single oral dose by about 100%. If moclobemide is to be used in a patient pretreated with cimetidine, treatment should therefore start with the lowest therapeutic dose and then be adjusted to clinical needs. Since moclobemide is devoid of anticholinergic effects, no interaction with alcohol was anticipated. High therapeutic doses (600 mg/day) induced an effect similar to that of low doses of a TCA, but with 100-300 mg no interaction with alcohol was seen, even in elderly people.

Antidepressive Agents↗
PubMed1990

Clinical and electrophysiologic correlates of sinus node dysfunction after orthotopic heart transplantation. Observations in 42 patients.

We assessed incidence and course of postoperative SN dysfunction in 42 cardiac transplant recipients. RHY, HR and CSNRT were compared in distinguishing between persistent (9 of 42 patients) and transient (11 of 42) SN dysfunction. Persistent SN dysfunction was distinguished by a significantly lower HR (day 14: 46.2 +/- 12 vs 67 +/- 19 bpm; day 21: 40.3 +/- 21 vs 70.8 +/- 16 bpm; p less than 0.05, respectively) and by RHY: postoperative AS (3 of 42) was found only in patients whose SN dysfunction persisted while patients with SR but prolonged CSNRT more often had transient impairment (6 of 42 vs 2 of 42); CSNRT, in contrast, is unlikely to be useful in distinguishing between transient and persistent SN dysfunction since exceptionally long CSNRTs (11,340 ms. 12,080 ms) occurred in patients with both types. Ischemic times were significantly longer in patients with transient impairment when compared with the group with normal SN function (155.1 +/- 36 vs 109.2 +/- 36 min, p less than 0.05) but did not differ significantly in patients with persistent SN dysfunction (124.8 +/- 32 min). Thus, (1) SN dysfunction after cardiac transplantation is common but most often transient; (2) RHY and HR are adequate follow-up parameters and best predictors of long-term SN function; (3) SN dysfunction after transplantation has important clinical implications given the unreliability of lower pacemakers to take over in 3 patients; (4) transient SN dysfunction is related to duration of ischemia during hypothermic preservation whereas pathogenesis of persistent SN dysfunction remains to be elucidated.

Adult↗
PubMed1989

Plasma concentrations of free and sulfoconjugated dopamine, epinephrine, and norepinephrine in healthy infants and children.

Plasma concentrations of free and sulfoconjugated catecholamines were measured in healthy infants and children under resting conditions. Free norepinephrine and epinephrine levels were up to three times higher in healthy children under 2 years than in adults, even under true resting conditions. In contrast, free dopamine concentrations of all age groups fell within the normal range for adults. The levels of sulfoconjugation were in the adult range.

Adolescent↗
PubMed1989

Cilazapril and enalapril inhibit local angiotensin I conversion in human veins but lack direct venodilating properties.

We studied the angiotensin-converting enzyme (ACE)-dependent and ACE-independent (direct) effects of two ACE inhibitors, cilazaprilat and enalaprilat, in 12 healthy human subjects. The dorsal hand vein compliance technique was used because venous constriction and relaxation, independent of reflex responses and systemic ACE inhibition, can be measured by local infusions of very small amounts of drugs. Angiotensin I (dose range 6-1,550 ng/min) was infused alone or coinfused with cilazaprilat or enalaprilat (dose range 7.8-3,900 ng/min). In separate experiments, cilazaprilat or enalaprilat (dose range 3.9-31 micrograms/min), or prostaglandin I2 (PGI2, dose range 0.13-32 ng/min) was infused into veins that had been submaximally preconstricted with phenylephrine. Angiotensin I caused a marked venoconstriction limited by rapid tachyphylaxis. At doses greater than 78 ng/min, cilazaprilat and enalaprilat completely inhibited angiotensin I-induced venoconstriction. This inhibition was reversible after 14-31 min, suggesting an inhibition of ACE associated with the vein wall. Infusions of cilazaprilat or enalaprilat had no effect on the diameter of the vein at rest or after submaximal preconstriction with phenylephrine. In contrast, exogenous PGI2 was a potent venodilator in our system. We conclude that cilazaprilat and enalaprilat are inhibitors of ACE associated with the vein wall, but there is no evidence for either drug of direct, ACE-independent, prostaglandin-mediated vasodilation.

Adult↗
PubMed1989

Effects of ACE inhibition with cilazapril on splanchnic and systemic haemodynamics in man.

1. There is recent experimental evidence that the renin-angiotensin-system may play an essential role in producing splanchnic vasoconstriction. However, controversy exists as to the influence of ACE inhibition on splanchnic haemodynamics in man. We therefore investigated whether cilazapril, a structurally new and long-acting ACE inhibitor, interacts with angiotensin I-dependent changes in splanchnic haemodynamics in man, using an experimental model. 2. The effects of cilazapril on angiotensin I-induced splanchnic and systemic haemodynamics were studied in seven normotensive men using the hepatic venous catheter technique (indocyanine-green dye), right-heart catheterisation (thermodilution method), intra-arterial blood pressure monitoring and systolic time-intervals. Dose-responses to angiotensin I were determined under control conditions and 60 min after ACE inhibition with 5 mg oral cilazapril. Angiotensin I was infused intravenously at constant rates in an increasing dose-sequence until systolic blood pressure was greater than 30 mm Hg. 3. ACE inhibition with cilazapril did not change basal splanchnic or systemic haemodynamics to any relevant extent. The angiotensin I dependent increase in systemic and pulmonary resistance and pulmonary capillary wedge pressure was attenuated by cilazapril, as indicated by the shift of the dose-response curves to the right. In the splanchnic vascular bed angiotensin I dose-dependently increased splanchnic vascular resistance and also wedge hepatic venous pressure and decreased splanchnic blood flow. These angiotensin I induced haemodynamic changes were clearly suppressed by cilazapril. The angiotensin I dose needed to produce a 30% increase in splanchnic vascular resistance, given as mean and s.e. mean, was 1.7 +/- 0.3 micrograms min-1 during control-trials vs 7.3 +/- 1.3 micrograms min-1 after ACE inhibition with cilazapril (P less than 0.001). 4. We conclude that, in man, the influence of cilazapril on acute angiotensin I-mediated haemodynamic responses is present in the splanchnic vascular bed, and that the overall effects of cilazapril are consistent with both arterial and venous effects of the ACE inhibitor. Cilazapril effectively counteracts angiotensin I-induced splanchnic vasoconstriction.

Adult↗
PubMed1988

Kinetics and disposition of fluorescein-labelled liposomes in healthy human subjects.

The in vivo kinetics and organ uptake of multilamellar liposomes have been studied in healthy volunteers. Sodium fluorescein-containing liposomes composed of equimolar amounts of egg phosphatidylocholine and cholesterol were injected into a peripheral vein in 4 healthy subjects. Blood samples collected from the femoral artery, hepatic vein and pulmonary artery, were analysed for liposomal dye content. The results, showing involvement of the reticuloendothelial system (RES) in the removal of liposomes, confirmed those previously obtained with radiolabelled preparations. Use of an innocuous liposomal marker (sodium fluorescein) and conventional vascular catheterization techniques, as employed here, may provide a reliable and clinically acceptable approach to establishing disease-induced changes in the kinetics of uptake of drug-containing liposomes by the RES, and thus help in the design of protocols for effective treatment.

Adult↗
PubMed1988

Splanchnic disposal of human atrial natriuretic peptide in humans.

In healthy men (n = 6), the splanchnic fractional extraction of human atrial natriuretic peptide (hANP), as determined by the hepatic venous catheter technique, was 75% under basal conditions resulting in a splanchnic uptake of hANP of 8.5 +/- 5.0 pmol/min. In spite of a drop (P less than .05) in splanchnic fractional extraction to about 50%, splanchnic uptake of hANP rose to 56 to 99 pmol/min (P less than .01) when pharmacologic plasma concentrations of hANP were induced during a bolus (100 micrograms)-primed intravenous (IV) infusion (100 micrograms/h; time, one hour) of hANP. This was accompanied by a fall in estimated hepatic blood flow (P less than .05), in pulmonary arterial pressure (P less than .01), and, in each individual, in systemic BP. Total metabolic clearance rates, splanchnic clearance rates, and production rates of hANP were 4.5 +/- 2.2 L/min, 0.4 +/- 0.1 L/min, and 46.1 +/- 20.1 pmol/min, respectively. Thus, in healthy men, the splanchnic area accounts for approximately 10% of total hANP clearance.

Adult↗
PubMed1988

Effect of moclobemide, a new reversible monoamine oxidase inhibitor, on absorption and pressor effect of tyramine.

We determined in healthy subjects the pressor effect and the plasma level of free tyramine in response to intravenous and oral tyramine doses before and after therapeutic doses (3 X 100 mg/day) of moclobemide, a new reversible, preferential type A monoamine oxidase (MAO) inhibitor. In fasting subjects moclobemide increased the pressor effect of intravenously and orally administered tyramine; the tyramine dose-pressor curve was shifted to the left by factors of 2.4 and 4.1, respectively. No increase in systolic blood pressure occurred at free plasma tyramine concentrations lower than 70 ng/ml before, and 20 ng/ml after, moclobemide. Peak plasma tyramine concentrations increased dose-dependently after oral tyramine; after moclobemide similar peak plasma concentrations of tyramine were obtained with 2.6 times smaller doses of tyramine. Thus, the potentiation by moclobemide of the pressor effect of oral tyramine appears to be due to inhibition of tyramine first-pass metabolism, as well as to inhibition of tyramine catabolism by MAO within adrenergic nerve terminals. The peak concentrations of free tyramine in plasma and the concomitant increase of systolic blood pressure were significantly (p less than 0.01) smaller when tyramine was administered with a meal (before or after moclobemide) than when given with tap water. We conclude that at doses of 3 X 100 mg/day moclobemide induces only a mild potentiation of the pressor effect of tyramine. This potentiation is virtually absent under natural conditions when tyramine is given with a meal.

Absorption↗
PubMed1988

Tyramine pressor effect in man: studies with moclobemide, a novel, reversible monoamine oxidase inhibitor.

The pressor effect of tyramine (TYR) administered i.v. and orally was measured in healthy volunteers during treatment with different therapeutic doses of moclobemide, a new, reversible, preferential type A monoamine oxidase inhibitor. With moclobemide 3 X 100 mg/day the systolic blood pressure (SBP) increase produced by TYR administered i.v. was potentiated 2.4-fold and that in response to TYR p.o. in the fasting state was increased 4.1-fold, as determined from equieffective TYR doses before and during moclobemide treatment. Peak concentrations of free TYR in plasma after oral doses of TYR were increased 2.6-fold, and a 2.5-fold smaller plasma TYR concentration produced the same SBP rise as before moclobemide treatment. No SBP increase was observed at plasma TYR concentrations below 20 ng/ml or after p.o. TYR does smaller than 80 mg. The potentiation of the pressor effect of i.v. TYR by single moclobemide doses up to 300 mg had disappeared 24 hrs after moclobemide administration. Peak TYR plasma concentration and concomitant SBP increments were considerably smaller when TYR was administered with a meal than when administered as a bolus with tap water, 2.1 times higher oral TYR doses being required to achieve similar peak TYR plasma concentration as in the fasting condition. The pressor effect of TYR was further, but only slightly, increased during treatment with moclobemide 3 x 200 mg/day, however SBP rises were again significantly smaller when TYR was given together with a meal. In contrast, tranylcypromine produced a 20 to 40-fold potentiation of the pressor effect of oral TYR and this potentiation was only slightly smaller when TYR was given with a meal. In conclusion the potentiation by moclobemide of the pressor response to oral TYR corresponds roughly to a fourfold left shift of the TYR dose-pressor response curve and is about 10 times less marked than after tranylcypromine. In real life situations, the ingestion of TYR in amounts less than 100 mg is highly unlikely to produce a clinically relevant blood pressure elevation.

Adult↗
PubMed1988

[Computer-assisted static and dynamic pupillometry for the characterization of tricyclic antidepressive agent, cianopramine].

Utilizing static and light-evoked dynamic pupillometry, in a placebo-controlled study 14 normal volunteers (9 males and 5 females) in the age range between 22 to 40 years were studied before and after administration of one single dose of 2 mg cianopramine (Ro 11-2465), further after 3 weeks therapy with 1, 2 and 3 mg cianopramine, respectively, and after a superimposed single dose of 3 mg cianopramine on the top of chronic administration. After acute administration of 2 mg cianopramine, marked pupillary changes started already in the 2nd h, peaked in the 4th h and lasted up to the 10th h. While the widening of the pupil indicates the adrenergic and possible noradrenergic effect of cianopramine on the pupil, the attenuation of spontaneous fluctuations suggests concomitant fatigue. The attenuation of the light-evoked narrowing of the pupillary diameter as well as the reduction of pupillary dynamics (increase of latency time and decrease of relative changes) reflect the direct and/or indirect efficacy of cianopramine on the light reaction of the pupil. After chronic administration the changes (as compared with baseline) are still visible although less pronounced than after acute therapy which suggests adaptation phenomena. A superimposed single dose of 3 mg cianopramine in addition to the 3-week chronic treatment did not result in further changes as compared with the chronic effect--with one exception of an additional decrease of spontaneous fluctuations.

Adult↗
PubMed1987

Effect of stress hormones on splanchnic substrate and insulin disposal after glucose ingestion in healthy humans.

To compare cortisol and epinephrine action on oral glucose tolerance, healthy humans were infused with either cortisol (0.1 mg X kg-1 X h-1), epinephrine (5.4 micrograms X kg-1 X h-1), or saline before and after a 75-g glucose load, thereby elevating the respective plasma hormone concentrations into the pathophysiologic range. In the basal state, epinephrine increased arterial concentrations of glucose, beta-hydroxybutyrate, and free fatty acids (FFA) as well as splanchnic output of glucose and beta-hydroxybutyrate and splanchnic FFA more than cortisol. Postprandially, C-peptide release and hyperinsulinemia were blunted by epinephrine initially and increased less thereafter than during cortisol infusion. The rise in arterial glucose after glucose ingestion as calculated by the area under the curve was more marked (P less than .01) after epinephrine [( 1.90 +/- 0.08 M) 150 min] and cortisol [( 1.41 +/- 0.05 M) 150 min] than in the control study [( 1.07 +/- 0.04 M) 150 min]. In parallel, the stress hormones induced an almost identical 24 and 31% rise in mean splanchnic glucose output versus control values (normal, 44.8 +/- 2.5; cortisol, 55.3 +/- 3.3; epinephrine, 58.9 +/- 6.9 g/150 min). The associated rise in arterial concentrations and splanchnic output of insulin above control values was considerably greater during cortisol but unchanged during epinephrine exposure. Epinephrine but not cortisol induced a rise versus the control study in splanchnic uptake of lactate and FFA, as well as in pyruvate output, whereas plasma beta-hydroxybutyrate and acetoacetate remained unchanged. The postprandial splanchnic glucose output-to-splanchnic C-peptide output ratio did not differ from normal during epinephrine but was reduced (P less than .01) during cortisol administration.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Hydroxybutyric Acid↗
PubMed1987

Nifedipine antagonizes alpha-adrenoceptor mediated splanchnic and systemic vasoconstriction in man.

Aim of the study was to investigate whether nifedipine interacts with alpha1-mediated splanchnic and systemic vasoconstriction in man. The effects of nifedipine on basal and phenylephrine (PE)-induced hemodynamic changes were studied in 6 normotensive men, using the hepatic venous catheter technique (indocyanine-green) and the thermodilution method. After a baseline period, nifedipine was given by constant infusion (0.5 microgram/kg/min) and, after equilibration, PE was infused at a constant rate in a dose sequence of 1, 2, 3, and 4 micrograms/kg/min, until the systolic blood pressure was raised by 30 mmHg. Control trials without nifedipine (saline) were also performed in each subject. At basal conditions nifedipine decreased systemic blood pressure and total systemic vascular resistance (TSVR) as well as total pulmonary vascular resistance (TPVR), and increased cardiac output (CO). PE provoked a dose-dependent increase in systemic blood pressure, TSVR and TPVR, and decreased CO. These PE-effects were clearly attenuated by nifedipine. In the splanchnic vascular bed nifedipine increased estimated splanchnic blood flow (ESBF) and decreased splanchnic vascular resistance (SVR) at basal conditions. The PE-induced decrease in ESBF and increase in SVR were inhibited or attenuated (depending on PE-dosage) by nifedipine. We conclude that nifedipine counteracts alpha1-adrenoceptor mediated systemic and splanchnic vasoconstriction and therefore, might also be useful in the treatment of intestinal vasospasm.

Adult↗