Slobodan Gasic

Regional effects and clearance of endothelin‐1 across pulmonary and splanchnic circulation

Abstract. To determine the impact of i.v. endothelin‐1 on systemic, pulmonary and splanchnic circulation, as well as the peptides regional clearance, hepatic venous and right heart catheterization was performed in healthy volunteers. During the peptides continuous i.v. administration (0.4 pmol x kg‐1 x min‐1, 60 min) its plasma concentration rose from 21±0.5 to 9.5 ± 5.3 pmol/1 (pulmonary artery), from 2.1±0.9 to 5.0±1.6 pmol/1 (femoral artery), and from 1.5 ± 0.6 to 2.9±1.2 pmol/1 (hepatic vein). This was accompanied by an increase in mean systolic arterial pressure from 127±14 to 131 ± 12mmHg(P<0.05). Concomitantly, cardiac output and heart rate decreased from 7.0 ±1.1 to 5.8 ±1.01/min and from 63 ± 6 to 56 ± 5 beats/min, respectively, while total vascular resistance increased from 964 ± 273 to 1204 ±338 dyn x cm x s‐5 (P<0.01). No major changes in pulmonary circulation were observed, while splanchnic vascular resistance increased from 4472±1056 to 5361 ± 1420 dyn x cm x s‐5 (P<0.01) and estimated hepatic blood flow decreased from 1403 ± 218 to 1218 ± 219 ml min‐1 (P<0.01).

Hepatic disposal of biosynthetic human insulin and porcine C-peptide in humans

To examine the fate of insulin across the liver bed, biosynthetic human insulin was infused in increasing amounts in six healthy men. Trapping of insulin by the liver was determined by means of the hepatic venous catheter technique. To minimize any possible error in the estimation of insulin removal as a result of endogenous insulin, pancreatic insulin secretion was suppressed by intravenous administration of somatostatin (500 micrograms/h). Infusion rates of human insulin were 30, 60, and 150 pmol/m2 X min (corresponding to 0.25, 0.5, and 1.25 U/m2 X h) for 70 minutes each. Steady-state insulin levels were within the physiologic range, ie, 69 +/- 2, 135 +/- 3, and 342 +/- 10 pmol/L, respectively. Euglycemia was maintained throughout the study by a variable glucose infusion. The output of C-peptide from the splanchnic bed was reduced by somatostatin by about 90%, indicating that endogenous insulin production only minimally contributed to total insulin levels achieved during infusion of exogenous human insulin. Fractional extraction of insulin by the liver (63 +/- 6%, 71 +/- 4%, and 74 +/- 5%) and hepatic insulin clearance (201 +/- 19, 235 +/- 23, and 245 +/- 29 mL/m2 X min) did not differ significantly during the three insulin infusion studies. The hepatic uptake of insulin rose with increasing insulin infusion rates, constituting 40% to 60% of total-body insulin removal. No change in the total metabolic clearance rate of insulin was observed between the groups (451 +/- 8 mL/m2 X min). To study the extraction rate of C-peptide by the liver, porcine C-peptide was also infused at the same increasing rates.(ABSTRACT TRUNCATED AT 250 WORDS)

Sinus Node Dysfunction After Orthotopic Cardiac Transplantation: Postoperative Incidence and Long-Term Implications

HEINZ, G., et al.: Sinus Node Dysfunction After Orthotopic Cardiac Transplantation: Postoperative Incidence and Long‐Term Implications. We investigated incidence, normalization rates, and clinical significance of sinus node (SN) dysfunction after cardiac transplantation. Thirty‐nine of 90 patients systematically evaluated presented with impaired SN function in the postoperative period. Of these, 22 normalized their SN function during follow‐up while 17 remained impaired after 3 months. The proportion normalized was higher in patients with prolonged SN recovery time (11/16, 68.8%) and those reverting from escape rhythm to sinus rhythm until discharge (5/8, 62.5%) when compared to patients in escape rhythm throughout the postoperative period (5/11, 45.5%) or pacemaker dependence (1/4, 25%). There was no reliable postoperative predictor of normalization and necessity of long‐term pacing. A postoperative heart rate consistently < 70 beats/min (irrespective of the native rhythm) was significantly related to outcome (P = 0.01), but revealed unacceptable sensitivity (61.5%) and specificity (81%). After all, both patients with severe symptoms (near syncopes and syncope), were derived from this group. These two patients, who had been discharged in sinus rhythm, had late pacemakers implanted. An additional 17 patients had early pacemaker placement, only seven of which were constantly paced during follow‐up. Given the low normalization rates, patients with postoperative escape rhythm are those most likely to benefit from pacemaker therapy over the long term. Even those in, or reverting back to, sinus rhythm until discharge may experience severe symptoms, particularly in the setting of a postoperative rate consistently < 70 beats/min since this indicates a relatively lower probability of recovery.

Fosinopril decreases levels of soluble vascular cell adhesion molecule-1 in borderline hypertensive type II diabetic patients with microalbuminuria

Angiotensin converting enzyme inhibitors (ACE-I) are a mainstay for the treatment of heart failure, and of diabetic microalbuminuria. Recently ACE-I have been found to decrease plasma levels of circulating vascular cell adhesion molecule-1 (cVCAM-1) in patients with congestive heart failure. As increased cVCAM-1 levels are pathognomonic for diabetics with microangiopathy, we investigated the effects of ACE-I on plasma levels of cVCAM-1, intercellular adhesion molecule (cICAM-1), and cE-selectin in microalbuminuric diabetics. In addition, the effects of ACE-I on plasma levels of plasminogen activator inhibitor (PAI-1) and of tissue plasminogen activator (TPA) were studied. Fosinopril (10 mg/day) was administered over 12 weeks to 11 microalbuminuric patients with non-insulin-dependent diabetes mellitus (NIDDM). As expected, baseline plasma concentrations of cE-selectin, cICAM-1, and cVCAM-1 were markedly higher in patients than in healthy control subjects (n = 82; P < .001). PAI-1 levels in NIDDM were similar to those in control subjects, whereas TPA levels were about 25% lower in patients than in control subjects (P = .013). Serum levels of cVCAM-1 decreased by -19% (CI: -25% to -13%) after treatment with fosinopril (P = .003) and were no longer different from those of the control group. In contrast, plasma levels of cE-selectin, cICAM-1, PAI-1, and TPA were unaffected. As expected microalbuminuria decreased by -44% (CI: -65 to -22; P = .004). In conclusion, fosinopril lowered cVCAM-1 levels along with microalbuminuria in NIDDM. This may represent a novel mechanism of action of ACE-I in diabetes-associated endothelial dysfunction. Whether decreased VCAM-1 expression is responsible for the observed reduction in microalbuminuria, deserves further investigation.

Oral glucose tolerance test: Effect of different glucose loads on splanchnic carbohydrate and substrate metabolism in healthy man

Abstract To evaluate the role of splanchnic metabolism in the disposal of orally ingested glucose and thereby to define the optimal glucose load for glucose tolerance testing, splanchnic glucose output (SGO), as determined by the hepatic-venous catheter technique, was estimated in 16 healthy male volunteers in the basal state and after different glucose loads. Following glucose ingestion of 12.5, 25, 50, 75, and 100 g glucose, mean SGO over 2 hours was 9, 10, 12.3, 20, and 24.7 g above basal hepatic glucose production or 72, 40, 25, 26, and 25 percent of the respective glucose load. Increasing glucose doses represented a greater and more prolonged insulinogenic stimulus as determined by insulin concentrations in hepatic venous plasma. Splanchnic lactate uptake decreased and finally reverted to a net output in most of the subjects studied, whereas pyruvate production increased with rising glucose loads. It is concluded that (1) maximal stimulation of insulin release by administration of 50 to 100 g glucose results in maximal splanchnic extraction (75%) of an ingested glucose load, whereas smaller amounts of glucose are retained to a lesser extent; (2) 100 g of glucose provide optimal conditions for performing an oral glucose tolerance test (OGTT), thereby provoking a relative as well as an absolute maximum of splanchnic glucose extraction; and (3) splanchnic uptake of pyruvate and lactate following ingestion of small amounts of glucose revert to a net output with utilization of increasing glucose loads.

In vivo clearance of antibody-sensitized human drug carrier erythrocytes.

Antibody coating of resealed drug carrier erythrocytes may be useful for drug targeting to the reticuloendothelial system. We have investigated the survival in the circulation of anti‐Rh antibody (IgG anti‐D)–coated autologous erythrocytes loaded with gentamicin by hypoosmotic dialysis. Five subjects were injected with 15.2 ± 0.4 ml and five additional subjects with 62.8 ± 1.5 ml carrier cells. Survival of the cells was monitored by intraerythrocytic gentamicin concentration in blood. In the first subject group initial t1/2 was 0.21 ± 0.06 hours and terminal t1/2 was 1.71 ± 0.36 hours. In the second group initial t1/2 was 0.59 ± 0.21 hours followed by a slow phase with a t1/2 of 89 ± 28 hours. Results indicate that rapid drug delivery to the reticuloendothelial system by antibody—sensitized carrier erythrocytes is possible, but small volumes of erythrocytes seem more efficient.

DEMOGRAPHIC AND PERIOPERATIVE FACTORS ASSOCIATED WITH INITIAL AND PROLONGED SINUS NODE DYSFUNCTION AFTER ORTHOTOPIC HEART TRANSPLANTATION : THE IMPACT OF ISCHEMIC TIME

The etiology of sinus node (SN) dysfunction after or-thotopic heart transplantation as assessed by the origin of rhythm, heart rate (HR), and, provided the origin of rhythm was sinus, by corrected sinus node recovery time (CSNRT) was studied in 50 patients. The possible influences on postoperative donor SN function of donor age, recipient age, underlying pretransplant heart disease, pretransplant amiodarone (AMIO) treatment, date of surgery, ischemic time, surgical technique of atrial incision, the use of different cardioplegic solutions during the study period, and rejection were evaluated. The results thus obtained indicate that SN dysfunction is common after cardiac transplantation and pinpoint to a different etiology of transient (restoration of normal SN function within 4 postoperative weeks) and persistent (SN function still impaired at 3 months) SN dysfunction. Of the several demographic and perioperative variables evaluated, only ischemic time had an influence on postoperative SN function in that ischemic times were significantly longer in patients with impaired SN function when compared with patients exhibiting normal SN function (148±39 min vs. 110.5±36 min, respectively, P=0.001). Further stratification according to the duration of SN dysfunction revealed significantly longer ischemic times in patients with transiently impaired SN function only (156.3±35 min vs. 110.5±36 min, P=0.0026). No relation to persistent SN dysfunction of ischemic time (130.5±36 min vs. 110.5±36 min, P=ns) or any other factor investigated was found.

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.

The Effect of Growth Hormone on Splanchnic Glucose and Substrate Metabolism Following Oral Glucose Loading in Healthy Man

Elevated plasma concentrations of growth hormone impair glucose tolerance and insulin sensitivity of peripheral tissues. To study the effect of short-term exposure to growth hormone concentrations elevated into the upper physiologic range (7–10 ng/ml) on splanchnic carbohydrate metabolism, both splanchnic glucose output (SGO) and substrate exchange after ingestion of a 75-g glucose load were determined by means of the liver vein catheter technique in six healthy volunteers after growth hormone administration. Growth hormone was infused at a rate of 2 μg/ kg · h starting 120 min before and continuing for 150 min following the glucose load. Control studies without growth hormone administration were performed in seven subjects. SGO was 104 ± 10 (SEM) mg/min in the postabsorptive state and increased to 43.4 ± 2.2 g during the 150-min period following glucose ingestion. Growth hormone infusion did not alter basal SGO (130 ± 14 mg/min), nor the splanchnic exchange of lactate, pyruvate, and free fatty acids, whereas basal production of β-OH-butyrate was increased twofold; following glucose ingestion a higher proportion of the given glucose load escaped the splanchnic bed after growth hormone exposure (66.9 ± 6.8 g/150 min; P < 0.005). The insulin production rate (basal 14 ± 2 mU/min; following oral glucose 7.0 ± 0.8 U/150 min) as calculated from C-peptide release from the splanchnic area was unaltered by growth hormone exposure in the basal state (14 ± 3 mU/min), but augmented after glucose ingestion (14.8 ± 1.5 U/150 min). The higher rate of glucose release by the splanchnic bed after glucose ingestion despite a more marked hyperglycemia and increased insulin secretion suggests that acute elevations of plasma growth hormone within the physiologic range, besides causing insulin resistance of peripheral tissues, affect glucose disposal of splanchnic tissues as well.

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 humanswere infused with either cortisol (0.1 mg · kg−1 · h−1), epinephrine (5.4 μg · kg−1 · h−1), or saline before and aftera 75-g glucoseload, thereby elevating the respective plasma hormone concentrations into the pathophysiologic range. In the basal state, epinephrine increased arterial concentrations of glucose, β-hydroxybutyrate, and free fatty acids (FFA) as well as splanchnic output of glucose and β-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 < .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 β-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 < .01) during cortisol administration. Hepatic insulin uptake was proportionate to insulin production rate, whereas hepatic insulin clearance was unaffected by stress hormone action. We conclude that besides inhibiting adequate insulin release to hyperglycemia, acute epinephrine exposure induces peripheral insulin resistance and increased splanchnic glucose output and lactate uptake. Such insulin resistance seems to be unveiled by normal but inappropriately low postprandial insulin release during epinephrine-induced basal and postprandial hyperglycemia but is partly disguised by secondary hyperinsulinemia after cortisol infusion.