Catecholamine receptor sensitivity and the regulation of lipolysis in adult diabetes

Summary The sensitivity of alpha- and beta-adrenergic receptors, and the antilipolytic actions of prostaglandin E₁ or insulin on adipose tissue of obese diabetic and non-diabetic subjects have been studied. Accumulation of cyclic AMP in adipose tissue and release of glycerol in response to several catecholamines (adrenaline, noradrenaline and isoprenaline) in the presence or absence of an alpha-adrenergic blocker (phentolamine) have been used to assess catecholamine receptor sensitivity. No differences in beta-receptor activity were observed between diabetics and non-diabetics, either on glycerol release or accumulation of cyclic AMP; alpha-receptor activity was also similar, except for significantly less accumulation of cyclic AMP in diabetic tissue incubated with noradrenaline and phentolamine (p<0.01). The antilipolytic action of prostaglandin E₁ (at concentrations of 30 fM to 30 pM) on lipolysis (stimulated submaximally with isoprenaline, 10^–7 M) was similar in diabetic and control groups. The antilipolytic action of insulin (from 10^–10 to 10^–6 M) on lipolysis was also similar between the groups. It is concluded that neither disorders of the catecholamine receptor nor of the antilipolytic actions of prostaglandin E₁ or insulin are responsible for the abnormalities of fatty acid metabolism in adult diabetes.     

Myocardial infarct size. Part 2. Comparison of anti-infarct effects of beta-blockade, glucose-insulin-potassium, nitrates, and hyaluronidase

Based on the principles discussed in the first part of this review, the following interventions (Table I) could be expected to limit infarct size: (1) relief of vascular obstruction, (2) increased collateral flow or diffusion to the ischemic zone, (3) relief of the load on the heart, thereby promoting a more favorable balance between the oxygen supply and demand, (4) catecholamine antagonism, and (5) specific metabolic measures. Table I lists those agents tested in patients for therapeutic effects on indices of infarct size. Because the role and exact nature of the vascular obstruction is so controversial, agents acting at that level have been omitted from further consideration, and one agent has been selected from each of the remaining categories (2 to 5) of Table I.Thus the four anti-infarct agents selected for consideration in further detail are: β-blockade, glucose-insulin-potassium, nitrates, and hyaluronidase. β-blockade is selected because of the exceptionally full experimental and clinical studies now available and because of a combined hemodynamic and metabolic action. Glucoseinsulin-potassium is selected as one of the first interventions introduced, and now well studied over many years; it is an agent likely to counteract undesirable metabolic changes in acute infarction. Glucose-insulin-potassium is compared with the use of a nicotinic acid analog which also has an antilipolytic action. Nitrates are selected because of their dual mechanism of action, both by causing coronary vasodilation and by reducing the pre- and afterload on the heart. In addition, nitrates, as therapeutic agents, are well known to all practicing cardiologists. Nitroprusside is considered together with the nitrates, although nitroprusside has a more definitive effect on the afterload than do nitrates. Finally, hyaluronidase is chosen as a well-investigated agent with minimal side effects and no known hemodynamic mode of action.Other promising agents have been omitted, although of great potential interest, because of the limited number of patient studies available. For example, the effects of steroids are well documented in experimental preparations. Although they diminish the features of acute ischemic injury, probably acting by means of “membrane stabilization,” they also inhibit wound healing¹³⁰ and hence increase the risk of ventricular rupture or aneurysm² (See also Table I, references 250, 251, 256, and 257). Another interesting category of agents, the calcium antagonists, are only now being studied in patients.     

Effects of chronic β-blockade on rest and exercise hemodynamics in mitral stenosi

β-blocker therapy for mitral stenosis is controversial. This study compares right and left heart hemodynamics at rest and supine submaximal exercise in patients (n = 7) receiving chronic β-antagonists with untreated patients (n = 17) matched for age (mean ± SD = 51 ± 12 years) and valve area (0.7 ± 0.2 cm²/m²). Little benefit was observed with treatment at rest. Although pulmonary capillary wedge pressures (PCWP) were lower during exercise in the β-blocker group (22±4 vs. 31 ± 9 mmHg; P>0.05), exercise performance was not enhanced and cardiac output response during exercise was reduced (control = 41% increase vs. 12% for β-blockade). PCWP rose rapidly when diastolic filling periods were >300 msec in both groups. Pulmonary capillary wedge pressure was found to be a nonlinear functions (P<0.001) of diastolic filling period (PCWP = 15.9 + 5.84 × 10⁵/dfp²). These data suggest that there is a critical heart rate in patients with mitral stenosis above which hemodynamic compromise rapidly occurs. © 1995 Wiley-Liss, Inc.

1 This article is a US Government work and, as such, is in the public domain in the United States of America.

     

Various phosphodiesterase subtypes mediate the in vivo antilipolytic effect of insulin on adipose tissue and skeletal muscle in man

Summary The antilipolytic effect of insulin on human abdominal subcutaneous adipose tissue and skeletal muscle during local inhibition of cAMP-phosphodiesterases (PDEs) was investigated in vivo, by combining microdialysis with a euglycaemic, hyperinsulinaemic clamp. During hyperinsulinaemia, the glycerol concentration decreased by 40 % in fat and by 33 % in muscle. Addition of the selective PDE3-inhibitor amrinone abolished the insulin-induced decrease in adipose glycerol concentration, but did not influence the glycerol concentration in skeletal muscle. Nor did the PDE4-selective inhibitor rolipram or the PDE5-selective inhibitor dipyridamole influence the insulin-induced decrease in muscle tissue glycerol. However, the non-selective PDE-inhibitor theophylline counteracted the antilipolytic action of insulin at both sites. The specific activity of PDEs was also determined in both tissues. PDE3-activity was 36.8 ± 6.4 pmol × min^–1× mg^–1 in adipose tissue and 3.9 ± 0.5 pmol × min^–1× mg^–1 in muscle. PDE4-activity in skeletal muscle was high, i. e., 60.7 ± 10.2 pmol × min^–1× mg^–1 but 8.5 pmol × min^–1× mg^–1 or less in adipose tissue. In conclusion, insulin inhibits lipolysis in adipose tissue and skeletal muscle by activation of different PDEs, suggesting a unique metabolic role of muscle lipolysis. [Diabetologia (1998) 41: 560–568] Received: 1 October 1997 and in revised form: 22 December 1997     

Comparison of the antilipolytic effects of an A1 adenosine receptor partial agonist in normal and diabetic rats

Introduction and Aims: Elevated plasma free fatty acid (FFA) concentrations play a role in the pathogenesis of type 2 diabetes (2DM). Antilipolytic agents that reduce FFA concentrations may be potentially useful in the treatment of 2DM. Our previous observation that CVT‐3619 lowered plasma FFA and triglyceride concentrations in rats and enhanced insulin sensitivity in rodents with dietary‐induced forms of insulin resistance suggested that it might be of use in the treatment of patients with 2DM. The present study was undertaken to compare the antilipolytic effects of CVT‐3619 in normal (Sprague Dawley, SD) and Zucker diabetic fatty (ZDF) rats. Results: ZDF rats had significantly higher fat pad weight, glucose, insulin and FFA concentrations than those of SD rats. EC₅₀ values for forskolin‐stimulated FFA release from isolated adipocytes from SD and ZDF rats were 750 and 53 nM, respectively (p < 0.05). Maximal forskolin stimulation of FFA release was significantly (p < 0.01) less in ZDF rats (133 ± 60 μM) compared with SD rats (332 ± 38 μM). EC₅₀ values for isoproterenol to increase lipolysis in adipocytes from SD and ZDF rats were 2 and 7 nM respectively. Maximal isoproterenol‐stimulated lipolysis was significantly (p < 0.01) lower in adipocytes from ZDF rats (179 ± 23 μM) compared with SD rats (343 ± 27 μM). Insulin inhibited lipolysis in adipocytes from SD rats with an IC₅₀ value of 30 pM, whereas adipocytes from ZDF rats were resistant to the antilipolytic actions of insulin. In contrast, IC₅₀ values for CVT‐3619 to inhibit the release of FFA from SD and ZDF adipocytes were essentially the same (63 and 123 nM respectively). CVT‐3619 inhibited lipolysis more than insulin in both SD (86 vs. 46%, p < 0.001) and ZDF (80 vs. 13%, p < 0.001) adipocytes. In in vivo experiments, CVT‐3619 (5 mg/kg, PO) lowered FFA to a similar extent in both groups. Plasma concentrations of CVT‐3619 were not different in SD and ZDF rats. There was no significant difference in the messenger RNA expression of the A₁ receptors relative to β‐actin expression in adipocytes from SD (0.98 ± 0.2) and ZDF rats (0.99 ± 0.3). Conclusion: The antilipolytic effects of CVT‐3619 appear to be independent of insulin resistance and animal model.     

W-5 and quin 2-AM reverse the inhibitory effect of insulin on lipolysis due to dibutyryl cAMP.

The effects of W-5, a weak calmodulin antagonist, and quin 2-AM, a cell permeant calcium chelator, on lipolysis and antilipolytic activity of insulin were studied in isolated rat adipocytes. We have previously shown that W-7, a strong calmodulin antagonist, suppresses the inhibitory effect of insulin on lipolysis due to dibutyryl cAMP (Bt2cAMP) in a dose-dependent manner [H. Goko, A. Matsuoka, Diabetes Res. Clin. Prac. 19 (1993) 177-181] and verapamil, a calcium antagonist, potentiates lipolysis due to Bt2cAMP. Like W-7, W-5 suppressed the antilipolytic action of insulin on lipolysis due to Bt2cAMP in a dose-dependent manner. However, when lipolysis was potentiated with 3-isobutyryl-1-methylxanthine (IBMX), W-5 did not suppress the antilipolytic action of insulin. At the same time, like verapamil, W-5 also potentiated lipolysis due to Bt2cAMP in a dose-dependent manner. Thus W-5 has the pharmaceutical effects of both W-7 and verapamil. The chelation of intracellular Ca2+ in adipocytes with quin 2-AM also produced a dose-dependent potentiation of lipolysis due to Bt2cAMP and suppression of the antilipolytic action of insulin on lipolysis due to Bt2cAMP. These effects of quin 2-AM are the same as those of W-5. Therefore, our results suggest that the cytoplasmic Ca2+ plays a pivotal role in mediating the potentiation of lipolysis and antilipolytic action of insulin when lipolysis is induced by Bt2cAMP in rat adipocytes and that W-5 appears to exert its pharmaceutical effects through the inhibition of intracellular calcium-dependent steps other than calmodulin.     

Decreased myocardial free fatty acid uptake in patients with idiopathic dilated cardiomyopathy: evidence of relationship with insulin resistance and left ventricular dysfunction

BackgroundResults on myocardial substrate metabolism in the failing heart have been contradictory. Insulin resistance, a common comorbidity in heart failure patients, and medical therapy may modify myocardial metabolism in complex fashions. Therefore, we characterized myocardial oxidative and free fatty acid (FFA) metabolism in patients with idiopathic dilated cardiomyopathy (IDCM) and investigated the contributions of insulin resistance and β-blocker therapy.Methods and ResultsNineteen patients with IDCM (age 58 ± 8 years, ejection fraction 33 ± 8.8%) and 15 healthy controls underwent examination of myocardial blood perfusion, oxidative and FFA metabolism using positron emission tomography and [¹⁵O]H₂O, [¹¹C]acetate and [¹¹C]palmitate, respectively. Echocardiography was used to assess myocardial function, work, and efficiency of forward work. Insulin resistance was calculated using the homeostasis model assessment index (HOMA index) and the degree of β-blockade was estimated with a β-adrenoceptor occupancy test. IDCM patients were characterized by decreased cardiac efficiency (35 ± 2 versus 57 ± 12 mm Hg·L·g⁻¹, P < .0001) and reduced myocardial FFA uptake (5.5 ± 2.0 versus 6.4 ± 1.2 μmol·100 g⁻¹·min⁻¹, P < .05), but the FFA β-oxidation rate constant was not changed. In the patients, myocardial FFA uptake was inversely associated with left ventricular (LV) ejection fraction (r = −0.63, P < .01), indicating that further depression of LV function induces an opposite switch to greater FFA uptake. The FFA β-oxidation rate constant correlated positively with the HOMA index (r = 0.53, P < .05). In patients on β-1 selective β-blockers, β-1 adrenoceptor occupancy correlated inversely with LV work, oxidative metabolism, and FFA uptake; similar relationships were not found in patients on nonselective β-blocker.ConclusionsMyocardial FFA metabolism is reduced in patients with IDCM. However, when LV function is further depressed and insulin resistance manifested, myocardial FFA uptake and oxidation are, in turn, upregulated. These findings may partly explain the discrepancies between previous studies about cardiac metabolism in heart failure.     

Electrophysiological and pharmacological study of the inotropic effects of adrenaline,dopamine and tryptamine on frog atrial fibres

In order to investigate the action of the sympathetic amines adrenaline, dopamine and tryptamine, electrophysiological and pharmacological studies were undertaken on frog heart atrial fibres, using a double sucrose gap technique. Electrophysiological measurements, under voltage clamp conditions have shown that adrenaline, dopamine and tryptamine induce a large increase of the slow inward current (I_slow) and tension amplitudes. Dose-response relationships show a direct correlation between the increase in both I_slow and phasic tension, with a half-response dose (K_0·5) of 4 × 10^?7m for adrenaline, 2.5 × 10^?6m for dopamine and 4 × 10^?6m for tryptamine. These effects are inhibited by the β blocker agent propranolol, but a competitive inhibition was only observed in the case of adrenaline. While the typical effect of adrenaline is still present on catecholamine depleted preparations (previously treated with 6-hydroxydopamine), dopamine and tryptamine do not have an effect on those pretreated preparations. Results provide evidence for an adrenaline release mediated type of action of dopamine and tryptamine. Our work also suggests the presence of specific presynaptic dopamine and tryptamine receptors on sympathic nerve terminals in frog atrial fibres.     

Glycosylphosphatidylinositol-anchored proteins coordinate lipolysis inhibition between large and small adipocytes

In response to palmitate, the antidiabetic sulfonylurea drug glimepiride, phosphoinositoglycans, or H₂O₂, the release of the glycosylphosphatidylinositol-anchored and cyclic adenosine monophosphate-degrading phosphodiesterase Gce1 from adipocytes into small vesicles (adiposomes) and its translocation from adiposomes to cytoplasmic lipid droplets (LD) of adipocytes have been reported. Here the role of Gce1-harboring adiposomes in coordinating lipolysis between differently sized adipocytes was studied. Separate or mixed populations of isolated epididymal rat adipocytes of small and large size and native adipose tissue pieces from young and old rats were incubated with exogenous adiposomes or depleted of endogenous adiposomes and then analyzed for translocation of Gce1 and lipolysis in response to above antilipolytic stimuli. Large compared with small adipocytes are more efficient in releasing Gce1 into adiposomes but less efficient in translocating Gce1 from adiposomes to LDs. Maximal lipolysis inhibition by above antilipolytic stimuli, but not by insulin, was observed with mixed populations of small and large adipocytes (1:1 to 1:2) rather than with separate populations. In mixed adipocyte populations and adipose tissue pieces from young, but not old, rats, lipolysis inhibition by above antilipolytic stimuli, but not by insulin, was dependent on the function of Gce1-harboring adiposomes. Inhibition of lipolysis in rat adipose tissue in response to palmitate, glimepiride, and H₂O₂ is coordinated via the release of adiposome-associated and glycosylphosphatidylinositol-anchored Gce1 from large “donor” adipocytes and their subsequent translocation to the LDs of small “acceptor” adipocytes. This transfer of antilipolytic information may be of pathophysiologic relevance.     

Atrial Natriuretic Peptide during Exercise in Patients with Coronary Heart Disease before and after Single Dose Atenolol and Acebutolol

Plasma atrial natriuretic peptide (ANP) was measured during dynamic exercise in 10 patients with coronary heart disease before and after single dose atenolol 50 mg and acebutolol 200 mg, respectively. Systolic blood pressure, heart rate and the rate-pressure product increased during exercise before and after β-blockade, but levels were lower after β-blockade. Plasma ANP levels at rest were unchanged after atenolol, but rose after acebutolol (p<0.01). During exercise plasma ANP increased significantly both before and after β-blockade, but plasma ANP levels were higher after acebutolol at all workloads (p<0.05), whereas plasma ANP levels after atenolol were higher at 125 W exclusively (p<0.05). The augmented ANP levels during exercise after β-blockade probably reflect catecholamine-stimulated ANP release, whereas the elevated plasma ANP levels after acebutolol at rest might be a β-adrenoceptor-mediated ANP release due to the intrinsic sympathomimetic effect of acebutolol.     

Role of phenolics as antioxidants,biomolecule protectors and as anti–diabetic factors – Evaluation on bark and empty pods of Acacia auriculiformis

ObjectiveTo search for an efficient and inexpensive source of phytoconstituents with antioxidant potential and health promoting traits from bark and empty pods of Acacia auriculiformis (A. auriculiformis).MethodsSamples of bark and empty pod extracts were analyzed for bioactives (phenolics, flavonoids and proanthocyanidins) and subjected to free radical scavenging activity on DPPH^˙, ABTS^˙+, OH^˙, O₂^?? and NO along with the determination of reducing power, iron chelating activity and peroxidation inhibition. Defensive action of extracts on biomolecules and cell membranes were evaluated by DNA nicking assay and haemolysis inhibition assay respectively. α-amylase and α-glucosidase inhibitory potentials were also determined.ResultsAll the bioactives analyzed were higher in bark (B) than empty pods (EP) [TPC: B (574.51±16.11); EP (96.80±3.45) mg GAE/g. TFC: B (94.71±7.65); EP (247.87±20.45) mg RE/g. Proanthocyanidins: B (2.81±0.31); EP (1.25±0.01) mg LE/100 g DM] except flavonoids. Both the extracts showed higher quenching capacity on DPPH and ABTS (DPPH: B (0.21±0.01); EP (1.51±0.17) g extract/g DPPH. ABTS: B (111 519.14±79 340.91); EP (80 232.55±32 894.12) mmol TE/g) with the FRAP of B (84 515.63±3 350.69) and EP (47 940.79±1 257.60) mmol Fe (II)/g. Iron chelation was not observed. In addition, they showed lower quenching activity on OH^˙ (B (48.95±1.72); EP (34.94±1.62)%) and equivalent quenching on O₂^?? (B (53.47±3.92); EP (24.41±2.61)%), NO (B (49.04±5.04); EP (51.00±5.13)%), peroxidation inhibition (B (67.50±5.50); EP (55.1±2.3)%) and antihaemolytic potential (B (87.60±6.84)%) towards authentic antioxidant standards. Interestingly, Empty pod extracts are devoid of antihaemolytic activity. Both the extracts showed dose dependent DNA protection. Besides this, bark and empty pod extracts exhibited dual inhibiting potential against α -amylase and α-glucosidase enzymes.ConclusionsOn summarization, it insinuated that both bark and empty pods can be used for the preparation of antioxidant/nutraceutical supplements and in anti–diabetic formulations.     

Losartan improves heart rate variability and heart rate turbulence in heart failure due to ischemic cardiomyopathy

BackgroundHeart rate variability (HRV) and heart rate turbulence are known to be disturbed and associated with excess mortality in heart failure. The aim of this study was to investigate whether losartan, when added on top of β-blocker and angiotensin-converting enzyme inhibitor (ACEI) therapy, could improve these indices in patients with systolic heart failure.Methods and ResultsSeventy-seven patients (mean age 60.4 ± 8.0, 80.5% male) with ischemic cardiomyopathy (mean ejection fraction 34.5 ± 4.4%) and New York Heart Association Class II-III heart failure symptoms, already receiving a β-blocker and an ACEI, were randomly assigned to either open-label losartan (losartan group) or no additional drug (control group) in a 2:1 ratio and the patients were followed for 12 weeks. The HRV and heart rate turbulence indices were calculated from 24-hour Holter recordings both at the beginning and at the end of follow-up. The baseline clinical characteristics, HRV, and heart rate turbulence indices were similar in the 2 groups. At 12 weeks of follow-up, all HRV parameters except pNN50 increased (SDNN: 113.2 ± 34.2 versus 127.8 ± 24.1, P = .001; SDANN: 101.5 ± 31.7 versus 115.2 ± 22.0, P = .001; triangular index: 29.9 ± 11.1 versus 34.2 ± 7.9, P = .008; RMSSD: 29.1 ± 20.2 versus 34.3 ± 23.0, P = .009; NN50: 5015.3 ± 5554.9 versus 6446.7 ± 6101.1, P = .024; NN50: 5.65 ± 6.41 versus 7.24 ± 6.99, P = .089; SDNNi: 45.1 ± 13.3 versus 50.3 ± 14.5, P = .004), turbulence onset decreased (−0. 61 ± 1.70 versus −1.24 ± 1.31, P = .003) and turbulence slope increased (4.107 ± 3.881 versus 5.940 ± 4.281, P = .004) significantly in the losartan group as compared with controls.ConclusionsA 12-week-long losartan therapy significantly improved HRV and heart rate turbulence in patients with Class II-III heart failure and ischemic cardiomyopathy already on β-blockers and ACEI.     

Contrasting action of short- and long-term adrenaline infusion on dog skeletal muscle glucose metabolism

Summary There are important differences between the short- and long-term effects of adrenaline on determinants of glucose tolerance. To assess this metabolic adaptation at tissue level, the present study examined the effect of acute and prolonged in vivo elevation of adrenaline on glycogen metabolism and glycolysis in skeletal muscle. Adrenaline (50 ng · kg⁻¹ · min⁻¹) was infused for 2 h or 74 h and the results compared with 1 h 0.9% NaCl infusion in six trained dogs. Muscle glycogen content was reduced by long-term adrenaline (161 ± 17 vs NaCl 250 ± 24 μmol/g dry weight;p < 0.05) but not short-term adrenaline (233 ± 21) indicating a sustained effect of adrenaline on glycogen metabolism. Acutely, glycogen synthase I was reduced (short-term adrenaline 12 ± 6 vs NaC122 ± 7μmol glycosyl units · g⁻¹ · min⁻¹;p < 0.05) but returned to normal with prolonged adrenaline infusion (20 ± 5). In contrast, K_m for glycogen phosphorylasea was not changed acutely (short-term adrenaline 31 ± 6 vs NaCl 27 ± 7 mmol/1 inorganic phosphate) but was reduced during long-term infusion (19 ± 4;p < 0.05 vs short-term adrenaline). Thus, with short- and long-term adrenaline infusion, there were different enzyme changes, although likely to promote glycogenolysis in both cases. In the glycolytic pathway the substrates glucose 6-phosphate and fructose 6-phosphate did not change significantly and hexokinase was not inhibited. Acutely, phosphofructokinase had reduced V_max (short-term adrenaline 34 ± 6 vs NaCl 44 ± 5 U/g; p < 0.05) but was still above the maximal operating rate in vivo. With prolonged adrenaline infusion, the K_m for phosphofructokinase was reduced (long-term adrenaline 0.32 ± 0.03 vs NaCl 0.44 ± 0.07 mmol/l fructose 6-phosphate;p < 0.05). In this situation of relatively low glycolytic flux, the sustained glycogenolytic effect of prolonged adrenaline infusion mediated by increased glycogen phosphorylase a ctivity occurs without a significant accumulation of hexose monophosphates or impairment of glycolysis.     

Effect of a toxic in vivo dose of ouabain on guinea-pig heart mitochondria

The effects of toxic doses of ouabain on two parameters of mitochondrial activity, oxidative phosphorylation and calcium uptake were examined. Ouabain was injected intraperitoneally into guinea-pigs until signs of severe intoxication appeared. State 3 oxygen consumption (Q_O2, State 3, in natom oxygen/mg/min) of isolated heart mitochondria was 314 ± 16 and 281 ± 16 (glutamate-malate) for treated and control group, respectively; 225 ± 21 and 207 ± 23 (pyruvate-malate), and 251 ± 12 and 230 ± 13 (succinate), respectively. The rate of calcium uptake was 411 nmol Ca²⁺/min/mg for treated and 329.6 nmol Ca²⁺/min/mg for control. The rate of calcium release was the same in control and treated groups.The data suggest that increases of respiration and calcium uptake in vitro, if they reflect similar increases in vivo, may contribute to digitalis intoxication by intracellular redistribution of calcium.     

Impact of α- Versus β-Blockers on Hypertensive Target Organ Damage: Results of a Double-Blind,Randomized, Controlled Clinical Trial

In hypertensive disease, the extent of target organ damage determines the prognosis. We conducted a 6-month, double-blind randomized study to compare the effects of an α₁-adrenoreceptor blocker (bunazosin) with those of a β₁-adrenoreceptor blocker (metoprolol) on early hypertensive target organ damage at a similar level of blood pressure reduction. The study consisted of 43 patients (29 men and 14 women) of varying ages (mean age 52 ± 9 years) with essential hypertension World Health Organization stage I–II. Both the α- and the β-blocker lowered blood pressure to a similar extent measured by 24-h blood pressure monitoring. The left ventricular mass was comparably reduced in both cohorts (α-blocker 284 ± 80 v 259 ± 67 g, P < .05, β-blocker 282 ± 74 v 254 ± 70 g, P < .05). Treatment with the α-blocker led to reduced total peripheral resistance (22.9 ± 8.0 v 19.9 ± 5.3 U, P < .05), whereas therapy with the β-blocker resulted in an elevated total peripheral resistance (25.5 ± 8.4 v 28.5 ± 9.3 U, P < .10; P < .05 for the difference in both groups). Renal plasma flow remained constant in the α-blocker treated group but decreased in the β-blocker treated group (508 ± 141 v 477 ± 134 mL/min/1.73 m², P < .05). Glomerular filtration rate as measured by inulin clearance tended to increase after treatment with the α-blocker (112 ± 20 v 115 ± 18 mL/min/1.73 m², P < .10) in accordance with a decrease of serum creatinine (1.00 ± 0.14 v 0.93 ± 0.12 mg/dL, P < .001). Plasma cholesterol and LDL cholesterol was lowered after treatment with the α-blocker (238 ± 48 v 312 ± 37 mg/dL; P < .001, and 153 ± 32 v 130 ± 25 mg/dL; P < .05) while remaining unchanged in group treated with the β-blocker. Left ventricular hypertrophy was similarily reduced with α- and with β-blockade at a comparable reduction of 24-h blood pressure. α-Blockers effected a more favorable renal and systemic hemodynamic profile than β-blockers, but only long-term prospective studies will answer the question whether these hemodynamic effects result into a better cardiovascular prognosis.     

Dynamic strength training improves insulin sensitivity and functional balance between adrenergic alpha 2A and beta pathways in subcutaneous adipose tissue of obese subjects

Aims/hypothesis The aim of this study was to investigate whether dynamic strength training modifies the control of lipolysis, with particular attention paid to the involvement of the antilipolytic adrenergic alpha 2A receptor (ADRA2A) pathway. Methods Twelve obese men (age: 47.4±2.8 years; BMI: 32.7±0.9) were investigated during a 210-min euglycaemic–hyperinsulinaemic clamp conducted before and after 3 months of dynamic strength training. Before and during the third hour of the clamp, the lipolytic effect of a perfusion of isoproterenol or adrenaline (epinephrine) alone or associated with the ADRA2A antagonist phentolamine was evaluated using the microdialysis method of measuring extracellular glycerol concentration (EGC) in subcutaneous abdominal adipose tissue (SCAAT). In addition, biopsies of SCAAT were carried out before and after training to determine mRNA levels Results The training increased insulin sensitivity in adipose tissue. The decrease of EGC was more pronounced during the clamp conducted after the training period than during the clamp done in pre-training conditions. Before and after the training, catecholamines induced an increase in EGC, the increase being lower during the clamp on each occasion. The isoproterenol-induced increase in EGC was higher after the training. Adrenaline-induced lipolysis was potentiated by phentolamine after but not before the training. There were no training-induced changes in mRNA levels of key genes of the lipolytic pathway in SCAAT. Conclusions/interpretation In obese subjects, dynamic strength training improves whole-body and adipose tissue insulin responsiveness. It increases responsiveness to the adrenergic beta receptor stimulation of lipolysis and to the antilipolytic action of catecholamines mediated by ADRA2As.     

The Effect of β-Blockade on Gastric Acid Secretion,Gastrin Release,and Plasma Catecholamine Concentrations during Modified Sham Feeding in Duodenal Ulcer Patients

The effects of β-blockade (propranolol, 100 mg orally) on gastric acid output and on circulating levels of gastrin, adrenaline, noradrenaline, and dopamine during modified sham feeding (MSF) were investigated by a randomized, double-blind method in six patients with asymptomatic duodenal ulcer disease. No differences occurred in peak acid output during MSF, whereas basal acid output was significantly suppressed by β-blockade and peak acid output was unaffected. Basal gastrin concentration was lower during β-blockade but rose in response to MSF. Without β-blockade serum gastrin levels were unaffected by MSF. Plasma catecholamine concentrations were not affected by the β-blockade. It is concluded that acid output and gastrin release in response to MSF, unlike that to insulin hypoglycaemia, is not influenced by β-adrenoceptor blockade.     

Cellular mechanisms of hypoxia-induced contraction in human and rat pulmonary arteries

The effect of hypoxia was investigated in human (HPA) and rat (RPA) pulmonary arteries. Hypoxia-induced contraction was 95 ± 8.7% and 9.3 ± 4.8% of the control response to K⁺-rich (80 mM) solution in HPA and RPA, respectively (n = 10). When RPA strips were precontracted with phorbol 12,13 dibutyrate (0.2 μM), hypoxia elicited a larger contraction (105 ± 13.4% of the control response, n = 8). In both types of artery, hypoxia-induced contraction was dependent on the extracellular calcium concentration (66 ± 8.4% and 40 ± 14.4%, reduction for 1.25 mM Ca^{2 +} in HPA and RPA, respectively, n = 6) and was inhibited by verapamil (0.05–10 μM) and nifedipine (0.05–1 μM). Glibenclamide (5–10 μM) increased the amplitude of hypoxia-induced contraction (+ 42 ± 5.3%, n = 5). Hypoxia-induced contraction was blocked by cromakalim (1 μM) and this effect was reversed by glibenclamide (5 μM). This contraction was also inhibited by iodoacetic acid (250 μM). In β-escin skinned pulmonary arterial strips, hypoxia had no effect on the calcium concentrationtension relationship. These results suggest that the O₂ sensor in the pulmonary artery is located on the vascular smooth muscle plasmalemma. Hypoxia-induced contraction is dependent on calcium influx through voltage sensitive calcium channels. Its amplitude is modulated by the functioning of potassium channels.     

Protective effects on isolated hearts with developing infarction: Slow channel blockade by diltiazem versus beta-adrenoceptor antagonism by metoprolol

Slow channel inhibitors (calcium antagonists) and beta-adrenoceptor antagonists may theoretically protect the infarcting myocardium by different mechanisms. Thus, beta-receptor antagonism reduces the oxygen demand by the combined effects of bradycardia, decreased arterial pressure, and reduced contractility, whereas slow channel inhibition chiefly increases coronary blood flow and decreases the afterload by peripheral vasodilation. The present study was designed to assess and compare the effects of the beta-receptor antagonist metoprolol with those of the calcium channel inhibitor diltiazem on cellular damage and mechanical function in the isolated working rat heart subject to coronary artery ligation. We compared the highest concentrations of both agents that could be tolerated in this preparation: diltiazem 4 × 10^{? 7} M and metoprolol 10^?4 M. These concentrations were equally effective in reducing enzyme release, which was taken as an index of cellular damage, and in preserving high energy phosphate contents in the infarcting myocardium. However, the 2 agents exhibited opposite effects on coronary flow rates and mechanical function. Compared with diltiazem metoprolol reduced total coronary flow, cardiac output, and left ventricular work and efficiency immediately after coronary artery ligation. However, diltiazem even favorably influenced the mechanical performance of the isolated heart compared with that of untreated control hearts during the 60 minutes of regional myocardial ischemia. These benefits were similarly apparent when the hearts were paced to the rate of control hearts. The presumed mechanism was coronary vasodilation, because afterload increased as left ventricular power production increased in this model.These results suggest that slow channel inhibition by diltiazem has advantages over beta-receptor antagonism by metoprolol in protecting the infarcting myocardium and that further evaluation of diltiazem in other preparations is warranted.     

Early and longer term effects of gastric bypass surgery on tissue-specific insulin sensitivity and beta cell function in morbidly obese patients with and without type 2 diabetes

Aims/hypothesis

Bariatric surgery consistently induces remission of type 2 diabetes. We tested whether there are diabetes-specific mechanisms in addition to weight loss.

Methods

We studied 25 morbidly obese patients (BMI 51.7?±?1.5?kg/m² [mean?±?SEM]), 13 with non-insulin-treated type 2 diabetes (HbA_1c 7.1?±?0.5% [54?±?5?mmol/mol]), before and at 2?weeks and 1?year after Roux-en-Y gastric bypass (RYGB). Lean (n?=?8, BMI 23.0?±?0.5?kg/m²) and obese (n?=?14) volunteers who were BMI-matched (36.0?±?1.2) to RYGB patients at 1?year after surgery served as controls. We measured insulin-stimulated glucose disposal (M) and substrate utilisation (euglycaemic clamp/indirect calorimetry), endogenous glucose production (EGP) by 6,6-[²H₂]glucose, lipolysis (rate of appearance of [²H₅]glycerol) and beta cell function (acute insulin response to i.v. glucose [AIR] as determined by C-peptide deconvolution).

Results

At baseline, all obese groups showed typical metabolic abnormalities, with M, glucose oxidation and non-oxidative disposal impaired, and EGP, lipolysis, lipid oxidation and energy expenditure increased. Early after RYGB plasma glucose and insulin levels, and energy expenditure had decreased, while lipid oxidation increased, with M, EGP and AIR unchanged. At 1?year post-RYGB (BMI 34.4?±?1.1?kg/m²), all diabetic patients were off glucose-lowering treatment and mean HbA_1c was 5.4?±?0.14% (36?±?2?mmol/mol) (p?=?0.03 vs baseline); AIR also improved significantly. In all RYGB patients, M, substrate oxidation, EGP, energy expenditure and lipolysis improved in proportion to weight loss, and were therefore similar to values in obese controls, but still different from those in lean controls.

Conclusions/interpretation

In morbidly obese patients, RYGB has metabolic effects on liver, adipose tissue, muscle insulin sensitivity and pattern of substrate utilisation; these effects can be explained by energy intake restriction and weight loss, the former prevailing early after surgery, the latter being dominant in the longer term.