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M P Macedo

Publications and source records attributed to M P Macedo.

16 recordsLinked to original sources
PubMed2005

Insulin resistance induced by sucrose feeding in rats is due to an impairment of the hepatic parasympathetic nerves.

AIMS/HYPOTHESIS: A considerable proportion of whole-body insulin-stimulated glucose uptake is dependent upon the hepatic insulin-sensitising substance (HISS) in a pathway mediated by the hepatic parasympathetic nerves (HPNs). We tested the hypothesis that a high-sucrose diet leads to the impairment of the HPN-dependent component of insulin action. METHODS: We quantified insulin sensitivity using the rapid insulin sensitivity test, a modified euglycaemic clamp. Quantification of the HPN-dependent component was achieved by administration of a muscarinic receptor antagonist (atropine, 3 mg/kg). RESULTS: Insulin sensitivity was higher in standard-fed than in sucrose-fed Wistar rats (305.6+/-34.1 vs 193.9+/-13.7 mg glucose/kg body weight; p<0.005) and Sprague-Dawley rats (196.4+/-5.9 vs 95.5+/-16.3 mg glucose/kg body weight; p<0.01). The HPN-independent component was similar in the two diet groups. Insulin resistance was entirely due to an impairment of the HPN-dependent component in both Wistar rats (164.3+/-28.1 [standard-fed] vs 26.5+/-7.5 [sucrose-fed] mg glucose/kg body weight; p<0.0001) and Sprague-Dawley rats (111.7+/-9.5 vs 35.3+/-21.4 mg glucose/kg body weight; p<0.01). Furthermore, HPN-dependent insulin resistance in Sprague-Dawley rats was already evident after 2 weeks of a high-sucrose diet (28.5+/-7.6 [2 weeks], 35.3+/-21.4 [6 weeks], 17.9+/-5.4 [9 weeks] mg glucose/kg body weight) and was independent of the nature of sucrose supplementation (12.3+/-4.7 [solid] and 17.9+/-5.4 [liquid] mg glucose/kg body weight). CONCLUSIONS/INTERPRETATION: Our results support the hypothesis that insulin resistance caused by sucrose feeding is due to an impairment of the HPN-dependent component of insulin action, leading to a dysfunction of the HISS pathway.

Animals↗
PubMed2001

Hepatic parasympathetic (HISS) control of insulin sensitivity determined by feeding and fasting.

In response to insulin, a hormone [hepatic insulin sensitizing substance (HISS)] is released from the liver to stimulate glucose uptake in skeletal muscle but not liver or gut. The aim was to characterize dynamic control of HISS action in response to insulin and regulation of release by hepatic parasympathetic nerves. Insulin action was assessed by the rapid insulin sensitivity test, where the index is the glucose required (mg/kg) to maintain euglycemia after a bolus of insulin. Blocking HISS release by interruption of the hepatic parasympathetic nerves by surgical denervation, atropine, or blockade of hepatic nitric oxide synthase produced similar degrees of insulin resistance and revealed a similar dynamic pattern of hormone action that began 3--4 min after, and continued for 9--10 min beyond, insulin action (50 mU/kg). HISS action accounted for 56.5 +/- 3.5% of insulin action at insulin doses from 5 to 100 mU/kg (fed). We also tested the hypothesis that HISS release is controlled by the feed/fast status. Feeding resulted in maximal HISS action, which decreased progressively with the duration of fasting.

Anesthesia↗
PubMed2000

Tonic activation of A(2A) adenosine receptors unmasks, and of A(1) receptors prevents, a facilitatory action of calcitonin gene-related peptide in the rat hippocampus.

1. We investigated how manipulations of the degree of activation of adenosine A(1) and A(2A) receptors influences the action of the neuropeptide, calcitonin gene-related peptide (CGRP) on synaptic transmission in hippocampal slices. Field excitatory post-synaptic potentials (EPSPs) from the CA1 area were recorded. 2. When applied alone, CGRP (1 - 30 nM) was without effect on field EPSPs. However, CGRP (10 - 30 nM) significantly increased the field EPSP slope when applied to hippocampal slices in the presence of the A(1) receptor antagonist, 1,3-dipropyl-8-cyclopenthyl xanthine (DPCPX, 10 nM), or in the presence of the A(2A) adenosine receptor agonist CGS 21680 (10 nM). 3. The A(2A) receptor antagonist, ZM 241385 (10 nM) as well as adenosine deaminase (ADA, 2 U ml(-1)), prevented the enhancement of field EPSP slope caused by CGRP (30 nM) in the presence of DPCPX (10 nM), suggesting that this effect of CGRP requires the concomitant activation of A(2A) adenosine receptors by endogenous adenosine. 4. The protein kinase-A inhibitors, N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA-1004, 10 microM) and adenosine 3',5'-cyclic monophosphorothioate, Rp-isomer (Rp-cAMPS, 50 microM), as well as the inhibitor of ATP-sensitive potassium (K(ATP)) channels, glibenclamide (30 microM), prevented the facilitation of synaptic transmission caused by CGRP (30 nM) in the presence of DPCPX (10 nM), suggesting that this effect of CGRP involves both K(ATP) channels and protein kinase-A. 5. It is concluded that the ability of CGRP to facilitate synaptic transmission in the CA1 area of the hippocampus is under tight control by adenosine, with tonic A(1) receptor activation by endogenous adenosine 'braking' the action of CGRP, and the A(2A) receptors triggering this action.

ATP-Binding Cassette Transporters↗
PubMed1998

Rapid insulin sensitivity test (RIST).

A rapid insulin sensitivity test (RIST) was recently introduced to assess insulin action in vivo (H. Xie, L. Zhu, Y.L. Zhang, D.J. Legare, and W.W. Lautt. J. Pharmacol. Toxicol. Methods, 35: 77-82. 1996). This technical report describes the current recommended standard operating procedure for the use of the RIST in rats based upon additional experience with approximately 100 tests. We describe the manufacture and use of an arterial-venous shunt that allows rapid multiple arterial samples and intravenous administration of drugs. The RIST procedure involves determination of a stable arterial glucose baseline to define the ideal euglycemic level to be maintained following a 5-min infusion of insulin, with the RIST index being the amount of glucose required to be infused to maintain euglycemia over the test period. Insulin administration by a 5-min infusion is preferable to a 30-s bolus administration. No significant difference was determined between the use of Toronto pork-beef or human insulin. Four consecutive RISTs were carried out in the same animal over 4-5 h with no tendency for change with time. The RIST index is sufficiently sensitive and reproducible to permit establishment of insulin dose-response curves and interference of insulin action by elimination of hepatic parasympathetic nerves, using atropine. This technical report provides the current recommended standard operating procedure for the RIST.

Animals↗
PubMed1998

Shear-induced modulation of vasoconstriction in the hepatic artery and portal vein by nitric oxide.

The effect of shear stress on nitric oxide (NO)-mediated suppression of sympathetic nerve (2-6 Hz)- and norepinephrine (0.5 microgram.kg-1.min-1)-induced vasoconstriction in the hepatic artery (HA) and portal vein (PV) was studied using a perfusion circuit to regulate blood pressure and flow in the cat liver in situ. Holding flow constant resulted in increased shear stress during constriction; holding pressure steady prevented changes in shear stress. When shear stress was allowed to rise, the vasoconstriction (indicated by elevation in perfusion pressure) in response to nerve stimulation and norepinephrine was significantly potentiated after NO synthase blockade using NG-nitro-L-arginine methyl ester (L-NAME, 2.5 mg/kg iv) in both the HA and PV (response to nerves: HA control 28.8 +/- 6.5 mmHg, L-NAME 62.7 +/- 14.6 mmHg; PV control 1.5 +/- 0.5 mmHg, L-NAME 3.3 +/- 0.5 mmHg; response to norepinephrine: HA control 32.4 +/- 9.0 mmHg, L-NAME 60.3 +/- 8.0 mmHg; PV control 1.3 +/- 0.3 mmHg, L-NAME 3.4 +/- 0.7 mmHg). The potentiation was reversed by L-arginine (75 mg/kg). When shear stress was held constant by maintaining constant perfusion pressure, L-NAME did not cause potentiation of vasoconstriction. The data are consistent with the hypothesis that elevated shear stress in the hepatic blood vessels leads to NO-dependent postjunctional modulation of vasoconstriction.

Animals↗
PubMed1997

Potentiation to vasodilators by nitric oxide synthase blockade in superior mesenteric but not hepatic artery.

Our objective was to determine the vasodilator effect of adenosine and isoproterenol on the hepatic artery (HA) and superior mesenteric artery (SMA) before and after blockade of nitric oxide (NO) production to evaluate the possibility of organ specificity. Vascular circuits supplied blood flow to the liver or intestine in cats under pentobarbital sodium anesthesia. The NO synthase (NOS) antagonist N(G)-nitro-L-arginine methyl ester (L-NAME; 2.5 mg/kg iv) increased arterial pressure from 106.4 +/- 7.6 to 141.4 +/- 8.1 mmHg and raised basal vascular tone in the SMA but not in the HA. The NOS substrate L-arginine (75 mg/kg) reversed these effects. The decrease in perfusion pressure in response to adenosine was 51.7 +/- 2.9, 135.2 +/- 6.1, and 16.7 +/- 2.4 mmHg, respectively, for control and after L-NAME and L-arginine. Isoproterenol was also potentiated in the SMA. Adenosine and isoproterenol were not potentiated in the HA by L-NAME. Potentiation did not occur when HA or SMA basal tone was elevated by norepinephrine. In conclusion, L-NAME increased basal tone for the SMA and potentiated the dilation induced by adenosine and isoproterenol in the SMA but not in the HA. This study provides evidence that there is a highly organ-specific compensatory mechanism in which the absence of NO promotes potentiation of other vasodilators.

Adenosine↗
PubMed1996

Autoregulatory capacity in the superior mesenteric artery is attenuated by nitric oxide.

The hypothesis that nitric oxide antagonizes pressure-flow autoregulation in the superior mesenteric artery was tested with the use of a nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), and L-arginine. Autoregulation was assessed with the use of two indexes: 1) the autoregulatory index (ARI), expressed as the ratio of change in flow to change in pressure tested over the nonautoregulatory range, 40-70 mmHg, and over the autoregulatory range, 70-140 mmHg; and 2) the slope index, an index of linearity of the pressure-flow curve calculated by dividing the slope of the pressure-flow curve over the autoregulatory range by the slope of the curve over the nonautoregulatory range, expressed as percent. L-NAME significantly increased autoregulation from an ARI of 0.06 +/- 0.05 to 0.28 +/- 0.09 over the autoregulatory range (P < 0.003), and the nitric oxide synthase substrate L-arginine reversed ARI to 0.12 +/- 0.07 (mean +/- SE, n = 7). ARI in the nonautoregulatory range was not altered. The slope index revealed that L-NAME enhanced autoregulation (61 +/- 5.6 compared with control, 93.4 +/- 7.9; P < 0.003), which was reversed by the action of L-arginine (88.5 +/- 5.5, P < 0.007). The data were consistent with the hypothesis that increased flow leads to nitric oxide-induced dilation, which counteracts autoregulation.

Animals↗
PubMed1996

Shear-induced modulation by nitric oxide of sympathetic nerves in the superior mesenteric artery.

We tested the hypothesis that nerve-induced constriction is modulated by nitric oxide only if shear stress is allowed to increase. Shear stress is the effect of moving fluid producing distortion of endothelial cells. Blood flow to the superior mesenteric artery in anesthetized cats was controlled using a perfusion circuit. Shear stress was increased by holding blood flow constant during vasoconstriction induced by nerve stimulation (2 and 10 Hz) or infusion of norepinephrine (0.5 microgram.kg-1.min-1). The increase in perfusion pressure in response to nerve stimulation when shear stress was allowed to rise was 24.8 +/- 4.7 mmHg (1 mmHg = 133.3 Pa) (2 Hz) and 100.0 +/- 17.8 mmHg (10 Hz). After NO synthase blockade using NG-nitro-L-arginine methyl ester (L-NAME) (2.5 mg/kg i.v.) potentiation occurred (74.0 +/- 21.6 mmHg at 2 Hz and 151.9 +/- 14.1 mmHg at 10 Hz). Potentiation was reversed after L-arginine (75 mg/kg i.v.). When shear stress was held constant, L-NAME did not affect the responses to nerve stimulation. In contrast, the vasoconstriction to norepinephrine was not affected by L-NAME. The data are compatible with the hypothesis that if vasoconstriction leads to increased shear stress, release of nitric oxide produces vasodilation subsequent to decreased sympathetic nerve activity. The absence of a similar effect with norepinephrine suggests that the shear-dependent release of nitric oxide at the site of constriction does not act directly on the vascular smooth muscle in the small resistance vessels.

Animals↗