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G Anfossi

Publications and source records attributed to G Anfossi.

At least 37 records · Page 2Linked to original sources
PubMed1996

Studies on the influence of insulin on cyclic adenosine monophosphate in human vascular smooth muscle cells: dependence on cyclic guanosine monophosphate and modulation of catecholamine effects.

Insulin increases both cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) in human vascular smooth muscle cells (hVSMC) and attenuates noradrenaline-induced vasoconstriction. In the present study, we aimed at investigation in hVSMC: 1) the interrelationships between insulin-induced increases of cGMP and cAMP; 2) the insulin effect on the catecholamine modulation of cAMP. Catecholamines cause both vasoconstriction and vasodilation. Vasoconstriction is attributable to the reduced synthesis of cAMP in hVSMC through alpha 2-adrenoceptors and to direct effects on calcium fluxes through alpha 1-adrenoceptors; vasodilation is attributable to the increased synthesis of cAMP through beta-adrenoceptors. In the present study, we determined the influence of insulin on cAMP in hVSMC incubated with or without: a) the inhibitor of guanylate cyclase methylene blue or the inhibitor of nitric oxide synthase NG-monomethyl-L-arginine (L-NMMA); b) the beta-adrenergic agonists isoproterenol and salbutamol; c) the physiological catecholamines noradrenaline and adrenaline; d) noradrenaline+the beta-adrenergic antagonist propranolol or the alpha 2-adrenergic antagonist yohimbine; e) noradrenaline+methylene blue of L-NMMA. We demonstrated that: 1) the inhibition of the insulin-induced cGMP synthesis blunts the insulin-induced increase of cAMP; 2) insulin induces a significant increase of cAMP also in the presence of isoproterenol, salbutamol, noradrenaline and adrenaline: the combined effects of insulin and catecholamines were additive in some, but not in all the experiments; 3) insulin enhances the cAMP concentrations induced by noradrenaline also in the presence of alpha 2- or beta-adrenergic antagonists; 4) in the presence of methylene blue or L-NMMA insulin does not modify the noradrenaline effects on cAMP.

Adrenergic alpha-Antagonists↗
PubMed1996

Nonenzymatic glycation of fibronectin impairs adhesive and proliferative properties of human vascular smooth muscle cells.

Nonenzymatic glycation of proteins is involved in the pathogenesis of diabetes vascular complications. Extracellular matrix proteins are a prominent target for nonenzymatic glycation because of their slow turnover rates. The aim of this study was to investigate the influence of human fibronectin (F) nonenzymatic glycation on adhesion and proliferation of cultured human vascular smooth muscle cells (hVSMC). Incubation of human F with 500 mmol/L D-glucose at 37 degrees C induced a time-dependent increase in fluorescence detectable at 440 nm after excitation at 363 nm. Nonenzymatic glycation did not affect binding of F itself to the plates. Adhesion of hVSMC to F increased with the increase of incubation time of the cells on the protein from 30 minutes up to 120 minutes and remained stable thereafter. Adhesion to glycated fibronectin (GF) was reduced in comparison to control F at all the different adhesion times. Adhesion of hVSMC to GF was reduced when F was exposed to glucose for 4, 9, or 28 days (P=.0417 to .0025), but not when F was exposed for 1 day. Adhesion of hVSMC to GF was reduced compared with adhesion to nonglycated F at all coating concentrations from 0.2 to 10 micrograms/mL (P=.05 to .014). Thus, nonenzymatic glycation of F impairs adhesion of hVSMC in vitro. Proliferation of hVSMC on F increased with increasing concentrations of the protein as coating agent (ANOVA:P<.0001 for both nonglycated F and GF). Proliferation with F glycated for 4, 9, and 28 days was reduced at concentrations of 1, 3, and 10 micrograms/mL as compared with proliferation with nonglycated F (P=.0253 to .0001). Proliferation on F glycated for only 1 day was not significantly reduced. When the number of hVSMC plated on control F was reduced by 25% to take into account the reduced adhesion, the number of cells that proliferated on F was still reduced. In conclusion, nonenzymatic glycation of F impairs adhesive and proliferative properties of hVSMC.

Cell Adhesion↗
PubMed1996

Interplay between milrinone and adenosine in the inhibition of human platelet response.

1. In this study, we investigated the influence of the inotropic agent and coronary vasodilator milrinone on platelet aggregation and intracellular levels of 3',5' cyclic adenosine monophosphate (cAMP) in human platelet-rich plasma (PRP) and whole blood (WB). Furthermore, we evaluated the influence of milrinone on the effects of adenosine, which reduces the platelet aggregation through an elevation of intraplatelet cAMP levels. 2. Milrinone decreased the platelet aggregation in response to agonists in both PRP and WB. A dose-dependent increase of intraplatelet cAMP levels was demonstrated: this result is in accordance with an effect on platelet phosphodiesterases. 3. Milrinone at low concentration and adenosine exerted additive effects on platelet aggregation and intraplatelet cAMP levels. 4. An interplay between milrinone and adenosine was shown in WB. Furthermore, dipyridamole, which prevents the uptake of endogenous adenosine, markedly enhanced the milrinone antiaggregating effect, whereas the adenosine receptor blocker, theophylline, decreased it. 5. The present data provide evidence that milrinone modulates the platelet function through an influence on intraplatelet levels of cAMP and it is able to interplay with substances stimulating adenylyl cyclase. 6. The interplay between milrinone and adenosine in the inhibition of the human platelet function could be effective during milrinone administration in the treatment of heart failure, when blood adenosine levels are significantly increased. These milrinone effects could be advantageous from a therapeutic point of view, since patients with heart failure are at risk of thrombosis and ischemic heart disease.

Adenosine↗
PubMed1996

Role of catecholamines in platelet function: pathophysiological and clinical significance.

Platelets are involved in the pathogenesis of vascular damage in both atherosclerosis and arterial hypertension. Their reactivity in vivo is influenced by different factors, including sympathoadrenal activation, plasma levels of atherogenic lipoproteins and haemorrheological changes. In the present review, we examine the modulation of platelet function by the sympathoadrenal system and concentrate on the role of circulating catecholamines in the control of platelet responses. Human platelets exhibit both adrenergic and dopaminergic receptors that are influenced by different catecholamines. alpha(2)-Adrenoceptors of alpha(2A) subtype prevail on platelet membrane; through their stimulation, catecholamines potentiate the effects of other agonists and, at higher concentrations, initiate platelet responses, including aggregation, secretion and arachidonate pathway activation. Physiological and pathological conditions causing sympathoadrenal activation in vivo, i.e. physical activity, mental stress, insulin-induced hypoglycaemia, acute coronary ischaemia and heart failure, modify the circulating platelet populations and modulate platelet reactivity through an increase in circulating catecholamines. A sympathoadrenal hyperactivation modifies the function of circulating platelets through direct catecholamine effects, catecholamine-induced changes of haemodynamic factors and lipid pattern and inhibition of the vascular eicosanoid synthesis. The catecholamine effects on platelet function can be involved in the interplay among stress, adrenomedullary system activation and cardiovascular diseases.

Adrenal Glands↗
PubMed1996

The insulin-induced increase of guanosine-3',5'-cyclic monophosphate in human platelets is mediated by nitric oxide.

To investigate whether the insulin-induced increase of guanosine-3',5'-cyclic monophosphate (cGMP) in human platelets is mediated by nitric oxide or is influenced by the nitric oxide precursor L-arginine, we measured cGMP in platelet-rich plasma obtained from healthy volunteers incubated for 3 min with human recombinant insulin (0, 240, 480, 960, and 1,920 pmol/l) both with and without 1) a 20-min incubation with the nitric oxide-synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA) (50, 70, 100, and 1,000 micromol/l; n = 5 for each dose) and 2) a 20-min incubation with the nitric oxide precursor L-arginine (300 micromol/l; n = 6). In a first set of experiments, insulin induced a dose-dependent cGMP increase, from 9.8 +/- 0.8 to 45.6 +/- 5.5 pmol/10(9) platelets (P = 0.0001); in the presence of 1 mmol/l L-NMMA, this increase was blunted, cGMP being 8.9 +/- 1.4 and 11.1 +/- 2.2 pmol/10(9) platelets at 0 and 1,920 pmol/l insulin, respectively (NS). In the experiments with 70 and 100 micromol/l L-NMMA, the insulin effect on cGMP was inhibited, whereas 50 micromol/l L-NMMA did not blunt this insulin effect. In another set of experiments carried out to investigate the effects of L-arginine, insulin induced a dose-dependent cGMP increase, from 23.6 +/- 6.9 to 59.0 +/- 12.0 pmol/10(9) platelets (P = 0.0001); with L-arginine, basal cGMP values increased to 35.5 +/- 6.6 pmol/10(9) platelets (P = 0.05), and insulin maintained its ability to enhance dose-dependently cGMP values, which rose to 76.8 +/- 19.4 pmol/10(9) platelets (P = 0.003). This study carried out in human platelets demonstrates that the cGMP increase induced by insulin, which accounts for the antiaggregating effect of the hormone, is mediated by nitric oxide.

Adult↗
PubMed1995

Studies on in vitro effect of picotamide on human platelet aggregation in platelet-rich plasma and whole blood.

Picotamide is a new antiaggregating agent influencing the platelet prostaglandin pathway through an inhibition of thromboxane A2 (TXA2) synthesis and a competitive antagonism of platelet TXA2 receptors. In the present study, we investigated the in vitro effect of this drug on human platelet aggregation induced by different agents (adenosine 5'-diphosphate [ADP], collagen, Na arachidonate) both in platelet-rich plasma (PRP; Born's method) and whole blood (WB; impedance method). For each aggregating agent, ED50 value (agonist concentration necessary to induce a maximal aggregation of 50%) was determined in control samples and following addition of different picotamide concentrations on the basis of dose-response curves. Picotamide decreased the response to each aggregating agent in both WB and PRP samples. In WB, 25 microM picotamide was able to induce a highly significant enhancement of ED50 values for ADP (from 6.6 +/- 1 microM to 12.7 +/- 1.7 microM, p < 0.01), Na arachidonate (from 740 +/- 240 microM to 1,080 +/- 280 microM, p < 0.01) and collagen (from 2.4 +/- 0.3 micrograms/ml to 3.8 +/- 0.15 micrograms/ml, p < 0.01). In PRP, the same picotamide concentration significantly enhanced ED50 for each aggregating agent (from 2.0 +/- 0.1 microM to 3.1 +/- 0.3 microM for ADP, p < 0.01; from 960 +/- 80 microM to 1,850 +/- 260 microM for Na arachidonate, p < 0.001; from 3.0 +/- 0.3 microgram/ml to 5.0 +/- 0.8 micrograms/ml for collagen, p < 0.01). Present results show that picotamide effect on platelet response is present also in WB. Data might support the use of picotamide as antiaggregating agent in vascular diseases.

Adenosine Diphosphate↗
PubMed1995

Insulin increases cyclic nucleotide content in human vascular smooth muscle cells: a mechanism potentially involved in insulin-induced modulation of vascular tone.

It has been suggested that insulin exerts a vasodilating effect, but the mechanisms involved are not completely understood. Since cyclic nucleotides mediate the vasodilation induced by endogenous substances, such as prostacyclin and nitric oxide, we aimed to investigate the influence of insulin (concentration range 240-960 pmol/l) on both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) content in human vascular smooth muscle cells. Insulin dose-dependently increased both nucleotides (cAMP: from 0.7 +/- 0.1 to 2.6 +/- 0.4 pmol/10(6) cells, p = 0.0001; cGMP: from 1.3 +/- 0.2 to 3.4 +/- 0.7 pmol/10(6) cells, p = 0.033). This increase is receptor-mediated, since it was blunted when cells were preincubated with the tyrosine kinase inhibitor genistein. The effect of insulin remained significant (p = 0.0001) when preincubation with the phosphodiesterase inhibitor theophylline prevented cyclic nucleotide catabolism. The increase of cGMP was blunted when the cells were preincubated with the guanylate cyclase inhibitor methylene blue, and with the nitric oxide-synthase inhibitor NG-monomethyl-L-arginine. At all the concentrations tested, insulin potentiated the increase of cAMP induced by the stable prostacyclin analogue Iloprost (p = 0.0001), whereas only at 1920 pmol/l did it potentiate the cGMP increase induced by glyceryltrinitrate (p = 0.05). This study demonstrates that the vasodilating effects exerted by insulin may at least in part be attributable to an increase of both cGMP and cAMP via a receptor-mediated activation of adenylate and guanylate cyclases in human vascular smooth muscle cells and that the insulin effect on cGMP is mediated by nitric oxide.

Arterioles↗
PubMed1995

Glyceryl trinitrate enhances the adenosine-induced inhibition of platelet responses: a mechanism potentially involved in the in vivo anti-aggregating effects of organic nitrates.

1. The present study investigated the influence of the organic nitrate glyceryl trinitrate (GTN) on the anti-aggregating effects of adenosine. We determined the effects of adenosine, GTN and their combination on platelet responses in platelet-rich plasma and whole blood, and on intracellular levels of 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP). 2. Adenosine inhibited the in vitro platelet aggregation in response to different agonists in a dose-dependent way through an elevation of intraplatelet cAMP levels. Effective adenosine concentrations were higher than those detectable under physiological conditions, but very close to levels achieved during myocardial ischaemia or haemorrhagic shock. 3. GTN was able to decrease platelet responses influencing intraplatelet cGMP levels. Furthermore, the drug increased the inhibitory effects of adenosine and enhanced its effects on intraplatelet cAMP levels. 4. The present data provides further evidence that compounds that increase intraplatelet levels of cGMP and cAMP act synergistically on the inhibition of platelet aggregability through the influence of increased cGMP levels on cAMP accumulation. The interplay between GTN and adenosine in the inhibition of platelet function could be effective during nitrate administration in the treatment of acute myocardial ischaemia when blood adenosine levels are significantly increased.

Adenosine↗
PubMed1995

Impaired insulin-induced platelet antiaggregating effect in obesity and in obese NIDDM patients.

To investigate the effects of insulin on platelets in obesity and in non-insulin-dependent diabetes mellitus (NIDDM)--classic insulin-resistant states--we determined ADP-induced platelet aggregation and platelet cGMP (guanosine 3',5'-cyclic monophosphate) content in platelet-rich plasma obtained from nine obese subjects and nine age-matched healthy volunteers and from eight NIDDM obese patients and nine age-matched healthy volunteers after a 3-min incubation with human recombinant insulin (0, 240, 480, 960, and 1,920 pmol/l). Platelet aggregation was evaluated using different ADP doses to measure the ADP concentration determined on the basis of a dose-response curve necessary to elicit a maximal aggregation of 50% (ED50). Insulin induced a dose-dependent decrease of platelet aggregation to ADP (P = 0.0001) in healthy subjects. A significant effect was evident starting from an insulin concentration of 240 pmol/l. On the contrary, in insulin-resistant subjects, insulin reduced platelet sensitivity to ADP only at a concentration of 1,920 pmol/l. When ADP ED50 values obtained in platelet-rich plasma incubated with insulin were expressed in percentage of the ADP ED50 values obtained in platelet-rich plasma without insulin, considered as 100%, we observed that ADP ED50 with 1,920 pmol/l insulin was 153.6 +/- 13.2% in the younger healthy subject group (P = 0.004), 150.0 +/- 3.8% in the older healthy subject group (P = 0.0001), 116.1 +/- 6.1% in obese subjects (P = 0.031), and 120.0 +/- 8.6% in NIDDM patients (P = 0.05). In healthy subjects, insulin induced a dose-dependent increase of platelet cGMP (P = 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗
PubMed1994

Effects of forskolin and organic nitrate on aggregation and intracellular cyclic nucleotide content in human platelets.

1. The present study investigated the effect of a combination between forskolin, a naturally occurring diterpene which directly activates adenylyl cyclase, and glyceryl trinitrate (GTN), which enhances intraplatelet cyclic guanosine monophosphate levels, on human platelet aggregation and intracellular content of cyclic nucleotides 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP). 2. Forskolin inhibited, in a dose-dependent way, platelet aggregation in response to collagen and adrenaline in platelet-rich plasma. In whole blood samples, forskolin inhibited collagen-stimulated aggregation. In presence of forskolin the intraplatelet cAMP levels were significantly increased. 3. GTN directly decreased the platelet response to collagen in whole blood samples (IC50 = 122 mumol/l) and it increased the intraplatelet levels of both cGMP and cAMP. 4. GTN at 20 and 40 mumol potentiated the inhibitory effects of forskolin on platelet aggregation in both platelet-rich plasma and whole blood. 5. Our results suggest a synergistic effect of the simultaneous increase of both cAMP and cGMP on the biochemical steps involved in the inhibition of the platelet response.

Adult↗
PubMed1994

Na+/H+ antiporter activity in peripheral blood lymphocytes of obese and type 2 diabetic patients is increased only in the presence of arterial hypertension.

The aim of this work is to evaluate whether type 2 diabetes mellitus, obesity and arterial hypertension, three conditions characterized by the presence of insulin resistance, share some common genetic markers. A potential candidate is the Na+/H+ antiporter, the increased activity of which is considered a marker of essential hypertension. This ion exchanger seems to be related to the Na+/Li+ countertransport, that is considered a marker of insulin resistance in essential hypertension and in type 1 diabetes mellitus. In this study we wished to clarify whether the activity of the Na+/H+ antiporter is increased not only in hypertensive subjects, but also in obese and type 2 diabetic patients, both in the presence and in the absence of arterial hypertension. The activity of the ion exchanger was measured in peripheral blood lymphocytes (PBL) by clamping intracellular pH (pHi) at 5.8-6.2 and then detecting the rate of the proton efflux after sodium addition. In the absence of arterial hypertension, no significant difference in this parameter was observed in obese and type 2 diabetic patients in comparison with normal subjects. In the presence of arterial hypertension, there was a significant increase in the Na(+)-induced H+ efflux at the internal pH (pHi) values of 5.8 and 6.2 both in hypertensive controls and in hypertensive obese and type 2 diabetic patients (P = 0.05-0.0001 vs. normotensive subjects and patients).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Insulin increases guanosine-3',5'-cyclic monophosphate in human platelets. A mechanism involved in the insulin anti-aggregating effect.

To investigate whether insulin reduces platelet aggregability through a modulation of the guanosine-3',5'-cyclic monophosphate (cGMP) concentrations, we determined by a radioimmunoassay the cGMP values in the platelet-rich plasma (PRP) obtained from 17 healthy volunteers and incubated for 3 min with different concentrations of human recombinant insulin (0, 240, 480, 720, 960, and 1,920 pM). Insulin induced a dose-dependent cGMP increase, from 18.5 +/- 3.3 to 42.0 +/- 6.4 pmol/10(9) platelets (P = 0.0001). This increase was completely blunted when PRP was preincubated for 20 min with the tyrosine kinase inhibitor genistein (10 microM) or with the guanylate cyclase inhibitor methylene blue (10 microM), but the increase remained highly significant (P = 0.003 and 0.009) when PRP was preincubated for 20 min with the phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine (IBMX, 500 microM) or with the nitric oxide synthase inhibitor NG-mono-methyl-L-arginine (L-NMMA, 30 microM). Finally, the insulin-induced decrease of platelet aggregability to collagen and ADP was completely blunted when PRP was preincubated with 10 microM of the guanylate cyclase inhibitor methylene blue. This study demonstrates that the platelet anti-aggregatory effect exerted by insulin is attributable to the insulin-induced increase of cGMP that is due to a direct receptor-mediated platelet guanylate cyclase activation.

1-Methyl-3-isobutylxanthine↗
PubMed1994

Expression of the c-myc protooncogene product in cells infected with the hepatitis delta virus.

The intrahepatic accumulation of the c-myc protooncogene product was observed on immunofluorescence in each of six patients with chronic hepatitis delta virus infection who exhibited the hepatitis D antigen in their livers. The c-myc product was stained in the same nuclei that contained the hepatitis D antigen. C-myc was not observed in acute hepatitis D or in cases of chronic hepatitis delta virus infection without expression of the hepatitis D antigen. The protooncogene product was detected in only 1 of 32 viral and nonviral liver disorders unrelated to hepatitis delta virus. To confirm these observations, we transfected HBsAg-positive (PCL/PRF/5) and HBsAg-negative (HepG2) transformed liver cell lines with a plasmid containing a hepatitis delta virus cDNA trimer under the control of the SV40 early enhancer/promoter sequences. Whereas baseline c-myc expression was barely detectable in mock-transfected PLC/PRF/5 or HepG2 cells, strong c-myc nuclear fluorescence was observed when these same cells were transfected with the hepatitis D antigen expression vector. Similar results were obtained after infection of HeLa cells with a recombinant vaccinia virus expressing the hepatitis D antigen. Detection of c-myc mRNA sequences by means of in situ hybridization suggested that the c-myc product accumulation was not due to increased amounts of its mRNA. The c-myc protein accumulates selectively in the livers of patients with chronic hepatitis delta virus infection and in the same nuclei that contain the hepatitis D antigen. The expression of c-myc in hepatitis D antigen-containing cells does not require the presence of hepatitis B virus infection.

Amino Acid Sequence↗
PubMed1993

Insulin influences immunoreactive endothelin release by human vascular smooth muscle cells.

This study sought to investigate whether insulin influences immunoreactive endothelin release from cultured human vascular smooth muscle cells. For this purpose, we incubated cultured vascular smooth muscle cells (VSMC) obtained from human microvessels with 0, 80, and 320 microU/mL insulin with or without arginine vasopressin (10 nmol/L) and angiotensin II (10 nmol/L). After 6 hours, the culture supernatant was collected and immunoreactive endothelin was determined by radioimmunoassay. Insulin at a concentration of 320 microU/mL induced a significant increase of immunoreactive endothelin levels in medium (from 15.2 +/- 0.8 to 20.6 +/- 0.8 pg/200 microL, P < .01) and potentiated arginine vasopressin- and angiotensin II-induced immunoreactive endothelin release (P < .0001 and P < .04, respectively). Insulin at a concentration of 80 microU/mL did not induce a significant increase of spontaneous immunoreactive endothelin release, but significantly increased the effects of arginine vasopressin (P < .05). In conclusion, insulin influences immunoreactive endothelin release from human VSMC in culture.

Angiotensin II↗
PubMed1993

Effect of dopamine on adenosine 3',5'-cyclic monophosphate levels in human platelets.

1. The dopamine effect on intraplatelet adenosine 3',5'-cyclic monophosphate (cAMP) levels was evaluated in healthy subjects. 2. Dopamine levels over 30 nmol/l increased cAMP concentration in a concentration-dependent way. 3. The platelet preincubation with propranolol (beta-adrenoceptor antagonist) prevented the dopamine effect, whereas phentolamine (alpha-adrenoceptor antagonist) failed to modify the platelet response to this catecholamine. Dopamine receptor antagonist domperidone directly increased cAMP levels and it enhanced the dopamine effects. 4. Our results indicate that dopamine effect is mainly mediated by beta-adrenoceptor stimulation.

Adult↗
PubMed1993

Organic nitrates and compounds that increase intraplatelet cyclic guanosine monophosphate (cGMP) levels enhance the antiaggregating effects of the stable prostacyclin analogue iloprost.

The present study investigated the effect of a combination between the stable prostacyclin (PGI2) analogue iloprost and compounds, glyceryl trinitrate (GTN) and L-arginine-, which enhance the intraplatelet cyclic guanosine monophosphate (cGMP) levels on platelet aggregation, release reaction and cyclic nucleotide content: in particular cyclic adenosine monophosphate (cAMP) and cGMP. Iloprost inhibited in a dose-dependent way the platelet aggregation in response to collagen, adenosine diphosphate (ADP) and adrenaline and it increased the intraplatelet cAMP concentrations. GTN directly decreased the platelet responses and increased the intraplatelet levels of both cGMP and cAMP. GTN (20 x 10(-6) mol/l) and L-arginine (0.2 x 10(-3) mol/l) potentiated the inhibitory effects of iloprost on platelet aggregation and release reaction. Our results suggest: 1. A synergistic effect of the simultaneous increase of both cAMP and cGMP on the biochemical steps involved in the inhibition of the platelet response; 2. An influence of cGMP on cAMP accumulation.

1-Methyl-3-isobutylxanthine↗