15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and Diabetes-Mellitus--Type-2

Postprandial hyperglycemia is associated with platelet activation. We thus investigated if meal-induced platelet activation could be attenuated by meal insulin. A randomized, double-blind, cross-over study was performed to compare postprandial platelet activation after premeal injections of placebo or insulin aspart (0.1 and 0.2 units/kg) in 18 patients with type 2 diabetes mellitus (T2DM). Platelet activation was assessed by flow cytometry, without and with stimulation by the thromboxane analog U46619 or ADP. Measurements were before and after premeal blood glucose standardization (to 6-7 mmol/L by insulin infusion, if needed) and at 90 min after the meal. Premeal insulin reduced postprandial hyperglycemia by 2-3 mmol/L compared with placebo. Postmeal insulin levels were doubled with placebo and further elevated with insulin injections. The standardized meal enhanced U46619-induced platelet P-selectin expression by 23% after placebo; this response was more than doubled after premeal insulin. U46619-induced fibrinogen binding was unchanged after meal intake with placebo but was markedly enhanced (by ~50-60%) after premeal insulin. Postprandial platelet activation correlated positively to postprandial insulin levels and inversely to glucose levels. Premeal insulin infusion was also associated with platelet activation. Our results suggest that postprandial insulin rather than glucose accounts for postprandial platelet activation in T2DM patients.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Aged; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Insulin; Insulin Aspart; Male; Middle Aged; P-Selectin; Platelet Activation; Postprandial Period

Diabetic coronary artery injury is closely associated with Ca

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Calcium; Calcium Channels, L-Type; Coronary Vessels; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Nifedipine; Rats; Rats, Zucker; Serotonin

We tested the hypothesis that crosstalk between cardiomyocyte-rich perivascular tissue (PVT) and coronary arteries is altered in diabetes.. We studied the vasoactive effects of PVT in arteries from the Zucker Diabetic Fatty (ZDF) rat model of type 2 diabetes, streptozotocin (STZ)-treated Wistar rats with type 1 diabetes, and corresponding - heterozygous Zucker Lean (ZL) or vehicle-treated Wistar - control rats. Vasocontractile and vasorelaxant functions of coronary septal arteries with and without PVT were investigated using wire myography.. After careful removal of PVT, vasoconstriction in response to serotonin and thromboxane analogue U46619 was similar in arteries from ZDF and ZL rats, whereas depolarization-induced vasoconstriction - caused by elevating extracellular [K. Anticontractile influences of PVT are attenuated in coronary arteries from ZDF rats but unaffected in arteries from STZ-treated rats. Signs of endothelial dysfunction are evident in coronary septal arteries - with and without PVT - from ZDF rats but not STZ-treated rats. We propose that altered signalling between cardiomyocyte-rich PVT and coronary arteries can contribute to cardiovascular complications in type 2 diabetes mellitus.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Coronary Vessels; Diabetes Mellitus, Type 2; Endothelium, Vascular; Male; Myocytes, Cardiac; Rats; Rats, Wistar; Rats, Zucker; Serotonin; Vasoconstriction; Vasodilation

We studied the relationship between 3-phosphoinositide-dependent protein kinase 1 (PDK1) and contractions induced by serotonin, phenylephrine, and thromboxane A

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 3-Phosphoinositide-Dependent Protein Kinases; Animals; Carotid Arteries; Chronic Disease; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Disease Models, Animal; Indazoles; Male; Nitric Oxide; Nitric Oxide Synthase; Phenylephrine; Pyrimidines; Rats; Rats, Wistar; Serotonin; Signal Transduction; Thromboxane A2; Vasoconstriction; Vasoconstrictor Agents

We previously determined that augmented EGFR tyrosine kinase (EGFRtk) impairs vascular function in type 2 diabetic mouse (TD2). Here we determined that EGFRtk causes vascular dysfunction through NADPH oxidase activity in TD2. Mesenteric resistance arteries (MRA) from C57/BL6 and db-/db- mice were mounted in a wired myograph and pre-incubated for 1h with either EGFRtk inhibitor (AG1478) or exogenous EGF. The inhibition of EGFRtk did not affect the contractile response to phenylephrine-(PE) and thromboxane-(U46619) or endothelium-dependent relaxation (EDR) to acetylcholine in MRA from control group. However, in TD2 mice, AG1478 reduced the contractile response to U46619, improved vasodilatation and reduced p22phox-NADPH expression, but had no effect on the contractile response to PE. The incubation of MRA with exogenous EGF potentiated the contractile response to PE in MRA from control and diabetic mice. However, EGF impaired the EDR and potentiated the vasoconstriction to U46619 only in the control group. Interestingly, NADPH oxidase inhibition in the presence of EGF restored the normal contraction to PE and improved the EDR but had no effect on the potentiated contraction to U46619. Vascular function improvement was associated with the rescue of eNOS and Akt and reduction in phosphorylated Rho-kinase, NOX4 mRNA levels, and NADPH oxidase activity. MRA from p47phox-/- mice incubated with EGF potentiated the contraction to U46619 but had no effect to PE or ACh responses. The present study provides evidence that augmented EGFRtk impairs vascular function by NADPH oxidase-dependent mechanism. Therefore, EGFRtk and oxidative stress should be potential targets to treat vascular dysfunction in TD2.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Cytochrome b Group; Diabetes Mellitus, Type 2; Diabetic Angiopathies; ErbB Receptors; Mice; Mice, Knockout; NADPH Oxidase 4; NADPH Oxidases; Phenylephrine; Quinazolines; Tyrphostins; Vasoconstriction; Vasodilation

Although it is known that blood vessels undergo remodeling in type 2 diabetes (T2D), the signaling pathways that underlie the structural and functional changes seen in diabetic arteries remain unclear. Our objective was to determine whether the remodeling in type 2 diabetic Goto-Kakizaki (GK) rats is evoked by elevated reactive oxygen species (ROS). Our results show that aortas from GK rats produced greater force (P < 0.05) in response to stimulation with KCl and U46619 than aortas from Wistar rats. Associated with these changes, aortic expression of contractile proteins (measured as an index of remodeling) and the microRNA (miR-145), which act to upregulate transcription of contractile protein genes, was twofold higher (P < 0.05) in GK than Wistar (age-matched control) rats, and there was a corresponding increase in ROS and decrease in nitric oxide signaling. Oral administration of the antioxidant Tempol (1 mmol/l) to Wistar and GK rats reduced (P < 0.05) myocardin and calponin expression. Tempol (1 mmol/l) decreased expression of miR-145 in Wistar and GK rat aorta. To elucidate the mechanism through which ROS increases miR-145, we measured their levels in freshly isolated aorta and cultured aortic smooth muscle cells incubated for 12 h in the presence of H2O2 (300 μmol/l). H2O2 increased expression of miR-145, and there were corresponding nuclear increases in myocardin, a miR-145 target protein. Intriguingly, H2O2-induced expression of miR-145 was decreased by U0126 (10 μmol/l), a MEK1/2 inhibitor, and myocardin was decreased by anti-miR-145 (50 nmol/l) and U0126 (10 μmol/l). Our novel findings demonstrate that ROS evokes vascular wall remodeling and dysfunction by enhancing expression of contractile proteins in T2D.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Aorta; Butadienes; Calcium-Binding Proteins; Calponins; Cells, Cultured; Cyclic N-Oxides; Diabetes Mellitus, Type 2; Microfilament Proteins; MicroRNAs; Muscle, Smooth, Vascular; Myosins; Nitric Oxide; Nitriles; Nuclear Proteins; Potassium Chloride; Protein Kinase Inhibitors; Rats; Rats, Wistar; Reactive Oxygen Species; Spin Labels; Trans-Activators; Transcription, Genetic; Up-Regulation; Vasoconstrictor Agents

Type 2 diabetes is associated with stroke and cardiac dysfunction. We therefore investigated isolated middle cerebral arteries and coronary septal arteries from the diabetic Goto-Kakizaki (GK) rat model of nonobese type 2 diabetes.. Myogenic tone and agonist-induced responses were investigated under isobaric conditions with simultaneous recording of [Ca2+]i. Rho-kinase and NO pathways were investigated using specific pharmacological tools.. Arteries from GK rats developed less tone at pressures from 20 to 100 mm Hg than arteries from control Wistar (CW) rats while [Ca2+]i was similar. Blocking the Rho-kinase pathway decreased the pressure-induced development of tone and after blockade no difference in myogenic tone between arteries from GK and CW rats was seen. Cerebral arteries had similar tone to a maximal concentration of U46619 (GK: 35.5±2% vs. CW: 31.6±5%), while coronary arteries from GK rats developed less tone than arteries from CW rats (12±3 vs. 26.1±3%). Endothelium-dependent vasodilation to A23187 (cerebral) and to acetylcholine (coronary) was not different between arteries from GK and CW rats.. Our data suggest that in resistance arteries from the brain and the heart of GK rats the myogenic tone is decreased due to impaired calcium sensitivity likely due to a defective Rho-kinase pathway.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Amides; Animals; Blood Glucose; Calcium; Coronary Vessels; Diabetes Mellitus, Type 2; Disease Models, Animal; Male; Middle Cerebral Artery; Nitric Oxide; Protein Kinase C; Pyridines; Rats; Rats, Wistar; rho-Associated Kinases

We have previously shown transient receptor potential vanilloid subtype 1 (TRPV1) channel-dependent coronary function is compromised in pigs with metabolic syndrome (MetS). However, the mechanisms through which TRPV1 channels couple coronary blood flow to metabolism are not fully understood. We employed mice lacking TRPV1 [TRPV1((-/-))], db/db diabetic, and control C57BKS/J mice to determine the extent to which TRPV1 channels modulate coronary function and contribute to vascular dysfunction in diabetic cardiomyopathy. Animals were subjected to in vivo infusion of the TRPV1 agonist capsaicin to examine the hemodynamic actions of TRPV1 activation. Capsaicin (1-100 μg·kg(-1)·min(-1)) dose dependently increased coronary blood flow in control mice, which was inhibited by the TRPV1 antagonist capsazepine or the nitric oxide synthase (NOS) inhibitor N-nitro-l-arginine methyl ester (L-NAME). In addition, the capsaicin-mediated increase in blood flow was attenuated in db/db mice. TRPV1((-/-)) mice exhibited no changes in coronary blood flow in response to capsaicin. Vasoreactivity studies in isolated pressurized mouse coronary microvessels revealed a capsaicin-dependent relaxation that was inhibited by the TRPV1 inhibitor SB366791 l-NAME and to the large conductance calcium-sensitive potassium channel (BK) inhibitors iberiotoxin and Penetrim A. Similar to in vivo responses, capsaicin-mediated relaxation was impaired in db/db mice compared with controls. Changes in pH (pH 7.4-6.0) relaxed coronary vessels contracted to the thromboxane mimetic U46619 in all three groups of mice; however, pH-mediated relaxation was blunted in vessels obtained from TRPV1((-/-)) and db/db mice compared with controls. Western blot analysis revealed decreased myocardial TRPV1 protein expression in db/db mice compared with controls. Our data reveal TRPV1 channels mediate coupling of myocardial blood flow to cardiac metabolism via a nitric oxide-dependent, BK channel-dependent pathway that is corrupted in diabetes.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Anilides; Animals; Capsaicin; Cinnamates; Coronary Vessels; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Enzyme Inhibitors; Large-Conductance Calcium-Activated Potassium Channels; Male; Mice; Mice, Inbred C57BL; Microvessels; NG-Nitroarginine Methyl Ester; Nitric Oxide; Peptides; TRPV Cation Channels; Vasoconstrictor Agents; Vasodilation

We investigated the effects of cardiopulmonary bypass (CPB) on peripheral arteriolar reactivity and associated signaling pathways in poorly controlled (UDM), controlled (CDM), and case-matched nondiabetic (ND) patients undergoing coronary artery bypass grafting (CABG).. Skeletal muscle arterioles were harvested before and after CPB from the UDM patients (hemoglobin A1c [HbA1c]=9.0 ± 0.3), the CDM patients (HbA1c=6.3 ± 0.15), and the ND patients (HbA1c=5.2 ± 0.1) undergoing CABG surgery (n=10/group). In vitro relaxation responses of precontracted arterioles to endothelium-dependent vasodilators adenosine 5'-diphosphate (ADP) and substance P and the endothelium-independent vasodilator sodium nitroprusside (SNP) were examined. The baseline responses to ADP, substance P, and SNP of arterioles from the UDM patients were decreased as compared with microvessels from the ND or CDM patients (P<0.05). The post-CPB relaxation responses to ADP and substance P were significantly decreased in all 3 groups compared with pre-CPB responses (P<0.05). However, these decreases were more pronounced in the UDM group (P<0.05). The post-CPB response to SNP was significantly decreased only in the UDM group, not in the other 2 groups compared with pre-CPB. The expression of protein kinase C (PKC)-α, PKC-β, protein oxidation, and nitrotyrosine in the skeletal muscle were significantly increased in the UDM group as compared with those of ND or CDM groups (P<0.05).. Poorly controlled diabetes results in impaired arteriolar function before and after CPB. These alterations are associated with the increased expression/activation of PKC-α and PKC-β and enhanced oxidative and nitrosative stress.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adenosine Diphosphate; Aged; Arterioles; Cardiopulmonary Bypass; Coronary Artery Bypass; Cyclic AMP-Dependent Protein Kinases; Diabetes Mellitus, Type 2; Disease Susceptibility; Endothelium, Vascular; Enzyme Induction; Female; Gene Expression Regulation; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Inflammation; Male; Microcirculation; Middle Aged; Muscle, Skeletal; Nitroprusside; Phosphorylation; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-akt; Substance P; Tyrosine; Vasoconstriction; Vasodilator Agents

In non-obese diabetic animals, protease-activated receptor-2 (PAR2) agonists are more effective vasodilators, which is attributed to increased COX-2 and endothelial NOS (eNOS) activities. Under conditions of diabetes and obesity, the effectiveness of PAR2 agonists is unknown. We compared the vasodilator responses of small calibre mesenteric arteries from obese diabetic B6.BKS(D)-Lepr(db) /J (db/db) induced by PAR2-activating agonists 2-furoyl-LIGRLO-amide (2fly) and trypsin to those obtained in controls [C57BL/6J (C57)], and assessed the contributions of COX, NOS and calcium-activated potassium channels (K(Ca)) to these responses.. Arteries mounted in wire myographs under isometric tension conditions were contracted submaximally by U46619 then exposed to vasodilators. mRNA and protein expression of PAR2, eNOS and soluble GC (sGC) were determined by real-time PCR and Western blots.. ACh- and nitroprusside-induced relaxations were attenuated in db/db compared with C57. In contrast, 2fly- and trypsin-induced relaxations were largely retained in db/db. A NOS inhibitor partly inhibited ACh- and 2fly-induced relaxations in C57, but not those in db/db. Inhibitors of the COX-cAMP pathway (FR122044, SC560, NS398, SC58125, SQ22536, CAY10441) did not affect these relaxation responses in either strain. Charybdotoxin (BK(Ca), SK3.1 blocker), but not iberiotoxin (BK(Ca) blocker), inhibited responses to the PAR2 agonists in db/db. In db/db protein levels of eNOS were higher, whereas those of sGC were lower than in C57. PAR2 mRNA expression in db/db was higher than in C57.. PAR2-mediated vasodilatation is protected against the negative effects of obesity and diabetes in mice. In diabetic vascular dysfunction, preserved PAR2 vasodilatation was linked to activation of SK3.1.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholinesterase; Alcohol Oxidoreductases; Animals; Arteries; Blood Glucose; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Endothelium, Vascular; Gene Expression Regulation, Enzymologic; Glucose; Glycosuria; Male; Mice; Mice, Inbred C57BL; Nitroprusside; Obesity; Oligopeptides; Phenylephrine; Potassium; Receptor, PAR-2; Receptors, Leptin; RNA, Messenger; Vasodilation

Type-2 diabetes is characterized by endotheliopathy, which increases target organ damage and mortality. There is excessive endothelin-1 and TXA(2) production, and abnormal vascular reactivity to endothelin-1, manifested as a paradoxical hypotensive action in Zucker diabetic, but not lean rats. We examined the hypothesis that there is an alteration in the ET-A/ET-B receptor subtype sensitivity, and/or the interaction or cross-talk between ET-1 and TXA(2) in type-2 diabetes, using Zucker diabetic rats and their lean littermates.. Hemodynamic studies were performed in lean and Zucker fatty diabetic rats of both sexes. Laser doppler flowmetry was used to measure renal cortical (RCF) and medullary blood flow (MBF) responses. Dose response curves for mean arterial blood pressure (MAP), MBF and RCF in response to ET-1, U46619, acetylcholine, and L-NAME (25mg/kg) were constructed after pre-treatment of the rats with either BQ610 1mg/kg i.v. or BQ788 0.5mg/kg i.v. The effects of BQ610 and BQ788 on whole blood impedance aggregation were also assessed.. BQ788, but not BQ610 abolished both the paradoxical hypotensive action of ET-1 in Zucker diabetic rats (n=7 each, P<0.001 ANOVA) as well as the dose-dependent rise in MBF (P<0.001 ANOVA). BQ788, but not BQ610 abolished the difference in response to ET-1 between lean and diabetic Zucker rats. U46619 caused a hypotensive action in male Zucker rats which was abolished by L-NAME 25mg/kg or indomethacin 10mg/kg i.v. The U46619 interaction with BQ788 on both MAP and MBF was significantly (P<0.03 ANOVA) different between lean and diabetic Zucker rats. BQ788, but not BQ610 attenuated both the MAP and MBF responses to acetylcholine or L-NAME P<0.02 ANOVA). However, BQ610 dose-dependently attenuated the slope of platelet aggregation in both lean and Zucker diabetic rats (P<0.02 ANOVA).. ET-B receptor antagonism abolished the abnormal vascular reactivity and MBF responses to ET-1, and also normalized the vasoactive responses to the level seen in healthy lean Zucker rats. ET-1 receptor blockade influences the responses to TXA(2) receptor activation. In the systemic and renal circulation, this interaction appears to be mostly ET-B receptor mediated, whilst in platelets, ET-A receptor role may be predominant. The interaction or cross-talk between ET-1 and TXA(2) is altered in the type-2 diabetic state. Collectively, these pathophysiological changes may contribute to the vicious circle of diabetic endotheliopathy.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Antihypertensive Agents; Blood Flow Velocity; Blood Pressure; Diabetes Mellitus, Type 2; Drug Interactions; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Enzyme Inhibitors; Hypertension; Kidney Cortex; Kidney Medulla; Male; NG-Nitroarginine Methyl Ester; Oligopeptides; Piperidines; Platelet Aggregation; Rats; Rats, Sprague-Dawley; Rats, Zucker; Receptor Cross-Talk; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Thromboxane A2

Male Zucker diabetic rats exhibit a more severe endotheliopathy in comparison with their female diabetic litter mates. The plasma concentrations of both thromboxanes and endothelins are elevated in diabetes, and the receptor cross-talk between TXA(2) and ET-1 receptors may be enhanced in type-2 diabetic Zucker rats.. To determine the role of the endogenous sex steroid hormones, testosterone and estradiol on the systemic and renal microvascular reactivity to ET-1, thromboxane-mimetic U46619, ET-TXA(2) receptor interaction, and the nitric oxide vasodilator system in Zucker hypertensive-diabetic rats.. Male and female Zucker rats aged 8-10 weeks were each divided into two groups. The male rats were castrated or underwent a sham operation. The female rats were spayed (bilateral ovariectomy and hysterectomy) or had a sham operation. All rats were studied 4-6 weeks after the gonadectomy or sham operations. Blood glucose and insulin as well as plasma concentrations of testosterone and estradiol were determined. Haemodynamic studies were undertaken with determination of the dose-response curve for mean arterial pressure (MAP), renal cortical flow (RCF) and renal medullary blood flow (MBF) in response to ET-1 and U46619, and the effect of interdiction of the ET-TXA(2) interaction with ET-antagonists BQ610 and BQ788. The role of endogenous NO was assessed by its response to graded acetylcholine doses and to a L-NG-nitro-arginine methyl ester (L-NAME) infusion.. Castrated male rats had a significantly lower blood glucose concentration (295 +/- 33 mg dL(-1)) compared with their sham-controls (481 +/- 40 mg dL(-1)), P = 0.008. Mean arterial pressure tended to be lower in the castrated rats. Gonadectomy reduced the plasma testosterone and estradiol concentrations. Castration abolished the hypotensive action of U46619 compared with sham-operated male rats (P < 0.0001, anova). Conversely, the pressor action of U46619 seen in the sham-operated female rats was reversed to a profound hypotensive action in the spayed rats (P < 0.001, anova). The change in MAP after U46619 was inversely correlated to the plasma testosterone concentration (r = -0.73, P = 0.027). The paradoxical hypotensive response elicited by ET-1 in the Zucker diabetic rats of both sexes was abolished by castration only (P < 0.005, anova). Castration caused a significant (P = 0.011) augmentation of the vasodilator response to acetylcholine, while spaying caused a slight attenuation. Castration, but not spaying, resulted in significant increases in MBF after U46619 (P = 0.003, anova), ET-1 (P = 0.005, anova) and acetylcholine (P = 0.053, anova). The ET-(B) antagonist BQ788 augmented the U46619-induced rise in MAP in castrated male rats, and also abolished the U46619-induced increase in MBF (P < 0.01 anova). L-NAME (25 mg kg(-1)) increased MAP and decreased MBF in the gonadectomized and sham-operated rats, except for the castrated male Zucker rats, where it significantly increased MBF (+90 +/- 31 PU) (P = 0.0004, anova) despite the increase in MAP.. Testosterone and estradiol regulate systemic and microvascular reactivity to TXA(2) receptor stimulation in type-2 diabetic Zucker rats. The impact of testosterone on blood glucose concentration, blood pressure, and the systemic and renal microcirculatory response to ET-1 and NO, as well as the endothelin-thromboxane receptor cross talk, is greater, and opposite to that of estradiol. The effects of testosterone withdrawal may at least in part be mediated by the ET-B receptor subtype and NO generation. Androgen blockade should be investigated further for the reversal or delay of hypertensive-diabetic endotheliopathy.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Blood Glucose; Castration; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Endothelin-1; Endothelium, Vascular; Estradiol; Female; Gonadal Steroid Hormones; Male; Microcirculation; Nitric Oxide; Ovariectomy; Rats; Rats, Zucker; Receptors, Thromboxane A2, Prostaglandin H2; Renal Circulation; Testosterone; Vasoconstrictor Agents

We examined the hypothesis that gender differences exist in platelet and vascular reactivity in type-2 diabetes mellitus, using Zucker fatty diabetic rats of both sexes and their lean littermates. Type-2 diabetes is characterized by excessive platelet production of TXA(2), which is thrombogenic. Testosterone up-regulates platelet TXA(2) receptors and the aggregation response to thromboxane mimetics. Conversely, estrogen increases vascular nitric oxide (NO) production and inhibits platelet aggregation. Hemodynamic studies were undertaken with the determination of dose-response curve for MAP and renal cortical blood flow (RCF) in response to U46619, angiotensin-II, phenylephrine and endothelin-1, as well as the systemic hemodynamic response to acetylcholine and L-NG nitro-arginine methylester (L-NAME). Platelet aggregation response was evaluated using whole blood impedance aggregometry. There were significant gender differences in the systemic blood pressure and RCF response to TXA(2)-mimetic U46619 and angiotensin-II (P<0.02, ANOVA) but not to phenylephrine or endothelin-1. Male rats exhibited a paradoxical hypotensive response to U46619 (-18+/-11 mmHg) compared with a peak pressor response of +6+/-1 mmHg in female rats (P<0.01, ANOVA). The male rats exhibited an attenuated systemic vasodilator response (P<0.001, ANOVA) to acetylcholine (fall in MAP in male diabetic rats being -24+/-8 mmHg, compared with a fall of -50+/-8 mmHg in females), but a greater rise in the renal cortical resistance in response to NO inhibition by L-NAME (P<0.03) compared with the female rats. Both the slope (46+/-2) and the peak magnitude of the U46619-induced whole blood platelet aggregation (13+/-1) ohms were significantly higher (P<0.01, ANOVA) in male (n=10) compared with female diabetic rats (n=8) (29+/-0.8 slope, 10.0+/-0.8 ohms, respectively). Thus, the male diabetic Zucker rats exhibited an impaired response to vasoconstrictors (U46619 and angiotensin-II) and to endothelial (NO)-mediated vasodilation. The male gender may therefore be associated with the greater prothrombotic activity and a worse impairment of endothelial reactivity in the type-2 diabetic state.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Angiotensin II; Animals; Blood Pressure; Diabetes Mellitus, Type 2; Endothelin-1; Endothelium, Vascular; Enzyme Inhibitors; Female; Kidney Cortex; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Phenylephrine; Platelet Aggregation; Rats; Rats, Zucker; Renal Circulation; Sex Characteristics; Vasoconstrictor Agents; Vasodilation