The apj receptor is expressed in pancreatic islets and its ligand, apelin, inhibits insulin secretion in mice

Apelin is the endogenous ligand of the G-protein coupled apj receptor. Apelin is expressed in the brain, the hypothalamus and the stomach and was recently shown also to be an adipokine secreted from the adipocytes. Although apelin has been suggested to be involved in the regulation of food intake, it is not known whether the peptide affects islet function and glucose homeostasis. We show here that the apj receptor is expressed in pancreatic islets and that intravenous administration of full-length apelin-36 (2 nmol/kg) inhibits the rapid insulin response to intravenous glucose (1 g/kg) by 35% in C57BL/6J mice. Thus, the acute (1-5 min) insulin response to intravenous glucose was 682+/-23 pmol/l after glucose alone (n=17) and 445+/-58 pmol/l after glucose plus apelin-36 (n=18; P=0.017). This was associated with impaired glucose elimination (the 5-20 min glucose elimination was 2.9+/-0.1%/min after glucose alone versus 2.3+/-0.2%/min after glucose plus apelin-36, P=0.008). Apelin (2 nmol/kg) also inhibited the insulin response to intravenous glucose in obese insulin resistant high-fat fed C57BL/6J mice (P=0.041). After 60 min incubation of isolated islets from normal mice, insulin secretion in the presence of 16.7 mmol/l glucose was inhibited by apelin-36 at 1 mumol/l, whereas apelin-36 did not significantly affect insulin secretion at 2.8 or 8.3 mmol/l glucose or after stimulation of insulin secretion by KCl. Islet glucose oxidation at 16.7 mmol/l was not affected by apelin-36. We conclude that the apj receptor is expressed in pancreatic islets and that apelin-36 inhibits glucose-stimulated insulin secretion both in vivo and in vitro. This may suggest that the islet beta-cells are targets for apelin-36.     

ACE activity during the hypotension produced by standardized aqueous extract of Cecropia glaziovii Sneth: A comparative study to captopril effects in rats

To evaluate the effect of the standardized aqueous extract (AE) of Cecropia glaziovii Sneth on the plasma angiotensin I converting enzyme (ACE-EC 3.4.15.1) activity, rats were treated with a single dose of AE (1 g/kg, p.o.) or repeatedly (0.5 g/kg/bid, p.o.) for 60 days. Captopril (50 mg/kg, p.o.) was used as positive control on the same animals. The effects on the blood pressure were recorded directly from the femoral artery (single dose), or indirectly by the tail cuff method (repeated doses) in conscious rats. The plasma ACE activity was determined spectrofluorimetrically using Hypuril-Hystidine-Leucine as substrate. The arterial blood pressure, heart rate and plasma ACE activity were not significantly modified within 24 h after a single dose administration of AE. Comparatively, blood pressure in captopril treated rats was reduced by 7-16% and heart rate was increased by 10-20% from 30 min to 24 h after drug administration. ACE activity after captopril presented a dual response: an immediate inhibition peaking at 30 min and a slow reversal to 32% up-regulation after 24 h. To correlate the drug effects upon repeated administration of either compound, normotensive rats were separated in three groups: animals with high ACE (48.8+/-2.6 nmol/min/ml), intermediate ACE (39.4+/-1.4 nmol/min/ml) and low ACE (23.5+/-0.6 nmol/min/ml) activity, significantly different among them. Repeated treatment with AE reduced the mean systolic blood pressure (121.7+/-0.5 mm Hg) by 20 mm Hg after 14 days. The hypotension was reversed upon washout 60 days afterwards. Likely, repeated captopril administration decreased blood pressure by 20 mm Hg throughout treatment in all groups. After 30 days treatment with AE (0.5 g/kg/bid, p.o.) the plasma ACE activity was unchanged in any experimental group. After captopril (50 mg/kg/bid, p.o.) administration the plasma ACE activity was inhibited by 50% within 1 h treatment but it was up-regulated by 120% after 12 h in all groups. It is concluded that the hypotension produced by prolonged treatment with AE of C. glaziovii is unrelated to ACE inhibition.     

Central and peripheral cardiovascular actions of apelin in conscious rats

APJ was cloned as an orphan G protein-coupled receptor and shares a close identity with angiotensin II type 1 receptor (AT1R). Apelin is a peptide that has recently been identified as an endogenous ligand of the APJ. Apelin and APJ mRNA are expressed in peripheral tissue and the central nervous system. However, little is known about the effects of apelin in cardiovascular regulation. To examine the central and peripheral role of apelin, we injected the active fragment of apelin [(Pyr1)apelin-13] intracerebroventricularly (ICV, 5 and 20 nmol, n=6) or intravenously (IV, 20 and 50 nmol, n=4 or 5) in conscious rats. ICV injection of (Pyr1)apelin-13 dose-dependently increased mean arterial pressure (MAP) and heart rate (HR) (19+/-3 mm Hg and 162+/-26 bpm at 20 nmol). Pretreatment with ICV injection of the AT1R antagonist (CV-11974, 20 nmol) did not alter the apelin-induced increase in MAP and HR. IV injection of (Pyr1)apelin-13 also dose-dependently increased MAP and HR (13+/-2 mm Hg and 103+/-18 bpm at 50 nmol); however, the peripheral effects of apelin were relatively weak compared to its central effects. Expression of c-fos in the paraventricular nucleus (PVN) of hypothalamus was increased in the rat that received ICV injection of (Pyr1)apelin-13 but not in the rat that received IV injection of (Pyr1)apelin-13. These results suggest that apelin plays a role in both central and peripheral cardiovascular regulation in conscious rats, and that the cardiovascular effects of apelin are not mediated by the AT1R.     

5-HT1A receptor agonist 8-OH-DPAT acts in the hindbrain to reverse the sympatholytic response to severe hemorrhage

Central administration of serotonergic 5-HT1A receptor agonists delays the reflex sympatholytic response to severe hemorrhage in conscious rats. To determine the region where 5-HT1A receptor agonists act to mediate this response, recovery of mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) was compared in hemorrhaged rats after injection of the selective 5-HT1A agonist, (+)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), in various regions of the cerebroventricular system or the systemic circulation. Three minutes after injection of 8-OH-DPAT (48 nmol/kg), MAP and RSNA were higher in hemorrhaged rats given drug in the fourth ventricle (94 +/- 5 mmHg, 82 +/- 18% of baseline) or the systemic circulation (90 +/- 4 mmHg, 113 +/- 15% of baseline) than in rats given drug in the Aqueduct of Sylvius (63 +/- 4 mmHg, 27 +/- 11% of baseline), the lateral ventricle (42 +/- 3 mmHg, -8 +/- 18% of baseline), or in rats given saline in various brain regions (47 +/- 5 mmHg, -42 +/- 10% of baseline). A lower-dose injection of 8-OH-DPAT (10 nmol/kg) also accelerated the recovery of MAP and RSNA in hemorrhaged rats when given in the fourth ventricle (94 +/- 26 mmHg, 72 +/- 33% of baseline 3 min after injection) but not the systemic circulation (46 +/- 4 mmHg, -25 +/- 30% of baseline). These data indicate that 8-OH-DPAT acts on receptors in the hindbrain to reverse the sympatholytic response to hemorrhage in conscious rats.     

Regular exercise enhances blood pressure lowering effect of acetylcholine by increased contribution of nitric oxide

This study is aimed to test the hypothesis, that short-term daily bouts of exercise alter the endothelial regulation of peripheral vascular resistance by nitric oxide. Rats ran on a treadmill once a day, 5 days a week, for an average of three weeks with gradually increasing intensity (EX), while a control group remained sedentary (SED). Dose dependent reductions in mean arterial blood pressure (resting MABP; SED: 120.0 +/- 3.4 and EX: 127.8 +/- 4.0 mm Hg) of pentobarbital anesthetized rats to intravenous endothelium independent dilator sodium nitropmsside (SNP; 0.6-3.0 microg/kg) were not different in EX and SED animals. In contrast, dose dependent reductions in MABP to endothelium dependent dilator acetylcholine (ACh) were significantly enhanced in EX compared to those in SED rats (at 0.5 and 1.0 microg/kg ACh: 60.3 +/- 2.4 and 66.5 +/- 1.8 vs 52.8 +/- 2.0 and 59.8 +/- 1.7 mmHg, respectively, p<0.01). There was no significant difference in the heart rate (HR) response to ACh and SNP in the two groups of rats. Intravenous administration of 20 mg/kg Nomega-nitro-L-arginine (L-NNA, a nitric oxide synthase inhibitor) elicited a similar increase (approximately 30%) in the MABP in the two groups and eliminated the difference between ACh-induced blood pressure lowering responses in EX and SED rats (at 0.5 and 1.0 microg/kg ACh: 44.6 +/- 4.7 and 56.3 +/- 4.4 vs 50.9 +/- 4.5 and 59.4 +/- 3.6 mm Hg, respectively). Thus, we suggest that the enhanced acetylcholine-induced decrease in systemic blood pressure following regular daily exercise is primarily due to the augmented synthesis of nitric oxide in the endothelium of peripheral vasculature. This change in the function of endothelium could be important in the adaptation of circulation to exercise training.     

Studies on the developmental pattern of rat ovarian 3 alpha-hydroxysteroid dehydrogenase: inhibition of the postpubertal activity with medroxyprogesterone acetate in vivo

The developmental pattern of rat ovarian 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD) activity was determined with respect to age, vaginal opening, ovarian histology and serum 5 alpha-androstane-3 alpha, 17 beta-diol (3 alpha-diol). The enzyme was assayed by the incubation of [3H]dihydrotestosterone with a portion of whole ovarian cytosol in the presence of 5 X 10(-4) M NADPH. Serum levels of 3 alpha-diol declined from 11.1 +/- 1.2 ng/ml on day 22-3.4 +/- 0.3 ng/ml on day 30 (P less than 0.01). There was no significant change in 3 alpha-HSD during that period which fluctuated from 6.0 +/- 4.0 nmol/h/organ on day 22-8.4 +/- 1.9 nmol/h/organ on day 39. A significant increase on day 42 of 21.1 +/- 6.1 nmol/h/organ occurred well after vaginal opening, corpus luteum formation and the presence of ovarian progesterone; the activity plateaued on day 49 at 31.2 +/- 3.7 nmol/h/organ. In an attempt to inhibit the developmental increase in 3 alpha-HSD activity, medroxyprogesterone acetate (MPA), known inhibitor in vitro was administered to three groups of developing rats in vivo. The administration of MPA at doses of 0.1, 1.0 and 10.0 mg/kg to 30 and 36 day did not inhibit activity when assayed on day 44. In 44-day old rats, the administration of MPA failed to inhibit 3 alpha-HSD activity at 24 h (C-21.1 +/- 2.6; 0.1 mg/kg-19.4 +/- 5.5; 1.0 mg/kg-20.7 +/- 3.7; 10.0 mg/kg-21.1 +/- 3.0 nmol/h/organ) yet there was a significant reduction of 3 alpha-HSD activity when assayed at 48 h (C-21.1 +/- 1.5; 01 mg/kg-9.6 +/- 1.3; 1.0 mg/kg-8.5 +/- 1.9; and 10 mg/kg 5.2 +/- 2.0 nmol/h/organ).     

Adrenoceptors modulate depressor responses of endothelin-1 into the superior colliculus of rats

Endothelin-1 (ET-1) (10 pmol) microinjected into the superficial layer of superior colliculus induces decreases in blood pressure (control, 108 +/- 5 mmHg, n=6; ET-1, 71 +/- 4 mmHg, n=5). The effects on blood pressure induced by endothelin-1 were significantly (p<0.05) reduced by pre-administration into the superior colliculus of the alpha1-adrenoceptor agonist phenylephrine (1 nmol) (46 +/- 5%, n=5), beta1-adrenoceptor antagonist acebutolol (5 nmol) (51 +/- 6%, n=5) or beta1/beta2-adrenoceptor antagonist propranolol (3.4 nmol) (51 +/- 11%, n=5). In contrast, endothelin-1-induced effects were increased (p<0.05) by microinjections into the superior colliculus of prazosin (2.4 nmol) (49 +/- 7%, n=5), an alpha1-adrenoceptor antagonist; dobutamine (4 nmol) (51 +/- 9%, n=5), a beta1-adrenoceptor agonist or isoprenaline (1 nmol) (49 +/- 6%, n=5), a beta1/beta2-adrenoceptor agonist. No involvement of alpha2- or beta2-adrenoceptors has been detected. Therefore, ET-1 induces decreases in blood pressure with selective involvement of alpha1- and beta1-adrenoceptors.     

Influence of nonselective ET(A)/ET(B) receptor blockade on renal function in conscious rats: effects of renal denervation.

The effects of nonselective ET(A)/ET(B) receptor blockade with intravenous bolus injection of bosentan (10 mg/kg) on renal excretory function and blood pressure were investigated in conscious, male, normotensive Wistar rats before and one week after bilateral renal denervation. Renal denervation was followed by an increase in urine flow rate from 4.54+/-0.38 to 5.72+/-0.36 microl/min x 100 g b.w. (p<0.05) and a decrease in urine osmolality from 855.5+/-44.6 to 707.4+/-47.5 mosm/kg H(2)O (p<0.05). Bosentan administration in sham-operated rats resulted in decrease in urine flow rate from 4.54+/-0.38 to 3.49+/-0.34 microl/min x 100 g b.w. (p<0.05), and increase in urine osmolality from 855.5+/-44.6 to 1075.0+/-76.1 mosm/kg H(2)O (p<0.05). Sodium excretion decreased from 226.9+/-20.0 to 155.1+/-11.0 nmol/min x 100 g b.w. (p<0.01). Bosentan administration in renal denervated rats did not produce any changes in renal water or electrolyte excrections. Blood pressure, heart rate, clearance of Inulin or clearance of paraaminohippuric acid (PAH) did not change in sham-operated or renal denervated rats during nonselective ET(A)/ET(B) receptor blockade. Bosentan did not alter the baroreflex sensitivity or sympatho-vagal balance in sham-operated or renal denervated rats. In conclusion, an interaction between renal nerves and endothelins appears to be involved in the regulation of the renal excretory function.     

The effect of ACTH on the plasma concentrations of the "hypertensinogenic" steroids, 17 alpha-hydroxyprogesterone and 17 alpha,20 alpha-dihydroxy-4-pregnen-3-one in sheep

The plasma concentrations of 17 alpha-hydroxyprogesterone (17 alpha OHP) and 17 a'20 alpha-dihydroxy-4-pregnen-3-one (17 alpha 20 alpha OHP) have been measured in sheep during 5 days of ACTH administration at 20 micrograms/kg/day a rate of infusion known to produce hypertension. Five days of ACTH administration produced a progressive increase in plasma 17OHP from 0.45 +/- 0.12 to 128.9 +/- 28.4 nmol/l and in 17 alpha 20 alpha OHP from 0.54 +/- 0.15 to 73.1 +/- 7.2 nmol/l. Calculation of the blood production rate of both steroids during ACTH treatment confirms that the rates of infusion of 17OHP (3.0 mumol/h) and 17 alpha 20 alpha OHP (1.5 mumol/h) used to produce hypertension, when infused together with the other major ovine adrenocortical steroids, produced plasma concentrations in the range as found following administration at a rate to increase blood pressure.     

Endothelin type A receptor antagonist normalizes blood pressure in rats exposed to eucapnic intermittent hypoxia

We have reported that eucapnic intermittent hypoxia (E-IH) causes systemic hypertension, elevates plasma endothelin 1 (ET-1) levels, and augments vascular reactivity to ET-1 and that a nonspecific ET-1 receptor antagonist acutely lowers blood pressure in E-IH-exposed rats. However, the effect of chronic ET-1 receptor inhibition has not been evaluated, and the ET receptor subtype mediating the vascular effects has not been established. We hypothesized that E-IH causes systemic hypertension through the increased ET-1 activation of vascular ET type A (ET(A)) receptors. We found that mean arterial pressure (MAP) increased after 14 days of 7 h/day E-IH exposure (109 +/- 2 to 137 +/- 4 mmHg; P < 0.005) but did not change in sham-exposed rats. The ET(A) receptor antagonist BQ-123 (10 to 1,000 nmol/kg iv) acutely decreased MAP dose dependently in conscious E-IH but not sham rats, and continuous infusion of BQ-123 (100 nmol.kg(-1).day(-1) sc for 14 days) prevented E-IH-induced increases in MAP. ET-1-induced constriction was augmented in small mesenteric arteries from rats exposed 14 days to E-IH compared with those from sham rats. Constriction was blocked by the ET(A) receptor antagonist BQ-123 (10 microM) but not by the ET type B (ET(B)) receptor antagonist BQ-788 (100 microM). ET(A) receptor mRNA content was greater in renal medulla and coronary arteries from E-IH rats. ET(B) receptor mRNA was not different in any tissues examined, whereas ET-1 mRNA was increased in the heart and in the renal medulla. Thus augmented ET-1-dependent vasoconstriction via vascular ET(A) receptors appears to elevate blood pressure in E-IH-exposed rats.     

内皮素通过最后区易化大鼠延髓腹外侧头端区神经元活动

在３５只切断双侧缓冲神经、用氨基甲酸乙酯－α氯醛糖混合麻醉的Ｓｐｒａｇｕｅ－Ｄａｗｌｅｙ大鼠,应用细胞外记录的电生理学方法,由ＲＭ－６０００型多道生理记录仪和ＷＳ－６８２Ｇ热阵记录器（频响范围０～２．８ｋＨｚ）同步记录血压、心率和单位神经元放电,观察颈动脉注射内皮素对８７个延髓腹是头端区（ＲＶＬＭ）自发放电神经元活动的影响,所得结果如下;（１）颈动脉注射ＥＴ－１（０．３ｎｍｏｌ／ｋｇ）时３６个单位     

Evidence of nitric oxide and angiotensin II regulation of circulation and cutaneous drinking in Bufo marinus

The nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (l-NAME) increased vascular resistance (VR) 10% above baseline of 3.08+/-0.08 (n=11) mmHg/mL/min at 10 mg/kg and 20% above 3.05+/-0.08 (n=9) at 50 mg/kg in anesthetized toads (Bufo marinus). Blood pressure was unaffected by either dose of L-NAME. Blood flow decreased at the higher dose of L-NAME. L-arginine (300 mg/kg) reversed the effects of L-NAME on VR and blood flow in toads treated with 10 mg/kg but not with 50 mg/kg. Injection of 50 mg/kg L-NAME into empty-bladder toads produced a 10% decrease in water uptake, J(v), resulting in a J(v) of 1,267+/-11 cm(3)/cm(2)/s x 10(-7) (n=9) compared to 1,385+/-12 (n=8) for controls. Injection of 10 microg/kg angiotensin II (ANG II) increased J(v) 15% across the pelvic patch (J(v), cm(3)/cm(2)/s x 10(-7)), resulting in a J(v) of 1,723+/-12 cm(3)/cm(2)/s x 10(-7) (n=8) compared to 1,471+/-12 (n=8) for controls. It is hypothesized that during cutaneous drinking blood flow into the capillary bed of the pelvic patch is regulated by nitric oxide and ANG II.     

Responsiveness vs. basal activity of plasma ANG II as a determinant of arterial pressure salt sensitivity

Infusion of angiotensin II (ANG II) causes salt-sensitive hypertension. It is unclear whether this is due to the body's inability to suppress ANG II during increased salt intake or, rather, an elevated basal level of plasma ANG II itself. To distinguish between these mechanisms, Sprague-Dawley rats were instrumented with arterial and venous catheters for measurement of arterial pressure and infusion of drugs, respectively. The sensitivity of arterial pressure to salt was measured in four groups with the following treatments: 1) saline control (Con, n = 12); 2) administration of the angiotensin-converting enzyme inhibitor enalapril to block endogenous ANG II (ANG-Lo, n = 10); 3) administration of enalapril and 5 ng.kg(-1).min(-1) ANG II to clamp plasma ANG II at normal levels (ANG-Norm, n = 10); and 4) administration of enalapril and 20 ng.kg(-1).min(-1) ANG II to clamp ANG II at high levels (ANG-Hi, n = 10). Rats ingested a 0.4% NaCl diet for 3 days and then a 4.0% NaCl diet for 11 days. Arterial pressure of rats fed the 0.4% NaCl diet was lower in ANG-Lo (84 +/- 2 mmHg) compared with Con (101 +/- 3 mmHg) and ANG-Norm (98 +/- 4 mmHg) groups, whereas ANG-Hi rats were hypertensive (145 +/- 4 mmHg). Salt sensitivity was expressed as the change in arterial pressure divided by the change in sodium intake on the last day of the 4.0% NaCl diet. Salt sensitivity (in mmHg/meq Na) was lowest in Con rats (0.0 +/- 0.1) and progressed from ANG-Lo (0.8 +/- 0.2) to ANG-Norm (1.5 +/- 0.5) to ANG-Hi (3.5 +/- 0.5) rats. We conclude that the major determinant of salt sensitivity of arterial pressure is the basal level of plasma ANG II rather than the responsiveness of the renin-angiotensin system.     

Effects of [des-Tyr-D-Phe3]beta-casomorphin (2-5) on sleep pattern in rats.

The effects of the antidepressant-like acting peptide [des-Tyr-D-Phe3]beta-casomorphin(2-5) (Pro-D-Phe-Pro-Gly, BCH-325) on sleep were studied in rats. The rats received subcutaneous injections of BCH-325 in acute experiments (doses: 4, 20, 100, 500 and 2500 nmol/kg) and in a 10-day chronic experiment (50 nmol/kg/day). Acute administration of 20 and 100 nmol/kg enhanced wakefulness, 500 and 2500 nmol/kg enhanced paradoxical sleep, and 4 nmol/kg had no effect. Chronic administration resulted in an increase of paradoxical sleep during the first 5 days of drug treatment. Thus the sleep effects of BCH-325 differ from those of typical antidepressants and other psychotropic drugs.     

Effects of chronic inhibition of inducible nitric oxide synthase in hyperthyroid rats

We hypothesized that nitric oxide generated by inducible nitric oxide synthase (iNOS) may contribute to the homeostatic role of this agent in hyperthyroidism and may, therefore, participate in long-term control of blood pressure (BP). The effects of chronic iNOS inhibition by oral aminoguanidine (AG) administration on BP and morphological and renal variables in hyperthyroid rats were analyzed. The following four groups (n = 8 each) of male Wistar rats were used: control group and groups treated with AG (50 mg.kg(-1).day(-1), via drinking water), thyroxine (T4, 50 microg.rat(-1).day(-1)), or AG + T4. All treatments were maintained for 3 wk. Tail systolic BP and heart rate (HR) were recorded weekly. Finally, we measured BP (mmHg) and HR in conscious rats and morphological, plasma, and renal variables. T(4) administration produced a small BP (125 +/- 2, P < 0.05) increase vs. control (115 +/- 2) rats. AG administration to normal rats did not modify BP (109 +/- 3) or any other hemodynamic variable. However, coadministration of T4 and AG produced a marked increase in BP (140 +/- 3, P < 0.01 vs. T4). Pulse pressure and HR were increased in both T4- and T4 + AG -treated groups without differences between them. Plasma NOx (micromol/l) were increased in the T4 group (10.02 +/- 0.15, P < 0.05 vs. controls 6.1 +/- 0.10), and AG reduced this variable in T4-treated rats (6.81 +/- 0.14, P < 0.05 vs. T4) but not in normal rats (5.78 +/- 0.20). Renal and ventricular hypertrophy and proteinuria of hyperthyroid rats were unaffected by AG treatment. In conclusion, the results of the present paper indicate that iNOS activity may counterbalance the prohypertensive effects of T4.     

Neuropeptide Y and peptide YY mediate nonadrenergic vasoconstriction and modulate sympathetic responses in rats

The modulation of cardiovascular sympathetic responses by neuropeptide Y (NPY) and peptide YY (PYY) was assessed in vivo, in pithed rats. Both peptides (0.02-2 nmol/kg) caused similar dose-dependent pressor responses, resistant to adrenergic blockade but antagonized by the calcium channel blocker, nifedipine. Only NPY, at the lowest dose, slightly accelerated heart rate (by 10 +/- 4 beats/min). At the pressor dose (0.6 nmol/kg) but not subpressor dose (0.2 nmol/kg), the increase in blood pressure induced by stimulation of the sympathetic outflow (ST: 0.3 Hz, 50 V, 1 min) was attenuated by PYY (by 40%), whereas ST-evoked tachycardia was reduced by NPY (by 35%). Neither NPY- nor PYY-pretreatment affected ST-induced increments in plasma norepinephrine (NE) and epinephrine concentrations. In addition, regional hemodynamic effects of NPY were studied in conscious rats instrumented with Doppler flow probes. The hypertension caused by NPY was attended by reflex bradycardia and marked rise in peripheral vascular resistance in renal (+ 233 +/- 59%), superior mesenteric (+ 183 +/- 65%) and hindquarter (+ 65 +/- 10%) circulation. The pattern of hemodynamic responses of NPY was similar to that of NE but, unlike the latter, persisted after adrenergic blockade.     

Cardiovascular effects of endomorphins in alloxan-induced diabetic rats

Endomorphins, the endogenous, potent and selective mu-opioid receptor agonists, have been shown to decrease systemic arterial pressure (SAP) in rats. In the present study, responses to endomorphins were investigated in systemic vascular bed of alloxan-induced diabetic rats and in non-diabetic rats. Diabetes was induced by alloxan (220 mg/kg, i.p.) in male Wistar rats. At 4-5 weeks after the onset of diabetes, intravenous injections of endomorphins (1-30 nmol/kg) led to an increase of SAP and heart rate (HR) consistently and dosed-dependently. SAP increased 7.68+/-3.73, 11.19+/-4.55, 21.19+/-2.94 and 27.48+/-6.21% from the baseline at the 1, 3, 10 and 30 nmol/kg dose, respectively, of endomorphin 1 (n=4; p<0.05), and similar changes were observed in response to endomorphin 2. The hypertension could be antagonized markedly by i.p. 2 mg/kg of naloxone. On the other hand, bilateral vagotomy would attenuate the effects of hypertension and diminished the changes of HR in response to endomorphins. With diabetic rats, 6-10 weeks after the induction of diabetes, intravenous injections of endomorphins produced non-dose-related various changes in SAP, such as a single decrease, or a single increase, or biphasic changes characterized by an initial decrease followed by a secondary increase, or no change at all. These results suggest that diabetes may lead to the dysfunction of the cardiovascular system in response to endomorphins. Furthermore, the diabetic rats of 4-5 weeks after alloxan-treatment, the increase in SAP and HR caused by i.v. endomorphins might be explained by a changed effect of vagus and by a naloxone-sensitive mechanism.     

Insulin sensitivity is mediated by the activation of the ACh/NO/cGMP pathway in rat liver

The hepatic parasympathetic nerves and hepatic nitric oxide synthase (NOS) are involved in the secretion of a hepatic insulin sensitizing substance (HISS), which mediates peripheral insulin sensitivity. We tested whether binding of ACh to hepatic muscarinic receptors is an upstream event to the synthesis of nitric oxide (NO), which, along with the activation of hepatic guanylate cyclase (GC), permits HISS release. Male Wistar rats (8-9 wk) were anesthetized with pentobarbital sodium (65 mg/kg). Insulin sensitivity was assessed using a euglycemic clamp [the rapid insulin sensitivity test (RIST)]. HISS inhibition was induced by antagonism of muscarinic receptors (atropine, 3 mg/kg i.v.) or by blockade of NOS [NG-nitro-L-arginine methyl ester (L-NAME), 1 mg/kg intraportally (i.p.v.)]. After the blockade, HISS action was tentatively restored using a NOdonor [3-morpholynosydnonimine (SIN-1), 5-10 mg/kg i.p.v.] or ACh (2.5-5 microg.kg(-1).min(-1) .i.p.v.). SIN-1 (10 mg/kg) reversed the inhibition caused by atropine (RIST postatropine 137.7 +/- 8.3 mg glucose/kg; reversed to 288.3 +/- 15.5 mg glucose/kg, n = 6) and by L-NAME (RIST post-L-NAME 152.2 +/- 21.3 mg glucose/kg; reversed to 321.7 +/- 44.7 mg glucose/kg, n = 5). ACh did not reverse HISS inhibition induced by L-NAME. The role of GC in HISS release was assessed using 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 5 nmol/kg i.p.v.), a GC inhibitor that decreased HISS action (control RIST 237.6 +/- 18.6 mg glucose/kg; RIST post-ODQ 111.7 +/- 6.2 mg glucose/kg, n = 5). We propose that hepatic parasympathetic nerves release ACh, leading to hepatic NO synthesis, which activates GC, triggering HISS action.     

Lymphocyte ecto-5'-nucleotidase activity in infancy: increasing activity in peripheral blood B cells precedes their ability to synthesize IgG in vitro

Ecto-5'-nucleotidase activity was measured in peripheral blood lymphocytes isolated from serial specimens from nine healthy full-term infants and two premature infants at 0, 2, 4, and 6 mo of age. The postnatal nadir in activity was 7.1 +/- 2.0 nmol/hr/10(6) cells, which is the same as the activity in cord blood lymphocytes (7.0 +/- 2 nmol/hr/10(6) cells). The activity rose twofold to 13.2 +/- 3.8 nmol/hr/10(6) cells at 6 mo of age (p less than 0.001, paired t-test), which is similar to the activity in adult peripheral blood lymphocytes (14.1 +/- 6.3 nmol/hr/10(6) cells). This increased activity in total lymphocytes reflects increased activity in the B cell population. B cell ecto-5'-nucleotidase activity in two infants at 12 to 13 mo of age was 19.3 and 25.2 nmol/hr/10(6) cells, values that are four-to fivefold higher than for cord blood B cells (5.6 +/- 2.8 nmol/hr/10(6) cells) and within the normal range for adult B cells (27.9 +/- 12 nmol/hr/10(6) cells). In spite of a greatly expanded peripheral blood B cell population, studies of immunoglobulin biosynthesis in vitro demonstrated that infant peripheral blood B cells are functionally immature with no synthesis of IgG in response to Epstein Barr virus. Thus, the increase in peripheral blood B lymphocyte ecto-5'-nucleotidase activity in infants precedes their acquisition of a capacity for IgG synthesis in vitro. Data from a hypogammaglobulinemic infant revealed a persistently low ecto-5'-nucleotidase activity over a 10-mo period until at 14 mo of age the activity was 8.8 nmol/hr/10(6) cells in total lymphocytes and 13.0 nmol/hr/10(6) cells in B cells, which correlated with in vivo and in vitro evidence of delayed B cell maturation. Thus, ecto-5'-nucleotidase activity may be a useful cell surface marker in studies of human postnatal B cell maturation.     

Asymmetric dimethylarginine, oxidative stress, and vascular nitric oxide synthase in essential hypertension

We reported impaired endothelium-derived relaxation factor/nitric oxide (EDRF/NO) responses and constitutive nitric oxide synthase (cNOS) activity in subcutaneous vessels dissected from patients with essential hypertension (n = 9) compared with normal controls (n = 10). We now test the hypothesis that the patients in this study have increased circulating levels of the cNOS inhibitor, asymmetric dimethylarginine (ADMA), or the lipid peroxidation product of linoleic acid, 13-hydroxyoctadecadienoic acid (HODE), which is a marker of reactive oxygen species. Patients had significantly (P < 0.001) elevated (means +/- SD) plasma levels of ADMA (P(ADMA), 766 +/- 217 vs. 393 +/- 57 nmol/l) and symmetric dimethylarginine (P(SDMA): 644 +/- 140 vs. 399 +/- 70 nmol/l) but similar levels of L-arginine accompanied by significantly (P < 0.015) increased rates of renal ADMA excretion (21 +/- 9 vs. 14 +/- 5 nmol/mumol creatinine) and decreased rates of renal ADMA clearance (18 +/- 3 vs. 28 +/- 5 ml/min). They had significantly increased plasma levels of HODE (P(HODE): 309 +/- 30 vs. 226 +/- 24 nmol/l) and renal HODE excretion (433 +/- 93 vs. 299 +/- 67 nmol/micromol creatinine). For the combined group of normal and hypertensive subjects, the individual values for plasma levels of ADMA and HODE were both significantly (P < 0.001) and inversely correlated with microvascular EDRF/NO and positively correlated with mean blood pressure. In conclusion, elevated levels of ADMA and oxidative stress in a group of hypertensive patients could contribute to the associated microvascular endothelial dysfunction and elevated blood pressure.