Captopril can have nephrotoxic effects, which are largely attributed to accumulated renin and "escaped" angiotensin II (Ang II). Here we test whether angiotensin converting enzyme-1 (ACE1) inhibition damages kidneys via alteration of renal afferent arteriolar responses to Ang II and inflammatory signaling. C57Bl/6 mice were given vehicle or captopril (60 mg/kg per day) for four weeks. Hypertension was obtained by minipump supplying Ang II (400 ng/kg per min) during the second 2 weeks. We assessed kidney histology by periodic acid-Schiff (PAS) and Masson staining, glomerular filtration rate (GFR) by FITC-labeled inulin clearance, and responses to Ang II assessed in afferent arterioles in vitro. Moreover, arteriolar H₂O₂ and catalase, plasma renin were assayed by commercial kits, and mRNAs of renin receptor, transforming growth factor-β (TGF-β) and cyclooxygenase-2 (COX-2) in the renal cortex, mRNAs of angiotensin receptor-1 (AT₁R) and AT₂R in the preglomerular arterioles were detected by RT-qPCR. The results showed that, compared to vehicle, mice given captopril showed lowered blood pressure, reduced GFR, increased plasma renin, renal interstitial fibrosis and tubular epithelial vacuolar degeneration, increased expression of mRNAs of renal TGF-β and COX-2, decreased production of H₂O₂ and increased catalase activity in preglomerular arterioles and enhanced afferent arteriolar Ang II contractions. The latter were blunted by incubation with H₂O₂. The mRNAs of renal microvascular AT₁R and AT₂R remained unaffected by captopril. Ang II-infused mice showed increased blood pressure and reduced afferent arteriolar Ang II responses. Administration of captopril to the Ang II-infused mice normalized blood pressure, but not arteriolar Ang II responses. We conclude that inhibition of ACE1 enhances renal microvascular reactivity to Ang II and may enhance important inflammatory pathways.
Angiotensin II/pharmacology* ; Animals ; Arterioles/metabolism* ; Captopril/pharmacology* ; Hydrogen Peroxide/pharmacology* ; Kidney ; Mice

INTRODUCTIONDiabetes mellitus induces microangiopathic changes that lead to endothelial dysfunction. This study investigated the effect of Xiaokening, a type of Chinese compound medicine, on the mesenteric arteriolar endothelial cell function of diabetic rats and its underlying mechanism.

METHODSDiabetes mellitus was induced in rat models via intraperitoneal injection of 60 mg/kg streptozotocin and observed over three weeks. Mesenteric arterioles, which were isolated in a cannulated and pressurised state, were incubated with intravascular injections of 1, 3 or 5 g/L Xiaokening for 24, 48 or 72 hours. The effects of Xiaokening on the release of nitric oxide (NO) on the mesenteric arterioles were detected under shear stress of 1, 10 and 20 dyn/cm(2). Biochemical methods were used to determine the activities of superoxide dismutase (SOD) and xanthine oxidase (XO). The expressions of endothelial NO synthase (eNOS), SOD and XO in the mesenteric arterioles were assessed using Western blot.

RESULTSCompared to normal rat arterioles, less NO was released in the mesenteric arterioles of diabetic rats. Xiaokening was found to have a concentration- and time-dependent effect on NO release; when the shear stress was increased, there was a gradual increase in the release of NO. Compared to normal arterioles, the expression of eNOS in the mesenteric arterioles of diabetic rats was lower. Incubation with Xiaokening increased SOD activity and expression, and decreased XO activity and expression in the mesenteric arterioles of the diabetic rats.

CONCLUSIONXiaokening was able to significantly increase NO release and improve the endothelial function of mesenteric arterioles through antioxidative mechanisms.

Animals ; Antioxidants ; chemistry ; Arterioles ; enzymology ; Diabetes Mellitus, Experimental ; drug therapy ; Dose-Response Relationship, Drug ; Drugs, Chinese Herbal ; pharmacology ; Endothelial Cells ; drug effects ; Injections, Intraperitoneal ; Male ; Nitric Oxide ; metabolism ; Nitric Oxide Synthase Type III ; metabolism ; Oxygen ; metabolism ; Rats ; Rats, Sprague-Dawley ; Streptozocin ; Superoxide Dismutase ; metabolism ; Xanthine Oxidase ; metabolism

OBJECTIVETo investigate the effect of panax notoginseng saponins (PNS) injection on pulmonary artery pressure and the expression of p38MAPK in lung tissue of rats subjected to chronic hypoxia.

METHODSThirty adult male Sprague Dawley rats were randomly divided into three groups (ten in each group): rats in control group were exposed to normoxic condition and the rats in hypoxia group and PNS group were subjected to 4-week hypoxia, and PNS injection (50 mg · kg(-1) · d(-1)) was administrated intraperitoneally at 30 min in the PNS group daily before the rats were kept in the hypoxic chamber, while rats in the other two groups received equal dose of normal saline instead. After chronic hypoxia, mean pulmonary artery pressure (mPAP) and mean carotid artery pressure (mCAP) were measured. The heart and lung tissues were harvested, and right ventricle (RV) and left ventricle plus ventricular septum (LV+S) were weighed to calculate the ratio of RV/(LV+S). The expression of p38MAPK mRNA was determined by reverse transcription-polymerase chain reaction, the quantity of phosphorylated p38MAPK (p-p38MAPK) in rat lung tissues and pulmonary arterioles was determined by Western blot and immunohistochemistry.

RESULTSCompared with the control group, mPAP and the ratio of RV/(LV+S) in the hypoxia group were increased, the expression of p-p38MAPK in pulmonary arterioles and p38MAPK mRNA in the lung were higher (P<0.05). The changes of these parameters in the hypoxia group were significantly attenuated by PNS treatment (P<0.05).

CONCLUSIONPNS injection was shown to prevent hypoxic pulmonary hypertension at least partly by regulating p38MAPK pathway.

Animals ; Arterioles ; drug effects ; metabolism ; Blood Pressure ; drug effects ; Blotting, Western ; Carotid Arteries ; drug effects ; physiopathology ; Disease Models, Animal ; Heart Ventricles ; drug effects ; physiopathology ; Hemodynamics ; drug effects ; Hypertension, Pulmonary ; complications ; enzymology ; physiopathology ; Hypoxia ; complications ; enzymology ; physiopathology ; Injections ; Lung ; drug effects ; enzymology ; pathology ; physiopathology ; MAP Kinase Signaling System ; drug effects ; Male ; Panax notoginseng ; chemistry ; Pulmonary Artery ; drug effects ; physiopathology ; RNA, Messenger ; genetics ; metabolism ; Rats, Sprague-Dawley ; Saponins ; administration & dosage ; pharmacology ; p38 Mitogen-Activated Protein Kinases ; genetics ; metabolism

OBJECTIVETo investigate the effect of adrenomedullin (ADM) on renal arteriole remodeling and phosphorylation of extracellular signal-regulated protein kinases 1/2 (p-ERK1/2) in spontaneous hypertensive rats (SHR).

METHODSMale SHR (4 weeks old) were randomized into hypertensive group (SHR) and ADM-treated group (ADM) to receive subcutaneous saline and ADM injections (daily dose of 1.0 nmol/kg, 5 days a week), respectively, with age-matched Wistar-Kyota (WKY) rats as the blank control. The systolic blood pressure (SBP) was measured at the end of each week, and histological changes of the renal arterioles were observed using HE and Weigert staining; the expression of P-ERK1/2 in the arterioles was detected with immunohistochemistry and Western blotting.

RESULTSAt 16 and 24 weeks of age, the rats in both SHR and ADM groups showed significantly higher SBP levels than WKY rats (P<0.05), and at 24 weeks, SBP was significantly lower in ADM group than in SHR group (P<0.05). The intima thickness/lumen diameter (IT/LD) ratio of the renal arterioles increased in both SHR and ADM groups at 16 and 24 weeks as compared with that of WKY rats (P<0.05), and for arterioles with an outer diameter <40 µm, the IT/LD ratio was significantly lower at 24 weeks in ADM group than in SHR group (P<0.05). The renal expression of p-ERK1/2, which increased significantly in SHR and ADM groups at 16 and 24 weeks (P<0.05), was significantly lower in ADM group than in SHR group at 24 weeks (P<0.05).

CONCLUSIONSLong-term ADM treatment can control SPB elevation in SHR rats and reduce renal arteriole remodeling by inhibiting the phosphorylation of ERK1/2.

Adrenomedullin ; pharmacology ; Animals ; Arterioles ; drug effects ; Blood Pressure ; Hypertension ; Kidney ; blood supply ; Male ; Mitogen-Activated Protein Kinase 1 ; metabolism ; Mitogen-Activated Protein Kinase 3 ; metabolism ; Rats ; Rats, Inbred SHR ; Rats, Wistar ; Vascular Remodeling

The aim of this study was to investigate the effect of integripetal rhodiola herb on pulmonary arterial remodeling and expression of vascular endothelial growth factor (VEGF) in high altitude pulmonary hypertension in rats. Fifty healthy male Wistar rats were divided into five groups randomly: Plain control group (LC group), 10-day plateau group (H(10) group), 30-day plateau group (H(30) group), 10-day rhodiola-treated plateau group (R(10) group), and 30-day rhodiola-treated plateau group (R(30) group). Each group included 10 rats. The rats in LC group were kept in Chengdu (500 meters above sea level), and rats in H and R groups were kept in Lhasa (3 700 meters above sea level). The rats in R group were daily treated with integripetal rhodiola herb extract (24%, 10 mL/kg) intragastrically for 10 d or 30 d, while rats in LC and H groups were treated with the same volume of saline. Mean pulmonary arterial pressure (mPAP) was detected via a catheter in the pulmonary artery by pressure waveform monitoring. The ratio value of right ventricle weight to left ventricle plus septum weight [RV/(LV + S)] was measured. The microstructure of pulmonary arterioles was examined by electron microscopy. The expression of VEGF in the lung was investigated using immunohistochemistry. The results showed that mPAP and [RV/(LV + S)] in H(10) group and H(30) group were higher than those in LC group (P < 0.05); but there was no significant difference between H(10) group and R(10) group (P < 0.05); and mPAP and [RV/(LV + S)] in H(30) group were lower than those in H(30) group (P < 0.05). Electron microscopy showed that compared to LC group, arteriolar endothelial cells were arranged in a columnar or palisading form, protruding into the lumen, accompanied with luminal stenosis, irregular internal elastic membrane, and proliferation of vascular smooth muscle cells in H groups, which was more obvious in H(30) group than in H(10) group; while these pathological changes were attenuated in the R groups compared to H groups. The levels of VEGF protein in H groups were also higher than those in LC group (P < 0.05); while the expression of VEGF in R(30) group was lower than that in H(30) group. In summary, the results show that the integripetal rhodiola herb can attenuate high altitude-induced pulmonary arterial remodeling in rats, and the inhibition of VEGF protein expression by rhodiola may be one of the mechanisms.
Altitude ; Altitude Sickness ; prevention & control ; Animals ; Arterioles ; metabolism ; pathology ; Drugs, Chinese Herbal ; pharmacology ; Hypertension, Pulmonary ; metabolism ; pathology ; physiopathology ; Male ; Pulmonary Artery ; metabolism ; pathology ; RNA, Messenger ; metabolism ; Rats ; Rats, Wistar ; Rhodiola ; Vascular Endothelial Growth Factor A ; metabolism

OBJECTIVETo investigate the distribution and mechanism of coronary arteriole (CA) cell resting membrane potential (RP) in guinea pigs.

METHODSCell RP was recorded by intracellular microelectrode in isolated guinea pig coronary arteriole (diameter < 100 microm).

RESULTS(1) Experiments were carried out in 112 cells with a mean RP of (-65 +/- 4.2)mV, the distribution of coronary arteriole cell RP fitted by Gaussian function was bimodal, one peak was -43 mV termed high RP, the other was -74 mV termed low RP. 10 mmol/L K+ and 3 micromol/ L acetylcholine(ACh) induced hyperpolarization in high-RP cells with (-7.4 +/- 0.87) mV (n = 13) and (-15 +/- 1.24) mV (n = 16) respectively, and induced depolarization in low-RP cells with (9.6 +/- 1.2) mV (n = 23) and (8.7 +/- 0.69) mV (n = 15) respectively. (2) The inward rectifier K+ channel (K(ir)) blocker Ba2+ caused concentration-dependent depolarization in low-RP cells with an EC50 of 120 micromol/L 100 micromol/L Ba2+ or higher could shift low-RP cells to high-RP state, the response of these cells to high K+ and ACh became a hyperpolarization.

CONCLUSIONThe distribution of coronary vascular cell RP is bimodal, high K+ and ACh induce different responses in low and high RP cells. The two RP states are exchangeable mainly due to all-or-none conductance changes of K(ir).

Acetylcholine ; metabolism ; Animals ; Arterioles ; cytology ; Coronary Vessels ; cytology ; physiology ; Female ; Guinea Pigs ; Male ; Membrane Potentials ; physiology ; Microelectrodes ; Myocardium ; metabolism ; Potassium Channels, Inwardly Rectifying ; physiology

OBJECTIVETo study the effect and mechanism of chimonin on pulmonary arterioles I and III type collagen metabolism in pulmonary hypertension rats induced by chronic hypoxic hypercapnia.

METHODSThirty-six Sprague-Dawley rats were randomly divided into three groups: normal control group(A), hypoxic hypercapnic group(B), hypoxic hypercapnia + chimonin group(C). Collagen I, III and their mRNA, Blood CO concentration (COHb%), activity of HO-1 in blood serum and lung homogenate, content of hydroxyproline in lung homogenate, pulmonary arteriole micromorphometric index were observed.

RESULTSHypoxic hypercapnic rats's mPAP, Hyr of lung homogenate, content of I type collagen and I type collagen mRNA in pulmonary arterioles, were significantly higher than those in control group, pulmonary vessel remodeling of hypoxic hypercapnic rats was significant, those changes in hypercapnia + chimonin group were significantly lower than those in hypoxic hypercapnic group. Blood CO concentration, activity of HO-1 in blood serum and lung homogenate in rats of hypoxic hypercapnic rats were significantly higher than those of control group, and those of hypercapnia + chimonin group were even higher than hypoxic hypercapnic group (P < 0.01). There was no significant difference in mCAP, content of III type collagen and their mRNA in three groups (P > 0.05).

CONCLUSIONChimonin can reduce pulmonary hypertension and pulmonary vessel remodeling induced by hypoxic hypercapnia through inhibiting proliferation of collagen I, the mechanism maybe is up regulating endogenous carbon monoxide system.

Animals ; Arterioles ; metabolism ; Carbon Monoxide ; metabolism ; Chronic Disease ; Collagen Type I ; metabolism ; Collagen Type III ; metabolism ; Drugs, Chinese Herbal ; pharmacology ; Hypercapnia ; complications ; physiopathology ; Hypertension, Pulmonary ; etiology ; metabolism ; physiopathology ; Hypoxia ; complications ; physiopathology ; Lung ; blood supply ; Male ; Rats ; Rats, Sprague-Dawley

BACKGROUNDSmall cerebrovascular lesions are one of the most important factors in cerebral amyloid angiopathy (CAA) and vascular dementia (VaD). We analyzed the difference of arteriolar pathology between CAA patients (CAAs) and vascular dementia patients without CAA (VaDs).

METHODSTen deceased CAAs and twelve deceased VaDs were available for this study. Five deceased patients without known cerebrovascular diseases served as controls. These patients were all autopsy cases. All transversely cut arterioles in the gray matter and white matter with an external diameter equal to or larger than 30 microm and with a maximum of 300 microm were examined. The internal and external diameters of arterioles were measured.

RESULTSThe external diameter of gray matter arterioles in the CAAs was significantly greater than in controls. In gray matter arterioles, the diameter of the lumen in VaDs was markedly smaller than in the CAAs, whereas there was no significant difference between CAAs and controls. CAAs and VaDs may cause remarkable thickening of the arteriolar walls in either white matter or gray matter. The sclerotic index of arterioles in VaDs was significantly greater than in CAAs and controls.

CONCLUSIONSStenosis of arterioles occurred in both CAA and VaD, but the tendency was greater in VaD. Arterioles of CAA were also expanded in gray matter, which may be related to lobar hemorrhage. The loss and/or degeneration of vascular smooth muscle cells was predominant in CAA, while the over-proliferation of vascular smooth muscle cells was greater in VaD.

Aged ; Aged, 80 and over ; Arterioles ; metabolism ; pathology ; Cerebral Amyloid Angiopathy ; metabolism ; pathology ; Dementia, Vascular ; metabolism ; pathology ; Female ; Humans ; Immunohistochemistry ; Male ; Middle Aged

AIMTo study the effect of curcumin on pulmonary arterial pressure and type I collagen of pulmonary arterioles in pulmonary hypertensive rats induced by chronic hypoxia and hypercapnia.

METHODSThirty six rats were randomly divided into three groups: normal control group (NC), hypoxic hypercapnic group (HH) and hypoxic hypercapnia + curcumin group (HC). Collagen I in pulmonary arterioles was observed by the technique of immunohistochemistry.

RESULTS(1) The findings from hemodynamics showed that the mPAP in group HH was significantly higher than that in group NC and HC. Differences of mCAP among groups were not significant (P > 0.05). (2) Light microscopy showed the value of WA/TA (vessel wall area/total area), SMC (the density of medial smooth muscle cells) and thickness of pulmonary arterial media smooth cell layer(PAMT) were significantly higher in group HH than group NC (P < 0.01) and group HC (P < 0.01). (3) Electron microscopy showed that structure of the endothelial cells in pulmonary arterioles in group HC was near to normal, and the proliferation of medial smooth muscle cells and collagen fibers in adventitia was much lighter than those of group HH. (4) Expression of collagen I in pulmonary arterioles was significantly higher in group HH than group NC (P < 0.01) and group HC (P < 0.01).

CONCLUSIONCurcumin can decrease pulmonary arterial pressure, improve pulmonary vessel remodeling and inhibit the deposition of collagen I in pulmonary arterioles.

Animals ; Arterioles ; drug effects ; metabolism ; Collagen Type I ; metabolism ; Curcumin ; pharmacology ; Extracellular Matrix ; metabolism ; Hypercapnia ; metabolism ; physiopathology ; Hypertension, Pulmonary ; metabolism ; physiopathology ; Hypoxia ; metabolism ; physiopathology ; Male ; Pulmonary Artery ; drug effects ; metabolism ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo investigate the effect of Ca(2+) influx through L-type Ca(2+) channels on normal and hyperpolarized membrane potential of arteriole smooth muscle cells (ASMCs) in rats.

METHODSThe ASMCs isolated from normal rats and those with severe hemorrhagic shock were labeled with DiBAC4 (3) for membrane potential detection.

RESULTSCa(2+) influx caused hyperpolarization of the membrane potential in the normal ASMCs but depolarization in the cells from rats with hemorrhagic shock, and this effect could be inhibited by TEA.

CONCLUSIONCa(2+)-activated potassium channels activated by Ca(2+) influx through L-type Ca(2+) channels in normal ASMCs to cause hyperpolarization but leads directly to membrane potential depolarization in ASMCs from rats with severe hemorrhagic shock. This finding can be meaningful for treatment of vascular hyporeactivity in advanced stage of severe shock.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester ; pharmacology ; Animals ; Arterioles ; physiopathology ; Calcium Channel Agonists ; pharmacology ; Calcium Channels, L-Type ; metabolism ; Female ; Male ; Membrane Potentials ; drug effects ; Muscle, Smooth, Vascular ; physiopathology ; Potassium Channels, Calcium-Activated ; metabolism ; Rats ; Rats, Wistar ; Shock, Hemorrhagic ; physiopathology