Cyclooxygenase pathway is involved in the vascular reactivity and inhibition of the Na+, K+-ATPase activity in the tail artery from L-NAME-treated rats

L-NAME (LN) induces hypertension by blocking nitric oxide (NO) synthesis. It produces vascular hyperreactivity to phenylephrine (PHE) associated with a reduced vascular Na+, K+-ATPase activity. The aim of this work was to investigate whether products of the cyclooxygenase pathway are involved in alterations of vascular reactivity and Na+-pump activity in the tail artery from LN-induced hypertension rats. Four groups of rats were used: Control (CT, normotensive), LN (50 mg/kg/day, hypertensive), indomethacin (Indo-4 mg/kg/day, normotensive), and LN plus Indo (LN + Indo, partially prevented hypertension). All drugs were administered in drinking water during 7 days. In isolated rat tail vascular beds; the reactivity to PHE, acetylcholine (ACh), sodium nitroprusside (SNP), the functional activity of the Na+, K+-ATPase (K+-induced relaxation) and the modulation of PHE-induced vasoconstriction by constitutively available NO were evaluated. LN increased vascular sensitivity (pD2) and reactivity (Emax) to PHE and Indo blocked the effect of LN on Emax without changing pD2. Emax and pD2 values for ACh were reduced by LN and partially reverted by Indo. SNP-induced vasodilatation was similar in all groups. LN reduced the activity of Na+, K+-ATPase and Indo prevented LN effects. LN also abolished NO ability to modulate PHE-induced contractions. This effect was partially prevented by Indo suggesting that products from the cyclooxygenase pathway might reduce NO actions. Indo itself did not affect vascular reactivity to PHE, ACh or SNP or the Na+,K+-ATPase activity. Results suggested that products from cyclooxygenase pathway are involved in the genesis or maintenance of LN-induced hypertension, playing a role in the increased vascular reactivity, in the reduction of the endothelium-dependent relaxation and in the inhibition of the functional activity of the Na+, K+-ATPase.     

Effects of estrogens and selective estrogen receptor modulators on vascular reactivity in the perfused mesenteric vascular bed

Estrogens and selective estrogen receptor modulators (SERMs), such as raloxifene (RAL) and tamoxifen (TAM), acutely relax arteries, but the long-term effects of estrogens and SERMs on vascular reactivity in the mesenteric vasculature have not been well defined. In this study, we used an isolated, perfused mesenteric vascular bed technique to investigate the effect of chronic treatment of estrogens and SERMs on vascular reactivity of the mesenteric bed. Ovariectomized female Sprague-Dawley rats were treated by gavage with vehicle (control, 2-hydroxypropyl-beta-cyclodextrin), ethinyl estradiol, estradiol benzoate, equilin (EQ), TAM, or RAL for 3 wk. EQ and TAM increased vasoconstriction in response to all three vasoconstrictors tested (KCl, norepinephrine, and 5-HT). Ethinyl estradiol increased vasoconstriction in response to KCl and 5-HT, whereas responses to estradiol benzoate and RAL were less consistent. Only EQ (134 +/- 4 mmHg) and TAM (104 +/- 4 mmHg) changed mean arterial blood pressure compared with control (117 +/- 4 mmHg). These data demonstrate that 3-wk gavage treatment with estrogens and SERMs affects vascular reactivity in the mesenteric vascular bed. However, the three formulations of estrogen did not produce equivalent effects, and the effects of the SERMs were different from those of the estrogens.     

Effects of prostanoids on phenylephrine-induced contractions in the mesenteric vascular bed of rats with streptozotocin-induced diabetes mellitus

The main aim of this study was to compare the vascular reactivity of the perfused (Krebs, 4 ml/min) mesenteric vascular bed (MVB) isolated from rats with streptozotocin (STZ)-induced diabetes of 8 weeks duration to that of the MVB from non-diabetic (ND) Wistar rats. There were no differences in basal perfusion pressure between the MVB isolated from STZ and ND rats. The addition of indomethacin to the perfusate increased the basal perfusion pressure in both ND (18.8 +/- 0.7 vs 29.4 +/- 3.7 mmHg, p < 0.05) and STZ rats (18.3 +/- 0.9 vs 27.2 +/- 2.6 mmHg, p < 0.05), suggesting the release of a vasodilator prostaglandin. Remotion of the endothelium did not affect this response, indicating that prostaglandin was released from vascular smooth muscle. The response to phenylephrine was reduced in STZ rats compared to ND rats (2.3 [1.6-3.8] vs 8.3 [3.5-19.4], ED50. [IC 95%]) and was not modified by removal of the endothelium or by perfusion of L-nitro-arginine (50 microM). In contrast, indomethacin was able to reduce the response to phenylephrine in ND but not in STZ rats (2.3 [1.6-3.8] vs 4.7 [3.2-6.0], ED50. [IC 95%], p=0.02), suggesting that the blunted response to phenylephrine observed in STZ was due to the abolition of the release of prostaglandin by vascular smooth muscle. In conclusion, experimental diabetes induction in the rat is followed by a reduction of the contractile effect of phenylephrine due to the lack of release of a vasoconstrictor prostaglandin from vascular smooth muscle.     

Low nanomolar concentration of mercury chloride increases vascular reactivity to phenylephrine and local angiotensin production in rats

Exposure to mercury at nanomolar level affects cardiac function but its effects on vascular reactivity have yet to be investigated. Pressor responses to phenylephrine (PHE) were investigated in perfused rat tail arteries before and after treatment with 6 nM HgCl2 during 1 h, in the presence (E+) and absence (E-) of endothelium, after L-NAME (10(-4) M), indomethacin (10(-5 )M), enalaprilate (1 microM), tempol (1 microM) and deferoxamine (300 microM) treatments. HgCl2 increased sensitivity (pD2) without modifying the maximum response (Emax) to PHE, but the pD2 increase was abolished after endothelial damage. L-NAME treatment increased pD2 and Emax. However, in the presence of HgCl2, this increase was smaller, and it did not modify Emax. After indomethacin treatment, the increase of pD2 induced by HgCl2 was maintained. Enalaprilate, tempol and deferoxamine reversed the increase of pD2 evoked by HgCl2. HgCl2 increased the angiotensin converting enzyme (ACE) activity explaining the result obtained with enalaprilate. Results suggest that at nanomolar concentrations HgCl2 increase the vascular reactivity to PHE. This response is endothelium mediated and involves the reduction of NO bioavailability and the action of reactive oxygen species. The local ACE participates in mercury actions and depends on the angiotensin II generation.     

Regional hemodynamics during postexercise hypotension. I. Splanchnic and renal circulations.

Moderate exercise elicits a relative postexercise hypotension that is caused by an increase in systemic vascular conductance. Previous studies have shown that skeletal muscle vascular conductance is increased postexercise. It is unclear whether these hemodynamic changes are limited to skeletal muscle vascular beds. The aim of this study was to determine whether the splanchnic and/or renal vascular beds also contribute to the rise in systemic vascular conductance during postexercise hypotension. A companion study aims to determine whether the cutaneous vascular bed is involved in postexercise hypotension (Wilkins BW, Minson CT, and Halliwill JR. J Appl Physiol 97: 2071-2076, 2004). Heart rate, arterial pressure, cardiac output, leg blood flow, splanchnic blood flow, and renal blood flow were measured in 13 men and 3 women before and through 120 min after a 60-min bout of exercise at 60% of peak oxygen uptake. Vascular conductances of leg, splanchnic, and renal vascular beds were calculated. One hour postexercise, mean arterial pressure was reduced (79.1 +/- 1.7 vs. 83.4 +/- 1.8 mmHg; P < 0.05), systemic vascular conductance was increased by approximately 10%, leg vascular conductance was increased by approximately 65%, whereas splanchnic (16.0 +/- 1.8 vs. 18.5 +/- 2.4 ml.min(-1).mmHg(-1); P = 0.13) and renal (20.4 +/- 3.3 vs. 17.6 +/- 2.6 ml.min(-1).mmHg(-1); P = 0.14) vascular conductances were unchanged compared with preexercise. This suggests there is neither vasoconstriction nor vasodilation in the splanchnic and renal vasculature during postexercise hypotension. Thus the splanchnic and renal vascular beds neither directly contribute to nor attenuate postexercise hypotension.     

Vascular reactivity to norepinephrine in rats with cirrhosis of the liver

Vascular reactivity to norepinephrine was studied in rats with early cirrhosis of the liver and in control rats. Cirrhotic rats showed water and sodium retention but not ascites. Studies were performed in whole animals, isolated hindquarters, and isolated femoral arteries. Plasma catecholamine levels were measured by radioenzymoassay and their urinary metabolites by gas-liquid chromatography. Plasma norepinephrine was 331 +/- 49 pg/mL (mean +/- SEM) in control rats and 371 +/- 66 pg/mL in cirrhotic animals (p greater than 0.05). No differences in plasma epinephrine or dopamine were observed. Urinary excretion of catecholamine metabolites was increased in cirrhotic rats. These data suggest a moderate activation of the sympathetic nervous system. In basal conditions, cirrhotic rats showed lower mean arterial pressure than controls (101 +/- 4 vs. 116 +/- 4 mmHg (1 mmHg = 133.3 Pa); p less than 0.01). However, perfused hindlimb resistance was similar in cirrhotic and in control animals. In the whole animal and in the perfused hindquarter, the contractile response to norepinephrine was similar for control and for cirrhotic rats. The contractile response to norepinephrine exhibited by isolated femoral arteries was similar in those from cirrhotic and control rats. This indicates that the peripheral vascular bed has a well-maintained ability to constrict in response to norepinephrine, suggesting that circulatory abnormalities in early experimental cirrhosis are not caused by refractoriness of the vascular smooth muscle to norepinephrine.     

Modulation of vascular reactivity to serotonin in the dog lung

Experiments were conducted to compare the effects of cyclooxygenase inhibition (COI) on vascular reactivity to serotonin (5-HT) in the isolated blood-perfused canine left lower lung lobe (LLL) and in isolated canine intrapulmonary lobar artery rings with and without a functional endothelium. LLLs (n = 6), perfused at constant blood flow, were challenged with bolus doses of 50, 100, and 250 micrograms 5-HT before COI, after COI with 45 microM meclofenamate, and after infusion of prostacyclin (PGI2) during COI. Lobar vascular resistance was segmentally partitioned by venous occlusion. Pulmonary arterial pressure increased from 13.5 +/- 1.0 to 16.3 +/- 0.8 cmH2O (P less than 0.01) after COI but declined to 13.1 +/- 1.1 cmH2O (P less than 0.01) subsequent to PGI2 infusion (91.3 +/- 14.5 ng.min-1.g LLL-1). The pulmonary arterial pressure changes were related to changes in postcapillary resistance. The dose-dependent pressor response to 5-HT was potentiated by COI (P less than 0.01) but reversibly attenuated (P less than 0.05) by PGI2 infusion. Isolated intrapulmonary artery rings (2-4 mm diam) exhibited a dose-related increase in contractile tension to 5-HT. The response to 5-HT was enhanced (P less than 0.05) in rings devoid of a functional endothelium. However, COI (10 microM indomethacin) did not alter (P greater than 0.05) the dose-related increase in contractile tension to 5-HT in rings with an intact endothelium. Our results suggest that both PGI2 and endothelium-derived relaxing factors modulate pulmonary vascular reactivity to 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)     

Phosphoinositide 3-kinase contributes to diabetes-induced abnormal vascular reactivity in rat perfused mesenteric bed

Phosphatidylinositol 3-kinase (PI3K) is a signaling enzyme that plays key roles in vascular growth, proliferation, and cellular apoptosis and is implicated in modulating vascular smooth muscle contractility. The aim of this study was to determine whether PI3K contributes to development of diabetes-induced abnormal vascular reactivity to selected vasoactive agonists. The effect of 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002), a selective PI3K inhibitor, on isolated perfused mesenteric vascular bed from streptozotocin (STZ)-diabetic rats was investigated. Changes in perfusion pressure, which reflected peripheral resistance, were measured using isolated perfused mesenteric vascular beds. Our results showed that STZ treatment produced an increase in the vasoconstrictor response to norepinephrine (NE), angiotensin II (Ang II) and endothelin-1 (ET-1), and an attenuated vasodilator response to carbachol and histamine in the isolated perfused mesenteric vascular bed from STZ-diabetic animals. Chronic inhibition of PI3K with LY294002 resulted in prevention of diabetes-induced abnormal vascular reactivity to the vasoactive agonists. However, the high blood glucose levels were not normalized. Results of this study indicate that selective inhibition of PI3K can attenuate the development of diabetes-induced abnormal vascular responsiveness in the isolated perfused mesenteric vascular bed.     

Systolic elastance and resistance in the regulation of cardiac pumping function in early streptozotocin-diabetic rats

We determined the roles of maximal systolic elastance (E(max)) and theoretical maximum flow ((max)) in the regulation of cardiac pumping function in early streptozotocin (STZ)-diabetic rats. Physically, E(max) can reflect the intrinsic contractility of the myocardium as an intact heart, and (max) has an inverse relation to the systolic resistance of the left ventricle. Rats given STZ 65 mg/kg i.v. (n = 17) were divided into two groups, 1 week and 4 weeks after induction of diabetes, and compared with untreated age-matched controls (n = 15). Left ventricular (LV) pressure and ascending aortic flow signals were recorded to calculate E(max) and (max), using the elastance-resistance model. After 1 or 4 weeks, STZ-diabetic animals show an increase in effective LV end-diastolic volume (V(eed)), no significant change in peak isovolumic pressure (P(iso)(max)), and a decline in effective arterial volume elastance (E(a)). The maximal systolic elastance E(max) is reduced from 751.5 +/- 23.1 mmHg/ml in controls to 514.1 +/- 22.4 mmHg/ml in 1- and 538.4 +/- 33.8 mmHg/ml in 4-week diabetic rats. Since E(max) equals P(iso)(max)/V(eed), an increase in V(eed) with unaltered P(iso)(max) may primarily act to diminish E(max) so that the intrinsic contractility of the diabetic heart is impaired. By contrast, STZ-diabetic rats have higher theoretical maximum flow (max) (40.9 +/- 2.8 ml/s in 1- and 44.5 +/- 3.8 ml/s in 4-week diabetic rats) than do controls (30.7 +/- 1.7 ml/s). There exists an inverse relation between (max) and E(a) when a linear regression of (max) on E(a) is performed over all animals studied (r = 0.65, p < 0.01). The enhanced (max) is indicative of the decline in systolic resistance of the diabetic rat heart. The opposing effects of enhanced (max) and reduced E(max) may negate each other, and then the cardiac pumping function of the early STZ-diabetic rat heart could be preserved before cardiac failure occurs.     

心房钠尿因子对麻醉家兔局部血流的影响

在42只麻醉家兔,观察了静脉注射心房肽Ⅱ(AtriopeptinⅡ,APⅡ)对局部血流量以及动脉内注射 AP Ⅱ 对局部血管阻力的影响。结果如下:(1)静脉注射 APⅡ(30μg/kg)5min后,平均动脉压(MAP)降低11.0±1.5mmHg(n=8,M±SE,下同),与溶剂对照组相比有明显差异(P相似文献   

Pulmonary vascular reactivity in Fischer rats

We previously reported that Fischer (F) rat lungs developed more extensive injury when challenged with oxidants than age-matched Sprague-Dawley (SD) rat lungs. We now describe a reduced pulmonary vascular response to alveolar hypoxia and angiotensin II (ANG II) in F compared with SD rats. The comparative studies were performed with isolated lungs perfused with salt solution or blood, catheter-implanted awake rats, and isolated main pulmonary arterial rings. Isolated lungs from F rats perfused with either blood or salt solution had reduced vasoconstriction in comparison with lungs from SD rats when exposed to alveolar hypoxia or challenged with ANG II. Instrumented awake F rats had a smaller mean increase in total pulmonary vascular resistance (PVR) than SD rats (35 vs. 94 mmHg.min.l-1, P less than 0.05) when challenged with 8% oxygen. The contractile response of isolated pulmonary artery but not thoracic aortic rings to KCl and ANG II was reduced in F compared with SD rats. In addition, F rats exposed to 4 wk of hypobaric hypoxia developed less pulmonary hypertension and right ventricular hypertrophy (when corrected for the hematocrit) than SD rats. We conclude that the oxidant stress-sensitive inbred F rat strain is characterized by a lung vascular bed that is relatively unresponsive to vasoconstricting stimuli. The mechanism underlying this genetic difference in lung vascular control remains to be defined.     

Effects of PPAR-gamma ligands on vascular smooth muscle marker expression in hypertensive and normal arteries

Having previously demonstrated that glucose transporter-4 (GLUT4) expression was reduced in aortas and carotid arteries of deoxycorticosterone acetate (DOCA) salt-hypertensive rats, we hypothesized that troglitazone (TG), through activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma), would stabilize GLUT4 expression and possibly preserve the differentiated phenotype in vascular smooth muscle cells. In DOCA salt-hypertensive rats treated with TG (100 mg/day), there was a significant (P < 0.001) decrease in systolic blood pressure (BP; 149.9 +/- 4.4 mmHg) compared with the untreated DOCA salt-hypertensive rats (202.2 +/- 10.34 mmHg). Separate trials with rosiglitazone (RS; 3 mg/day) demonstrated a significant (P < 0.001) decrease in BP (DOCA salt, 164.2 +/- 9.8 vs. DOCA-RS, 124.9 +/- 3.7 mmHg) comparable to that with TG. Expression of GLUT4, h-caldesmon, and smooth muscle myosin heavy chain SM2 was significantly decreased in aortas of DOCA salt-hypertensive rats and was reversed by TG to levels similar to those in aortas of sham-treated rats. TG (50 microM) induced GLUT4 and h-caldesmon expression in 24-h culture of explanted carotid arteries of DOCA salt-hypertensive rats, and the endogenous PPAR-gamma ligand 15-deoxy-Delta(12-14)-prostaglandin J(2) (PGJ(2); 20 microM) and TG (50 microM) similarly increased GLUT4, h-caldesmon, and SM2 protein expression in explanted aortas. The expression of activated, phosphorylated Akt was increased by PGJ(2) and TG with no significant effect on total Akt levels. Inhibition of phosphorylated Akt expression using the phosphatidylinositol 3-kinase inhibitor LY-294002 (16 microM) abrogated the increased expression of h-caldesmon and SM2. These data demonstrate that PPAR-gamma agonists maintain or induce expression of markers of the contractile phenotype independently of their effects on hypertension, and that this effect may be mediated through activation of phosphatidylinositol 3-kinase/Akt.     

Analysis of tert-butyl hydroperoxide induced constrictions of perfused vascular beds in vitro

tert-Butyl hydroperoxide (t-BOOH), an inducer of oxidative stress in vitro, elicits constrictor responses of the isolated, rat kidney and mesenteric arteries perfused (5 ml/min) with physiological salt solutions (PSS) at 37 degrees C gassed with carbogen. We hypothesized that generation of superoxide anions (O(2)(-)) accounts for these responses. We assessed responses to t-BOOH in preparations with/without endothelium, and in the absence/presence of antioxidant compounds, catalase and tempol, scavengers of hydroxyl (OH(-)) radical and O(2)(-), respectively. t-BOOH (0.01-50 micromol) induced (expressed as % of 50 micromol KCl vasoconstriction) were abolished by endothelium denudation, perfusion with Ca(2+)-free PSS and by nifedipine, (1 nM). Infusion of t-BOOH (0.1 microM) did not significantly (P > 0.05) affect phenylepherine E(max) in the mesenteric arteries, however it reduced phenylepherine E(max) responses in the kidney from 94.9 +/- 3.9 % to 64.7 +/- 4.7 %. Nitroblue tetrazolium, as well as alpha-phenyl N-tert-butyl nitrone, at 100 microM, but not catalase (500 IU) significantly attenuated t-BOOH (10 micromol) vasoconstrictor responses. Tempol (100 microM), a membrane permeable antioxidant, also significantly reduced t-BOOH (10 micromol) responses from 17.0 +/- 1.9 % (control) to 9.6 +/- 0.5 % (+tempol) in the mesenteric arteries and from 40.4 +/- 4.2 % (control) to 20.7 +/- 1.5 % (+tempol) in the kidney. Our data suggest that t-BOOH elicits vasoconstriction via two distinct mechanisms: (i) increased influx of extracellular Ca(2+), and (ii) generation of free radicals including O(2)(-) anions.     

Effects of exercise training on the vascular reactivity of the whole kidney circulation in rabbits.

Exercise training is known to improve vasodilating mechanisms mediated by endothelium-dependent relaxing factors in the cardiac and skeletal muscle vascular beds. However, the effects of exercise training on visceral vascular reactivity, including the renal circulation, are still unclear. We used the experimental model of the isolated perfused rabbit kidney, which involves both the renal macro- and microcirculation, to test the hypothesis that exercise training improves vasodilator mechanisms in the entire renal circulation. New Zealand White rabbits were pen confined (Sed; n = 24) or treadmill trained (0% grade) for 5 days/wk at a speed of 18 m/min during 60 min over a 12-wk period (ExT; n = 24). Kidneys isolated from Sed and ExT rabbits were continuously perfused in a nonrecirculating system under conditions of constant flow and precontracted with norepinephrine (NE). We assessed the effects of exercise training on renal vascular reactivity using endothelial-dependent [acetylcholine (ACh) and bradykinin (BK)] and -independent [sodium nitroprusside (SNP)] vasodilators. ACh induced marked and dose-related vasodilator responses in kidneys from Sed rabbits, the reduction in perfusion pressure reaching 41 +/- 8% (n = 6; P < 0.05). In the kidneys from ExT rabbits, vasodilation induced by ACh was significantly enhanced to 54 +/- 6% (n = 6; P < 0.05). In contrast, BK-induced renal vasodilation was not enhanced by training [19 +/- 8 and 13 +/- 4% reduction in perfusion pressure for Sed and ExT rabbits, respectively (n = 6; P > 0.05)]. Continuous perfusion of isolated kidneys from ExT animals with N(omega)-nitro-L-arginine methyl ester (L-NAME; 300 microM), an inhibitor of nitric oxide (NO) biosynthesis, completely blunted the additional vasodilation elicited by ACh [reduction in perfusion pressure of 54 +/- 6 and 38 +/- 5% for ExT and L-NAME + ExT, respectively (n = 6; P < 0.05)]. On the other hand, L-NAME infusion did not affect ACh-induced vasodilation in Sed animals. Exercise training also increased renal vasodilation induced by SNP [36 +/- 7 and 45 +/- 10% reduction in perfusion pressure for Sed and ExT rabbits, respectively (n = 6; P < 0.05)]. It is concluded that exercise training alters the rabbit kidney vascular reactivity, enhancing endothelium-dependent and -independent renal vasodilation. This effect seems to be related not only to an increased bioavailability of NO but also to the enhanced responsiveness of the renal vascular smooth muscle to NO.     

Repeated pregnancies (multiparity) increases venous tone and reduces compliance

In humans, multiparity (repeated pregnancy) is associated with increased risk of cardiovascular disease. In rats, multiparity increases the pressor response to phenylephrine and to acute stress, due in part to changes in tone of the splanchnic arterial vasculature. Given that the venous system also changes during pregnancy, we studied the effects of multiparity on venous tone and compliance. Cardiovascular responses to volume loading (2 ml/100 g body wt), and mean circulatory filling pressure (MCFP, an index of venomotor tone) were measured in conscious, repeatedly bred (RB), and age-matched virgin rats. In addition, passive compliance and venous reactivity of isolated mesenteric veins were measured by pressure myography. There was a greater increase in mean arterial pressure after volume loading in RB rats (+7.2 +/- 2.5 mmHg, n = 8) than virgin rats (-1.4 +/- 1.7 mmHg, n = 7) (P < 0.05). The increase in MCFP in response to norepinephrine (NE) was also greater in RB rats [half maximal effective dose (ED(50)) 3.1 +/- 0.5 nmol.kg(-1).min(-1), n = 6] than virgins (ED(50): 12.1 +/- 2.7 nmol.kg(-1).min(-1), n = 6) (P < 0.05). Pressure-induced changes in passive diameter were lower in isolated mesenteric veins from RB rats (29.3 +/- 1.8 microm/mmHg, n = 6) than from virgins (36.9 +/- 1.3 microm/mmHg, n = 6) (P < 0.05). Venous reactivity to NE in isolated veins was also greater in RB rats (EC(50): 2.68 +/- 0.37x10(-8) M, n = 5) than virgins (EC(50): 4.67 +/- 0.93 x 10(-8) M, n = 8). We conclude that repeated pregnancy induces a long-term reduction in splanchnic venous compliance and augments splanchnic venous reactivity and sympathetic tonic control of total body venous tone. This compromises the ability of the capacitance (venous) system to accommodate volume overloads and to buffer changes in cardiac preload.     

Regional venous outflow, blood volume, and sympathetic nerve activity during hypercapnia and hypoxic hypercapnia.

We examined the changes in systemic blood volume and regional venous outflow from the splanchnic, coronary, and other remaining vascular beds in response to acute hypercapnia or hypoxic hypercapnia in dogs, using cardiopulmonary bypass and a reservoir. Hypercapnia (PCO2 = 105 mmHg) (1 mmHg = 133 Pa) and hypoxic hypercapnia (PO2 = 23 mmHg, PCO2 = 99 mmHg) caused marked decreases in systemic blood volume of 14 +/- 3 and 16 +/- 3 mL/kg in spleen-intact dogs, and 3 +/- 2 and 10 +/- 2 mL/kg in splenectomized dogs, respectively. Splanchnic venous outflow increased by 12% at 3.5 min hypercapnia, whereas it decreased by 60% at 3.5 min hypoxic hypercapnia. Coronary venous outflow increased by 85 and 400% at 3.5 min hypercapnia and hypoxic hypercapnia, respectively. Sympathetic efferent nerve activity revealed a significant augmentation during hypoxic hypercapnia and a relatively smaller increase (30% of the response to hypoxic hypercapnia) during hypercapnia. Carotid and aortic chemoreceptor and baroreceptor denervation attenuated significantly the response of systemic blood volume to hypercapnia and hypoxic hypercapnia. The regional venous outflow responses to hypercapnia were not altered after chemodenervation, but those to hypoxic hypercapnia were significantly attenuated after chemodenervation. These results suggest that acute hypercapnia and hypoxic hypercapnia caused a marked decrease in vascular capacitance owing primarily to an increase in sympathetic efferent nerve activity via chemoreceptor stimulation. They also indicate that blood flow to the splanchnic vascular bed during hypercapnia increased (even though the cardiac output was constant), whereas it increased to the extrasplanchnic and coronary vascular beds during hypoxic hypercapnia.     

Defibrotide modulates prostaglandin production in the rat mesenteric vascular bed

Defibrotide 1 microM, a polydeoxyribonucleotide extracted from mammalian organs, reduced the contractile responses to noradrenaline (NA) in the rat isolated and perfused mesenteric vascular bed, in intact as well as in de-endothelialized preparations. Defibrotide was without effect on the acetylcholine-induced relaxations of U-46619-precontracted mesenteric vascular beds. Moreover, defibrotide increased 6-keto prostaglandin (PG) F(2alpha) (stable metabolite of prostacyclin) release sixfold in the presence, but not in the absence of the endothelium, with no modification on the release of other prostanoids. Defibrotide also inhibited the NA-induced increase in PGF(2alpha) release, in both intact and de-endothelialized mesenteric vascular beds. In conclusion, the present results show that defibrotide modulates PG production in the mesenteric bed and that the observed inhibition of the contractile responses should be due to the impairment of the NA-induced increase in PGF(2alpha) release.     

Effects of lung volume and alveolar surface tension on pulmonary vascular resistance

Utilizing the arterial and venous occlusion technique, the effects of lung inflation and deflation on the resistance of alveolar and extraalveolar vessels were measured in the dog in an isolated left lower lobe preparation. The lobe was inflated and deflated slowly (45 s) at constant speed. Two volumes at equal alveolar pressure (Palv = 9.9 +/- 0.6 mmHg) and two pressures (13.8 +/- 0.8 mmHg, inflation; 4.8 +/- 0.5 mmHg, deflation) at equal volumes during inflation and deflation were studied. The total vascular pressure drop was divided into three segments: arterial (delta Pa), middle (delta Pm), and venous (delta Pv). During inflation and deflation the changes in pulmonary arterial pressure were primarily due to changes in the resistance of the alveolar vessels. At equal Palv (9.9 mmHg), delta Pm was 10.3 +/- 1.2 mmHg during deflation compared with 6.8 +/- 1.1 mmHg during inflation. At equal lung volume, delta Pm was 10.2 +/- 1.5 mmHg during inflation (Palv = 13.8 mmHg) and 5.0 +/- 0.7 mmHg during deflation (Palv = 4.8 mmHg). These measurements suggest that the alveolar pressure was transmitted more effectively to the alveolar vessels during deflation due to a lower alveolar surface tension. It was estimated that at midlung volume, the perimicrovascular pressure was 3.5-3.8 mmHg greater during deflation than during inflation.     

CYP4A1 antisense oligonucleotide reduces mesenteric vascular reactivity and blood pressure in SHR

The cytochrome P-450 4A (CYP4A)-derived arachidonic acid metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) affects renal tubular and vascular functions and has been implicated in the control of arterial pressure. We examined the effect of antisense oligonucleotide (ODN) to CYP4A1, the low K(m) arachidonic acid omega-hydroxylating isoform, on vascular 20-HETE synthesis, vascular reactivity, and blood pressure in the spontaneously hypertensive rat (SHR). Administration of CYP4A1 antisense ODN decreased mean arterial blood pressure from 137 +/- 3 to 121 +/- 4 mmHg (P < 0.05) after 5 days of treatment, whereas treatment with scrambled antisense ODN had no effect. Treatment with CYP4A1 antisense ODN reduced the level of CYP4A-immunoreactive proteins along with 20-HETE synthesis in mesenteric arterial vessels. Mesenteric arteries from rats treated with antisense ODN exhibited decreased sensitivity to the constrictor action of phenylephrine (EC(50) 0.69 +/- 0.17 vs. 1.77 +/- 0.40 microM). Likewise, mesenteric arterioles from antisense ODN-treated rats revealed attenuation of myogenic constrictor responses to increases of transmural pressure. The decreased vascular reactivity and myogenic responses were reversible with the addition of 20-HETE. These data suggest that CYP4A1-derived 20-HETE facilitates myogenic constrictor responses in the mesenteric microcirculation and contributes to pressor mechanisms in SHR.     

Role of oxidative stress in age-related reduction of NO-cGMP-mediated vascular relaxation in SHR

The incidence of hypertension increases during the late stages of aging; however, the vascular mechanisms involved are unclear. We investigated whether the late stages of aging are associated with impaired nitric oxide (NO)-mediated vascular relaxation and enhanced vascular contraction and whether oxidative stress plays a role in the age-related vascular changes. Aging (16 mo) male spontaneously hypertensive rats (SHR) nontreated or treated for 8 mo with the antioxidant tempol (1 mM in drinking water) or vitamin E (E; 5,000 IU/kg chow) and vitamin C (C; 100 mg. kg-1. day-1 in drinking water) and adult (12 wk) male SHR were used. After the arterial pressure was measured, aortic strips were isolated from the rats for measurement of isometric contraction. The arterial pressure and phenylephrine (Phe)-induced vascular contraction were enhanced, and the ACh-induced vascular relaxation and nitrite/nitrate production were reduced in aging compared with adult rats. In aging rats, the arterial pressure was nontreated (188 +/- 4), tempol-treated (161 +/- 6), and E + C-treated (187 +/- 1 mmHg). Phe (10-5 M) caused an increase in active stress in nontreated aging rats (14.3 +/- 1.0) that was significantly (P < 0.05) reduced in tempol-treated (9.0 +/- 0.7) and E + C-treated rats (9.8 +/- 0.6 x 104 N/m2). ACh produced a small relaxation of Phe contraction in nontreated aging rats that was enhanced (P < 0.05) in tempol- and E + C-treated rats. l-NAME (10-4 M), inhibitor of NO synthase, or ODQ (10-5 M), inhibitor of cGMP production in smooth muscle, inhibited ACh relaxation and enhanced Phe contraction in tempol- and E + C-treated but not the nontreated aging rats. ACh-induced vascular nitrite/nitrate production was not different in nontreated, tempol- and E + C-treated aging rats. Relaxation of Phe contraction with sodium nitroprusside, an exogenous NO donor, was smaller in aging than adult rats but was not different between nontreated, tempol- and E + C-treated aging rats. Thus, during the late stages of aging in SHR rats, an age-related inhibition of a vascular relaxation pathway involving not only NO production by endothelial cells but also the bioavailability of NO and the smooth muscle response to NO is partially reversed during chronic treatment with the antioxidants tempol and vitamins E and C. The data suggest a role for oxidative stress in the reduction of vascular relaxation and thereby the promotion of vascular contraction and hypertension during the late stages of aging.