High NaCl Intake Decreases both Flow‐Induced Dilation and Pressure‐Induced Myogenic Tone in Resistance Arteries from Normotensive Rats: Involvement of Cyclooxygenase‐2

Abstract: The effect of high NaCl diet on resistance arteries is not yet fully documented. In order to assess the effect of NaCl on myogenic tone and flow‐induced dilation independent of arterial blood pressure change, we used normotensive rats which did not develop hypertension upon high NaCl intake. Normotensive Wistar Kyoto Rats received a high (8%) or a normal NaCl diet (0.4%). Mesenteric resistance arteries (150 μm, internal diameter) were cannulated in an arteriograph to allow perfusion of arteries under controlled pressure and flow. Pressure‐induced myogenic tone was lower in the high NaCl group than in the control group. Cyclooxygenase inhibition with indomethacin and (N‐(2‐cyclohexyloxy)‐4‐nitro‐phenyl)‐methanesulphonamide, 1 μmol/l) NS 398 (specific cyclooxygenase‐2 inhibitor) similarly decreased myogenic tone in rats fed high NaCl but had no effect in those fed a normal NaCl diet. Flow‐induced dilation was decreased in the high NaCl group. Inhibition of nitric oxide synthesis with N^G‐nitro‐L‐arginine methyl ester decreased flow‐induced dilation in both groups. Indomethacin and NS 398 did not change flow‐induced dilation. As shown by immunofluorescence COX‐2 was present in the endothelium of arteries from rats with a high NaCl diet but not in those fed a normal NaCl diet. Thus, chronic high NaCl intake decreased both flow‐induced dilation and myogenic tone in resistance arteries. The chronic high NaCl did not affect the participation of nitric oxide on flow‐induced dilation, but induced the expression of cyclooxygenase‐2, which participates in myogenic tone. These results suggest that high NaCl changes flow and pressure mechanosensing processes and strengthen the hypothesis that sodium ions have an important role in both pressure and flow‐mechanotransduction in vascular cells.     

Myogenic tone and reactivity of cerebral arteries in type II diabetic BBZDR/Wor rat

BBZDR/Wor rat is a new model of type II diabetes with spontaneous obesity and clinical characteristics close to human diabetes. In this study the time-course of cerebroarterial dysfunction was characterized. Posterior cerebral arteries from BBZDR/Wor rats and their age-matched lean controls were pressurized to 70 mm Hg in an arteriograph. Effects of intraluminal pressure and different pharmacological agents on myogenic tone were evaluated. Pressure-myogenic tone curves in diabetic arteries were similar to that in non-diabetic arteries at pre-diabetic age, showed leftward shift at 4 weeks and were significantly different with higher myogenic tone at 5 and 8 months of diabetes. Age-dependent decrease in myogenic tone was observed in non-diabetic arteries. Dilation to histamine was similar to that in non-diabetic arteries at pre-diabetic and at 4 weeks but significantly reduced at 5 and 8 months of diabetes. Bradykinin-mediated dilation was significantly reduced in early and chronic diabetes, whereas (+/-)-S-nitroso-N-acetylpenicillamine (SNAP)-mediated dilation was decreased modestly at 8 months of diabetes. Sensitivity and constriction to 5-hydroxytryptamine were increased in early and chronic diabetes. Responses to bradykinin and 5-hydroxytryptamine were decreased and increased, respectively. Myogenic tone was significantly less sensitive to (lower pIC(50)) U-73122 than normal arteries at 4 weeks and 8 months of diabetes suggesting an increased activation of phospholipase C (PLC). This study shows that pressure-mediated autoregulation of cerebral arteries in type II diabetes operates at higher resistance. Endothelium-dependent dilation was decreased with chronic diabetes with increased sensitivity to constrictor agonist. Endothelium-independent dilation was modestly affected. Arterial hyper-reactivity to pressure and constrictor agonist were likely due to increased PLC activation.     

Effects of Angiotensin II AT1–Receptor Blockade on High Fat Diet–Induced Vascular Oxidative Stress and Endothelial Dysfunction in Dahl Salt-Sensitive Rats

We examined the effects of angiotensin II AT₁–receptor blockade with olmesartan on high fat (HF) diet–induced vascular oxidative stress and endothelial dysfunction in normal salt (NS) diet–fed Dahl salt-sensitive (DSS) rats. Treatment with NS + HF diet (32% crude fat, 0.3% NaCl) for 20 weeks significantly increased blood pressure in DSS rats. NS + HF diet–fed DSS rats also showed higher plasma levels of thiobarbituric acid–reactive substances, aortic superoxide production, and mRNA levels of p22^phox and gp91^phox in aortic tissues than NS diet–fed DSS rats. Furthermore, acetylcholine-induced vasorelaxation of aorta from NS + HF diet–fed DSS rats was significantly reduced. In NS + HF diet–fed DSS rats, treatment with olmesartan medoxomil (10 mg/kg per day, p.o.) and hydralazine (25 mg/kg per day, p.o.) similarly decreased blood pressure. However, in these animals, only olmesartan normalized plasma levels of thiobarbituric acid–reactive substances, vascular superoxide in aortic tissues, and acetylcholine-induced vasorelaxation. These data indicate that HF diet–induced hypertension is associated with vascular oxidative stress and endothelial dysfunction in NS diet–treated DSS rats. Inhibition of angiotensin II AT₁ receptors may elicit beneficial effects on HF-induced hypertension and vascular injury in subjects that have genetically enhanced sodium-sensitive blood pressure.     

ROLE OF NITRIC OXIDE AND ENDOTHELIUM IN THE FLOW-INDUCED DILATION OF RAT CORONARY ARTERIES UNDER TWO PRECONSTRICTION CONDITIONS

1. Pressure-induced tone and flow-induced dilations were studied in a rat perfused epicardial coronary artery mounted in an arteriograph. Spontaneous tone was assessed in arteries submitted either to 60 or 90 mmHg intraluminal pressure either under control conditions, after incubation with NG-nitro-L-arginine methyl ester (L-NAME; 100 mumol/L) or after endothelial denudation. Flow-induced dilation was quantified under these conditions in preparations either submitted to 60 mmHg and preconstricted with 10 mumol/L 5-hydroxytryptamine (5-HT) or exhibiting spontaneous tone at 90 mmHg. 2. Spontaneous tone was greater at 90 mmHg compared with tone obtained at 60 mmHg (21 +/- 2 vs 10 +/- 2% reduction of the fully dilated diameter after sodium nitroprusside incubation, respectively). Incubation with L-NAME or removal of the endothelium significantly increased spontaneous tone at both pressures compared with control. 3. In arteries submitted to 60 mmHg and preconstricted with 10 mumol/L 5-HT, flow (0-800 microL/min) induced a continuous dilation (maximal value 63 +/- 4%). As a function of flow, shear stress first increased and then plateaued at values of approximately 76 +/- 6 dyn/cm2. After L-NAME incubation or endothelial denudation, the flow-induced dilation was reduced to the same extent and was obtained for higher values of shear stress (172 +/- 14 and 150 +/- 14 dyn/cm2, respectively). 4. In arteries exhibiting spontaneous tone, starting flow led, first, to a constriction followed by a dilation up to 76 +/- 4% of the initial tone. Incubation with L-NAME greatly altered flow-induced dilation. Endothelium removal further reduced the dilation obtained for very high values of shear stress (up to 300 dyn/cm2). 5. The present study shows that different patterns of vasodilation induced by flow can be observed, depending on the initial vasoconstrictor stimulus. In 5-HT-preconstricted arteries, flow-induced dilation appears to be fully dependent on the synthesis and release of nitric oxide. In arteries with spontaneous tone, a vasoconstrictor substance could be released for low values of flow. Nitric oxide is mainly, but not exclusively, responsible for the vasodilation. For both experimental conditions, removal of the endothelium greatly reduced the response, but a dilation was still observed.     

Role of angiotensin II,sympathetic stimulation and salt in the development of structural vascular changes in rat kidney

1. Functional and structural vasoconstriction of renal cortical arteries is the earliest change leading to hypertension. In the present study, the interaction of a subpressor dose of angiotensin (Ang) II, a 2% NaCl diet and sympathetic stimulation in the form of overnight cold exposure was investigated in the development of renal structural vascular changes in male Sprague-Dawley rats. 2. Morphometric measurements of renal cortical resistance arteries and volume density measurements of renal cortical components were performed in eight groups of rats after 12 weeks of treatment: AngII; 2% NaCl diet; cold exposure (5 degrees C); AngII plus 2% NaCl diet; AngII plus cold exposure; cold exposure plus 2% NaCl diet; ANG II plus 2% NaCl diet plus cold exposure; and sham operation and treatment (control). 3. The average weekly systolic blood pressure of AngII-treated plus salt-fed rats was increased, whereas that of cold-stressed plus salt-fed rats at room temperature decreased compared with controls. The blood pressure rise of the former group was accompanied by an increased wall-to-lumen ratio (WLR) of cortical resistance arteries and decreased glomerular volume, whereas the reduction in blood pressure in the latter group was accompanied by a decreased WLR of cortical resistance arteries and increased volume density of cortical renal tubules. There were no changes in either the blood pressure or renal structure of the other groups. 4. There is a parallel relationship between changes in preglomerular structural vascular resistance and changes in blood pressure in rats. It remains to be determined whether renal cortical structural changes are the cause of, or are compensatory for, chronic changes in blood pressure.     

Effects of Ginkgo biloba extract feeding on salt-induced hypertensive Dahl rats

We previously demonstrated that Ginkgo biloba extract (GBE) produced vasodilation via the nitric oxide synthesis and release by increasing the intracellular calcium level in vascular endothelial cells of rats. The present study aimed to clarify the effects of dietary administration of GBE on the blood pressure and vascular tone of hypertensive Dahl salt-sensitive (Dahl) rats in order to evaluate its therapeutic actions and availability. Dahl rats were fed an 8.0% NaCl diet or an 8.0% NaCl plus 0.5% GBE diet for 24 d. The feeding of GBE did not change the heart rate, but significantly decreased systolic blood pressure. After 24 days' administration, the effects of GBE on the atria and aorta isolated from Dahl rats were examined. The GBE-containing diet did not affect the negative and positive actions of isolated atria that were produced by acetylcholine and isoproterenol, respectively. In the aortic preparations, the relaxation in response to acetylcholine was significantly potentiated by a GBE-containing diet. Sodium nitroprusside-induced relaxation was unchanged by GBE-containing diet. These results demonstrated that GBE reduced salt-related elevation of blood pressure and restored the impaired acetylcholine-induced vasodilation in aortic segments.     

Raloxifene improves vascular reactivity in pressurized septal coronary arteries of ovariectomized hamsters fed cholesterol diet

Although vascular effects of selective estrogen receptor modulators (SERMs) have been extensively examined in conduit arteries, whether SERMs could favorably modulate myogenic response in resistance arteries is unknown. The impact of raloxifene therapy and cholesterol diet on myogenic constriction during estrogen deficiency is unresolved. This study investigated changes in vascular reactivity and myogenic responses in female ovariectomized (Ovx) hamsters fed high-cholesterol diet (HCD) with and without chronic treatment of raloxifene. Functional studies were performed on hamster septal coronary arteries cannulated in a pressure myograph. Acetylcholine (ACh)-induced dilatation was reduced in arteries from cholesterol-fed Ovx hamsters, but not in those from cholesterol-fed hamsters, while pressure-induced myogenic constriction was unaffected. Chronic treatment with raloxifene restored ACh-induced dilatation in cholesterol-fed Ovx hamsters. U46619-induced constriction was increased in arteries from cholesterol-fed Ovx hamsters but not from cholesterol-fed control hamsters, which was normalized by chronic raloxifene treatment. The pressure-diameter relationship is presented as normalized diameter versus intraluminal pressure, while the effect of ACh or U46619 is expressed as percentage of tone at 80 mm Hg. Two-way analysis of variance (ANOVA) followed by Bonferroni post-tests were used for statistical evaluation among different treatment groups. P<0.05 was taken as statistically significant. The present results show that chronic treatment with raloxifene could benefit myogenically active coronary arteries by (i) restoring ACh-induced dilatation and (ii) reducing U46619-induced constriction without affecting pressure-induced myogenic responses in cholesterol-fed hamsters during estrogen deficiency. If such benefit can be observed in humans, raloxifene and other SERMs may be useful to preserve endothelial function and curtail vascular hypersensitivity in resistance coronary arteries in post-menopausal women with hypercholesterolemia or hyperlipidemia, a lipid condition implicated in the pathogenesis of myocardial infarction.     

Increased salt sensitivity induced by sensory denervation： role of superoxide

AIM:Totestthehypothesisthatproductionofsuperoxideinmesentericresistancearteriesisincreasedandcon-tributestothedevelopmentofhypertensioninducedbysensorydenervationplushighsaltintake.METHODS:NewbornWistarratsweregivencapsaicin50mg/kgsconthe1stand2nddoflife.Afterweaning,maleratsweregroupedasfollowsandtreatedfor3weekswith:capsaicinpretreatmentplusnormalsodiumdiet(0.5%,CAP-NS),CAPplushighsodiumdiet(4%,CAP-HS),controlplusNS(CON-NS),orCON-HS.Bothtail-cuffsystolicbloodpressureandmeanarte…     

Effect of ouabain in pressurized middle cerebral arteries from normotensive and hypertensive rats.

The aim of the present study was to assess the ability of ouabain to induce vasomotor responses and interfere with the myogenic tone in isolated segments of middle cerebral arteries from male Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) subjected to different pressures and no-flow conditions using a pressure myograph. At 60 mmHg, ouabain (1 nM-1 mM) caused relaxations at concentrations of 10 microM and up in segments from WKY while 1 nM ouabain produced a relaxation that was unaltered by the remaining concentrations in SHR segments. The relaxations were higher in SHR than in WKY arteries. Endothelium removal practically abolished the relaxation in arteries from both strains, whereas 10 microM L-NAME (an inhibitor of nitric oxide synthase) had no effect. When arteries were pressurized from 20-120 mmHg, myogenic activity developed in 3 out of 10 WKY arteries while SHR arteries did not show myogenic tone. Endothelium removal did not alter the effects of pressure increase in both strains, and incubation of segments in a Ca(2+)-free medium to abolish myogenic tone, shifted the pressure-response curve of WKY segments to the left; pressure-response curves from SHR were not modified. Although ouabain (0.1 mM) did not alter the pressure-response curve from WKY segments, curves obtained from SHR were shifted to the left. These results suggest that: 1) ouabain produces vasodilation in pressurized middle cerebral arteries of WKY and SHR which is positively modulated by an endothelial factor distinct from nitric oxide; and 2) only WKY arteries develop myogenic activity while the diameter of SHR arteries is passively enhanced with increases in intraluminal pressure. This passive increase is facilitated by ouabain. Therefore, hypertension modifies the mechanical properties of cerebral arteries resulting in a loss in the capacity for autoregulation.     

Inhibitory effect of nitric oxide on the renin-angiotensin system in Dahl salt-sensitive rats

1. To explore the role of nitric oxide (NO) in the regulation of the renin-angiotensin system (RAS) in Dahl salt-sensitive (DS) rats, the effects of NG-nitro-L-arginine methyl ester (L-NAME) on plasma renin activity (PRA), and concentrations of angiotensin (Ang)I and AngII in the plasma, aorta and kidney were investigated in DS and Dahl salt-resistant (DR) rats. 2. NG-Nitro-L-arginine methyl ester (12-18 mg/kg per day) administration for 1 week increased mean arterial pressure (MAP) in DS and DR rats fed a 0.3% NaCl diet and in DR rats fed an 8% NaCl diet compared with corresponding vehicle (water)-treated groups. However, L-NAME administration did not change MAP in DS rats fed an 8% NaCl diet. 3. NG-Nitro-L-arginine methyl ester administration increased PRA in DS rats fed an 8% NaCl diet, but not in DR rats fed an 8% NaCl diet. NG-Nitro-L-arginine methyl ester administration increased AngI and AngII concentrations in plasma, aorta and kidney only in DS rats fed an 8% NaCl diet. The ratio of AngI to AngII did not change following L-NAME administration in any rats. 4. These results suggest that NO has an inhibitory role on renin release in DS rats fed a high-salt diet.     

Adenosine- and hypoxia-induced dilation of human coronary resistance arteries: evidence against the involvement of K(ATP) channels

1. The ATP-sensitive potassium (K(ATP)) channel may be an important mediator of metabolic dilation in the human coronary circulation. As adenosine and hypoxia are considered to be major mediators of metabolic dilation in the coronary circulation, we investigated the effect of glibenclamide (a K(ATP) channel blocker) on adenosine and hypoxic dilation of human coronary resistance arteries, with myogenic tone, in vitro. 2. Vessels were dissected from the atrial appendage from consenting patients and studied in vitro using a pressure arteriograph system. Segments of coronary resistance artery were pressurized to 60 mmHg and the vessels studied developed spontaneous myogenic tone. 3. The K(ATP) opener pinacidil (final conc. 5 x 10(-6) M) resulted in dilation, which was completely reversed by 5 x 10(-6) glibenclamide (84+/-14 vs -10+/-9%, pinacidil and pinacidil plus glibenclamide, respectively, P=0.009, n=5). 4. Adenosine (final conc. 10(-5) M) resulted in dilation, glibenclamide (5 x 10(-6) and 10(-5) M) was without effect (118+/-12 vs 104+/-16% adenosine and adenosine plus 10(-5) glibenclamide, respectively, n.s., n=4). 5. Hypoxia (8+/-3 mmHg O2) resulted in a dilation that reversed when normoxic conditions were restored (60+/-9 vs 3+/-11% hypoxia and post-hypoxia, respectively, P=0.014, n=3). The hypoxic dilation was not affected by glibenclamide (63+/-14 vs 55+/-6% hypoxia and hypoxia plus glibenclamide, respectively, n.s., n=4). In a further series of experiments, vessels were incubated with glibenclamide (5 x 10(-6)) prior to a hypoxic challenge; again, glibenclamide was without effect on the hypoxic dilation (-0.008+/-2 vs 95+/-3% glibenclamide and glibenclamide plus hypoxia, respectively, P=0.0005, n=3). 6. These data demonstrate that glibenclamide is without effect on both adenosine and hypoxic dilation of human coronary resistance arteries with myogenic tone, from the right atrial appendage in vitro. Our findings suggest that the K(ATP) channel is unlikely to be a major mediator of metabolic dilation in these arteries.     

Dietary intake of rapeseed oil or soybean oil as the only fat nutrient in spontaneously hypertensive rats and Wistar Kyoto rats - blood pressure and pathophysiology

Spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) rats were fed a diet containing 10% rapeseed (canola) oil or soybean oil as dietary fat, and given drinking water containing 1% NaCl for 26 weeks. From the 10th week and later, systolic blood pressure in the canola oil group became higher than that in the soybean oil group in each strain. The 26-week feeding of canola oil increased plasma lipids and the neutrophil counts, and decreased the platelet counts. In the canola oil group the heart and kidney tended to become heavier with sporadically found histologic lesions. Acetylcholine- and nitroprusside-induced dilating responses of isolated aortic rings and norepinephrine- and veratridine-induced increases in vascular tone of isolated perfused mesenteric arteries were not different between the two groups in each strain. These results demonstrate that canola oil intake as the only dietary fat elevates blood pressure of the rat provided with drinking water containing 1% NaCl through mechanisms other than blunt dilating response of the blood vessel due to dysfunction of the endothelium or vascular smooth muscle, the augmented response to norepinephrine in the arteries and the increased amount of norepinephrine in the sympathetic nerve endings. The lesions in the heart and kidney in SHR may be related to a strain-specific peripheral vascular deterioration which was disclosed by the extremely high blood pressure in the canola oil group.     

Sodium regulation of alpha 2-adrenoreceptors in Dahl rats. Effect of feeding a low or high salt diet

Sodium regulation of alpha 2-adrenoreceptors was investigated in inbred salt-sensitive (S) and inbred salt-resistant (R) rats fed a high or low salt diet. The systolic blood pressure was higher in S rats than in R rats, and this difference was obviously greater on a high salt diet. In rats fed a low or high salt diet, S rats had higher alpha 2-adrenoreceptor density in the kidneys compared with R rats as measured by [3H]yohimbine binding and Scatchard analysis. The affinity of the receptors in the kidney for the antagonist, yohimbine, was nearly the same in these two strains either on a low or high salt diet. In the brain, the affinities or the numbers of receptors were not significantly different whether these two strains were fed a low or high salt diet. Inclusion of NaCl up to 80 mM in the assay medium did not alter the in vitro binding of [3H]yohimbine in the kidney or brain. On the other hand, inclusion of NaCl in the assay medium reduced the ability of epinephrine in competing with [3H]yohimbine for the receptor sites in the kidney and in the brain, and this effect of NaCl was the same in a given tissue between S and R rats, whether they were fed a low or high salt diet. These results suggest that: (1) in the kidneys, the receptor density and not the receptor affinity was different between S and R strains whether they were fed a low or high salt diet; (2) in the brain, the receptor density and affinity were the same between S and R rats regardless of the diet (low or high salt), indicating that the sodium salt diet modulates the peripheral but not the central alpha 2-adrenoreceptors; and this modulatory effect was observed only in S rats; (3) Na+ was able to reduce the affinity of the agonist (epinephrine) for the receptors in both S and R rats, and this effect of Na+ on central and peripheral alpha 2-adrenoreceptors was similar in prehypertensive rats and rats with salt-induced hypertension; and (4) the resistance of R rats to salt-induced hypertension was not due to the absence of Na+ binding component involved in the regulation of alpha 2-adrenoreceptor-adenylate cyclase complex.     

Alteration of flow-induced dilatation in mesenteric resistance arteries of L-NAME treated rats and its partial association with induction of cyclo-oxygenase-2

1. We investigated the response to pressure (myogenic tone) and flow of rat mesenteric resistance arteries cannulated in an arteriograph which allowed the measurement of intraluminal diameter for controlled pressures and flows. Rats were treated for 3 weeks with N^G-nitro-L-arginine methyl ester (L-NAME, 50 mg kg⁻¹ day⁻¹) or L-NAME plus the angiotensin I converting enzyme inhibitor (ACEI) quinapril (10 mg kg⁻¹ day⁻¹).
2. Mean blood pressure increased significantly in chronic L-NAME-treated rats (155±4 mmHg, n=8, vs control 121±6 mmHg, n=10; P<0.05). L-NAME-treated rats excreted significantly more dinor-6-keto prostaglandin F_1α (dinor-6-keto PGF_1α), the stable urinary metabolite of prostacyclin, than control rats. The ACEI prevented the rise in blood pressure and the rise in urinary dinor-6-keto PGF_1α due to L-NAME.
3. Isolated mesenteric resistance arteries, developed myogenic tone in response to stepwise increases in pressure (42±6 to 847±10 mN mm⁻¹, from 25 to 150 mmHg, n=9). Myogenic tone was not significantly affected by the chronic treatment with L-NAME or L-NAME+ACEI.
4. Flow (100 μl min⁻¹) significantly attenuated myogenic tone by 50±6% at 150 mmHg (n=10). Flow-induced dilatation was significantly attenuated by chronic L-NAME to 22±6% at 150 mmHg (n=10, P=0.0001) and was not affected in the L-NAME+ACEI group.
5. Acute in vitro N^G-nitro-L-arginine (L-NOARG, 10 μM) significantly decreased flow-induced dilatation in control but not in L-NAME or L-NAME+ACEI rats. Both acute indomethacin (10 μM) and acute NS 398 (cyclo-oxygenase-2 (COX-2) inhibitor, 1 μM) did not change significantly flow-induced dilatation in controls but they both decreased flow-induced dilatation in the L-NAME and L-NAME+ACEI groups. Acute Hoe 140 (bradykinin receptor inhibitor, 1 μM) induced a significant contraction of the isolated mesenteric arteries which was the same in the 3 groups.
6. Immunofluorescence analysis of COX-2 showed that the enzyme was expressed in resistance mesenteric arteries in L-NAME and L-NAME+ACEI groups but not in control. COX-1 expression was identical in all 3 groups.
7. We conclude that chronic inhibition of nitric oxide synthesis is associated with a decreased flow-induced dilatation in resistance mesenteric arteries which was compensated by an overproduction of vasodilator prostaglandins resulting in part from COX-2 expression. The decrease in flow-induced dilatation was prevented by the ACEI, quinapril.

     

Tissue angiotensin II and endothelin-1 modulate differently the response to flow in mesenteric resistance arteries of normotensive and spontaneously hypertensive rats

In resistance arteries pressure-induced (myogenic) tone (MT) and flow (shear stress)-induced dilation (FD) are potent determinant of vascular resistance. We investigated the role of angiotensin II and endothelin-1 in FD and MT in resistance arteries and their potential change in hypertension. Flow - diameter - pressure relationship was established in situ, under anaesthesia, in two daughter branches of a mesenteric resistance artery (180 microM, n=7 per group) from spontaneously hypertensive (SHR) or normotensive (WKY) rats. One artery was ligated distally, so that it was submitted to pressure only, while the other was submitted to pressure and flow. Drugs were added to the preparation and external diameter, pressure and flow measured continuously. External diameter (with flow) ranged from 150+/-3 to 191+/-7 microM in WKY (n=28) rats and from 168+/-6 to 186+/-6 microM in SHR (n=28). Flow induced a dilation of the non-ligated arteries which was lower in SHR (13+/-5 - 31+/-4 microM vs WKY: 5+/-5 - 44+/-4 microM). In the ligated artery, the diameter did not significantly change, due to MT. In the vessels submitted to flow angiotensin converting enzyme inhibition (perindopril, 10 micromol L(-1)) increased the diameter in SHR (+11+/-2 microM) significantly more than in WKY (+2+/-1 microM). Angiotensin type 1 receptor (AT(1)R) blockade (losartan, 10 micromol L(-1)) increased the diameter in the vessels with flow in SHR only (+6+/-1 microM). Angiotensin type 2 receptor (AT(2)R) blockade (PD 123319, 1 micromol L(-1)) decreased arterial diameter in WKY only (9+/-2). Endothelin-1 type A receptor (ET(A)R) blockade (LU135252, 0.1 micromol L(-1)) increased the diameter only in SHR in the artery submitted to flow (by 6+/-1 microM). Thus FD was counteracted by a flow-dependent AT(1) and ET(A) receptors-activation in SHR whereas in WKY FD AT(2)-dependent dilation is involved.     

High NaCl diets increase alpha 2-adrenoceptors in renal cortex and medulla of NaCl-sensitive spontaneously hypertensive rats

Diets high in NaCl simultaneously elevate renal alpha 2-adrenoceptor binding and exacerbate hypertension in young NaCl-sensitive spontaneously hypertensive rats (SHR-S). The present study tests the hypothesis that in SHR-S on a high NaCl diet, an upregulation of renal alpha 2-adrenoceptors is present in densely innervated areas of the kidney, and this precedes the increase in blood pressure. Seven week old SHR-S fed on a high (8%) compared to basal (1%) NaCl diet for 2 weeks displayed significantly exacerbated hypertension and elevated renal alpha 2-adrenoceptor binding in both cortex and medulla. In contrast one week on the high NaCl diet did not alter renal alpha 2-adrenoceptor number or blood pressure in SHR-S. Autoradiographic experiments demonstrated that the NaCl-induced upregulation of alpha 2-adrenoceptors occurs in all areas of the renal cortex and medulla. None of these differences were observed in NaCl-resistant, Wistar-Kyoto rats (WKY). Further, the high NaCl diet did not alter renal alpha 1-adrenoceptor binding in SHR-S or WKY. Together with previous findings, these data suggest that the NaCl-induced upregulation of renal alpha 2-adrenoceptors is not specific to densely innervated regions of the kidney.     

Endothelial dysfunction and improvement of the angiotensin II-reactivity in hypercholesterolemic rabbits: role of cyclooxygenase metabolites

The aim of this paper was to study the effect of high cholesterol diet on endothelial function and vascular reactivity to angiotensin II and to test the role of vasoconstrictor cyclooxygenase metabolites in this experimental condition. Rabbits were fed with either normal chow or a diet containing 1% cholesterol for 6-7-week. Isometric contractions were measured in rubbed or unrubbed aortic rings. Arteries were contracted with noradrenaline and then exposed to one cumulative dose-response curve to acetylcholine in absence (control) or in presence of indomethacin, (N-[2-cyvlohexyloxy)-4-nitrophenyl]-methanesulfonamide) (NS 398) or 4-hydroxy-2,2,6,6-tetraethylpiperidine-N-oxyl (tempol). After washing the arteries, one cumulative dose-response curve to angiotensin II was constructed in absence or presence of indomethacin, NS 398, [1S-[1 alpha,2 beta (5Z),3 beta,4 alpha]-7-[3-[[2-[(phenylamino) carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1] hept-2-yl]-5-heptenoic acid (SQ29548) or 17-octadecynoic acid (17-ODYA). In other group, resting potential was recorded in basal and angiotensin II-stimulated conditions. Indomethacin, NS 398 or 17-ODYA were added to the bath before angiotensin II-stimulation. Rabbits fed on a diet enriched with cholesterol showed higher plasma levels of total cholesterol and LDL. Hypercholesterolemic diet impaired acetylcholine relaxation. Indomethacin normalized endothelium-dependent relaxation whereas NS 398 and tempol had no effect on this phenomenon. Angiotensin II-reactivity was increased in endothelium intact hypercholesterolemic aortic rings and indomethacin, SQ29548 or 17-ODYA blocked this effect. The resting potential of unrubbed hypercholesterolemic arteries was significantly less negative to control after angiotensin II-stimulation. 17-ODYA but not indomethacin prevented angiotensin II-depolarization. High cholesterol diet caused endothelial dysfunction and increased the angiotensin II-reactivity. Both effects were cyclooxygenase1-dependent. Deficit in the NO-production might improve 20-hydroxyeicosatrienoic acid availability, which induces depolarization and angiotensin II-sensitization. In addition, 20-hydroxyeicosatrienoic acid would be metabolized by cyclooxygenase1 to 20-endoperoxides which act through thromboxane A(2)/prostaglandin H(2) receptors contributing to angiotensin II-reactivity increase.     

Prevention of hypertensive vasculopathy by nifedipine in salt-loaded Dahl rats

In female "salt-sensitive" (S) Dahl rats, with hypertension induced by 8% sodium chloride (NaCl) in the diet for six weeks, a severe generalized arteriopathy was observed histopathologically. Fibrinoid degeneration, medial hyperplasia and periarteritis were especially pronounced in the preglomerular arterial system of the kidneys. Necrosis of afferent glomerular arterioles led to regressive changes in the renal corpuscles. Numerous dilated renal tubules were filled with protein casts. In the heart, arterial lesions were predominantly localized in the outer wall of the right ventricle. Occlusion of intracardiac arteries was accompanied by focal myocardial necrosis and fibrous replacement of the myocardial fibres. A left ventricular hypertrophy was found. The degree of renal arteriopathy inversely correlated with the magnitude of the hematocrit. S rats treated with nifedipine, 300 ppm in addition to 8% NaCl in the diet remained normotensive. No changes in vessels, tissues or in the hematocrit were seen in any of the nifedipine-treated rats. The same picture was observed in "salt-resistant" (R) rats on a high (8%) and on a low (0.4%) NaCl diet. S rats fed a low NaCl diet showed only dilated renal tubules containing protein casts. It is assumed that nifedipine primarily decreases the renovascular resistance in S rats under salt load, enabling the kidney to eliminate excess sodium without inducing pressure natriuresis. Organ damage in salt-loaded S rats is thus due to a fulminant increase in blood pressure, compensating for the sluggish natriuresis.     

Distinct endothelial pathways underlie sexual dimorphism in vascular auto-regulation

BACKGROUND AND PURPOSE Pre-menopausal females have a lower incidence of cardiovascular disease compared with age-matched males, implying differences in the mechanisms and pathways regulating vasoactivity. In small arteries, myogenic tone (constriction in response to raised intraluminal pressure) is a major determinant of vascular resistance. Endothelium-derived dilators, particularly NO, tonically moderate myogenic tone and, because the endothelium is an important target for female sex hormones, we investigated whether NO-mediated moderation of myogenic tone differed between the sexes. EXPERIMENTAL APPROACH Pressure-diameter or relaxation concentration-response curves to the NO donor spermine-NO or soluble guanylate cyclase (sGC) stimulation (BAY41-2272) were constructed before and following drug intervention in murine mesenteric resistance arteries. Hypotensive responses to activators of the NO-sGC pathway were determined. Quantitative PCR and Western blotting were used for expression analysis. KEY RESULTS NO synthase inhibition enhanced myogenic tone of arteries of both sexes while block of endothelium-derived hyperpolarizing factor (EDHF) enhanced responses in arteries of females only. Spermine-NO concentration-dependently relaxed mesenteric arteries isolated from either sex. However, while inhibition of sGC activity attenuated responses of arteries from male mice only, endothelial denudation attenuated responses of arteries from females only. BAY41-2272 and spermine-NO-induced vasodilatation and hypotension were greater in males than in females. CONCLUSIONS AND IMPLICATIONS NO moderated myogenic tone in arteries of male mice by a sGC-dependent pathway while EDHF was the predominant endothelial regulator in arteries of females. This is a potentially important sexual dimorphism in NO-mediated reactivity and further implicates EDHF as the predominant endothelial vasodilator in female resistance arteries.     

Carbon monoxide enhances development of hypertension in Dahl rats

The influence of carbon monoxide (CO) on the development of systemic hypertension was studied in Dahl rats selectively bred for susceptibility (DS) and resistance (DR) to NaCl-induced hypertension. This study was designed to examine the interactions among rat line (DS or DR), NaCl content of diet, and exposure to CO. The rats were exposed to 500 ppm CO or conditioned air, 21 hr/day, for 62 to 63 consecutive days. Carbon monoxide exposures affected blood pressure only in DS rats fed a high NaCl diet, where it enhanced the development of NaCl-induced hypertension. Whole-body weights were not affected by CO, but organ weight changes in the form of cardiomegaly ranging from 22% (DR, low NaCl) to 36% (DS, high NaCl), and splenomegaly ranging from 29% (DR, low NaCl) to 98% (DS, high NaCl) were observed. The mean equilibrium carboxyhemoglobin concentration was 42% in the CO-exposed rats. The hematologic responses to the CO exposures were elevated total hemoglobin and hematocrit.