The effects of short-term nifedipine treatment on responsiveness of aortic rings of cadmium-hypertensive rats.

The effects of short-term antihypertensive treatment with nifedipine on blood pressure and vascular responsiveness were studied in cadmium-hypertensive and normotensive control rats. Cadmium administration caused a significant increase in mean arterial blood pressure. Endothelin-1, noradrenaline and angiotensin II produced concentration dependent contractions of aortic rings that attained a lower maximal contraction in cadmium-hypertensive rats. Responses of aortic rings to KCl did not show a significant difference between the groups. Nifedipine administered simultaneously with cadmium inhibited the induction of hypertension. Nifedipine treatment for 5 days significantly reduced the blood pressure in cadmium-hypertensive and normotensive rats. Neither inhibition of hypertension nor normalization of blood pressure in cadmium-hypertensive rats caused an alteration in contractile responses of aortic rings to vasoconstrictors which suggested that development of decreased vascular reactivity and of hypertension occurs simultaneously in cadmium-hypertensive rats but the role of decreased vascular reactivity in maintenance of hypertension is questionable in cadmium-hypertension.     

Antihypertensive and vasodilator actions of antioxidants in spontaneously hypertensive rats

This study was designed to determine whether the antioxidants ascorbic acid, aminotriazole, and glutathione acutely reduce blood pressure (BP) by endothelium-independent or -dependent vasorelaxation in spontaneously hypertensive rats. Blood pressure of male Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) was measured before and 4 h after administration of antioxidants. Thoracic aortic rings with and without endothelium were suspended in organ chambers for isometric tension recordings. Each of the antioxidants, administered in vivo, significantly decreased blood pressure in SHR but had no significant effect on BP in WKY rats. The endothelium-dependent impaired relaxation of SHR aortic rings to acetylcholine (ACh) was improved by prior in vivo administration of each antioxidant. ACh-induced relaxations of aortic rings from WKY was not affected by prior antioxidant treatment. Addition of each antioxidant directly to the organ chamber containing SHR or WKY aortas produced dose- and endothelium-dependent relaxations. Moreover, antioxidant pretreatment of SHR aortic rings significantly potentiated ACh-induced relaxations in these aortas, suggesting that this effect was endothelium dependent. Relaxations induced by the antioxidants alone or by ACh in the presence of antioxidants were inhibited by addition of either xanthine plus xanthine oxidase or nitro-l-arginine. These findings suggest that either excess production of oxidants or a deficiency of antioxidant systems may contribute to the high blood pressure and the endothelium-dependent impairment of vascular relaxation in SHR.     

Simvastatin improves endothelial function in spontaneously hypertensive rats through a superoxide dismutase mediated antioxidant effect

BACKGROUND : Hydroxymethylglutaryl coenzyme A (HMGCoA) reductase inhibitors have beneficial effects beyond their cholesterol-lowering properties. The antioxidant mechanism of HMGCoA reductase inhibitors is not completely understood. OBJECTIVES : To elucidate the antioxidant effect of simvastatin. METHODS : We studied the influence of simvastatin treatment on the development of hypertension, modification of antioxidant systems, and reactivity of aortic rings in Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. RESULTS : Simvastatin had no effect on blood pressure (BP). Simvastatin treatment (either 1 or 2 mg/kg body weight for 12 or 20 weeks) increased superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities in SHR rats compared with untreated control SHR rats. Carbachol-induced relaxation of aortic rings was impaired in control SHR rats and was restored by simvastatin treatment. Addition of SOD improved the response in control SHR rats and did not have any effect in treated SHR rats. Addition of diethyldithiocarbamic acid, a selective inhibitor of SOD, produced a mild non-significant impairment in carbachol-induced relaxation in control SHR rats, suggesting a deficient antioxidant system in these animals. However, in treated SHR and in WKY rats, impairment of the relaxation was marked, implying that SOD activity in these animals was important to maintain endothelial function. In aortic rings without endothelium from SHR rats, contraction induced by free radicals was substantially higher than in WKY rats. This effect was attenuated in 1-mg-treated rats and abolished in 2-mg-treated rats. CONCLUSIONS : Simvastatin promotes intracellular antioxidant systems, fundamentally SOD, restoring endothelial function but not having any effect on blood pressure.     

Effect of aspirin on the contractility of aortic smooth muscle and the course of blood pressure development in male spontaneously hypertensive rats

The effects of acetylsalicylic acid (ASA) on aortic smooth muscle contractility were studied in aortic rings of male SHR and WKY rats. The rats were administered two intraperitoneal injections of 10 mg/kg of ASA per week for ten weeks. Blood pressure of each rat was monitored twice weekly prior to the i.p. injections. Twenty four hours after the last injection the aortic smooth muscles were evaluated for generation of active tension in response to KCl, Phenylephrine (PE), Clonidine and Norepinephrine (NE). In another set of experiments calcium conductance was evaluated in the presence or absence of endothelium both in ASA treated and non treated animals. We report that aortic rings from ASA-treated SHR animals were more responsive to contractile agents than rings from non-treated SHR male rats. Also, the Ca2+ conductance in vitro was enhanced appreciably in SHR aortic rings denuded of their monolayer of endothelium in response to ASA treatment. No decrease in systolic blood pressure was observed in response to ASA treatment in SHR male rats. These results suggest that acetylsalicylic acid not only may modulate aortic smooth muscle contractility through the metabolites of arachidonic acid but may repair to a great extent the hypertension associated plasma membrane permeability defect of vascular myocytes.     

Cardiovascular effects of Helichrysum ceres S Moore [Asteraceae] ethanolic leaf extract in some experimental animal paradigms

The aim of this study was to examine some in vivo and in vitro cardiovascular effects of Helichrysum ceres leaf ethanolic extract (HCE) in experimental animal paradigms. The acute effects of HCE on blood pressure were studied in anaesthetised normotensive male Wistar rats challenged with intravenous hypotonic saline infusion after a 3.5-hour equilibration for four hours of one-hour control, 1.5-hour treatment and 1.5-hour recovery periods. HCE was added to the infusate during the treatment period. Sub-chronic hypotensive effects of HCE were examined in weanling Dahl saltsensitive (DSS) genetically hypertensive rats, which progressively develop hypertension with age, treated with HCE (80 mg/kg) every third consecutive day for seven weeks. Isolated atrial muscle strips, portal veins and descending thoracic aortic rings of healthy normotensive Wistar rats were used to investigate the vascular effects of HCE. Acute HCE administration caused a significant (p < 0.05) fall in blood pressure in the normotensive anaesthetised Wistar rats. DSS hypertensive rats treated with HCE displayed low arterial blood pressure and heart rate values from weeks five to seven. HCE produced concentrationdependent negative inotropic and chronotropic effects on rat isolated electrically driven left, and spontaneously beating right atrial muscle preparations, respectively. HCE also evoked concentration-dependent relaxation responses of endothelium-intact aortic rings and portal veins isolated from healthy normotensive Wistar rats. The vasorelaxant effects of HCE in intact aortic rings were significantly reduced, but not completely abolished by adding endothelial- derived factor (EDRF) inhibitor, L-NAME, suggesting that the vasorelaxant effect of the extract is mediated via EDRF-dependent and independent mechanisms. The results of the study suggest that the hypotensive action of HCE is elicited, in part, directly by decreasing myocardial contractile performance and total peripheral vascular resistance due to its negative inotropic and chronotropic effects on rat isolated atrial muscle strips; and vasorelaxant effects on isolated vascular smooth muscles. The observed cardiovascular effects of HCE partly support the basis for its use in the management of high blood pressure in folkloric medicine.     

Improved myocardial capillarisation in spontaneously hypertensive rats treated with nifedipine

The effect of long term administration of nifedipine on myocardial capillarity was studied in spontaneously hypertensive rats. Nifedipine was given for 20 weeks, mixed into commercial rat chow (0.3 g per 1 kg). Untreated spontaneously hypertensive rats had higher arterial blood pressure and developed cardiomegaly when compared with Wistar-Kyoto rats used as controls. Nifedipine administration in spontaneously hypertensive rats lowered the arterial blood pressure and reduced cardiac weight; however, both values remained far above those for controls. Myocardial capillarity was determined using the recently introduced method of capillary domains. Hearts from untreated spontaneously hypertensive rats were characterised by greater and more variable intercapillary spacing than those from controls. The treatment of spontaneously hypertensive rats with nifedipine resulted in normalisation of morphometric indices characterising capillary spacing, probably as a result of stimulation of capillary growth as indicated by a significant decrease in myocyte to capillary ratio. Thus, despite persistent hypertension and cardiomegaly the treatment of spontaneously hypertensive rats with nifedipine restored mean intercapillary distance and index of heterogeneity of capillary spacing to normal values.     

Correlation with blood pressure of the acetylcholine-induced endothelium-derived contracting factor in the rat aorta.

To examine a relation between the production of acetylcholine-induced endothelium-derived contracting factor and an increase in blood pressure, endothelium-dependent contraction and relaxation were evaluated by measuring the isometric tension of aortic rings from spontaneously hypertensive rats and Wistar-Kyoto rats at 5, 10, 20, and 30 weeks of age. In norepinephrine-precontracted rings, acetylcholine (10(-8) to 10(-5) M)-induced relaxations diminished at the doses of 10(-6) to 10(-5) M in both strains except at 5 weeks of age. Treatment with a thromboxane A2/prostaglandin H2 antagonist (ONO-3708) prevented this reduction in acetylcholine-induced relaxations in both strains and induced dose-dependent relaxations, which were completely inhibited by treatment with a nitric oxide inhibitor, NG-nitro-L-arginine methyl ester. In aorta treated with NG-nitro-L-arginine methyl ester without precontraction, acetylcholine induced dose-dependent contractions, which were greater in spontaneously hypertensive rats than in Wistar-Kyoto rats. These acetylcholine-induced contractions, which were observed only in rings with endothelium, were completely inhibited by treatment with ONO-3708 but not with a thromboxane A2 synthetase inhibitor (OKY-046). There was a statistically significant correlation between the acetylcholine-induced contractions and blood pressure. Release of 6-ketoprostaglandin F1 alpha by acetylcholine from the aorta was greater in spontaneously hypertensive rats. In vivo administration of another thromboxane A2/prostaglandin H2 antagonist (ONO-8809) (10 or 30 micrograms per body per day) for 3 weeks (5-8 weeks of age) did not affect blood pressure in either rat strain.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of aspirin on the contractility of aortic smooth muscle in female spontaneously hypertensive rats.

The effects of acetylsalicylic acid (ASA), on aortic smooth muscle contractility during hypertension were studied in female SHR and WKY rats. The rats were administered two intraperitoneal injections of 10 mg/kg of ASA per week for three weeks. Twenty four hours after the last injection the aortic smooth muscles were evaluated for generation of active tension in response to KCl, phenylephrine, clonidine and norepinephrine. We report that aortic rings from ASA-treated SHR animals were more responsive than rings from non-treated SHR female rats. ASA treatment of SHR animals restored the contractile response to the level shown by non-treated WKY control female rats. The response from aortic rings of ASA-treated SHR to KCl, phenylephrine and clonidine was essentially similar to the response of rings from non-ASA-treated WKY control female rats. We did not observe any decrease in the systolic blood pressure during the ASA treatment in SHR female rats. These results suggest that acetylsalicylic acid modulates aortic smooth muscle contractility either through the metabolites of arachidonic acid or through alpha-adrenoceptors.     

Hypercholesterolemia and Changes of Vascular Contractile Responses in Experimentally Uremic Rats

Arterial contractile responses were studied in experimentally uremic rats. The ligation of 75% of the terminal branches of the left renal artery, followed by contralateral nephrectomy induced a chronic renal failure, as evidenced by significantly higher BUN concentrations and an elevation in blood pressure. Uremic rats exhibited elevations in total and HDL cholesterol, increased triglyceride levels, and significantly lowered HDL/total cholesterol ratios compared to control groups: 1) untreated control, 2) experimental control receiving renal infarction without contralateral nephrectomy, and 3) two kidney, one clip (2K1C) model of hypertension. Plasma total cholesterol levels in uremic rats increased by 50% in the first week following final surgery and plateaued at approximately 100% above control levels during postoperative weeks 3 through 10. Plasma transaminase levels were similar among all of the groups of rats studied indicating no effects of surgery on hepatic function. The contractile responses of aortic rings from uremic rats to submaximal concentrations of serotonin and clonidine were significantly increased and decreased, respectively, whereas the contractile response to norepinephrine was not altered. The enhanced sensitivity to serotonin of aortic rings from uremic rats was abolished following disruption of the endothelium. Neither the alteration of aortic contractile properties nor changes in plasma BUN and cholesterol concentrations were observed in hypertensive 2K1C rats. However, there was a tendency for decreased acetylcholine-induced relaxation in aortic rings of uremic and 2KlC rats. No significant histological evidence of atherosclerosis was found in aortic tissues of uremic rats during the interval of study. These results indicate that hypercholesterolemia, hypertriglyceridemia, and altered vascular sensitivity to serotonin and clonidine are likely to be primary changes in the uremic rat and are not secondary to the development of blood pressure elevation or overt evidence of structural change in the vessels of this model.     

Angiotensin II type 1 receptor blocker irbesartan ameliorates vascular function in spontaneously hypertensive rats regardless of oestrogen status

BACKGROUND : Angiotensin II type 1 (AT1) receptor overexpression may play a decisive role in endothelial dysfunction during oestrogen deficiency in spontaneously hypertensive rats (SHRs). Similarly, exaggerated production of angiotensin II and enhanced expression of AT1 receptor have been reported in vessels of SHRs compared with normotensive rats. OBJECTIVE : To test the hypothesis that antihypertensive treatment with the AT1 receptor antagonist, irbesartan, could not only decrease blood pressure but also ameliorate endothelial dysfunction associated with both hypertension and oestrogen deficiency. METHODS : Ovariectomized and sham-ovariectomized SHRs were treated with 50 mg/kg irbesartan per day, administered with chow for 30 weeks. Sham-ovariectomized and ovariectomized rats receiving no treatment were used as control groups. At the end of the treatment period, the vascular reactivity of aortic rings was studied. RESULTS : In the irbesartan-treated groups, vasoconstriction induced by Nomega-nitro-l-arginine methyl ester (l-NAME) was increased and the response to phenylephrine exhibited greater potentiation in the presence of l-NAME, demonstrating a greater availability of basal nitric oxide in these groups. In addition, chronic treatment with irbesartan similarly enhanced the responsiveness of aortic rings from ovariectomized or sham-ovariectomized rats to acetylcholine and sodium nitroprusside. Incubation with indomethacin did not significantly alter acetylcholine- and sodium nitroprusside-induced relaxations in the irbesartan-treated rats. However, relaxations induced by acetylcholine and sodium nitroprusside in aortic rings from non-treated rats were significantly greater in the presence of indomethacin. CONCLUSION : Our data suggest that irbesartan enhances basal nitric oxide availability and ameliorates vascular relaxations in SHRs, by decreasing the production of cyclooxygenase-dependent contracting factors in smooth muscle cells, regardless of oestrogen status.     

Mechanisms of oxidative stress-induced increase in salt sensitivity and development of hypertension in Sprague-Dawley rats

High salt intake produces vascular changes that contribute to the development of hypertension in salt-sensitive individuals. Because reactive oxygen species play a role in the pathogenesis of cardiovascular diseases, we investigated whether oxidative stress contributes to salt-sensitive hypertension. Sprague-Dawley rats were divided in different groups and received tap water (vehicle), 30 mmol/L of l-buthionine sulfoximine ([BSO] an oxidant), high salt ([HS] 1% NaCl), and BSO plus HS without and with antioxidant tempol (1 mmol/L) in drinking water for 12 days. Compared with vehicle, BSO treatment caused oxidative stress and mild increase in blood pressure. Thoracic aortic rings from BSO-treated rats exhibited decreased response to endothelium-independent vasorelaxants. In HS-treated rats, the response to vasoactive agents, as well as blood pressure, was unaffected. Concomitant treatment of rats with BSO and HS produced a marked increase in blood pressure and a decreased response to both endothelium-dependent and endothelium-independent vasorelaxants with an increase in EC(50). Incubation of aortic tissue from BSO-treated rats with sodium nitroprusside showed decreased cGMP accumulation, whereas HS rats had decreased basal NO synthase activity. Tempol decreased oxidative stress, normalized blood pressure, and restored NO signaling and responses to vasoactive compounds in BSO and BSO plus HS rats. We conclude that BSO increases oxidative stress and reduces NO signaling, whereas HS reduces NO levels by decreasing the NO synthase activity. These phenomena collectively result in reduced responsiveness to both endothelium -dependent and endothelium- independent vasorelaxants and may contribute to salt-sensitive hypertension.     

Treatment with the arginase inhibitor N(omega)-hydroxy-nor-L-arginine improves vascular function and lowers blood pressure in adult spontaneously hypertensive rat

OBJECTIVE: High vascular arginase activity and subsequent reduction in vascular nitric oxide production were recently reported in animal models of hypertension. The present study investigated the effects of in-vivo arginase inhibition on blood pressure and vascular function in adult spontaneously hypertensive rats. METHODS: Ten-week-old spontaneously hypertensive rats and normotensive age-matched Wistar-Kyoto rats were treated with or without the selective arginase inhibitor N-hydroxy-nor-L-arginine for 3 weeks (10 or 40 mg/kg per day, intraperitoneally). Systolic blood pressure and cardiac rate were measured before and during treatment. Flow and pressure-dependent reactivity as well as remodeling of mesenteric arteries, acetylcholine-dependent vasodilation of aortic rings, cardiac hypertrophy, arginase activity and nitric oxide production were investigated in 13-week-old spontaneously hypertensive rats. RESULTS: In spontaneously hypertensive rats, N-hydroxy-nor-L-arginine treatment decreased arginase activity (30-40%), reduced blood pressure ( approximately 35 mmHg) and improved the reactivity of mesenteric vessels. However, vascular and cardiac remodeling was not different between treated and untreated spontaneously hypertensive rats. In Wistar-Kyoto rats, N-hydroxy-nor-L-arginine did not affect blood pressure. Finally, arginase inhibition was associated with increased nitric oxide production. Consistent with this, the response of aortic rings to acetylcholine was fully restored by N-hydroxy-nor-L-arginine, and the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester significantly reduced the effect of N-hydroxy-nor-L-arginine on flow-dependent vasodilation. CONCLUSION: Pharmacological inhibition of arginase in adult spontaneously hypertensive rats decreases blood pressure and improves the reactivity of resistance vessels. These data represent in-vivo argument in favor of selective arginase inhibition as a new therapeutic strategy against hypertension.     

Cardiovascular effects of Ekebergia capensis Sparrm (Meliaceae) ethanolic leaf extract in experimental animal paradigms

Summary

The purpose of this study was to examine the in vivo effects of Ekebergia capensis leaf ethanolic extract (EKE) on the blood pressure of anaesthetised normotensive male Wistar rats and conscious weanling Dahl salt-sensitive (DSS) rats, which develop hypertension as they age. To investigate possible mechanism(s) of the extract’s hypotensive effects, the contractile or relaxant responses to EKE in the absence or presence of reference drugs were evaluated in Wistar rat isolated aortic rings precontracted with methoxamine hydrochloride (ME, 10 μM).Acute intravenous administration of EKE elicited hypotensive responses in anaesthetised animals, while sub-chronic treatment with the extract averted the development of high blood pressure in weanling DSS rats. Isometric recordings of methoxamine hydrochloride (ME) pre-contracted, isolated, endothelium-intact and -denuded aortic rings revealed concentration-dependent relaxation responses to EKE (1–160 mg/ml). The potency was significantly less in the endothelium-denuded rings. Inhibitors of endothelium-derived relaxing factor (EDRF), L-NAME, methylene blue and indomethacin significantly reduced EKE-evoked vasorelaxations in endothelium-intact aortic rings.These results indicate that the vasorelaxant effect of EKE was in part mediated via EDRF-dependent or -independent pathways. These observations suggest that the hypotensive effect of EKE was in part mediated via modulation of total peripheral resistance of the vascular smooth muscles.     

Effect of Red Blood Cells and Hemoglobin on Spontaneously Hypertensive and Normotensive Rat Aortas

Experiments were designed to compare the contractile effect of red blood cells (RBC) on aortic rings with and without endothelium from normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Red blood cells of 4 week old WKY and SHR rats induced a negligible increase in tension of aortic rings, either with or without endothelium, being slightly more effective in SHR rats. However, red blood cells of 16 week old rats increased tension of WKY and SHR aortic rings, with endothelium at this age being more pronounced then red blood cells in 4 week old animals. The contractions induced by WKY and SHR red blood cells both in WKY and SHR aortic rings without endothelium at this age are significantly greater compared to the effect on aortic rings with endothelium. Red blood cell ghosts of rats of both strains increased the tension of the rings without endothelium of SHR aorta to near 50% of those induced by red blood cells, whereas they were ineffective in aortic rings without endothelium of WKY rats. Oxyhemoglobin increased the tension of 16 week SHR aortic rings both with and without endothelium, whereas the effect on the rings of WKY rats was negligible. This increase in tension was inhibited by BM 13505, nordihydroguaiaretic acid, and indomethacin in SHR rings both with and without endothelium, demonstrating an eicosanoid involvement in oxyhemoglobin-induced contractions. Hemoglobin or its metabolites may be involved in development or in maintenance of spontaneous hypertensin.     

Pioglitazone, a PPARgamma agonist, restores endothelial function in aorta of streptozotocin-induced diabetic rats

OBJECTIVE: To study the effect of pioglitazone (a PPAR gamma agonist) treatment on blood pressure, endothelial function, and oxidative stress in streptozotocin (STZ)-induced diabetic rats. METHODS: Sprague-Dawley rats were randomized into control (n=32) and STZ-diabetic (n=32) groups. Rats were further randomized to receive pioglitazone (10 mg/kg) or placebo for 4 weeks, and the following protocols were carried out. Blood pressure, blood glucose level, and body weight were measured. Thoracic aorta was isolated and the dose-response curve of phenylephrine (PE) in the presence or absence of Nomega-nitro-L-arginine-methyl ester (L-NAME) was recorded. The dose-response curve of acetylcholine (Ach) in the presence or absence of indomethacin, L-NAME, and methylene blue was recorded. Tone-related basal nitric oxide release experiments were carried out. Lipid peroxidation, superoxide dismutase, catalase, and reduced glutathione were estimated in liver, kidney, and aorta. Aortic nitrite levels were also measured. Further, in vitro effects of PE and Ach in the presence of pioglitazone (0.1 M-10 mM) were measured in aortic rings of nondiabetic and STZ-diabetic rats. Pioglitazone-induced relaxations were recorded in PE-contracted rings (with intact and denuded endothelium) in the presence of L-NAME and in KCl-contracted rings. RESULTS: Pioglitazone treatment reduced blood pressure without having any significant effect on blood glucose level and body weight of STZ-diabetic rats. Enhanced PE-induced contraction and impaired Ach-induced relaxations in STZ-diabetic rats were restored to normal by pioglitazone treatment. The presence of L-NAME but not indomethacin blocked Ach-induced relaxation in pioglitazone-treated STZ-diabetic rats. Basal nitric oxide release was significantly higher in pioglitazone-treated STZ-diabetic rats. Oxidative stress was significantly higher in STZ-diabetic rats and pioglitazone treatment significantly reduced it. High aortic nitrite levels of STZ-diabetic rats were significantly reduced by pioglitazone treatment. The presence of pioglitazone at higher concentrations (>10 muM), but not at lower concentrations, significantly changed the dose-response curve of PE or Ach. Pioglitazone relaxations at lower concentrations but not at higher concentrations were blocked by endothelium removal or by the presence of L-NAME. CONCLUSION: Pioglitazone administration reduced oxidative stress, which prevented the breakdown of nitric oxide and increased nitric oxide levels, thereby restoring the endothelial function in aorta of STZ-diabetic rat. Hence, from the present study it can be concluded that pioglitazone administration in STZ-diabetic rats lowers blood pressure, protects against oxidative stress, and restores endothelial function.     

Effects of chronic treatment with simvastatin on endothelial dysfunction in spontaneously hypertensive rats.

OBJECTIVE: To investigate the effects of chronic treatment with simvastatin (SV) on endothelium-dependent relaxation and ouabain-induced contractions in aortic rings from spontaneously hypertensive rats (SHR), comparing with normotensive Wistar-Kyoto rats (WKY). METHODS: After a 12-week period of administration of 1 or 2 mg/kg SV to SHR and WKY, systolic blood pressure (SBP) and vascular reactivity in endothelium-intact aortic rings were assessed. RESULTS: Relaxation in response to acetylcholine (ACh) in WKY remained unaltered, but in SHR treated with 1 mg/kg SV, enhanced ACh-induced relaxation (P<0.05 versus untreated SHR) reached values observed in untreated WKY. The 2 mg/kg treatment also improved ACh relaxation (P<0.01 and P<0.05 versus untreated SHR and WKY respectively). Inhibiting cyclo-oxygenase (COX) with indomethacin (INDO) improved ACh relaxation in SHR (P<0.05) but not in WKY, independent of treatment with SV. Inhibition of nitric oxide synthase (NOS) with N(G)-nitro-L-arginine (L-NOARG) abolished ACh relaxations in all cases (P<0.001). The result was unaltered when combining INDO plus L-NOARG. SV treatment also decreased ouabain-induced contractions in endothelium-intact aortic rings from SHR, diminishing the percentage effect of contraction from 64.56+/-2.95 (untreated SHR) to 26.98+/-7.06 and 38.10+/-8.21 (1 and 2 mg/kg treated SHR respectively). Response to ouabain in WKY was not significantly affected by SV treatment CONCLUSIONS: Chronic treatment of SHR with SV improves endothelium-dependent ACh relaxation of the aortic rings, probably by an NO-involving mechanism more than by inhibiting contractile COX-derived factors. An improvement in endothelial modulation of ouabain-induced contractions was also observed after treatment with SV in SHR, which might be due to an inhibition of a calcium-sodium exchanger.     

Lacidipine prevents endothelial dysfunction in salt-loaded stroke-prone hypertensive rats

Endothelium-dependent vasorelaxation is defective in hypertensive rats, especially in conduit arteries. In the stroke-prone spontaneously hypertensive rat, impaired endothelium-dependent vasorelaxation appears to contribute to the pathogenesis of stroke independent of blood pressure. Because treatment with lacidipine, a long-acting calcium channel blocker, protects against stroke and cardiovascular remodeling in this model, we investigated the effect of this treatment on endothelium-dependent vasorelaxation in the aorta. Stroke-prone rats were exposed to a salt-rich diet (1% NaCl in drinking water) with or without lacidipine (1 mg. kg(-1). d(-1)) for 6 weeks. A high-sodium diet (1) increased systolic blood pressure, aortic weight, and wall thickness and plasma renin activity (P<0.05); (2) markedly reduced nitric oxide (NO)-mediated, endothelium-dependent relaxation of aortic rings to acetylcholine and the sensitivity to the relaxing effect of S-nitroso-N-acetylpenicillamine, an NO donor (P<0.001); and (3) induced an elevation of preproendothelin-1 mRNA levels in aortic tissue (P<0.01) without affecting endothelial NO synthase mRNA levels. Lacidipine treatment prevented the salt-dependent functional and structural alterations of the aorta, including the overexpression of the preproendothelin-1 gene, and increased endothelial NO synthase mRNA levels in aortic tissue (P<0.01). In conclusion, lacidipine protects stroke-prone hypertensive rats against the impairment of endothelium-dependent vasorelaxation evoked by a salt-rich diet, and this effect may contribute to its beneficial effect against end-organ damage and stroke.     

Sensitivity and Reactivity to Endothelin-1 in Mesenteric Beds and Aortic Rings of 4-Week-Old Spontaneously Hypertensive Rats

The vasoconstrictor effects of endothelin-1 were studied in perfused mesenteric vascular beds (MVB) and aortic rings of 4-week-old spontaneously hypertensive rats (SHR) and age-matched Wistar Kyoto rats (WKY). Mean blood pressure (124×4 vs. 97×3 mmHg) and initial perfusion pressure in the MVBs (25×2 vs. 19.7×1.2) were significantly higher in SHR. Reactivity to endothelin-1 was increased in MVBs of SHR, as indicated by the maximum perfusion pressure obtained (223 × 8 vs 155 × 7 mmHg, p > 0.001), whereas there was no significant difference in sensitivity between the two strains (EC₅₀ values: 50 × 12 and 80 × 15 pmol, respectively). By contrast, in aortic rings reactivity and sensitivity to endothelin-1 were similar in both strains, (EC₅₀ s: 1.8 × 0.12 and 1.4 × 0.1 nM). Reactivity to norepinephrine was increased in MVBs, but reduced in aortic rings of SHR. The unchanged sensitivity to endothelin-1 and the unspecifically increased reactivity in the MVBs of SHR to endothelin-1 and norepinephrine indicate rather a change in vascular structure and not a functional abnormality. These results suggest that hyperreactivity to endothelin-1 may not be a primary hypertensive mechanism in genetic hypertension.     

Effect of chronic treatment with captopril on reactivity of aortic smooth muscle from normotensive and renal hypertensive rats

Acute administration of the angiotensin I converting enzyme inhibitor, captopril (2 X 10(-4) M), was shown in an earlier study to attenuate the contractile responses of aortic rings of rats to alpha-adrenergic agonists in vitro. The objective of the present study was to determine the effect of chronic treatment with captopril on reactivity of aortic rings from both normotensive and renal hypertensive rats when captopril was no longer present. Four groups of rats were used: (1) normotensive, untreated; (2) normotensive, captopril-treated (48 mg/kg b.w. per day for five weeks); (3) hypertensive (bilateral renal encapsulation for five weeks), untreated and (4) hypertensive, captopril-treated. Renal encapsulation was associated with a significant increase in systolic blood pressure, which was prevented by concomitant treatment with captopril. At the end of the five weeks treatment aortic rings, 4 mm in length, were washed for 2 h to remove the captopril, following which contractile responses to various vasoactive agents were studied in vitro. Chronic treatment with captopril attenuated significantly contractile responses to both norepinephrine (10(-9) to 10(-5) M) and phenylephrine (10(-8) to 10(-4) M) but had no effect on isoproterenol-induced relaxation of KCl-depolarized tissue in the presence of 10(-5) M phentolamine. Contractile responses to angiotension I (10(-10) to 10(-7) M) did not differ statistically among the four groups. Following addition of captopril (2 X 10(-4) m) to the bath for 30 min, contractile responses to angiotensin I were attenuated in all four groups of rings.(ABSTRACT TRUNCATED AT 250 WORDS)