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 KC1 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     

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 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.     

Lipoxygenase-dependent mechanisms in hypertension

This study was designed to examine the contribution of lipoxygenase products to mechanisms of vascular contraction and elevated blood pressure in rats with aortic coarctation-induced hypertension. In cytosolic fractions of aortae taken from hypertensive rats, 12-lipoxygenase protein was increased as compared to normotensive controls. Aortic rings from hypertensive, but not from normotensive rats, exhibited a basal tone which was reduced 74+/-12 and 71+/-22%, respectively, by the lipoxygenase inhibitors cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate (CDC, 10(-5) mol/L) and 5,8,11-eicosatriynoic acid (ETI, 10(-5) mol/L). CDC (8 mg/kg s.c.) did not affect the blood pressure of normotensive rats but decreased that of hypertensive rats from 182+/-6 to 151+/-10 mm Hg. The blood pressure lowering effect of CDC was blunted in hypertensive rats pretreated with indomethacin or antibodies against 5,6-dihydro-prostaglandin I2. These data suggest contribution of lipoxygenase-derived products to mechanisms underlying aortic smooth muscle basal tone and elevated blood pressure in rats with aortic coarctation-induced hypertension. The vasodepressor effect of CDC depends on a mechanism involving vasodilatory prostaglandins.     

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.     

Calcium Supplementation Is Associated With Endothelium Dependent Attenuation of Vascular Smooth Muscle Reactivity in Normotensive Pregnant and Nonpregnant Rats

The study tests the hypothesis that the blood pressure lowering effect of a high calcium diet is mediated through attenuation of vascular reactivity and examined the mechanisms involved in both normotensive pregnant and nonpregnant rats. The contractile responses of aortic rings of Wistar rats fed on high (1.7%, 2.1%) and normal (0.9%) calcium diets to phenylephrine, angiotensin II, KCl, and CaCl₂ were studied. The relaxations to acetylcholine and potassium chloride, as well as the effects of endothelial denudation, pretreatment with indomethacin (10⁻⁶ mol/L), methylene blue (10⁻⁶ mol/L), and calcium free solution on the responses to phenylephrine were also examined.In both pregnant and nonpregnant rats, the contractile responses of aortic rings of animals fed a high calcium diet to all the agents were significantly attenuated, compared with those of controls. After endothelial denudation, or treatment with methylene blue, but not with indomethacin, the responses of the rings to phenylephrine were enhanced and not different from similarly treated rings from rats on a normal calcium diet. There was no difference in the contractile responses to phenylpehrine in calcium free solution. The relaxation to acetylcholine, but not to potassium chloride, was enhanced in rings from rats on a high calcium diet. The diminution in reactivity was not associated with corresponding changes in sensitivity of the tissues.It is concluded that in normotensive rats a high calcium diet is associated with diminished vascular smooth muscle reactivity that is endothelium dependent, and involves increased stimulation of the nitric oxide–guanylate cyclase pathway but not of the sodium–potassium ATPase or prostacyclin.     

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.     

Role of endothelium-derived prostanoid in angiotensin-induced vasoconstriction

To test the hypothesis that prostanoids contribute to angiotensin II-induced vascular contraction, we compared the effect of angiotensin II on isometric tension development by rings of descending thoracic aorta bathed in Krebs' bicarbonate buffer with and without indomethacin (10 microM) to inhibit cyclooxygenase, CGS13080 (10 microM) to inhibit thromboxane A2 synthesis, or SQ29548 (1 microM) to block thromboxane A2/prostaglandin endoperoxide receptors. The comparisons were made in rings of aorta taken from normotensive rats and from rats with aortic coarctation-induced hypertension at 12 days and 90-113 days after coarctation. These rings released thromboxane B2, which was found to be endothelium dependent, increased in hypertensive rats, and stimulated by angiotensin II (10(-6) M) in normotensive rats and in hypertensive rats at 12 days after coarctation. The angiotensin II (10(-6) to 10(-5)M)-induced contraction of aortic rings was increased by about 30% at 12 days after coarctation and decreased at 90-113 days after coarctation. Removal of the endothelium increased the contractile effect of angiotensin II (10(-6) M) in aortic rings of normotensive rats and hypertensive rats at 90-113 days after coarctation but decreased the effect in aortic rings of hypertensive rats at 12 days after coarctation. In rats at 12 days after coarctation, the angiotensin II (10(-6) M)-induced contraction of aortic rings with endothelium was attenuated by indomethacin and SQ29548 but not by CGS13080. These data suggest that a prostanoid-mediated and endothelium-dependent mechanism of vasoconstriction contributes to the constrictor effect of angiotensin II in aortic rings of rats in the early phase of aortic coarctation-induced hypertension.     

Action of E and A prostaglandins on isolated aorta of rats with spontaneous hypertension.

The action of prostaglandins of the E and A groups on isolated aortic smooth muscle strips of rats with spontaneous hypertension (Okamoto-Aoki) (SHR) was investigated in order to follow up whether, and to what extent, an alteration of vascular reactivity exists in this model of hypertension, as well as to test the effect of vasodepressor prostaglandins on vessels of spontaneously hypertensive rats. The experiments were carried out on aortic strips of 10 control normotensive rats, and of 10 SHR. The contractions of the isolated vessel strips were recorded by means of an induction coil displacement transducer on an ink-writing electron compensated registration device. The results of the study indicate that the isolated aortic strips of normotensive rats and of SHR respond by contraction to the action of vasodepressor prostaglandins, i.e. paradoxically. It was also established that the reactivity of the isolated aortic strip of SHR to vasodepressor prostaglandins is smaller in comparison to the reactivity of the aorta of control normotensive rats. An attempt is made to explain the paradoxical response of isolated aortic strips of normotensive rats, and of SHR. It is pointed out that contrary to studies on the action of angiotensin, in studies on the vasodepressor action of prostaglandins isolated aortic smooth muscle strips cannot be used as an indicator of vascular reactivity, and especially of resistance vessels reactivity, since their response to hypotensive prostaglandins is paradoxical in both normotensive and spontaneously hypertensive rats.     

Increased resistance and impaired maximal vasodilation in normotensive vascular beds of rats with coarctation hypertension

To study the resistance of normotensive vascular beds in coarctation hypertension, we measured perfusion pressures of pump-perfused (blood), innervated, isolated hindlimbs of 12 rats (Group A) with 4 weeks of hypertension due to partial contriction of the abdominal aorta above the renal arteries, and of three control groups: 11 normotensive rats (Group B) with aorta sham-constricted, nine normotensive rats (Group C) with slight (5%) hindquarters atrophy due to partial constriction of the abdominal aorta below the renal arteries, and six rats with two-kidney, one clip Goldblatt hypertension (Group D). After aortic constriction, measured femoral arterial pressures in Group A rats remained normotensive. In hypertensive rats of Groups A and D, compared to normotensive Group B or C rats, hindlimb pressure-flow curves were displaced toward the pressure axis (p < 0.05). Compared to normotensive rats, drop in hindlimb resistance after acute local nerve section was increased in rats with coarctation hypertension. Residual resistance after maximal vasodilation with intraarterial sodium nitroprusside remained elevated in hypertensive rats of Groups A and D (p < 0.05), as compared to normotensive Group B or C rats; compared to Group B rats, this residual resistance in the coarcted rats of Group A was increased by 9%. Thus, in normotensive vascular beds of rats with chronic hypertension caused by aortic coarctation, resistance is elevated. The neurogenic component contributes to this high resistance, and structural vascular changes, indicated by impaired maximal vasodilation, may also contribute to the elevated resistance. It is most unlikely that these resistance changes are attributable to elevated hindlimb intravascular pressures.     

Dietary gamma-linolenic acid lowers blood pressure and alters aortic reactivity and cholesterol metabolism in hypertension.

OBJECTIVE: To determine the effects of dietary gamma-linolenic acid upon blood pressure, aortic reactivity and cholesterol metabolism in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. DESIGN: Randomized parallel-group study. METHODS: SHR and WKY rats were fed a purified diet containing either sesame or borage oil rich in gamma-linolenic acid for 7 weeks. Blood pressure measured by the tail-cuff method and weight were monitored weekly. At the end of the study, intra-arterial pressor responses to norepinephrine and angiotensin II, and reactivity of isolated aortic rings to norepinephrine, angiotensin II, KCl and acetylcholine were determined. Serum cholesterol and triglycerides were measured. Hepatic and intestinal enzymes and receptors of cholesterol metabolism were also measured. RESULTS: Dietary borage oil significantly decreased blood pressure in SHR and WKY rats compared with sesame oil-fed rats. Pressor responses to norepinephrine and angiotensin II, and aortic reactivity to norepinephrine, angiotensin II, KCl and acetylcholine were not significantly different. The borage oil diet increased serum cholesterol levels in WKY rats and hepatic B-hydroxy-3-methylglutaryl coenzyme A reductase in SHR. CONCLUSION: These data indicate that dietary borage oil has a blood pressure lowering effect in hypertensive and normotensive rats. However, the effect cannot be explained by altered sensitivity to humoral and neural vasoconstrictors or changes in cholesterol metabolism. Other mechanisms should be investigated.     

Increased arginase activity in aorta of mineralocorticoid-salt hypertensive rats

The present study was designed, first to investigate aortic arginase activity during the development and the establishment of mineralocorticoid-salt (DOCA-salt) hypertension, and second, to determine the relationship between arginase activity and blood pressure by giving a protein-supplemented diet (50% casein) known to increase hepatic arginase activity. Our results showed that aortic arginase activity in established hypertension of DOCA-salt rats was higher than in normotensive rats. The protein-supplemented diet (50% casein) accelerated the development of DOCA-salt hypertension. There was a positive correlation between arginase activity and the level of blood pressure in these DOCA-salt hypertensive rats fed 50% casein but not in DOCA-salt hypertensive rats on a normal (20% casein) diet. In normotensive rats, the protein-supplemented diet decreased aortic arginase activity and produced no change in systolic blood pressure. Our data suggest that aortic arginase activity is modified in established DOCA-salt hypertension and could participate in the physiopathology of arterial hypertension.     

INCREASED ARGINASE ACTIVITY IN AORTA OF MINERALOCORTICOID-SALT HYPERTENSIVE RATS

The present study was designed, first to investigate aortic arginase activity during the development and the establishment of mineralocorticoid-salt (DOCA-salt) hypertension, and second, to determine the relationship between arginase activity and blood pressure by giving a protein-supplemented diet (50% casein) known to increase hepatic arginase activity. Our results showed that aortic arginase activity in established hypertension of DOCA-salt rats was higher than in normotensive rats. The protein-supplemented diet (50% casein) accelerated the development of DOCA-salt hypertension. There was a positive correlation between arginase activity and the level of blood pressure in these DOCA-salt hypertensive rats fed 50% casein but not in DOCA-salt hypertensive rats on a normal (20% casein) diet. In normotensive rats, the protein-supplemented diet decreased aortic arginase activity and produced no change in systolic blood pressure. Our data suggest that aortic arginase activity is modified in established DOCA-salt hypertension and could participate in the physiopathology of arterial hypertension.     

Role of aortic nitric oxide synthase 3 (eNOS) in the systemic vasodilation of portal hypertension

BACKGROUND & AIMS: In portal hypertension, the mechanisms responsible for nitric oxide (NO) overproduction and vasodilation have not yet been clearly identified. One hypothesis is that NO synthase (NOS) 3 is overactivated because of shear stress in endothelial cells caused by hyperkinetic circulation. The aim of this study was to evaluate aortic NOS3 after a reduction of blood flow by long-time beta-adrenoceptor antagonist administration. METHODS: Propranolol or atenolol was administered by gavage in portal vein-stenosed and sham-operated rats. The vascular reactivity of thoracic aortic rings to phenylephrine, total aortic NOS activity, and aortic NOS3 messenger RNA and protein expressions were studied. RESULTS: After propranolol or atenolol administration, the aortic hyporesponse returned to normal in portal vein-stenosed rats. Total aortic NOS activity was higher in portal vein-stenosed aortas and significantly decreased after beta-blocker administration. Aortic NOS3 expressions were more marked in portal vein-stenosed aortas than in controls, but NOS3 expressions were reduced after propranolol administration. CONCLUSIONS: In portal hypertension, aortic NOS3 activity and expressions are enhanced but return to normal after beta-blocker administration. These results suggest that in portal hypertension, increased shear stress, related to high blood flow, induces enhanced aortic NOS3.     

Cyclooxygenase inhibition reduces blood pressure elevation and vascular reactivity dysfunction caused by inhibition of nitric oxide synthase in rats

In the present study we investigated the role of cyclooxygenase (COX)-dependent vasoconstrictors in the hypertension and altered vascular reactivity following prolonged nitric oxide (NO) synthase inhibition. Male Wistar rats (250-270 g) were divided into four groups and treated for 7 days with Placebo (control), L-NAME (48 mg/kg/day), indomethacin (4 mg/kg/day) and L-NAME in combination with indomethacin. L-NAME treatment induced arterial hypertension, in vitro aortic hyperresponsiveness to phenylephrine, impaired vasodilatory response to acetylcholine and no significant change in response to sodium nitroprusside. Indomethacin co-treatment partially prevented blood pressure elevation, restored responsiveness to phenylephrine and improved sensitivity to acetylcholine. Indomethacin treatment alone did not modify blood pressure and aortic vascular reactivity. Both enhanced phenylphrine-induced contraction and impaired acetylcholine-evoked vasodilation induced by acute NO synthase inhibition with L-NAME (10(-4) M) in normal rat aortas were not modified by indomethacin (10(-5) M). These results are consistent with the hypothesis that constricting factors, which arise from the COX pathway, contribute to hypertension and altered vascular reactivity following continued inhibition of NO synthase.     

Polyamines, vascular smooth muscle, and deoxycorticosterone acetate-salt hypertension

This study was performed to determine if an alteration in vascular polyamine contents is associated with the development of deoxycorticosterone acetate-salt hypertension. The effects of chronic administration of alpha-difluoromethylornithine, a specific irreversible inhibitor of ornithine decarboxylase and thus polyamine biosynthesis, on vascular polyamine contents, structure, and function as well as the development of hypertension was studied. Control and deoxycorticosterone acetate-salt rats received either tap water or a drinking solution containing alpha-difluoromethylornithine for 6 weeks, during which period systolic blood pressures were recorded. Vascular reactivity studies were performed on rings of aorta and tail artery. Medial thickness, vessel weight, and vascular polyamine contents were also assessed in these arteries. alpha-difluoromethylornithine treatment had no significant effect on either systolic blood pressure or vascular structure, function, and polyamine contents of control animals. The elevation in blood pressure and the increase in medial thickness, ring weight, and vascular polyamine contents as well as altered vascular reactivity observed in deoxycorticosterone acetate-salt rats was significantly attenuated by alpha-difluoromethylornithine treatment. These results are the first to demonstrate that vascular polyamine contents are elevated in the deoxycorticosterone acetate-salt rat and that chronic alpha-difluoromethylornithine treatment prevents the rise in vascular polyamines as well as the elevation in blood pressure and attendant changes in the vasculature. Thus, the increase in vascular polyamines may comprise a critical link between the initiating stimuli and the alterations in vascular structure and function implicated in the pathogenesis of deoxycorticosterone acetate-salt hypertension.     

Blood pressure response to a calcium entry blocker in normotensive subjects with or without a family history of hypertension

The possibility that a familial background of hypertension might influence the blood pressure response to a calcium entry blocker was evaluated in 15 normotensive relatives of patients with essential hypertension and 18 normotensive subjects with no family history of hypertension. Under control conditions, blood pressure, heart rate, plasma noradrenaline, adrenaline, and renin activity did not differ between the two groups. Nifedipine, at a dose of 10 mg administered sublingually, lowered the blood pressure and increased the heart rate, plasma noradrenaline, and renin activity. The normotensive relatives of patients with essential hypertension did not differ in their responses from the normotensive subjects with no family history of hypertension, with the exception of plasma noradrenaline thirty minutes after nifedipine. These results provide evidence to suggest that there is no functional abnormality with increased dependency of vascular smooth muscle tone on calcium influx in the prehypertensive state.     

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.     

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.     

Vascular contractile response and signal transduction in endothelium-denuded aorta from cirrhotic rats

AIM: The mechanism of decreased vascular reactivity to vasoconstrictors in portal hypertension is still unclear. In addition to nitric oxide, defects in post-receptor signal transduction pathway have been suggested to play a role. However, substantial evidences observed equivocal changes of vascular reactivity following different agonists that challenged the hypothesis of the post-receptor defect. The current study was to evaluate the vascular reactivity to different agonists and the inositol trisphosphate (IP3) changes in signal transduction cascade from cirrhotic rats with portal hypertension. METHODS: The endothelial denuded aortic rings from cirrhotic and sham-operated rats were obtained for ex vivo tension study and measurement of the corresponding [3H] IP3 formation following different receptor and nonreceptor-mediated agonists' stimulation. Additionally, iNOS protein expression was measured in thoracic aorta. The contractile response curves to phenylephrine were performed in endothelial denuded aortic rings with and without preincubation with a specific iNOS inhibitor (L-N (6)-(1-iminoethyl)-lysine, L-NIL). RESULTS: In endothelial denuded aortic rings of cirrhotic rats, the vascular responses were reduced with phenylephrine and arginine vasopressin (AVP) stimulation but were normal with U-46619, NaF/AlCl3, and phorbol esterdibutyrate (PdBU) stimulation. Compared to the corresponding control groups, the degree of the increment of [3H] IP3 formation from basal level was also decreased with phenylephrine and AVP stimulation, but was normal with U-46619 and NaF/AlCl3 stimulation. The preincubation with L-NIL did not modify the hyporesponsiveness to phenylephrine. Additionally, the iNOS protein expression in thoracic aorta was not different in cirrhotic and sham-operated rats. CONCLUSION: Without the influence of nitric oxide, vascular hyporeactivity to vasoconstrictors persisted in cirrhotic rats with portal hypertension. However, the decreased vascular reactivity is an agonist-specific phenomenon. In addition, G-protein and phospholipase C pathway associated with the IP3 productions may be intact in cirrhotic rats with portal hypertension.