Losartan and enalapril therapies enhance vasodilatation in the mesenteric artery of spontaneously hypertensive rats.

We studied the effects of 10-week long enalapril and losartan treatments (4 and 15 mg kg(-1) day(-1), respectively) on mesenteric arterial function in vitro in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). The relaxations of noradrenaline-precontracted rings to acetylcholine, nitroprusside and cromakalim were similar in WKY and enalapril- and losartan-treated SHR, and more pronounced than in untreated SHR. The responses to acetylcholine were attenuated by N(G)-nitro-L-arginine methyl ester in WKY and drug-treated SHR, but were completely inhibited in untreated SHR. When hyperpolarization of smooth muscle was prevented by KCl-induced precontractions, no differences were found in the relaxations to acetylcholine and nitroprusside between the groups, and the dilatations to cromakalim were abolished. Moreover, in noradrenaline-precontracted rings of drug-treated SHR, the addition of tetraethylammonium attenuated the nitric oxide synthase and cyclooxygenase-resistant relaxations to acetylcholine and abolished the enhanced dilatations to nitroprusside. In conclusion, since the enhancement of vasorelaxation in enalapril- and losartan-treated SHR was abolished by conditions preventing hyperpolarization, the improved vasodilatation following these therapies could be attributed to enhanced vasodilatation via K+ channels in this model of hypertension.

Exercise enhances vasorelaxation in experimental obesity associated hypertension.

OBJECTIVE: Regular exercise is recommended for the non-pharmacological treatment of hypertension, but the mechanisms underlying the lowering of blood pressure remain controversial. Therefore, we studied the effects of 22-week-long training on blood pressure, arterial reactivity, and metabolic abnormalities in a model of genetic obesity and moderate hypertension. METHODS: Obese and lean Zucker rats were subjected to treadmill exercise from 8 to 30 weeks of age. Blood pressures were measured by the tail-cuff method, and urine was collected in metabolic cages. At the end of the study, the samples for biochemical determinations were taken, and reactivity of isolated mesenteric and carotid arterial rings was examined in standard organ chambers. RESULTS: The exercise prevented the elevation of blood pressure which was observed in non-exercised obese Zucker rats, and also reduced blood pressure in the lean rats. The relaxations of norepinephrine-preconstricted mesenteric and carotid arterial rings to acetylcholine and nitroprusside were clearly improved by exercise in the obese rats. In the lean rats exercise enhanced vasorelaxation to nitroprusside in the mesenteric and carotid rings, and to acetylcholine in the carotid preparations. The exercise-induced improvement of endothelium-mediated dilatation to acetylcholine was abolished by nitric oxide synthesis inhibition with NG nitro-L-arginine methyl ester, but not by cyclooxygenase inhibition with diclofenac or functional inhibition of endothelium-dependent hyperpolarization by precontractions with KCl. The urinary excretion of the systemic prostacyclin metabolite (2,3-dinor-6-ketoprostaglandin F1 alpha) was increased two-fold by exercise in the obese and lean rats, whereas that of the thromboxane A2 metabolite (11-dehydrothromboxane B2) remained unaffected. Treadmill training reduced blood glucose, cholesterol, and triglycerides, but did not affect the high levels of insulin in obese Zucker rats. CONCLUSIONS: These results suggest that the antihypertensive effect of long-term exercise in experimental obesity related hypertension is associated with improved vasodilatation. This is expressed as enhanced relaxation via endogenous and exogenous nitric oxide, and increased endothelial prostacyclin production. The improved control of arterial tone after training could be attributed to the alleviation of hyperlipidemia and insulin resistance, whereas hyperinsulinaemia per se remained unaffected.

Effects of calcium and potassium supplements on arterial tone in vitro in spontaneously hypertensive rats.

1. Calcium and potassium intakes inversely correlate with blood pressure in experimental hypertension. Therefore, we examined the effects of calcium and potassium supplements alone and in combination on arterial tone in spontaneously hypertensive rats (SHR). Wistar-Kyoto (WKY) rats served as normotensive controls. Calcium and potassium contents in the control diet were both 1%, while those in supplemented chows were 3% and 3.5%, respectively. The sodium content of all diets was moderately elevated to 1.1%. 2. After 12 weeks of the study systolic blood pressures in SHR on high calcium and on high potassium diets were markedly lower (about 53 and 58 mmHg, respectively) than in hypertensive controls, while combined supplementation of these cations reduced blood pressure even further (about 69 mmHg). 3. Responses of mesenteric arterial rings in vitro were examined at the end of the study. Both high calcium and high potassium diets improved the impaired relaxation to acetylcholine (ACh) in SHR, while the combination of these supplements completely normalized this response. Cyclo-oxygenase inhibition by diclofenac augmented the relaxation to ACh in hypertensive controls but not in the other groups. Nevertheless, enhanced endothelium-mediated dilatation was still observed in the presence of diclofenac and the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) in all supplemented groups. Interestingly, additional blockade of Ca2+-activated K+ channels by tetraethylammonium abolished the improved relaxation to ACh in SHR on high calcium and on high potassium, but distinct responses were still observed in WKY rats and SHR on the combined supplement. 4. When hyperpolarization of smooth muscle was prevented by precontraction of the preparations with 50 mM KCl, only marginal differences were observed in the diclofenac and L-NAME-resistant relaxations to ACh between the study groups. Finally, endothelium-independent vasorelaxations of noradrenaline-precontracted rings to nitroprusside, isoprenaline and cromakalim were comparably augmented by all supplements. 5. In conclusion, the vascular mechanisms underlying the antihypertensive effect of high calcium and high potassium diets during moderately elevated sodium intake in SHR may involve enhanced arterial hyperpolarization, increased smooth muscle sensitivity to nitric oxide and decreased production of vasoconstrictor prostanoids. The administration of these cations in combination was more effective than either of them alone in reducing blood pressure and restoring arterial tone.

Comparison of the effects of supplementation with whey mineral and potassium on arterial tone in experimental hypertension.

OBJECTIVE: The aim of this work was to compare the effects of supplementation of rat chow diet with potassium (K+) and whey mineral concentrate (Whey), a diet rich in milk minerals, on blood pressure and arterial responses in vitro in spontaneously hypertensive rats (SHR). METHODS: Thirty young SHR and twenty Wistar-Kyoto rats (WKY) were allocated into five groups: SHR, Whey-SHR, K(+)-SHR, WKY and Whey-WKY. Whey-supplementation was performed by adding 25% whey mineral concentrate to the chow, which in particular increased the intake of potassium (from 1.0% to 3.6%) and also that of calcium (from 1.0% to 1.3%) and magnesium (from 0.2% to 0.3%) in the rats. The K(+)-SHR were given extra potassium chloride (KCl) so that the final potassium content in the chow was 3.6%. Blood pressures were measured indirectly by the tail-cuff method. Responses of mesenteric arterial rings were examined in standard organ chambers after 12 study weeks. RESULTS: During the 12-week study systolic blood pressures in control SHR increased steadily from 160 to about 230 mmHg, while supplementation with either Whey or potassium had a clear antihypertensive effect of about 50 mmHg in the hypertensive rats. Blood pressures in the WKY and Whey-WKY groups remained comparable during the whole study. In noradrenaline-precontracted arterial rings, endothelium-dependent relaxation to acetylcholine (ACh), as well as endothelium-independent relaxations to nitroprusside and isoprenaline were attenuated in untreated SHR, while all these dilatory responses were similarly improved by Whey and potassium supplementation. The cyclooxygenase inhibitor diclofenac, which reduces the synthesis of dilatory and constricting prostanoids, clearly enhanced the relaxation to ACh in untreated SHR, but was without effect in the other groups. In the presence of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester the relaxation to ACh was markedly reduced in all SHR groups, whereas in the two WKY groups, distinct relaxations to ACh were still present. The remaining responses were partially prevented by tetraethylammonium, an inhibitor of calcium-activated potassium channels, and the difference between untreated and potassium-supplemented SHR was abolished. When endothelium-mediated hyperpolarization of smooth muscle was prevented by precontracting the preparations with 50 mM KCl, only marginal differences were observed in relaxations to ACh between untreated SHR and the other groups. Interestingly, the impaired endothelium-independent relaxations to cromakalim, a hyperpolarizing vasodilator acting via ATP-sensitive potassium channels, were normalized by Whey mineral and potassium diets. CONCLUSION: Supplementation with Whey mineral and a comparable dose of potassium similarly opposed the development of experimental genetic hypertension, an effect which was associated with improved arterial dilatory properties. Both supplements augmented the hyperpolarization-related component of arterial relaxation, increased the sensitivity of smooth muscle to nitric oxide, and decreased the production of vasoconstrictor prostanoids. Therefore, the beneficial effects of the Whey diet could be attributed to increased intake of potassium in SHR.

Arterial function in mineralocorticoid-NaCl hypertension: influence of angiotensin-converting enzyme inhibition.

Angiotensin-converting enzyme inhibitors have been suggested to improve the function of arterial endothelium and smooth muscle not only through inhibition of angiotensin II formation and reduction of blood pressure, but also via additional pathways, e.g. potentiation of endogenous kinins and enhancement of endothelial autacoid formation. Therefore, we investigated whether 10-week-long quinapril therapy (10 mg kg-1 day-1) could beneficially influence the function of mesenteric arterial rings in vitro in deoxycorticosterone-NaCl-treated Wistar-Kyoto rats, a model of hypertension which is known to be resistant to angiotensin-converting enzyme inhibition. The quinapril treatment had no long-term blood pressure-lowering effect nor did it reduce the associated cardiac hypertrophy in deoxycorticosterone-NaCl hypertension. In noradrenaline-precontracted arterial rings the endothelium-dependent relaxations to acetylcholine and adenosine 5'-diphosphate as well as the endothelium-independent relaxations to nitroprusside and isoprenaline were clearly attenuated in the deoxycorticosterone-NaCl-treated rats. However, the quinapril therapy was without significant effect on any of these dilatory responses. In the presence of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester, the relaxations to acetylcholine in untreated and quinapril-treated hypertensive animals were practically absent, whereas in normotensive rats distinct relaxations to higher concentrations of acetylcholine were still present. Interestingly, when endothelium-dependent hyperpolarization was prevented by precontracting the preparations with potassium chloride, no differences were found in relaxations to acetylcholine and adenosine 5'-diphosphate between the study groups. Exogenous bradykinin induced small comparable contractions in endothelium-intact mesenteric arterial rings from all study groups. In conclusion, the 10-week-long quinapril therapy did not have any significant effects on arterial function in deoxycorticosterone-NaCl hypertensive rats. Therefore, the present results stress the roles of reduced blood pressure and diminished angiotensin II formation in the beneficial vascular effects of long-term angiotensin-converting enzyme inhibition in the present model of hypertension. Furthermore, since the relaxations to acetylcholine and adenosine 5'-diphosphate in the deoxycorticosterone-NaCl-treated rats were attenuated in the absence and presence of nitric oxide synthase inhibition but not under conditions which prevented hyperpolarization, impaired endothelium-dependent relaxation to agonists can be attributed to diminished endothelium-dependent hyperpolarization in this model of hypertension.

Whey mineral supplementation and arterial tone in mineralocorticoid-NaCl hypertension.

OBJECTIVE: The aim was to study the effects of supplementation of rat chow diet with whey mineral concentrate (Whey), a diet rich in milk minerals, on arterial responses in vitro in mineralocorticoid-NaCl hypertension. METHODS: Forty young Wistar rats were allocated to four groups: Wistar, Whey-Wistar, deoxycorticosterone (DOC), and Whey-DOC. DOC (10 mg kg-1 s.c.) was given twice a week and these rats drank 0.7% NaCl solution, while the others received equal volumes of vehicle (sesame oil) and drank tap water. The supplementation was performed by adding 25% whey mineral concentrate to the chow, which in particular increased the intake of potassium and also that of calcium and magnesium in the rats. Responses of mesenteric arterial rings were examined in standard organ chambers after 10 study weeks. RESULTS: During the 10 week study the DOC-NaCl treatment had a marked hypertensive effect in rats, while the whey mineral supplementation was without significant effect on blood pressure in the Whey-DOC and Whey-Wistar groups. Arterial relaxation induced by nitroprusside was attenuated in the DOC-treated rats, but was significantly shifted towards that of controls in the Whey-DOC group. Interestingly, endothelium-dependent relaxation to acetylcholine (ACh), which was clearly impaired in the DOC group, was comparable in the Whey-DOC and Wistar groups. Moreover, only in the DOC group the relaxation was improved by diclofenac suggesting that ACh was releasing cyclo-oxygenase-derived contractile factors from the endothelium, and the response was completely abolished by NG-nitro-L-arginine methyl ester (L-NAME). In contrast, diclofenac had a negligible effect on the response in the other groups which also showed distinct relaxations to ACh in the presence of L-NAME. This remaining response to ACh in Wistar rats was inhibited by the addition of apamin and glibenclamide, inhibitors of calcium-activated and ATP-sensitive potassium channels, respectively, suggesting that it was mediated by endothelium-dependent hyperpolarization. In the Whey-Wistar group arterial function did not differ from control Wistars. CONCLUSIONS: Supplementation with whey mineral concentrate had a protective effect on endothelium-mediated control of arterial tone in experimental DOC-NaCl hypertension.

Effect of celiprolol therapy on arterial dilatation in experimental hypertension.

1. It has recently been suggested that therapy with beta-adrenoceptor blockers reduces peripheral arterial resistance via enhanced vascular dilatation. Therefore, we studied the effects of celiprolol, which is a specific beta 1-antagonist that has a weak beta 2-agonist action, on arterial tone in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. 2. Two doses of celiprolol (5 and 50 mg kg-1 day-1) were administered to the SHR, while the WKY rats received only the higher dose of the drug. During the 12-week treatment period the higher dose attenuated the increase in blood pressure by approximately 20 mmHg in SHR, whereas the lower dose was without significant antihypertensive effect. Celiprolol therapy did not affect blood pressure in the normotensive WKY rats. 3. Responses of mesenteric arterial rings in vitro were examined at the end of the study. Interestingly, endothelium-mediated relaxations of noradrenaline (NA)-precontracted rings to acetylcholine (ACh) in the absence and presence of the cyclo-oxygenase inhibitor, diclofenac, were equally enhanced in both celiprolol-treated SHR groups. The nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) practically abolished the relaxations to ACh in all SHR irrespective of whether they had received celiprolol, whereas in WKY rats L-NAME only attenuated the responses to ACh. However, no differences were found between the SHR groups in relaxations to ACh when hyperpolarization of smooth muscle was prevented by precontractions induced by 50 mM KCl. Vasorelaxation of NA-precontracted rings to the exogenous nitric oxide donor, nitroprusside, was also moderately augmented in both celiprolol-treated SHR groups, while the relaxation to beta-adrenoceptor agonist, isoprenaline, remained equally impaired in all SHR whether or not they had received celiprolol. No differences were observed between the two WKY groups in the responses to ACh, nitroprusside or isoprenaline. 4. Contractile sensitivity of mesenteric arterial rings to the receptor-mediated agonists, NA and 5-hydroxytryptamine, was comparable in all study groups. 5. In conclusion, SHR treatment with either the low or the higher dose of celiprolol was accompanied by enhancement of both endothelium-dependent and endothelium-independent nitric oxide-mediated arterial relaxation, possibly via a hyperpolarization mechanism. Interestingly, this effect appeared to be independent of the reduction in blood pressure.

Angiotensin-converting enzyme inhibition attenuates arterial constrictor responses in experimental hypertension.

Angiotensin-converting enzyme inhibition has been shown to attenuate arterial contractions, but the underlying mechanisms have not been clarified in detail. Therefore, we investigated the effects of 10-week-long quinapril therapy (10 mg kg-1 day-1) on responses of mesenteric arterial rings in vitro in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats. The hypertrophy of cardiac muscle and mesenteric arterial smooth muscle was effectively reduced in SHR by quinapril treatment. Maximal contractile force generation to 5-hydroxy-tryptamine was reduced in endothelium-intact and -denuded rings of quinapril-treated SHR when compared with untreated SHR. Contractile sensitivity of endothelium-intact rings to 5-hydroxytryptamine was also attenuated in SHR by quinapril, whereas no differences were found between the study groups in sensitivity of endothelium-denuded rings. Inhibition of NO synthesis by NG-nitro-L-arginine methyl ester increased the sensitivity and contractile force generation of endothelium-intact rings to 5-hydroxytryptamine more effectively in quinapril-treated than in untreated SHR, whereas indomethacin had only minor effects on the responses in the study groups. Maximal responses and sensitivity to norepinephrine were also reduced in SHR by quinapril and were more effectively increased by NG-nitro-L-arginine in quinapril-treated than in untreated SHR. In addition, KCI-induced maximal contractions of endothelium-denuded rings were attenuated in quinapril-treated SHR. However, when the release of norepinephrine from vascular adrenergic nerve endings was eliminated by sympathectomy, no differences were found in maximal KCI-induced contractions between the study groups; this suggests that diminished contractions to KCI in quinapril-treated SHR resulted from reduced release of endogenous norepinephrine from vascular nerve endings during depolarization. The inhibitory effects of the calcium channel blocker nifedipine on arterial contractions in the Wistar-Kyoto rat groups and the quinapril-treated SHR were similar and were lower than in untreated SHR. In conclusion, the present findings suggest that effective reversal of cardiovascular hypertrophy, normalization of the function of voltage-dependent calcium channels, sympathoinhibitory action and enhanced endothelium-derived NO release can explain the attenuated arterial constrictor responses that occur after the long-term inhibition of angiotensin-converting enzyme.

Reversal of hypertension and endothelial dysfunction in deoxycorticosterone-NaCl-treated rats by high-Ca2+ diet.

We tested the effect of high-Ca2+ diet on blood pressure and responses of mesenteric arterial rings in vitro in established deoxycorticosterone (DOC)-NaCl hypertension. Ca2+ supplementation (2.5%) of Wistar rats, which was commenced 8 wk after initiation of DOC-NaCl treatment (Ca(2+)-DOC group), reversed the development of hypertension, whereas in animals ingesting a normal diet (1.1% Ca2+; DOC group) blood pressure continued to rise until the end of the 12-wk study. In norepinephrine-precontracted arterial rings, relaxations to acetylcholine (ACh) and sodium nitroprusside were attenuated in the DOC group, but these responses were significantly improved by Ca2+ supplementation. The nitric oxide (NO) synthesis inhibitor NG-nitro-L-arginine methyl ester, in the presence of diclofenac, totally abolished ACh-induced relaxations in the DOC group but only attenuated them in the Ca(2+)-DOC group. The remaining relaxation was further inhibited by apamin, an inhibitor of Ca(2+)-activated K+ channels, and practically abolished after blockade of ATP-dependent K+ channels by glyburide. Interestingly, when endothelium-dependent hyperpolarization was prevented using precontractions induced by KCl, no differences were found in relaxations to ACh between the groups. In conclusion, high-Ca(2+) diet effectively reduced blood pressure in DOC-NaCl hypertension and concomitantly enhanced arterial relaxation. Because the relaxations to ACh in the Ca(2+)-DOC group were augmented in the absence and presence of NO synthesis inhibition but not under conditions of prevented hyperpolarization, these enhanced relaxations could be attributed to promoted endothelium-dependent hyperpolarization in the Ca(2+)-supplemented animals.

Antihypertensive therapy and arterial function in experimental hypertension.

1. Alterations in the function of the endothelium and arterial smooth muscle may be important in the establishment of hypertension. Thus, the possible favorable influences of blood pressure-lowering agents on vascular responsiveness may be important in the chronic antihypertensive actions of these compounds. 2. A number of reports have suggested that ACE inhibitors can improve arterial function in hypertension, whereas the knowledge about the vascular effects of other antihypertensive drugs, like beta-blockers, calcium channel blockers, and diuretics remains rather limited. 3. In this article, the effects of antihypertensive therapy on arterial function in human and experimental hypertension are reviewed.

Mesenteric arterial function in vitro in three models of experimental hypertension.

OBJECTIVE: To investigate arterial function in three models of experimental hypertension. METHODS: Twenty-five-week-old spontaneously hypertensive rats (SHRs), deoxycorticosterone-sodium chloride-treated Wistar-Kyoto rats (DOCs), and obese Zucker rats (OZRs) were used. Untreated Wistar-Kyoto rats (WKYs) and lean Zucker rats (LZRs) served as normotensive control rats. The function of mesenteric arterial rings was investigated in organ baths. RESULTS: In norepinephrine-precontracted rings, the relaxations to acetylcholine (ACh) and nitroprusside were reduced in SHRs, DOCs, and OZRs. NG-nitro-L-arginine methyl ester attenuated the dilations to ACh effectively in all study groups, the inhibitory effect being more potent in SHRs and DOCs and similar in OZRs when compared with corresponding controls. Unlike in norepinephrine-precontracted rings, the relaxations to ACh during precontraction with 60 mmol/l potassium chloride (prevention of endothelium-dependent hyperpolarization) were not impaired in the hypertensive animals. Nifedipine inhibited the contractile responses induced by cumulative addition of Ca2+ during stimulation with norepinephrine more effectively in SHRs and DOCs than in WKYs, whereas no such difference was seen between OZRs and LZRs. CONCLUSIONS: Experimental models of genetic, mineralocorticoid-sodium chloride-induced, and obesity-related hypertension were associated with attenuated arterial dilation. The defect of endothelium-mediated relaxation most likely resulted from impaired endothelium-dependent hyperpolarization of vascular smooth muscle in these hypertensive models, whereas the endothelial L-arginine-nitric oxide pathway appeared to be preserved. The function of voltage-dependent Ca2+ channels, as evaluated by enhanced inhibitory effect of nifedipine on the arterial contractions, was abnormal in smooth muscle from SHRs and DOCs, whereas such an abnormality was not observed in obesity-related hypertension.

Endothelial function in deoxycorticosterone-NaCl hypertension: effect of calcium supplementation.

BACKGROUND: Dietary calcium intake has been suggested to correlate inversely with blood pressure in humans and experimental animals. However, the effects of calcium supplementation on hypertensive disturbances of the endothelium have not been well characterized. METHODS AND RESULTS: Wistar-Kyoto rats made hypertensive by deoxycorticosterone (DOC)-NaCl treatment, but a concurrent increase in chow calcium content from 1.1% to 2.5% markedly attenuated the rise in blood pressure. The function of isolated mesenteric arterial rings in vitro was investigated at the close of the 10-week study. In norepinephrine-precontracted rings, the relaxations to acetylcholine (ACh) and ADP, as well as to nitroprusside, 3-morpholinosydnonimine, and isoproterenol were attenuated in hypertensive rats on 1.1% calcium supplementation. In the presence of NG-nitro-L-arginine methyl ester (L-NAME), the relaxations to ACh in hypertensive animals on normal calcium were practically absent, whereas in normotensive rats and calcium-supplemented hypertensive rats, distinct relaxations to higher concentrations of ACh were still present. These responses were reduced by 30% to 50% with apamin, a blocker of Ca2+-activated K+ channels, and were further inhibited by blockade of ATP-dependent K+ channels with glyburide. Interestingly, relaxations elicited by ACh and ADP during precontraction with 60 mmol/L KCl (preventing endothelium-dependent hyperpolarization) were not impaired in hypertensive animals. The contractile sensitivity of endothelium-intact arterial rings to 5-hydroxytryptamine and norepinephrine was higher in hypertensive rats on either normal or high-calcium diet, whereas the increase in contractile sensitivity caused by L-NAME corresponded in all groups. CONCLUSION: High-calcium diet markedly opposed experimental DOC-NaCl hypertension, an effect associated with improved arterial relaxation, while abnormalities of vascular contractile properties remained unaffected. In particular, the hyperpolarization-related component of endothelium-dependent arterial relaxation, mediated via opening of arterial K+ channels, could be augmented by calcium supplementation in DOC-NaCl hypertension.

Plasma digoxin immunoreactivity and arterial potassium relaxation after quinapril therapy in hypertensive rats.

Plasma digitalis-like substance and altered function of arterial Na+,K(+)-ATPase have both been linked with elevated blood pressure, but the influence of antihypertensive therapy on these factors remains unknown. Therefore, we treated spontaneously hypertensive rats and normotensive Wistar-Kyoto rats with the angiotensin-converting enzyme inhibitor quinapril for 10 weeks. The therapy markedly reduced blood pressure and plasma digoxin immunoreactivity, and it normalized the elevated plasma Na+:K+ ratio in the hypertensive animals. Relaxations of endothelium-denuded denervated arterial rings induced by return of potassium to the organ bath upon precontractions elicited by potassium-free solution were used to evaluate the function of vascular Na+,K(+)-ATPase. The rate of potassium relaxation was faster in quinapril-treated hypertensive rats and in both Wistar-Kyoto groups than in the hypertensive controls. Potassium relaxation was also effectively inhibited by the Na+,K(+)-ATPase inhibitor ouabain in all groups. In addition, arterial contractions to potassium chloride and relaxations to nitroprusside were examined. The contractions to lower concentrations of potassium chloride (20 mM) were enhanced in untreated hypertensive rats when compared with the other groups, although the maximal responses were corresponding in all groups. The time to reach base-line tension after washout of potassium chloride (125 mM) and the relaxations to nitroprusside did not differ in the study groups. In conclusion, the present results showed that long-term angiotensin-converting enzyme inhibition in parallel reduced plasma digoxin-like factor, enhanced arterial potassium relaxation (probably reflecting enhanced function of Na+,K(+)-ATPase) and normalized plasma Na+:K+ ratio in this type of genetic hypertension.

Dietary calcium intake: effects on central blood pressure control.

Low dietary intake of calcium has been found to be a risk factor for the development of hypertension in a number of epidemiological studies. Moreover, increased dietary calcium intake has been reported to beneficially influence on blood pressure in both humans and animal models of hypertension, suggesting the relative calcium deficiency may indeed be present in these conditions. The underlying mechanisms for the beneficial effect of positive calcium balance on blood pressure have been a subject for extensive research in essential and experimental hypertension. In this article, the possible beneficial effects of increased dietary calcium intake on central blood pressure control are reviewed.

Dietary calcium and magnesium supplements in spontaneously hypertensive rats and isolated arterial reactivity.

1. High calcium diet attenuates the development of hypertension but an associated undesirable effect is that Mg2+ loss to the urine is enhanced. Therefore, we studied the effects of high calcium diet alone and in combination with increased magnesium intake on blood pressure and arterial function. 2. Forty-eight young spontaneously hypertensive rats (SHR) were allocated into four groups, the dietary contents of Ca2+ and Mg2+ being: 1.1%, 0.2% (SHR); 2.5%, 0.2% (Ca-SHR); 2.5%, 0.8% (CaMg-SHR); and 1.1%, 0.8% (Mg-SHR), respectively. Development of hypertension was followed for 13 weeks, whereafter electrolyte balance, lymphocyte intracellular free calcium ([Ca2+]i), and mesenteric arterial responses in vitro were examined. Forty normotensive Wistar-Kyoto (WKY) rats were investigated in a similar manner. 3. Calcium supplementation comparably attenuated the development of Lypertension during normal and high magnesium intake in SHR, with an associated reduced lymphocyte [Ca2+]i and increased Mg2+ loss to the urine. 4. Endothelium-dependent arterial relaxation to acetylcholine was augmented in Ca-SHR and CaMg-SHR, while the relaxations to isoprenaline and the nitric oxide donor SIN-1 were similar in all SHR groups. Relaxation responses induced by the return of K+ to the organ bath upon precontractions in K(+)-free solution were used to evaluate the function of arterial Na+, K(+)-ATPase. The rate of potassium relaxation was similar in Ca-SHR and CaMg-SHR and faster than in untreated SHR. 5. Contractile responses to high concentrations of potassium and noradrenaline, and the ability of vascular smooth muscle to sequester Ca2+, which was evaluated by eliciting responses to caffeine or noradrenaline after loading periods in different Ca2+ concentrations, were comparable in all SHR groups. In SHR with increased magnesium intake, and in WKY rats with calcium or magnesium supplementation, no detectable effects on blood pressure and arterial function were observed.6. In conclusion, high calcium diet attenuated the development of hypertension in SHR, with an associated augmented endothelium-dependent relaxation, promoted recovery rate of ionic gradients across the cell membrane via Na+, K+-ATPase, and reduced basal [Ca2+ ]i. Dietary magnesium supplementation, whether combined with normal or high calcium intake, had no beneficial effects on blood pressure or arterial function.

Endothelial function in spontaneously hypertensive rats: influence of quinapril treatment.

1. Angiotensin converting enzyme (ACE) inhibition has been shown to restore the impaired endothelial function in hypertension, but the mediators underlying the promoted endothelium-dependent dilatation have not been fully characterized. Therefore, we investigated the effects of 10-week-long quinapril therapy (10 mg kg-1 day-1) on responses of mesenteric arterial rings in vitro from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. 2. Endothelium-dependent relaxations of noradrenaline (NA)-precontracted rings to acetylcholine (ACh) and adenosine 5'-diphosphate (ADP) were similar in WKY rats and quinapril-treated SHR and more pronounced than in untreated SHR. The nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) attenuated the relaxations in both WKY groups and quinapril-treated SHR, and completely inhibited them in untreated SHR. When endothelium-dependent hyperpolarization was prevented by precontraction of the preparations with potassium chloride (KCl), no differences were found in relaxations to ACh and ADP between the study groups. In addition, in NA-precontracted rings the L-NAME- and indomethacin-resistant relaxations to ACh were partially prevented by apamin, an inhibitor of calcium-activated potassium channels. 3. Interestingly, in quinapril-treated SHR but not in the other groups, exogenous bradykinin potentiated the relaxations to ACh in both NA- and KCl-precontracted arterial rings. 4. Contractile sensitivity of endothelium-intact rings to NA was reduced in SHR by quinapril, and was more effectively increased by L-NAME in quinapril-treated than untreated SHR. 5. In conclusion, since the relaxations to ACh and ADP in quinapril-treated SHR were augmented in the absence and presence of NO synthesis inhibition but not under conditions which prevented hyperpolarization, enhanced endothelium-dependent relaxation after long-term ACE inhibition can be attributed to increased endothelium-dependent hyperpolarization. However, the potentiation of the response to ACh by exogenous bradykinin in quinapril-treated SHR, as well as the increased attenuating effect of the endothelium on NA-induced contractions in these animals appear to result from enhanced endothelium-derived NO release.

Arterial function after trichlormethiazide therapy in spontaneously hypertensive rats.

Inasmuch as the long-term influences of diuretic therapy on arterial function remain largely unknown, the effects of trichlormethiazide (8 mg kg-1 day-1) on vascular responses were studied in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. The 14-week treatment attenuated the increase in blood pressure by approximately 20 mm Hg in SHR, but did not affect blood pressure in WKY rats. Responses of mesenteric arterial rings in vitro were examined at the end of the study. Endothelium-dependent relaxation induced by acetylcholine was more pronounced in normotensive than in hypertensive rats and was improved by trichlormethiazide in SHR, whereas endothelium-independent relaxation to the nitric oxide donor 3-morpholinosynonimine was comparable in all study groups. Arterial relaxation to isoproterenol also was attenuated in SHR when compared with WKY rats, and remained unaffected by trichlormethiazide in both strains. Relaxation responses induced by return of K+ to the organ bath upon precontractions elicited by K(+)-free solution were used to evaluate the function of vascular smooth muscle Na+,K(+)-adenosine 5'-triphosphatase. The maximal rate of K+ relaxation was fastest in the normotensive groups, but also was clearly faster in trichlormethiazide-treated SHR when compared with untreated SHR. Furthermore, arterial contractile force generation to KCl and norepinephrine, and vascular calcium sensitivity during stimulation with these agonists, were not affected by trichlormethiazide in either strain. The ability of arterial smooth muscle to sequester calcium was evaluated by means of caffeine- and norepinephrine-induced contractions after loading periods in different organ bath calcium concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Enhancement of arterial relaxation by long-term atenolol treatment in spontaneously hypertensive rats.

1. The effects of long-term atenolol (25 mg kg-1 day-1) therapy on arterial function were studied in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. The 14-week treatment attenuated the increase in blood pressure by approximately 30 mmHg in SHR, but did not affect blood pressure in WKY rats. 2. Responses of mesenteric arterial rings in vitro were examined at the end of the study. The relaxation to acetylcholine was similar in WKY rats and atenolol-treated SHR and more pronounced than in untreated SHR, whereas the relaxation to the nitric oxide donor 3-morpholinosydnonimine (SIN-1) was comparable in all study groups. Moreover, after maximal relaxations to acetylcholine, marked recontractions developed in untreated SHR but not in the other groups. Vasorelaxation to isoprenaline was also attenuated in SHR and was moderately improved by the atenolol therapy. 3. Arterial relaxation induced by return of potassium to the organ bath upon precontractions elicited by potassium-free solution were used to evaluate vascular smooth muscle Na+, K+-ATPase. The rate of potassium relaxation was fastest in WKY rats and was also faster in atenolol-treated than in untreated SHR. 4. The ability of vascular smooth muscle to sequester calcium was evaluated by eliciting responses to caffeine or noradrenaline after loading periods in different organ bath calcium concentrations. The subsequent contractions were lower in untreated SHR than in WKY rats, and augmented in SHR by the atenolol treatment. 5. Smooth muscle contractions to noradrenaline were comparable in SHR and WKY rats, while atenolol treatment slightly increased the maximal response to this agonist in SHR. Responses to potassium chloride were not affected by atenolol and contractions following cumulative re-addition of calcium to the organ bath after precontraction with potassium chloride and noradrenaline in calcium free solution were comparable in all study groups.6. In conclusion, the moderate antihypertensive effect of atenolol in SHR was accompanied by enhancement of beta-adrenoceptor-mediated and normalization of endothelium-dependent arterial relaxation.Furthermore, ability to sequester calcium into cellular stores, and function of Na+,K+-ATPase were augmented in vascular smooth muscle. Therefore, the present results suggest that the long-term blood pressure-lowering action of atenolol in this type of genetic hypertension is accompanied by improved arterial relaxation and normalization of endothelial function.