(Hypertension. 1996;28:58-63.)
© 1996 American Heart Association, Inc.
Articles |
Benidipine Improves Endothelial Function in Renal Resistance Arteries of Hypertensive Rats
the Division of Hypertension and Vascular Research, Second Department of Internal Medicine, Nagoya City University Hospital (Y.D., M.K., K.S.), and Department of Internal Medicine, Nagoyashi Kohseiin Geriatric Hospital (Y.D.), Nagoya, Japan.
Correspondence to Yasuaki Dohi, MD, Department of Internal Medicine, Nagoyashi Kohseiin Geriatric Hospital, Sekobo 2-1501, Meito-ku, Nagoya 465, Japan.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
We studied the effects of long-term antihypertensive treatment on endothelial function in renal resistance arteries from spontaneously hypertensive rats (SHR). Wistar-Kyoto rats (WKY) were used as a normotensive reference. Adult SHR were treated with benidipine (a calcium antagonist) or ecarazine (a vasodilator) for 10 weeks; the drugs caused similar reductions in blood pressure. Changes in isometric tension of rings prepared from the third-order branches of the renal arteries were recorded. Endothelium-dependent relaxations induced by acetylcholine in rings contracted with norepinephrine were smaller in SHR than in WKY. The impaired relaxation was improved by benidipine treatment, but ecarazine had no significant effect. In vitro treatment with meclofenamic acid, a cyclooxygenase inhibitor, did not alter the differences in the relaxations. In the presence of meclofenamic acid, N
-nitro-L-arginine methyl ester slightly reduced the relaxations; the relaxation was smaller in SHR than in WKY and was not affected by benidipine treatment. In rings contracted with 40 mmol/L KCl, the relaxations induced by acetylcholine in the presence of meclofenamic acid were smaller than those in rings contracted with norepinephrine. The relaxation was smaller in SHR than in WKY but was normalized by benidipine treatment. Thus, acetylcholine relaxes rat renal resistance arteries by releasing nitric oxide and endothelium-derived hyperpolarizing factor from the endothelium, which is impaired in SHR. Long-term benidipine treatment improves the impaired relaxation in SHR by enhancing nitric oxide–mediated relaxation.
Key Words: acetylcholine • benidipine • calcium antagonists • endothelium • nitric oxide • relaxation • renal artery • rats, inbred SHR
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The endothelium can respond to many vasoactive substances by releasing relaxing and contracting factors.1 2 The relaxing factors include NO, which is produced by NO synthetase through the L-arginine pathway,3 4 EDHF,5 6 7 and prostacyclin.8 The EDCFs include superoxide anions,9 endoperoxides,10 and endothelin.11 Balance between relaxing and contracting factors plays an important role in the regulation of vascular tone.
Chronic hypertension is associated with altered endothelial function in large conduit and small resistance arteries,12 13 14 15 although data regarding an alteration in renal circulation, which is closely related to hypertension, are limited.16 Endothelium-dependent relaxations to acetylcholine,17 18 19 adenosine,20 serotonin,17 and histamine21 are impaired, and abnormal endothelium-dependent contractions to acetylcholine have been observed.22 The underlying mechanisms are not completely understood. Excessive production of EDCFs in hypertension has been suggested,10 16 22 23 24 but some investigators have reported a reduced production of relaxing factors such as NO25 and EDHF.26 27 Antihypertensive treatment is able to induce an improvement of the impaired endothelial response in SHR.28 29 30 We recently observed an improvement of the functional alterations of the endothelium in SHR after long-term treatment with a calcium antagonist.31 However, the effects of antihypertensive treatment on each factor released from the endothelium have not been intensively studied.
Benidipine, a novel calcium antagonist characterized by long-lasting effects both in vivo and in vitro,32 33 has been reported to improve the endothelial dysfunction observed in systemic shock.34 Thus, we designed the present study to investigate (1) the effects of hypertension on endothelium-derived factors released after stimulation with acetylcholine and (2) the effects of long-term antihypertensive treatment with the calcium antagonist benidipine on each endothelium-derived factor in rat renal resistance arteries. For comparison, we used ecarazine, a derivative of the vasodilator hydralazine.35
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Animals
Male WKY and SHR, 13 weeks of age, were obtained from Charles River Japan (Yokohama) and used in this study, which had been approved in advance by our institutional animal care committee. All rats were maintained on standard chow with free access to drinking water. At 16 weeks of age, the SHR were divided into three groups. One group was treated with benidipine (6 mg/kg per day) and another group with ecarazine (6.5 mg/kg per day; both mixed with the chow) for 10 weeks until the day of the experiment (26 weeks old). Untreated groups of SHR and WKY were fed standard chow during the 10 weeks. In a separate experiment, some SHR were treated with benidipine for 7 days (from 25 to 26 weeks of age) for evaluation of the effects of short-term benidipine treatment.
Preparation of Renal Resistance Arteries
When rats were 26 weeks of age, blood pressure was measured by the tail-cuff method, after which rats were anesthetized with pentobarbital (50 mg/kg IP) and exsanguinated. The kidneys were removed and placed in a modified Krebs-Ringer bicarbonate solution of the following composition (mmol/L): NaCl 118.6, KCl 4.8, CaCl2 2.5, MgSO4 1.2, KH2PO4 1.2, NaHCO3 25.1, Na2EDTA 0.026, and glucose 10.1, pH 7.4 (Krebs solution). Intrarenal arteries were exposed by a tangential longitudinal incision through the kidney starting at the hilum.16 Branches of the interlobar arteries (internal diameter, about 200 µm) were cleaned of adhering tissue and cut into rings (width, 1 mm) under a dissection microscope. In some preparations, the endothelium was removed by gentle rubbing of the intimal surface with a thin glass rod. Endothelium removal was confirmed later by an inability of acetylcholine to relax the arteries.
Organ Chamber Experiments
Rings were suspended horizontally by means of two -shaped stainless steel holders in the vessel lumen in small organ chambers (5 mL) filled with the Krebs solution (37°C) aerated with 95% O2/5% CO2. One of the holders was fixed and the other was connected to a force displacement transducer (UM-203, Kishimoto) for measurement of isometric tension development. The rings were equilibrated under a resting tension of 200 mg for 60 minutes. The tension was found to be optimal for contraction of the preparation as assessed by repeated exposure to a 60 mmol/L KCl solution (obtained by equimolar replacement of NaCl by KCl in the Krebs solution) under various resting tensions. After the equilibration period, rings were maximally contracted by the 60 mmol/L KCl solution two times at 45-minute intervals.
Protocol
Concentration-response curves to acetylcholine were constructed in rings with endothelium contracted with (1) the EC50 values of norepinephrine in the presence of the ß-adrenoceptor antagonist timolol (3x10-7 mol/L) or (2) a 40 mmol/L KCl solution. In the preparations studied, the EC50 values of norepinephrine and the 40 mmol/L KCl solution evoked comparable contractions in both WKY and SHR (data not shown). In some preparations, concentration-response curves to acetylcholine were obtained in the presence of meclofenamic acid (10-5 mol/L), a cyclooxygenase inhibitor, or L-NAME (10-4 mol/L), an inhibitor of endogenous production of NO from L-arginine.36 These drugs were applied 30 minutes before the start of the experiments and were present throughout the experiments. Endothelium-independent relaxations to sodium nitroprusside were studied in rings without endothelium contracted with the EC50 values of norepinephrine in the presence of timolol (3x10-7 mol/L).
Drugs and Solutions
The following drugs were used (unless otherwise stated, drugs were from Sigma Chemical Co): acetylcholine chloride, benidipine hydrochloride (Kyowa Hakko Kogyo Co, Ltd), ecarazine hydrochloride (Kyowa Hakko Kogyo), L-norepinephrine bitartrate, L-NAME, sodium nitroprusside, and timolol maleate (Banyu Pharmaceutical Co, Ltd). The 40 mmol/L KCl solution was obtained by an equimolar replacement of NaCl by KCl in the Krebs solution.
Calculations and Statistical Analysis
Relaxations are expressed as the percentage of the preceding contraction induced by the EC50 values of norepinephrine or the 40 mmol/L KCl solution. Data are given as mean±SE. The concentration of an agonist causing half-maximal relaxation (EC50 value) was calculated for each experiment and is expressed as negative log molar (pD2). The shift of concentration-response curves induced by in vivo treatment is expressed as the concentration shift at pD2 values. In each set of experiments, n equals the number of rats studied. Statistical analysis was performed by ANOVA followed by Scheffe's F test. Means were considered to be significantly different at a value of P<.05.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Blood Pressure
Systolic pressure was markedly higher in untreated SHR than in WKY (Table
). Long-term treatment with benidipine or ecarazine reduced blood pressure, but the blood pressure levels of SHR remained higher than those of WKY. Blood pressure significantly decreased after a week of the start of treatment with these drugs and then remained unaltered throughout the administration period (data not shown). Body weight and heart rate did not differ at 26 weeks of age in all the groups.
|
Long-term Treatment and Relaxation
Relaxation in Rings Contracted With Norepinephrine
In WKY, acetylcholine (10-9 to 10-7 mol/L) evoked concentration-dependent relaxations of renal resistance arteries with endothelium contracted with norepinephrine (pD2, 7.8±0.1; maximum, 82±3%); at higher concentrations, relaxations were reversed to a contractile response (Fig 1, left). The responses to acetylcholine were absent in arteries without endothelium (data not shown). In SHR, the pD2 values (6.9±0.1) but not the maximal responses (73±5%) for the relaxation induced by acetylcholine were smaller than in WKY (P<.0001). Long-term benidipine treatment improved the impaired relaxation (pD2, 7.3±0.1 [shift of the concentration-response curve by benidipine, 2.6-fold], P<.005; maximum, 91±2%, P<.01 versus SHR), although the pD2 values remained lower than in WKY (P<.0001) (Fig 1, left). Ecarazine treatment had no significant effect on relaxation (pD2, 7.0±0.1; maximum, 83±3%; P=NS versus SHR). In contrast to the relaxation induced by low concentrations of acetylcholine, the contraction observed at higher concentrations was not affected by hypertension or antihypertensive treatment.
|
Sodium nitroprusside (10-9 to 10-4 mol/L) evoked concentration-dependent relaxations in WKY arteries without endothelium (pD2, 7.1±0.1; maximum, 99±1%) (Fig 1
, right). In contrast to the endothelium-dependent relaxation induced by acetylcholine, the endothelium-independent relaxation was not decreased in SHR (pD2, 7.3±0.1; maximum, 99±1%), and long-term treatment with benidipine (pD2, 7.1±0.1; maximum, 100±1%) or ecarazine (pD2, 7.1±0.1; maximum, 99±1%) did not affect the relaxation.
Meclofenamic acid (10-5 mol/L), a cyclooxygenase inhibitor, prevented the contraction induced by high concentrations of acetylcholine (P<.05 to .0001) without affecting the pD2 values in all the groups studied (Figs 2 and 3). In the presence of meclofenamic acid, the pD2 values and maximal responses were smaller in SHR (pD2, 7.0±0.1; maximum, 88±3%) than in WKY (pD2, 7.8±0.1, P<.0001; maximum, 98±1%, P<.05). Long-term benidipine treatment increased the pD2 values (7.4±0.1 [threefold]; P<.005 versus SHR) but not the maximal responses (95±1%; P=NS) in SHR; ecarazine treatment did not alter the reduced relaxation in SHR (pD2, 7.1±0.1; maximum, 93±1%; P=NS versus SHR) (Fig 3).
|
) or norepinephrine. Note the prevention of relaxation by L-NAME in arteries contracted with 40 mmol/L KCl (d).
|
To evaluate a possible role of endogenous NO in the cyclooxygenase-independent relaxation, we investigated the effects of L-NAME (10-4 mol/L) on the response to acetylcholine in the presence of meclofenamic acid (Figs 2 and 4). In WKY, L-NAME slightly reduced but did not prevent the relaxation (pD2, 7.5±0.1, P=NS; maximum, 82±4%, P<.05) (Figs 3 and 4). In the presence of L-NAME, the relaxation was reduced in SHR (pD2, 7.0±0.1, P<.005; maximum, 71±4%, P=NS) compared with WKY. Neither benidipine (pD2, 7.1±0.1; maximum, 75±6%; P=NS versus SHR) nor ecarazine (pD2, 7.0±0.1; maximum, 64±9%; P=NS versus SHR) affected the impaired relaxation in SHR (Fig 4).
|
Relaxation in Rings Contracted With KCl
We also investigated the responses to acetylcholine (in the presence of meclofenamic acid) in arteries contracted with 40 mmol/L KCl solution (Figs 2 and 5) because this condition may minimize the effects of EDHF.37 In arteries contracted with KCl, the relaxation was abolished by the presence of L-NAME (Fig 2) in all the groups studied (data not shown, n=5 or 6). In the presence of the cyclooxygenase inhibitor, the relaxation obtained in WKY arteries contracted with KCl was smaller (pD2, 7.3±0.1, P<.01; maximum, 77±3%, P<.005) than in arteries contracted with norepinephrine (Figs 3 and 5). The relaxation was decreased in SHR (pD2, 6.6±0.1, P<.0001; maximum, 73±2%, P=NS) compared with WKY (Fig 5). Long-term benidipine treatment normalized the decreased relaxation in SHR (pD2, 7.1±0.1 [2.9-fold]; maximum, 85±2%; P=NS versus WKY), but ecarazine had no effect (pD2, 6.7±0.1; maximum, 72±3%; P=NS versus SHR) (Fig 5).
|
Short-term Treatment
Short-term (7 days) treatment with benidipine reduced blood pressure in SHR (163±7 mm Hg, P<.05 versus untreated SHR) but did not alter the impaired response to acetylcholine in arteries contracted with norepinephrine (pD2, 6.9±0.1; maximum, 80±2%; P=NS versus untreated SHR, n=5).
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The present study demonstrates that acetylcholine evokes relaxations of rat renal resistance arteries by releasing NO and cyclooxygenase-independent, non-NO relaxing factor (possibly EDHF) from the endothelium. In SHR, the relaxation is impaired because of decreased effects of both relaxing factors. Long-term antihypertensive treatment with benidipine improves the impaired relaxation in SHR by enhancing NO production and/or release. Because short-term treatment with benidipine did not improve the impaired relaxation in the renal resistance arteries from SHR and ecarazine, which reduced blood pressure to a similar extent as benidipine, had no significant effect on the impaired relaxation, the improvement of the endothelial dysfunction observed must be related to the long-term application and action of benidipine.
Acetylcholine induced endothelium-dependent relaxations and contractions (at high concentrations) of renal resistance arteries from WKY. Meclofenamic acid, a cyclooxygenase inhibitor, abolished the contraction without affecting the relaxation induced by low concentrations of acetylcholine, indicating that high concentrations of acetylcholine release EDCF, which evokes contractions of the vascular smooth muscle through a cyclooxygenase-dependent pathway. In the presence of the cyclooxygenase inhibitor, L-NAME reduced but did not prevent the relaxation. This suggests that NO derived from the endothelial L-arginine pathway contributes to the relaxation, but another factor must be involved in the relaxation. Acetylcholine (in the presence of meclofenamic acid) evoked less potent relaxation in arteries contracted with KCl than in those contracted with norepinephrine. High K+ depolarizes the membrane of vascular smooth muscle cells, and thus the membrane potential of the renal resistance artery may be fixed during the contraction induced by KCl.37 Since EDHF induces relaxations of vascular smooth muscle by opening potassium channels in the smooth muscle membrane, resulting in hyperpolarization,7 37 38 the effects of EDHF are abolished in high-K+ solutions.7 37 Thus, it is speculated that besides NO, EDHF is also involved in the relaxation induced by acetylcholine. Since depolarization of endothelial cells caused by high K+ may impair the release of NO and depolarization of vascular smooth muscle cells may impair the response to NO, this may also contribute to the impairment of the relaxation in high-K+ solutions. In arteries contracted with KCl (in the presence of meclofenamic acid), L-NAME prevented the relaxation induced by acetylcholine, indicating that NO is the only factor that mediates the relaxation in this condition. These results indicate that in rat renal resistance arteries, relaxing factors released from the endothelium after stimulation with acetylcholine are NO and cyclooxygenase independent, non-NO relaxing factors that are not effective in high-K+ solutions (most likely EDHF).
In SHR, the relaxation induced by acetylcholine in arteries contracted with norepinephrine was markedly reduced compared with WKY, confirming previous studies with conduit or other resistance artery preparations.12 13 14 15 16 17 18 19 20 21 Since relaxations induced by sodium nitroprusside were not different in WKY and SHR, an endothelial dysfunction rather than an impaired response of the vascular smooth muscle is responsible for the impaired relaxation.16 39 40 Several groups have reported that the reduced endothelium-dependent relaxation observed in arteries from hypertensive animals results from the excessive production of EDCF.10 16 22 23 24 In the present study, the contraction induced by EDCF (at high concentrations of the muscarinic agonist) was not different in WKY and SHR, and in vitro treatment with meclofenamic acid did not improve the impaired relaxation in SHR. Thus, an excessive production of EDCF cannot account for the impaired relaxation in SHR. The differences in the results may be explained at least in part by the differences in the preparations and ages used.41 In contrast to the contraction induced by EDCF, the relaxation obtained in the presence of meclofenamic acid was impaired in SHR, indicating that the effects of NO and/or EDHF are decreased in SHR. Because the relaxations obtained either in the presence of L-NAME (in arteries contracted with norepinephrine) or in arteries contracted with KCl (in the absence of L-NAME) were smaller in SHR than in WKY, relaxations mediated by both NO and EDHF are attenuated in renal resistance arteries from SHR.
Several studies with animal models of hypertension have demonstrated the beneficial effects on endothelial function of in vivo treatment with angiotensin-converting enzyme inhibitors or calcium antagonists.28 29 30 31 However, effects of the in vivo treatment on each endothelium-derived factor have not been intensively studied. In the present study, long-term benidipine treatment normalized the impaired relaxation obtained in arteries contracted with KCl in the presence of meclofenamic acid. Since the relaxation in this condition is mediated by NO, long-term benidipine treatment enhances the effects of NO. The fact that in vitro treatment with L-NAME (along with meclofenamic acid) abolished the improvement induced by the long-term benidipine treatment further reinforces this concept. The enhancement of the effects of NO may be related to an increase in NO production and/or release in benidipine-treated SHR because relaxations induced by sodium nitroprusside were not changed by long-term treatment. This must be particularly important because NO derived from the endothelium not only evokes relaxations of vascular smooth muscles but also plays a protective role (inhibition of platelet aggregation) in the circulation against important clinical implications for the pathogenesis of cardiovascular disorders in hypertension.2 Indeed, long-term in vivo inhibition of NO synthase produces severe hypertensive nephrosclerosis in SHR42 and causes hypertension with a high frequency of stroke and high mortality in Wistar rats.43 The mechanisms underlying the improvement in NO production and/or release by benidipine are not clear. Since the improvement was not observed in SHR treated with benidipine for 7 days, a direct action of the calcium antagonist can be excluded. Furthermore, the reduction in blood pressure cannot fully account for the improvement, as ecarazine did not affect the impaired response in SHR. It is speculated that calcium overload44 may play an important role in the impairment of endothelial function in hypertension and that benidipine may normalize the altered calcium regulation in the hypertensive endothelium by blocking calcium channels, resulting in the improvement of endothelial function.
In contrast to the relaxation induced by NO, NO-independent relaxation to acetylcholine (obtained in arteries contracted with norepinephrine in the presence of L-NAME along with the cyclooxygenase inhibitor) was not altered by benidipine treatment, indicating that endothelium-dependent, NO-independent relaxation to acetylcholine (possibly mediated by EDHF) is insensitive to long-term benidipine treatment. On the other hand, long-term benidipine treatment did not affect the contraction induced by EDCF.
In conclusion, long-term antihypertensive treatment with the calcium antagonist benidipine reduces blood pressure and improves endothelial dysfunction in renal resistance arteries from SHR by enhancing NO release and/or production. These beneficial effects of long-term treatment may contribute to the antihypertensive properties of benidipine and to its beneficial effects on hypertensive vascular complications.
|
Selected Abbreviations and Acronyms |
|---|
|
Received November 27, 1995;
first decision January 9, 1996; first decision February 21, 1996;
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980;299:373-376.
2. Luscher TF, Vanhoutte PM. The Endothelium: Modulator of Cardiovascular Function. Boca Raton, Fla: CRC Press; 1991.
3. Palmer RMJ, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium derived relaxing factor. Nature. 1987;327:524-526.[Medline] [Order article via Infotrieve]
4. Palmer RMJ, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature. 1988;333:664-666.[Medline] [Order article via Infotrieve]
5.
Komori K, Suzuki H. Electrical responses of smooth muscle cells during cholinergic vasodilation in the rabbit saphenous artery. Circ Res. 1987;61:586-593.
6.
Chen G, Suzuki H. Some electrical properties of the endothelium-dependent hyperpolarization recorded from rat arterial smooth muscle cells. J Physiol. 1989;410:91-106.
7. Garland CJ, Plane F, Kemp BK, Cocks TM. Endothelium-dependent hyperpolarization: a role in the control of vascular tone. Trends Pharmacol Sci. 1995;16:23-30.[Medline] [Order article via Infotrieve]
8. Moncada S, Vane JR. Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane A2 and prostacyclin. Pharmacol Rev. 1979;30:293-331.[Medline] [Order article via Infotrieve]
9.
Rubanyi GM, Vanhoutte PM. Superoxide anions and hyperoxia inactivate endothelium-derived relaxing factor(s). Am J Physiol. 1986;250:H822-H827.
10.
Kato T, Iwama Y, Okumura K, Hashimoto H, Ito T, Satake T. Prostaglandin H2 may be the endothelium-derived contracting factor released by acetylcholine in the aorta of the rat. Hypertension. 1990;15:475-481.
11. Yanagisawa M, Kurihara H, Kimura S, Mitsui Y, Kobayashi M, Watanabe TX, Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332:411-415.[Medline] [Order article via Infotrieve]
12.
Konishi M, Su C. Role of endothelium in dilator responses of spontaneously hypertensive rat arteries. Hypertension. 1983;5:881-886.
13. Luscher TF, Dohi Y, Tschudi M. Endothelium-dependent regulation of resistance arteries: alterations with aging and hypertension. J Cardiovasc Pharmacol. 1992;19(suppl 5):S34-S42.
14. Luscher TF, Tanner FC, Dohi Y. Age, hypertension and hypercholesterolaemia alter endothelium-dependent vascular regulation. Pharmacol Toxicol. 1992;70(suppl 2):S32-S39.
15. Vanhoutte PM, Boulanger CM. Endothelium-dependent responses in hypertension. Hypertens Res. 1995;18:87-98.[Medline] [Order article via Infotrieve]
16.
Fu-Xiang D, Skopec J, Diederich A, Diederich D. Prostaglandin H2 and thromboxane A2 are contractile factors in intrarenal arteries of spontaneously hypertensive rats. Hypertension. 1992;19:795-798.
17.
Mayhan WG, Faraci FM, Heistad DD. Impairment of endothelium-dependent responses of cerebral arterioles in chronic hypertension. Am J Physiol. 1987;253:H1435-H1440.
18.
Tesfamariam B, Halpern W. Endothelium-dependent and endothelium-independent vasodilation in resistance arteries from hypertensive rats. Hypertension. 1988;11:440-444.
19.
Dohi Y, Thiel MA, Buhler FR, Luscher TF. Activation of endothelial L-arginine pathway in resistance arteries: effect of age and hypertension. Hypertension. 1990;16:170-179.
20. Takase H, Dohi Y, Kojima M, Sato K. Changes in the endothelial cyclooxygenase pathway in resistance arteries of spontaneously hypertensive rats. J Cardiovasc Pharmacol. 1994;23:326-330.[Medline] [Order article via Infotrieve]
21.
Suzuki H, Zweifach BW, Schmid-Schonbein GW. Vasodilator response of mesenteric arterioles to histamine in spontaneously hypertensive rats. Hypertension. 1995;26:397-400.
22.
Luscher TF, Vanhoutte PM. Endothelium-dependent contractions to acetylcholine in the aorta of the spontaneously hypertensive rat. Hypertension. 1986;8:344-348.
23.
Koga T, Takata Y, Kobayashi K, Yamashita Y, Fujishima M. Age and hypertension promote endothelium-dependent contractions to acetylcholine in the aorta of the rat. Hypertension. 1989;14:542-548.
24.
Diederich D, Yang Z, Buhler FR, Luscher TF. Impaired endothelium-dependent relaxations in hypertensive resistance arteries involve cyclooxygenase pathway. Am J Physiol. 1990;258:H445-H451.
25.
Hoshino J, Sakamaki T, Nakamura T, Kobayashi M, Kato M, Sakamoto H, Kurashina T, Yagi A, Sato K, Ono Z. Exaggerated vascular response due to endothelial dysfunction and role of the renin-angiotensin system at early stage of renal hypertension in rats. Circ Res. 1994;74:130-138.
26.
Van de Voorde J, Vanheel B, Leusen I. Endothelium-dependent relaxation and hyperpolarization in aorta from control and renal hypertensive rats. Circ Res. 1992;70:1-8.
27.
Fujii K, Tomonaga M, Ohmori S, Kobayashi K, Koga T, Takata Y, Fujishima M. Decreased endothelium-dependent hyperpolarization to acetylcholine in smooth muscle of the mesenteric artery of spontaneously hypertensive rats. Circ Res. 1992;70:660-669.
28.
Clozel M, Kuhn H, Hefti F. Effects of angiotensin converting enzyme inhibitors and of hydralazine on endothelial function in hypertensive rats. Hypertension. 1990;16:532-540.
29. Rubanyi GM, Kauser K, Graser T. Effect of cilazapril and indomethacin on endothelial dysfunction in the aortas of spontaneously hypertensive rats. J Cardiovasc Pharmacol. 1993;22(suppl 5):S23-S30.
30.
Rizzoni D, Castellano M, Porteri E, Bettoni G, Muiesan ML, Cinelli A, Rosei EA. Effects of low and high doses of fosinopril on the structure and function of resistance arteries. Hypertension. 1995;26:118-123.
31. Dohi Y, Criscione L, Pfeiffer K, Luscher TF. Angiotensin blockade or calcium antagonists improve endothelial dysfunction in hypertension: studies in perfused mesenteric resistance arteries. J Cardiovasc Pharmacol. 1994;24:372-379.[Medline] [Order article via Infotrieve]
32. Karasawa A, Kubo K. Calcium antagonistic effects and the in vitro duration of actions of KW-3049, a new 1.4-dihydropyridine derivative, in isolated canine coronary arteries. Jpn J Pharmacol. 1988;47:35-44.[Medline] [Order article via Infotrieve]
33. Karasawa A, Kubo K, Oka T, Nakamizo N. Antihypertensive effects of intravenous administration of benidipine hydrochloride and some other calcium antagonists in conscious spontaneously hypertensive rats. Arzneimittelforschung. 1988;38:1691-1694.[Medline] [Order article via Infotrieve]
34. Karasawa A, Rochester JA, Ma X-I, Lefer AM. Protection of endothelial damage and systemic shock by benidipine, a calcium antagonist, in rats subjected to splanchnic ischemia and reperfusion. Circ Shock. 1991;33:135-141.[Medline] [Order article via Infotrieve]
35. Swales JD. Vasodilators. In: Swales JD, ed. Textbook of Hypertension, Part 8: Treatment. London, UK: Blackwell Scientific Publications; 1994:1104-1110.
36. Rees DD, Palmer RMJ, Schulz R, Hodson HF, Moncada S. Characterization of three inhibitors of endothelial nitric oxide synthase in vivo and in vitro. Br J Pharmacol. 1990;101:746-752.[Medline] [Order article via Infotrieve]
37.
Nagao T, Vanhoutte PM. Hyperpolarization as a mechanism for endothelium-dependent relaxations of the porcine coronary artery. J Physiol (Lond). 1992;445:355-367.
38.
Cowan CL, Cohen RA. Two mechanisms mediate relaxation by bradykinin of pig coronary artery: NO-dependent and -independent responses. Am J Physiol. 1991;261:H830-H835.
39. Van de Voorde J, Leusen I. Endothelium-dependent and independent relaxation of aortic rings from hypertensive rats. Am J Physiol. 1986;250:H711-H717.
40.
Papapetropoulos A, Marczin N, Snead MD, Cheng C, Milici A, Catravas JD. Smooth muscle cell responsiveness to nitrovasodilators in hypertensive and normotensive rats. Hypertension. 1994;23:476-484.
41. Dohi Y, Kojima M, Sato K, Luscher TF. Age-related changes in vascular smooth muscle and endothelium. Drugs Aging. 1995;7:278-291.[Medline] [Order article via Infotrieve]
42.
Ono H, Ono Y, Frohlich ED. Nitric oxide synthase inhibition in spontaneously hypertensive rats: systemic, renal, and glomerular hemodynamics. Hypertension. 1995;26:249-255.
43. Blot S, Arnal J-F, Xu Y, Gray F, Michel J-B. Spinal cord infarcts during long-term inhibition of nitric oxide synthase in rats. Stroke. 1994;25:1666-1673.[Abstract]
44. Rusch NJ, Hermsmeyer K. Vascular muscle calcium channels in hypertension. In: Coca A, ed. Ionic Transport in Hypertension: New Perspectives. Boca Raton, Fla: CRC Press; 1993:197-227.
This article has been cited by other articles:
 |
|
 |
|
  P. M. Vanhoutte and E. H. C. Tang Endothelium-dependent contractions: when a good guy turns bad! J. Physiol., November 15, 2008; 586(22): 5295 - 5304. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Feletou and P. M. Vanhoutte Endothelial dysfunction: a multifaceted disorder (The Wiggers Award Lecture) Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H985 - H1002. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Kitakaze, K. Node, T. Minamino, H. Asanuma, T. Kuzuya, and M. Hori A Ca channel blocker, benidipine, increases coronary blood flow and attenuates the severity of myocardial ischemia via NO-dependent mechanisms in dogs J. Am. Coll. Cardiol., January 1, 1999; 33(1): 242 - 249. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Onaka, K. Fujii, I. Abe, and M. Fujishima Antihypertensive Treatment Improves Endothelium-Dependent Hyperpolarization in the Mesenteric Artery of Spontaneously Hypertensive Rats Circulation, July 14, 1998; 98(2): 175 - 182. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||