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Gentamicin blocks ACh-evoked K⁺ current in guinea-pig outer hair cells by impairing Ca²⁺ entry at the cholinergic receptor

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JOURNAL OF PHYSIOLOGY-LONDON 2000年第3期525卷 641-654页

作者： Blanchet, C Eróstegui, C Sugasawa, M Dulon, D Univ Bordeaux 2 CHU Hop Pellegrin INSERM 99 27 Equipe MixteLab Biol Cellulaire & Mol Audit F-33076 Bordeaux France

1. Aminoglycoside antibiotics such as gentamicin are known to block the medial olivocochlear efferent system. In order to determine whether this inhibition takes place at the postsynaptic cholinergic receptors in outer hair cells (OHCs), we studied the effects of these polycationic molecules on cholinergic currents evoked in isolated guinea-pig OHCs. 2. The cholinergic response of OHCs involves nicotinic-like receptors (nAChRB) permeable to Ca2+ ions that activate nearby Ca2+-sensitive K+ channels (K-Ca(ACh) channels). The extracellular application of gentamicin and neomycin reversibly blocked ACh-evoked K+ current (I-K(ACh)) with IC50 values Of 5.5 and 3.2 mu M, respectively. The results showed that the Mocking mechanism of I-K(Ach) was due to inhibition of Ca2+ influx via nAChRs. 3. Our study also provides interesting insights into the functional coupling between nAChRs and K-Ca(Ach) channels in OHCs. By directly recording the cation current flowing through nAChRs I-n(Ach) using an intracellular solution containing 10 mM BAPTA, we measured an EC50 near 110 mu M for ACh-evoked I-n(Ach). This EC50 for ACh is one order of magnitude higher than that measured indirectly on I-K(Ach). This reveals a rather low affinity of ACh for its receptor but a very efficient coupling between nAChRs and K-Ca(ACh) channels. 4. We also show that a high external Ca2+ concentration reverts the gentamicin inhibition of I-K(Ach) and that gentamicin directly alters the cation current flowing through the nAChRs of OHCs. We propose that gentamicin acts as a non-competitive cholinergic blocker by displacing Ca2+ From specific binding sites at the nAChRs. This Mock of the nAChRs at the level of the postsynaptic membrane in OHCs could explain the inhibitory effect of gentamicin reported on the crossed medial olivocochlear efferent system in vivo.

关键词：乙酰胆碱/药理学抗菌药/药理学钙/代谢剂量效应关系药物庆大霉素类/药理学毛细胞听觉外/化学毛细胞听觉外/生理学离子通道闸门/药物作用离子通道闸门/生理学膜电位/药物作用膜电位/生理学膜片钳术钾通道/生理学受体胆碱能/生理学血管舒张药/药理学动物豚鼠

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Long-lasting changes of rat blood pressure to vasoconstrictors and vasodilators induced by nitric oxide donor infusion: Involvement of potassium channels

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第1期290卷 380-387页

作者： Da Silva-Santos, JE Assreuy, J Univ Fed Santa Catarina Dept Pharmacol BR-88015420 Florianopolis SC Brazil

We investigated the effects of the exposure of the rat vascular system to nitric oxide (NO), using infusion of either NO donor sodium nitroprusside (SNP) or S-nitroso-acetyl-DL-penicillamine (SNAP) on mean arterial pressure (MAP) responses to vasoconstrictors (phenylephrine, angiotensins I and ii) and to vasodilators (bradykinin, acetylcholine, SNP, and iloprost). SNP (250 nmol/kg/min) or SNAP (85 nmol/kg/min) infused for 30 min decreased MAP by 40 to 60 mm Hg. MAP returned to normal levels 5 to 10 min after the end of infusion. After infusion of SNP or SNAP the effects of phenylephrine, angiotensin I, and angiotensin II were reduced by 40 to 80%, whereas the responses to bradykinin or acetylcholine were enhanced by 50 to 80%. These changes in vascular responsiveness persisted for at least 24 h after the SNP infusion. Pretreatment with either tetraethylammonium (360 mu mol/kg) or 4-aminopyridine (4-AP;1 mu mol/kg) did not alter the effects of phenylephrine or bradykinin in control animals, but prevented SNP-induced changes in responsiveness to phenylephrine or bradykinin. On the other hand, administration of tetraethylammonium, even 24 h after SNP infusion, reversed hyporesponsiveness to phenylephrine, whereas 4-AP was ineffective. Tetraethylammonium and 4-AP did not alter the increased responses to bradykinin. Glibenclamide was without effect in any situation. These results indicate that NO-induced changes on vascular responsiveness to vasoconstrictors and vasodilators are much more profound and long-lasting than described previously and that the effects of NO appear to be, at least in part, mediated by persistent activation of a tetraethylammonium-sensitive population of K+ channels.

关键词：血压/药物作用一氧化氮供体/投药和剂量一氧化氮供体/药理学硝普钠/投药和剂量硝普钠/药理学青霉胺/投药和剂量青霉胺/类似物和衍生物青霉胺/药理学苯福林/药理学钾通道阻滞剂钾通道/药物作用大鼠 Wistar S-亚硝基-N-乙酰基青霉胺血管收缩药/药理学血管舒张药/药理学动物女(雌)性男(雄)性大鼠

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Rationale for the combination of PGE₁ and S-nitrosoglutathione to induce relaxation of human penile smooth muscle

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第2期295卷 586-593页

作者： Angulo, J Cuevas, P Moncada, I Martín-Morales, A Allona, A Fernández, A Gabancho, S Ney, P De Tejada, IS Fdn Invest & Desarrollo Androl Madrid Spain Hosp Ramon y Cajal Dept Invest E-28034 Madrid Spain Schwarz Pharma AG Corp Dev D-4019 Monheim Germany

Many men with erectile dysfunction have been successfully treated with intracavernosal injection of prostaglandin E-1 (PGE(1)) but this treatment is ineffective in 30 to 40% of patients. The goals of this study were to characterize PGE(1)-induced relaxation of isolated human penile smooth muscle (penile arteries and trabecular strips), correlating this in vitro response with the clinical response to this drug, and to evaluate the effects of the combination of PGE(1) with S-nitrosoglutathione (SNO-Glu) on relaxation of isolated human penile smooth muscle. Large variability in the EC50 and maximal relaxation induced by PGE(1) was observed between tissues of different patients. Patients with poor clinical response to intracavernosal alprostadil (PGE(1)) had significantly larger EC50 values and smaller maximal relaxation compared with patients with partial or complete clinical response to this drug. SNO-Glu consistently produced complete or near complete relaxation of human corpus cavernosum strips and penile arteries, even when the tissue responded poorly to PGE(1). In trabecular strips, the combination of PGE(1) and SNO-Glu in a 1:100 ratio demonstrated a synergistic relaxation effect. The combination of PGE(1) and SNO-Glu simultaneously increased the levels of both cAMP and cGMP in human corpus cavernosum tissue. Our results suggest that the clinical effectiveness of intracavernosal administration of PGE(1) is related to the variability of the relaxation responses of human trabecular tissue and penile arteries to this drug. The synergistic interaction of PGE(1) and SNO-Glu makes this combination an effective method to cause penile smooth muscle relaxation, a necessary step to initiate and maintain penile erection.

关键词：前列地尔/药理学环GMP/代谢药物协同作用谷胱甘肽/类似物和衍生物谷胱甘肽/药理学肌松弛/药物作用肌平滑/血液供给肌平滑/药物作用肌平滑/代谢一氧化氮供体/药理学亚硝基化合物/药理学阴茎/血液供给阴茎/药物作用阴茎/代谢 S-亚硝基谷胱甘肽血管阻力/药物作用血管舒张药/药理学人类男(雄)性

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Nuclear factor-κB as a molecular target for migraine therapy

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ANNALS OF NEUROLOGY 2002年第4期51卷 507-516页

作者： Reuter, U Chiarugi, A Bolay, H Moskowitz, MA Harvard Univ Sch Med Massachusetts Gen Hosp Dept RadiolStroke & Neurovasc Regulat Lab Charlestown MA 02129 USA

Nitric oxide (NO) generated from inducible NO synthase (iNOS) participates in immune and inflammatory responses in many tissues. The NO donor glyceryl trinitrate (GTN) provokes delayed migraine attacks when infused into migraineurs and also causes iNOS expression and delayed inflammation within rodent dura mater. Sodium nitroprusside, an NO donor as well, also increases iNOS expression. Because inflammation and iNOS are potential therapeutic targets, we examined transcriptional regulation of iNOS following GTN infusion and the consequences of its inhibition within dura mater. We show that intravenous GTN increases NO production within macrophages. L-N(6)-(1-iminoethyl)lysine, a selective iNOS inhibitor, attenuates the NO signal, emphasizing the importance of enzymatic activity to delayed NO production. iNOS expression is preceded by significant nuclear factor kappa B (NF-kappaB) activity, as reflected by a reduction in the inhibitory protein-K-Bot (lkappaBalpha) and activation of NF-kappaB after GTN infusion. IkappaBalpha degradation, NF-kappaB activation, and iNOS expression were attenuated by parthenolide (3mg/kg), the active constituent of feverfew, an anti-inflammatory drug used for migraine treatment. These findings suggest that GTN promotes NF-kappaB activity and inflammation with a time course consistent with migraine attacks in susceptible individuals. We conclude, based on results with this animal model, that blockade of NF-kappaB activity provides a novel transcriptional target for the development of anti-migraine drugs.

关键词：消炎药非甾类/药理学 DNA结合蛋白质类/代谢硬膜/酶学 I-κB蛋白质类巨噬细胞/代谢偏头痛/药物疗法偏头痛/代谢 NF-κB/拮抗剂和抑制剂 NF-κB/代谢一氧化氮供体/药理学一氧化氮合酶/生物合成一氧化氮合酶/代谢一氧化氮合酶Ⅱ型硝酸甘油/药理学大鼠 Sprague-Dawley S-亚硝基-N-乙酰基青霉胺/药理学倍半萜类/药理学血管舒张药/药理学动物男(雄)性大鼠

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Carvedilol prevents remodeling in patients with left ventricular dysfunction after acute myocardial infarction

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AMERICAN HEART JOURNAL 1999年第4期137卷 646-652页

作者： Senior, R Basu, S Kinsey, C Schaeffer, S Lahiri, A Northwick Pk & St Marks NHS Trust Hosp Dept Cardiovasc Med Harrow HA1 3UJ Middx England

Objective The aim of the study was to assess the effects of carvedilol, a vasodilating nonselective P-blocker, on the indexes of left ventricular remodeling after acute myocardial infarction in those with left ventricular dysfunction. Methods and Results Forty-nine patients with predischarge left ventricular election fraction <45% after acute myocardial infarction were evaluated in a double-blind, randomized, placebo-controlled, parallel group study (selected from the database of the Carvedilol Heart Attack Pilot Study: CHAPS). Patients received medication after thrombolysis and continued to do so for 6 months. Two-dimensional echocardiography was performed before discharge (7 to 10 days after admission) and at 3 months after acute myocardial infarction. Analysis of variance showed that wall thickness opposite the site of infarction decreased from (mean +/- SD) 12.3 +/- 2.1 mm to 11.0 +/- 2.4 mm with carvedilol compared with 11.6 +/- 1.9 mm to 12.2 +/- 1.9 mm with placebo (P = .01). left ventricular mass changed from 235 +/- 74 g to 217 +/- 64 g with carvedilol compared with 227 +/- 80 g to 252 +/- 85 g with placebo (P = .02). Carvedilol prevented alteration of sphericity index (ratio of long and short axis of left ventricle) that changed from 1.65 +/- 0.29 to 1.66 +/- 20 with carvedilol compared with 1.58 +/- 0.33 to 1.39 +/- 0.19 with placebo (P = .02);alteration was also prevented of wail thickening abnormality at infarct site, which changed from 9.2 +/- 3.1 cm(2) to 9.1 +/- 3.5 cm(2) with carvedilol compared with 10.3 +/- 3.3 cm(2) to 13.5 +/- 4.6 cm(2) with placebo (P = .002). Conclusion Carvedilol administered early after acute myocardial infarction results in attenuation of left ventricular remodeling in patients with persistent left ventricular dysfunction before discharge.

关键词：肾上腺素能β受体拮抗剂/药理学肾上腺素能β受体拮抗剂/治疗应用卡唑类/药理学卡唑类/治疗应用双盲法超声心动描记术心肌梗死/药物疗法丙醇胺类/药理学丙醇胺类/治疗应用治疗结果血管舒张药/药理学血管舒张药/治疗应用心室功能障碍左/病理生理学心室功能障碍左/超声检查心室重构/药物作用成年人老年人女(雌)性人类男(雄)性中年人

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Sildenafil citrate and blood-pressure-lowering drugs: Results of drug interaction studies with an organic nitrate and a calcium antagonist

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AMERICAN JOURNAL OF CARDIOLOGY 1999年第5A期83卷 21C-28C页

作者： Webb, DJ Freestone, S Allen, MJ Muirhead, GJ Univ Edinburgh Dept Med Sci Edinburgh Midlothian Scotland Inveresk Clin Res Edinburgh Midlothian Scotland Pfizer Cent Res Sandwich Kent England

Sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), is a well-tolerated and highly effective treatment for erectile dysfunction. The mechanism of action of sildenafil depends on activation of the nitric oxide (NO)cGMP pathway during sexual stimulation, which results In corpus cavernosal smooth muscle relaxation and penile erection. Endogenously derived NO is also involved in blood pressure regulation through its effect on basal vascular tone, which is mediated by cGMP levels. Organic nitrates and NO donors exert their therapeutic effects on blood pressure and vascular smooth muscle by the same mechanism as endogenous NO. Since both sildenafil and organic nitrates exert their pharmacologic effects via increases in cGMP concentrations, a double-blind, placebo-controlled, crossover study was undertaken to investigate the effects of sildenafil coadministered with glyceryl trinitrate on blood pressure and heart rate in healthy male subjects. The hemodynamic effects of sildenafil were also evaluated in a second placebo-controlled crossover study in men with hypertension who were taking the calcium antagonist amlodipine, which has a mechanism of action that does not involve the cGMP pathway. In the first crossover study, subjects were treated with oral sildenafil (25 mg, 3 times a day for 4 days) or placebo and then challenged on day 4 with a 40-minute, stepwise, intravenous infusion of glyceryl trinitrate (0.5 mg/mL in 5% dextrose at an initial infusion rate of 2.5 mu g/min and doubling every 5 minutes to a maximum rate of 40 mu g/min) 1 hour after taking sildenafil or placebo. On day 5, subjects received a sublingual glyceryl trinitrate tablet (500 mu g) 1 hour after taking 25 mg of sildenafil or placebo. During sildenafil treatment, the subjects were significantly less tolerant of intravenously administered glyceryl trinitrate than during placebo treatment based on the occurrence of a >25 mm Hg decrease in

关键词：氨氯地平/药理学抗高血压药/药理学血压/药物作用交叉研究双盲法用药计划表药物相互作用心率/药物作用高血压/药物疗法高血压/病理生理学硝酸甘油/药理学磷酸二酯酶抑制剂/药理学哌嗪类/药理学参考值血管舒张药/药理学成年人老年人人类男(雄)性中年人

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Experimental study of faecal continence and colostomy irrigation

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BRITISH JOURNAL OF SURGERY 2000年第7期87卷 902-908页

作者： O'Bichere, A Sibbons, P Doré, C Green, C Phillips, RKS St Marks Hosp Northwick Pk St Marks NHS Trust Harrow HA1 3UJ Middx England Northwick Pk Inst Med Res Harrow Middx England

Background: Colostomy irrigation is a useful mettled of achieving faecal continence in selected conditions, but remains largely underutilized because it is time consuming. This study investigated the effect of modifying irrigation technique (route, infusion regimen and pharmacological manipulation) on colonic emptying time in a porcine model. Methods: An end-colostomy and caecostomy were fashioned in six pigs. Twenty markers were introduced into the caecum immediately before colonic irrigation. Irrigation route (antegrade or retrograde), infusion regimen (tap water, polyethylene glycol (PEG), 1.5 per cent glycine) and pharmacological agent (glyceryl trinitrate (GTN) 0.25 mg/kg, diltiazem 3.9 mg/kg, bisacodyl 0.25 mg/ kg) were assigned to each animal at random. Colonic transit was assessed by quantifying cumulative expelled markers (CEM) and stool every hour for 12 h. Results: Mean CEM at 6 h for bisacodyl, GTN and diltiazem were 18.17, 12.17 and zero respectively;all pairwise differences in means were significant (P < 0.001). The difference at 12 h between the two routes (P = 0.001) and three fluids (tap water 6.75, glycine 14.83, PEG 16.33;P < 0.001) was significant, but not for PEG versus glycine and bisacodyl versus GTN. Cumulative output was significantly more with the antegrade than retrograde route using PEG, but the difference in mean cumulative output for bisacodyl and GTN at 12 h was not significant. Conclusion: Colonic emptying is more efficient with antegrade than retrograde irrigation. PEG and glycine enhance emptying similar to bisacodyl and GTN solution. These findings shelf promise for improved faecal continence by colostomy irrigation and may justify construction of a Malone conduit at the time of colostomy in selected patients who wish to irrigate.

关键词：方差分析比沙可啶/药理学结肠造口术/方法地尔硫|艹卓|/药理学大便失禁/预防和控制胃肠通过试验/药物作用灌洗/方法硝酸甘油/药理学猪血管舒张药/药理学动物

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Mechanisms of action of OPC-28326, a selective hindlimb vasodilator

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第2期291卷 604-611页

作者： Orito, K Imaizumi, T Yoshida, K Fujiki, H Kishi, M Teramoto, S Tanaka, M Shimizu, H Tominaga, M Kimura, Y Kambayashi, J Mori, T Otsuka Pharmaceut Co Ltd Thrombosis & Vasc Res Lab Tokushima Inst New Drug Res 2 Tokushima 7710192 Japan

The unique cardiovascular profile of OPC-28326 [4-(N-methyl-2-phenylethylamino)-1-(3,5-dimethyl-4-propionylaminobenzoyl)piperidine hydrochloride monohydrate] provides insight into basic mechanisms of this new drug as determined by experiments in dogs and rats. In anesthetized open-chest dogs, an i.v. administration of a low dose (0.3 and 1.0 mu g/kg) of OPC-28326 selectively increased femoral artery blood flow with only minimal action on systemic blood pressure, heart rate and coronary, carotid, vertebral, renal, and mesenteric blood flows. Biochemical study suggests that OPC-28326 had no effect on phosphodiesterase-3 and -5. OPC-28326 dose-dependently inhibited phenylephrine-induced increases in blood pressure in spinally anesthetized dogs. The potency of OPC-28326 was, however, about 180 times lower than that of prazosin. Although binding studies have revealed an affinity of OPC-28326 to serotonin 5-HT2 receptors, the drug is without effect, except at very high concentrations, on serotonin-induced contraction in an isolated canine femoral artery preparation. The potency of OPC-28326 on the increase in femoral artery blood flow was about 14 times higher than that of prazosin but was at about the same level as that obtained with yohimbine in canine autoperfused femoral artery preparations. In perfused rat hindlimb preparations, OPC-28326 inhibited the decrease in perfusion flow induced by brimonidine, a selective alpha(2)-adrenoceptor agonist. The potency of OPC-28326 was at least 10 times less than that of yohimbine. Taken together, the results show that at low doses, OPC-28326 selectively exerts a potent vasodilating effect on the femoral arterial bed, in part due to an alpha(2)-adrenoceptor-blocking activity.

关键词：肾上腺素能拮抗剂/药理学麻醉苯胺化合物/药理学血压/药物作用剂量效应关系药物药物相互作用酶抑制剂/药理学股动脉/药物作用血流动力学/药物作用后肢/血液供给后肢/药物作用灌流苯福林/药理学哌啶类/药理学哌唑嗪/药理学喹恶啉类/药理学放射配体测定大鼠 Sprague-Dawley 受体肾上腺素能α2/药物作用血管舒张药/药理学育亨宾/药理学动物狗女(雌)性男(雄)性大鼠

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Nitrovasodilators inhibit platelet-derived growth factor-induced proliferation and migration of activated human hepatic stellate cells

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GASTROENTEROLOGY 2000年第2期119卷 479-492页

作者： Failli, P DeFranco, RMS Caligiuri, A Gentilini, A Romanelli, RG Marra, F Batignani, G Guerra, CT Laffi, G Gentilini, P Pinzani, M Univ Florence Dipartimento Med Interna I-50134 Florence Italy Univ Florence Dipartimento Farmacol Preclin & Clin I-50134 Florence Italy Univ Florence Dipartimento Fisiopatol Clin Unita Chirurg I-50134 Florence Italy

Background & Aims: Nitrovasodilators have been proposed for the treatment of portal hypertension alone or in combination with beta-blockers. In addition to their vasodilatory properties, nitric oxide (NO) donors may exert direct antifibrogenic properties. We evaluated the effect of nitroglycerin (NTG) and S-nitroso-N-acetyl penicillamine (SNAP) on the mitogenic and chemotactic properties of platelet-derived growth factor (PDGF)BB and the modulation of the relative intracellular signaling pathways in fully activated human hepatic stellate cells (HSCs), a cell type that plays an active role in liver fibrogenesis and portal hypertension. Methods Br Results: Both NTG and SNAP induced a dose-dependent decrease in PDGF-induced DNA synthesis and cell migration, which was associated with a decrease in PDGF-induced intracellular Ca2+ increase and extracellular signal-regulated kinase (ERK) activity. These effects were not related to activation of the classic soluble guanylate cyclase (sGC)/guanosine 3',5'-cyclic monophosphate pathway;accordingly, Western blot analysis of HSC lysates revealed the absence of the alpha(1)beta(1) ubiquitous subunits of sGC, whereas they were detectable in quiescent HSCs, freshly isolated from normal human liver. Conversely, both NTG and SNAP induced a more than 10-20-fold increase in prostaglandin E-2 in cell supernatants within 1 minute, associated with an increase in intracellular adenosine 3',5'-cyclic monophosphate levels. Accordingly, the inhibitory effects of NO donors on PDGF action and signaling were eliminated after preincubation with ibuprofen, Conclusions: These results suggest that NO donors may exert a direct antifibrogenic action by inhibiting proliferation, motility, and contractility of HSCs in addition to a reduction of fibrillar extracellular matrix accumulation.

关键词：钙/代谢细胞分裂/药物作用细胞运动/药物作用细胞培养的趋化作用/药物作用环GMP/代谢地诺前列酮/代谢鸟苷酸环化酶/代谢止血药/药理学肝/细胞学肝/酶学一氧化氮供体/药理学硝酸甘油/药理学青霉胺/类似物和衍生物青霉胺/药理学血小板源性生长因子/药理学信号传导/药物作用凝血酶/药理学 C型磷脂酶类/代谢血管舒张药/药理学人类

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Nephroprotective effect of treatment with calcium channel blockers in spontaneously hypertensive rats

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第3期294卷 948-954页

作者： Sabbatini, M Vitaioli, L Baldoni, E Amenta, F Univ Camerino Dipartimento Sci Farmacol & Med Sperimentale Sez Anat Umana I-62032 Camerino Italy Univ Camerino Dipartimento Sci Morfol & Biochim Comparate I-62032 Camerino Italy

The influence of hypertension and of treatment with some dihydropyridine-type Ca2+ channel blockers and with the nondihydropyridine-type vasodilator hydralazine on the morphology of kidney was investigated in 26-week-old spontaneously hypertensive rats (SHR) and in age-matched Wistar-Kyoto rats. Fourteen-week-old SHR were treated for 12 weeks with a nonhypotensive dose of lercanidipine or with equihypotensive doses of lercanidipine, manidipine, nicardipine, and hydralazine. In control SHR, systolic pressure values were significantly higher in comparison with Wistar-Kyoto rats. Treatment with the low dose of lercanidipine did not reduce systolic blood pressure in SHR, whereas the higher dose of lercanidipine or other compounds tested significantly decreased systolic pressure values. Glomerular hypertrophy accompanied by signs of glomerulosclerosis, increase of mesangial cells, and convoluted tubules degeneration were observed in control SHR. Hypotensive doses of Ca2+ antagonists countered glomerular injury, the increase of mesangial cells, the reduction of capsular space, and tubular degeneration. Hydralazine, in spite of its hypotensive activity, displayed a slight nephroprotective action. The nonhypotensive dose of lercanidipine countered in part glomerular injury, narrowing of capsular space, and tubular degeneration, and decreased mesangial cell augmentation in SHR. These results suggest that treatment with dihydropyridine-type Ca+2 antagonists counters hypertensive glomerular and tubular changes occurring in SHR. The demonstration of nephroprotection by the nonhypotensive dose of lercanidipine suggests that the renal effects of the compound may be in part unrelated to its hemodynamic activity.

关键词：血压/药物作用钙通道阻滞药/药理学二氢吡啶类/药理学肼苯哒嗪/药理学肾/血液供给肾/药物作用肾/病理学肾皮质/药物作用肾皮质/病理学肾小球/药物作用肾小球/病理学肾小管/药物作用肾小管/病理学尼卡地平/药理学大鼠近交SHR 大鼠近交WKY 血管舒张药/药理学动物男(雄)性大鼠

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