The renal response to neuroendocrine inhibition in chronic heart failure: double-blind comparison of captopril and prazosin

Activation of the renin–angiotensin and sympathetic systemsin chronic heart failure causes important renal vasoconstriction.In a double-blind cross-over study, treatment with captoprilfor one month reduced systemic and renal vascular resistanceby 14% and 25%, increased renal blood flow by 12%, and increasedthe percentage of the cardiac output perfusion to the kidneyby 13%. Treatment with prazosin for one month also reduced systemicvascular resistance by 8%, renal vascular resistance increasedby 20%, and renal blood flow and the percentage of the cardiacoutput going to the kidney fell by 14% and 26%. During captopriltreatment, plasma aldosterone concentration was reduced to normal,but during prazosin treatment there was an initial increasein aldosterone of 45%, and a sustained increase in plasma noradrenalineconcentration of 26%. Body weight decreased by 1.7kg on captopril,but increased by 3.0 kg on prazosin, correlating inversely withthe changes in renal blood flow. Sympathetic inhibition withprazosin causes systemic vasodilatation which diverts bloodfrom the kidney and may result in fluid retention. Inhibitionof the renin system with captopril causes preferential renalvasodilatation and can improve renal perfusion in chronic heartfailure.     

Mediation of 5-HT-induced external carotid vasodilatation in GR 127935-pretreated vagosympathectomized dogs by the putative 5-HT7 receptor

1. The vasodilator effects of 5-hydroxytryptamine (5-HT) in the external carotid bed of anaesthetized dogs with intact sympathetic tone are mediated by prejunctional sympatho-inhibitory 5-HT_1B/1D receptors and postjunctional 5-HT receptors. The prejunctional vasodilator mechanism is abolished after vagosympathectomy which results in the reversal of the vasodilator effect to vasoconstriction. The blockade of this vasoconstrictor effect of 5-HT with the 5-HT_1B/1D receptor antagonist, GR 127935, unmasks a dose-dependent vasodilator effect of 5-HT, but not of sumatriptan. Therefore, the present study set out to analyse the pharmacological profile of this postjunctional vasodilator 5-HT receptor in the external carotid bed of vagosympathectomized dogs pretreated with GR 127935 (20 μg kg⁻¹, i.v.).
2. One-minute intracarotid (i.c.) infusions of 5-HT (0.330 μg min⁻¹), 5-carboxamidotryptamine (5-CT; 0.010.3 μg min⁻¹), 5-methoxytryptamine (1100 μg min⁻¹) and lisuride (31000 μg min⁻¹) resulted in dose-dependent increases in external carotid blood flow (without changes in blood pressure or heart rate) with a rank order of agonist potency of 5-CT>>5-HT⩾5-methoxytryptamine>lisuride, whereas cisapride (1001000 μg min⁻¹, i.c.) was practically inactive. Interestingly, lisuride (mean dose of 85±7 μg kg⁻¹, i.c.), but not cisapride (mean dose of 67±7 μg kg⁻¹, i.c.), specifically abolished the responses induced by 5-HT, 5-CT and 5-methoxytryptamine, suggesting that a common site of action may be involved. In contrast, 1 min i.c. infusions of 8-OH-DPAT (33000 μg min⁻¹) produced dose-dependent decreases, not increases, in external carotid blood flow and failed to antagonize (mean dose of 200±33 μg kg⁻¹, i.c.) the agonist-induced vasodilator responses.
3. The external carotid vasodilator responses to 5-HT, 5-CT and 5-methoxytryptamine were not modified by intravenous (i.v.) pretreatment with either saline, (±)-pindolol (4 mg kg⁻¹) or ritanserin (100 μg kg⁻¹) plus granisetron (300 μg kg⁻¹), but were dose-dependently blocked by i.v. administration of methiothepin (10 and 30 μg kg⁻¹, given after ritanserin plus granisetron), mesulergine (10 and 30 μg kg⁻¹), metergoline (1 and 3 mg kg⁻¹), methysergide (1 and 3 mg kg⁻¹) or clozapine (0.3 and 1 mg kg⁻¹). Nevertheless, the blockade of the above responses, not significant after treatment with the lower of the two doses of metergoline and mesulergine, was nonspecific after administration of the higher of the two doses of methysergide and clozapine.
4. Based upon the above rank order of agonist potencies and the antagonism produced by a series of drugs showing high affinity for the cloned 5-ht₇ receptor, our results indicate that the 5-HT receptor mediating external carotid vasodilatation in GR 127935-pretreated vagosympathectomized dogs is operationally similar to the putative 5-HT₇ receptor mediating relaxation of vascular and non-vascular smooth muscles (e.g. rabbit femoral vein, canine coronary artery, rat systemic vasculature and guinea-pig ileum) as well as tachycardia in the cat.

     

Tachykinin regulation of basal synovial blood flow

1. Experiments were performed to investigate the role of endogenously released tachykinins in the regulation of blood flow to the rat knee joint. Synovial perfusion was assessed by laser Doppler perfusion imaging, which permitted spatial measurement of relative changes in perfusion from control (pre drug administration), expressed as the percentage change. Most experiments were performed on the exposed medial aspect of the knee joint capsule.
2. Neither the selective tachykinin NK₁ receptor antagonist, FK888, nor the selective tachykinin NK₂ receptor antagonist, SR48968, significantly influenced synovial blood flow at doses of 10⁻¹², 10⁻¹⁰ and 10⁻⁸ mol. However, topical co-administration of these agents produced significant dose-dependent reductions in basal synovial perfusion of 6.3±4.6, 12.0±3.4 and 19.9±2.6%, respectively; n=29. The non-selective tachykinin NK₁/NK₂ receptor antagonist, FK224, also produced significant (at 10⁻¹⁰ and 10⁻⁸ mol), but less potent, reductions in perfusion of 5.3±4.0, 8.4±2.2 and 5.9±2.8%, respectively; n=25.
3. Topical administration of the α₁-, α₂-adrenoceptor antagonist phenoxybenzamine elicited a 31.3±6.2% increase in blood flow which was substantially reduced to 10.4±3.8% by co-administration of the FK888 and SR48968 (both at 10⁻⁸ mol; n=8–13), suggesting that normally there is sympathetic vasoconstrictor ‘tone'' which is opposed by the vasodilator action of endogenous tachykinins.
4. One week after surgical interruption of the nerve supply to the knee joint, co-administration of FK888 and SR48968 (both at 10⁻⁸ mol) now produced slight vasodilatation (6.7±4.6%; n=9) which did not differ significantly from vehicle treatment. Depletion of tachykinins from sensory nerve fibres by systemic capsaicin administration also resulted in abolition of the vasoconstrictor effect of FK888 and SR48968 (both at 10⁻⁸ mol), with these agents only producing a slight vasodilatation (2.5±5.3%; n=6).
5. By use of a near infra-red laser source it was possible to image knee joint perfusion transcutaneously, the overlying skin being left intact. In this more physiological situation, close intra-arterial injection of the combination of FK888 and SR48968 (both at 10⁻⁸ mol) again elicited vasoconstriction (48.8±16.2% reduction in blood flow; n=4).
6. These results indicate that endogenous tachykinins may be continuously released from sensory fibres innervating the joint. Basal release of tachykinins could therefore be an important physiological influence opposing sympathetic vasoconstrictor tone.

     

硫化氢缓释剂GYY4137对自发性高血压大鼠胸主动脉舒张功能的影响及机制研究

目的:研究硫化氢缓释剂GYY4137对自发性高血压大鼠(spontaneously hypertensive rats,SHR)胸主动脉舒张功能的影响,并初步探讨其机制?方法:健康12周龄雄性SHR随机分为高血压对照组(SHR组)和GYY4137组,雄性12周龄WKY大鼠为非高血压对照组(WKY组)?GYY4137组分别腹腔注射10 mg/(kg·d)(GYY10组)?25 mg/(kg·d)(GYY25组)或50 mg/(kg·d)(GYY50组)的GYY4137,SHR组和WKY组给予等量生理盐水,连续4周,给药期间每周测定尾动脉收缩压?给药4周后观察各组大鼠胸主动脉舒张功能,通过DHE染色?丙二醛(MDA)和总抗氧化能力(T-AOC)测定评价胸主动脉氧化应激水平,Western blot方法检测PI3K亚单位p85α蛋白水平,Akt及eNOS的磷酸化及总蛋白水平?结果:GYY4137治疗后,胸主动脉内皮依赖性舒张功能明显改善,DHE染色荧光强度减弱,MDA含量降低,而T-AOC有所上升,p85α蛋白水平以及Akt?eNOS 磷酸化水平增加?结论:GYY4137可以改善SHR胸主动脉内皮依赖性舒张功能,其机制可能与抗氧化应激以及激活PI3K/Akt/eNOS信号通路有关?     

Topical treatment for 1 week with latanoprost but not diclofenac reduces the diameter of dilated retinal arterioles in patients with type 1 diabetes mellitus and mild retinopathy

Purpose: Diabetic retinopathy is characterised by morphological lesions secondary to retinal vascular impairment, and it is assumed that changes in the diameter regulation of retinal arterioles are involved in the disease pathogenesis. It has previously been shown that prostaglandin F2α can constrict retinal arterioles in vitro. In the present study, we investigated whether a similar effect could be achieved by topical administration in diabetic patients with dilated retinal arterioles and retinopathy. Methods: Twenty‐two type 1 diabetic patients with mild retinopathy and twenty‐four matched normal controls were randomized to topical treatment with the prostaglandin F2α agonist latanoprost twice daily for 1 week, followed by similar treatment with the cyclo‐oxygenase inhibitor diclofenac, or to receive the two medications in the reverse order. The Dynamic Vessel Analyzer was used to assess the effect of the interventions on the resting diameter of retinal vessels and on the diameter response of retinal arterioles to increased blood pressure (BP) induced by isometric exercise and flicker stimulation. Results: Latanoprost reduced the resting diameter of retinal arterioles significantly in patients with diabetes (p = 0.01), but had no effect on normal persons. Diclofenac had no effect on the resting diameter of arterioles in either of the groups. The diameter responses to increased BP and flicker stimulation were not significantly changed by any of the treatments. Conclusion: Long‐term prospective studies are needed to study the effect of topical treatment with latanoprost on the consequences of retinal hyperperfusion in retinal vascular diseases such as diabetic retinopathy.     

生、炒决明子水提物抗氧化及对一氧化氮、内皮素影响的比较研究

目的：对生、炒决明子水提物抗氧化及舒张血管的作用进行比较,探讨决明子明目的作用机制。方法：小鼠连续给药1个月,摘除眼球组织匀浆,取上清液测定超氧化物岐化酶(SOD)、丙二醛(MDA)、乳酸脱氢酶(LDH)及一氧化氮(NO),同时眼眶后静脉丛采血测定内皮素(ET)含量。结果：生、炒决明子水提物有提高小鼠眼组织中SOD和LDH活性、降低MDA含量的作用,以生决明子作用为强。二者均能提高眼组织中NO含量及NO/ET比值,炒决明子作用强于生决明子。结论：生、炒决明子均有一定抗氧化及调节舒张血管作用,决明子明目作用可能是通过此方面来实现。     

The clinical pharmacokinetics of buflomedil in normal subjects after intravenous and oral administration

Summary A dose-ranging pharmacokinetic study of buflomedil was carried out in eight subjects to determine the pharmacokinetic parameters of the drug after oral and intravenous administration. Based on AUC analyses, the pharmacokinetics of buflomedil were found to be linear within the dose ranges studied (50 to 200 mg for i. v. injection and 150 to 450 mg for oral administration). In the oral study, the mean biological half-life of the drug was 2.97 h, while after intravenous dose it was 3.25 h. The apparent volume of distribution after the pseudodistribution equilibrium (F_d) and volume of distribution at the steady state (V_dss) were 1.43±0.24 l/kg and 1.32±0.26 l/kg, respectively. The mean urinary recovery of intact drug and the metabolite, paradesmethyl buflomedil, after intravenous dosing, were 23.6% and 18.7%, respectively, while after oral dosing, they were 18% and 14.8%, respectively. On the average, 72% of the dose was obserbed into the systemic circulation after oral administration. This level of bioavailability was attributed to the hepatic first-pass effect.     

原发性高血压患者血管内皮依赖性舒张功能障碍与血栓前状态的相关性研究

目的　探讨原发性高血压患者血管内皮功能损伤、血栓前状态及两者间的关系。方法　对原发性高血压Ⅰ级 (n =2 0 )、Ⅱ级 (n =2 0 )患者及正常人 (n =2 0 )采用高分辨率超声技术检测血流介导的肱动脉舒张功能(FMD) ,并分别测定血清一氧化氮 (NO)水平和血浆血栓素B2 (TXB2 )和 6 -酮 -前列腺素 1a(6 -K -PGF1a)水平 ,并进行相互比较。结果　与正常对照组比较 ,原发性高血压Ⅰ级、Ⅱ级患者血浆TXB2 的水平明显升高 ,差别有统计学意义 (P <0 .0 5 ) ,FMD、NO、6 -K -PGF1a水平明显下降 ,差别有统计学意义 (P <0 .0 5 ) ;与原发性高血压Ⅰ级组比较 ,原发性高血压Ⅱ级组TXB2 的水平明显升高 ,差别有统计学意义 (P <0 .0 5 ) ,FMD、NO、6 -K -PGF1a水平明显下降 ,差别有统计学意义 (P <0 .0 5 ) ;经直线相关分析显示 :血清NO、FMD与血浆 6 -K -PGF1a呈正相关 (P <0 .0 5 ) ,血清NO、FMD与血浆TXB2 呈负相关 (P <0 .0 5 )。结论　原发性高血压患者血管内皮明显受损 ,存在血栓前状态 ,可能是血栓性疾病如急性心梗、脑卒中发生的机制 ,将有助于对高血压患者心血管事件的预测。     

Determinants of atherosclerosis in an Egyptian cohort of systemic sclerosis: Relation to disease activity and severity

BackgroundSystemic sclerosis (SSc) is a rare multi-system autoimmune disease characterized by vascular abnormalities with an increased prevalence of macrovascular disease.Aim of the workTo evaluate macro-vascular disease (atherosclerosis) in SSc patients and determine its relation to the disease activity and severity.Patients and methodsTwenty-five SSc patients and 20 matched controls were included. The modified Rodnan skin score (mRss) and disease severity by Medsger’s severity score were assessed. Carotid intima-media thickness (IMT) and flow mediated vasodilatation (FMD) of the brachial artery were measured. Traditional vascular risk factors were assessed by thorough history taking and laboratory investigations.ResultsThe age of the patients ranged from 15 to 60 years and they were 22 females and 3 males. 15 had limited and 10 diffuse cutaneous SSc. All SSc patients had an increased IMT (1.24 ± 0.29 mm) which was normal in the control subjects (0.77 ± 0.09 mm) (p < 0.0001). SSc patients had significantly lower HDL, thickened IMT and lower FMD than controls (p = 0.005, p < 0.0001 and p < 0.0001 respectively). The younger age of disease onset was significantly associated with more FMD impairment (r = −0.4, p = 0.04) and Medsger’s severity score (r = 0.5, p = 0.009). The mRss and Medsger’s severity score significantly correlated with the IMT (r = 0.84, p = 0.01 and r = 0.56, p = 0.003 respectively). A significant negative correlation was found between FMD and IMT (r = −0.77, p < 0.0001). Medsger’s severity score significantly correlated with FMD (r = −0.44, p = 0.02).ConclusionSSc is associated with an increased risk of atherosclerosis when compared to age and sex-matched controls. Determinants of this include; younger age of disease onset and more sever disease and low levels of HDL.     

Nitric oxide donors - current trends in therapeutic applications

The nitric oxide (NO) radical, endogenously produced from L-arginine, is a natural vasodilator also involved in many other physiological and pathological processes. The increasing knowledge of the multiple roles of NO keeps extending its range of potential therapeutic applications. However, these many applications require individually designed exogenous molecular sources of NO. To date, NO donors such as diazeniumdiolates, S-nitrosothiols, sydnonimines, nitroso complexes, organic nitrates and nitrites are claimed to be useful for the treatment of cardiovascular, renal, respiratory, gastrointestinal, neurodegenerative, inflammatory and infectious diseases. Development of new NO donors differs from common drug development because the active drug (NO) has already been determined, therefore research involves the development of devices to deliver NO. An alternative strategy is to link an NO releasing moiety to other well-established bioactive molecules creating NO donor hybrids. Different hybrid compounds can offer various drug actions with synergistic effects, reduced toxicity and no detrimental side effects. Among others, Hou, Janczuk and Wang [1], and a few years previously Stamler and Feelisch [2], have issued systematic and comprehensive reviews on NO donors. In view of the huge number of publications on this topic, this article will restrictively focus on NO donors and pathological situations and diseases which are claimed in the important therapeutic patents issued between 1997 and 2000. Table 1 gives the relevant diseases and classes of NO donors, gathered from these patents.