Pentaerythritol trinitrate and glyceryl trinitrate on myocardial oxygen consumption and haemodynamics in the dog

1. The effects of pentaerythritol trinitrate (pentrinitrol) and glyceryl trinitrate on myocardial oxygen consumption and myocardial and systemic haemodynamics were studied in anaesthetized open-chest dogs. An in vivo oximeter in the coronary sinus permitted continuous determination of arteriovenous oxygen difference and myocardial oxygen consumption. All parameters were determined simultaneously at various intervals after drug administration. 2. Myocardial oxygen consumption was diminished by both nitrates for more than 16 min. Changes in arteriovenous oxygen difference and coronary sinus oxygen content were variable between drugs. Following an initial transient increase, coronary blood flow was reduced by both nitrates. Aortic blood pressure, aortic blood flow, left ventricular end-diastolic pressure and left ventricular dP/dt were also reduced. Heart rate and contractile force were not appreciably altered by either nitrate. 3. The decrease in myocardial oxygen consumption appears to be associated with the haemodynamic profile of these drugs. Both nitrates produced comparable reductions in preload (left ventricular end-diastolic pressure) and afterload (aortic pressure) as well as dP/dt.     

Effects of Dipyridamole on the Glyceryl–trinitrate–induced Inhibition of Coronary Artery Muscle Tone and Platelet Aggregation in Relation to Cyclic Nucleotide Metabolism

Abstract: The effects of glyceryl–trinitrate (GTN) and dipyridamole (DIP) on relaxation of bovine coronary arteries and on inhibition of aggregation of human platelets have been studied in vitro with special reference to the cyclic GMP (cGMP) system. GTN had a dose–dependent relaxant effect on bovine coronary arteries, and at a high concentration (10^–5 M) it had an inhibiting effect on platelet aggregation. The effects were associated with an increase in the cGMP levels of the tissues. DIP (5 × 10^–7 M respectively 5 × 10^–6 M) potentiated the coronary artery relaxation induced by GTN (10^–8 M) and the inhibition of platelet aggregation caused by GTN in the concentrations 10^–7–10^–4 M. The potentiation was associated with higher levels of cGMP than those produced by GTN alone, at least in bovine coronary arteries. However, at a concentration of 10^–4 M, GTN, in combination with DIP, caused a significant fall in the cGMP level compared to GTN alone. GTN and DIP were not found to significantly increase the cAMP levels in the concentrations tested. DIP was shown to inhibit phosphodiesterase (PDE) from both platelets and bovine coronary arteries. This might be one of the possible mechanisms that can explain the above mentioned potentiation. It is suggested that the combination of DIP+GTN may be of some clinical importance since the potentiating effects were seen at concentrations comparable to the therapeutic plasma concentration for the respective drugs     

Differential mechanisms of urethral smooth muscle relaxation by several NO donors and nitric oxide

We have examined the mechanisms of action of a broad spectrum of nitric oxide (NO) donors, including several S-nitrosothiols, sodium nitroprusside (SNP) and nitroglycerine (GTN), in relation to their relaxant activity of urethral smooth muscle. For all the compounds examined, NO release (in solution and in the presence of urethral tissue), relaxation responses, elevations in cGMP levels and the effect of thiol modulators were evaluated and compared with the effect of NO itself. Whilst all NO donors, except GTN, released NO in solution due to photolysis or chemical catalysis, this release was not correlated with their relaxant activity in sheep urethral preparations, which were furthermore not affected by the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (cPTIO; 0.3 mM). A substantial NO-generating activity was found for S-nitroso-L-cysteine (CysNO) and S-nitroso-N-acetyl-D,L-penicillamine (SNAP) in the presence of urethral cytosolic fractions, suggesting metabolic activation to NO in the cytosol of the target tissue. In contrast, NO generation from S-nitroso-N-acetyl-L-cysteine (N-ac-CysNO), S-nitrosoglutathione (GSNO) and SNP were reduced by the presence of urethral homogenate and/or subcellular fractions, suggesting direct NO transfer to tissue constituents. NO donors and NO gas induced dissimilar degrees of cGMP accumulation in urethral tissue, while they were essentially equipotent as urethral relaxants. Furthermore, 1H-[1,2,4]-oxadiazole-[4,3-a]-quinoxalin-1-one (ODQ; 10 μM) inhibited both relaxation and cGMP accumulations, but with different potency for the different compounds. Oxidation of sarcolemmal thiol groups with 5-5′-dithio-bis[2-nitrobenzoic acid] (DTNB; 0.5 mM) enhanced relaxations to GSNO, an effect that was reversed by dithiotreitol (DTT; 1 mM), suggesting a direct effect through nitrosylation/oxidation reactions at the cell membrane, while relaxations to NO and to all the other compounds were not affected by these treatments. Finally, photodegradation of SNP induced the formation of a stable intermediate that still evoked NO-cGMP-mediated relaxations. This indicates that the assumption that SNP is fully depleted of NO by exposure to light should be revised. It can be concluded that important differences exist in the mechanisms by which distinct NO donors relax urethral smooth muscle and they cannot be regarded simply as NO-releasing prodrugs. Received: 28 December 1998 / Accepted: 14 April 1999 / Published online: 22 June 1999     

Determination of the optimal dose of glyceryl trinitrate in the treatment of stable angina

There has been recent controversy over the efficacy of transdermalglyceryl trinitrate (GTN) preparations in the treatment of anginaand their effects on exercise tolerance. To determine the doseof GTN that produces significant anti-anginal effects, symptomlimited exercise testing has been undertaken in seven patientswith stable angina. Doses of 10, 20, 40 and 80 µg min^-1of GTN or placebo were infused during treadmill exercise untilsymptom limiting chest pain or 3 mm ST segment depression occurred.Compared with placebo, total exercise time increased by 47%at 20 µg min^-1 (P<0.05) with no further change at thehigher doses. Duration of exercise before the onset of significantST segment depression increased by 51% at 20 µg min^-1(P<0.05) with no further increase at the higher doses. Thesechanges were accompanied by a 21% increase double product (heartrate x systolic blood pressure) at 20 µg min^-1 (P<0.05)reflecting a higher heart rate achieved as a result of the increasedduration of exercise. These results suggest that 20 µgmin ^-1 may be the optimal dose of GTN to achieve significantantianginal effects as demonstrated by the improved exercisetolerance and reduction of myocardial ischaemia. This impliesthat the dose of GTN delivered by transdermal preparations maybe below the therapeutic level.     

硝酸甘油透皮吸收膜主药的HPLC测定

硝酸甘油透皮吸收膜是近年来发展的一种新剂型。用于治疗心绞痛,心肌梗塞和慢性充血性心力衰竭等症,它使用方便,生物利用度较高。膜中三硝酸甘油酯的含量,直接影响疗效,其降解产物二硝酸甘油酯和单硝酸甘油酯的疗效均不及三硝酸甘油酯。本文应用HPLC法,在所选定的流动相甲醇-水(4:6v/v)条件下,可直接测定药膜中三硝酸甘油酯的含量,而不受其它硝酸盐(酯)的干扰。模拟试验6份的平均回收率为100.33%,变异系数为0.80%。     

Progress in the understanding and treatment of chronic anal fissure

BACKGROUND—Chronic anal fissure is a common and painful condition associated with internal anal sphincter hypertonia. Reduction of this hypertonia improves the local blood supply, encouraging fissure healing. Surgical sphincterotomy is very successful at healing these fissures but requires an operation with associated morbidity. Temporary reduction in sphincter tone can be achieved on an outpatient basis by applying a topical nitric oxide donor (for example, glyceryl trinitrate) or injecting botulinum toxin into the anal sphincter.
METHODS—A Medline database was used to perform a literature search for articles relating to the non-surgical treatment of chronic anal fissure.
RESULTS—Review of the literature shows botulinum toxin injection to be more effective at healing chronic anal fissures than topical glyceryl trinitrate. Topical isosorbide dinitrate has not been directly compared with either of these two agents but has a healing rate approaching that of botulinum toxin injection. The main side effect of botulinum toxin injection is temporary faecal incontinence in approximately 2% of cases, whereas topical nitrates cause headaches in 20%-100% of cases. No long term side effects were identified with any of the medical treatments.
CONCLUSION—Chemical sphincterotomy is an effective treatment for chronic anal fissure and has the advantages over surgical treatment of avoiding long term complications (notably incontinence) and not requiring hospitalisation.


     

Inhibitors of cytochrome P-450 reduce cyclic GMP stimulation by glyceryl trinitrate in LLC-PK1 kidney epithelial cells

Summary The inhibitor of cytochrome P-450 cimetidine was used to asses the role of cytochrome P-450-dependent enzymes for cyclic GMP stimulation by glyceryl trinitrate in a kidney epithelial cell line (LLC-PK₁). Pretreatment of the cells with 0.1 mmol/1 cimetidine markedly decreased cyclic GMP stimulation by glyceryl trinitrate (0.03 –1 mol/l). In the presence of 0.1 mmol/1 cimetidine, the 14-fold cyclic GMP stimulation observed at 1 mol/l glyceryl trinitrate was reduced by 66%. Glyceryl trinitrate-induced cyclic GMP stimulation remained unaltered by ranitidine (0.1 mmol/1), which has a much lower affinity for the cytochrome P-450 enzyme system. Another inhibitor of cytochrome P-450, miconazole (0.1 mmol/1), also attenuated glyceryl trinitrate-induced cyclic GMP stimulation. In contrast, cimetidine and miconazole did not affect cyclic GMP stimulation by sodium nitroprusside that spontaneously releases nitric oxide. These results suggest that in intact cells, glyceryl trinitrate-induced cyclic GMP stimulation is dependent on cytochrome P-450 enzymes which may be relevant for nitric oxide formation from organic nitrates.Send offprint requests to K. Schrör at the above address     

一氧化氮供体硝酸甘油治疗妊高征的疗效观察

 目的 探讨一氧化氮(NO)供体硝酸甘油对妊高征(PIH)患者的治疗效果。方法 于用药前后分别抽取肘静脉血,以Griess反应测定血清中NO的代谢产物的含量,并半定量测定尿蛋白,同时采用心功能监测仪及彩超分别测定用药前后母体心功能及胎儿脐血流的变化。结果用药后血中NO代谢产物显著增多(P＜0.05),每搏血量(SV)、心输出量(CO)显著上升(P＜0.05),平均动脉压(MAP)、总血管阻抗(TPR)、心肌耗氧量(MVO)显著下降(P＜0.05),心率(HR)无明显差异(P＞0.05)。脐动脉指数(PI)、阻力指数(RI)及脐动脉收缩期最高流速／舒张期末流(S／D)显著下降(P＜0.05)。结论硝酸甘油通过增加PIH患者体内NO含量,不仅改善其症状,而且增加脐-胎盘灌流量,是治疗PIH较理想的药物。