Effects of isosorbide 5-mononitrate on cardiovascular function. (II). Effects on pre-load and after-load

Effects of isosorbide 5-mononitrate (5-ISMN) on cardiovascular function were compared with those of verapamil hydrochloride and propranolol hydrochloride in anesthetized open-chest dogs. Intravenous injection of 5-ISMN (3 mg/kg) considerably lowered systolic blood pressure (SBP). Especially, stroke volume (SV), cardiac output (CO), cardiac work (CW) and systolic right ventricular pressure (SRVP) were significantly decreased. 5-ISMN also produced a continuous reduction in mean pulmonary artery pressure (MPAP), mean pulmonary capillary wedge pressure (MPCWP) and mean right atrium pressure (MRAP), while heart rate (HR) and total peripheral resistance (TPR) were not altered significantly. Intravenous injection of verapamil (0.3 mg/kg) considerably lowered diastolic blood pressure (DBP). Verapamil also caused a significant decrease in HR, CW and TPR and a slight decrease in SRVP and MPCWP. However, SV was significantly increased, and slight increases in MPAP and MRAP were also observed. Propranolol (0.5 mg/kg, i.v.) greatly decreased HR together with CO, CW, SRVP and MPAP and slightly decreased MPCWP, while it caused a considerable increase in 3V and a slight increase in TPR. The finding that administration of 5-ISMN resulted in reduction of pre-load and after-load suggests the possibility that this drug might decrease venous return and thereby reduce myocardial oxygen requirements.     

Contribution of isosorbide-5-mononitrate, a major metabolite of isosorbide dinitrate (ISDN), to the hemodynamic effect of ISDN administered orally in conscious dogs

This study was designed to determine the extent, to which isosorbide-5-mononitrate (5-ISMN) contributes to the hemodynamic effect of isosorbide dinitrate (ISDN) in conscious dogs. Test drugs (ISDN or 5-ISMN) were given orally. Either ISDN or 5-ISMN produced a decrease in blood pressure dose-dependently, the decrease in pulse pressure being specific; the pattern of blood pressure change induced by ISDN or 5-ISMN was different from that induced by nifedipine or prazosin. The effect of ISDN (2 mg/kg) was almost equivalent to that of 5-ISMN (4 mg/kg) and the effect of ISDN (4 mg/kg) to that of 5-ISMN (8 mg/kg). After administration of ISDN, both ISDN and 5-ISMN appeared in the plasma, and the effect of ISDN well-correlated with the increase in the plasma concentration of 5-ISMN. Contribution of 5-ISMN to the effect of ISDN was estimated to be about 30% from the value of the plasma concentration of 5-ISMN at 3 to 4 hr after administration, when the maximal response to ISDN occurred. Based on the data of the area under the plasma concentration curve of 5-ISMN (from 0 to 10 hr after administration), the fraction of biotransformation to 5-ISMN from ISDN was calculated to be 73.6 to 76.6% (based on moles). Because the ability of 5-ISMN to decrease pulse pressure was about 1/2 (or 41% based on moles) of that of ISDN, the contribution of 5-ISMN to the effect of ISDN was estimated to be about 30% in total, the value being similar with that estimated at 3 to 4 hr after administration.     

Effects and pharmacokinetics of isosorbide dinitrate in normal man

Summary 18 subjects were given isosorbide dinitrate (ISDN) 5 mg sublingually and serum concentrations of ISDN, 2-isosorbide mononitrate (2-ISMN) and 5-isosorbide mononitrate (5-ISMN) were measured, as well as changes in digital plethysmographic amplitude, heart rate, ECG, blood pressure and Schellong's test. ISDN was rapidly absorbed and metabolized, having an elimination half-life of 29 min. Its metabolites 2-ISMN and 5-ISMN had longer half-lives of 1.75 and 7.6 h respectively. The amplitude of the -wave of the digital plethysmograph did not change significantly either in the predrug period or after placebo administration. It increased within 4 min of administration of ISDN, and reached a maximum after 14 min; the effect lasted for about 2 h. ISDN lowers blood pressure and increases heart rate in most volunteers, but in 3 of the 18 subjects severe hypotension occurred, accompanied by severe, reversible bradycardia, which was probably due to vagal reflexes initiated by the markedly diminished ventricular enddiastolic volume (LVEDV) and pressure (LVEDP). No correlation could be demonstrated between the serum concentration of ISDN and/or its vasoactive metabolites and changes in plethysmographic amplitude.     

地奥心血康对肾性高血压大鼠血流动力学的影响

肾性高血压大鼠（ＲＨＲ）较对照假手术大鼠的ＳＢＰ，ＤＢＰ，ＬＶＥＳＰ，ＬＶＥＤＰ，＋ｄｐ／ｄｔ及｜－ｄＰ／ｄｔ｜值均显著增加（Ｐ均＜０．０１）。应用地奥心血康较用生理盐水对照的ＲＨＲ上述指标分别减少３１．２％，３５．９％，３２．６％，５０．８％，２５．７％和３０．２％（Ｐ均＜０．０１）。心率降低１７．５％（Ｐ＜０．０１）。提示地奥心血康对大鼠心脏具有负性变时、变力作用，可明显改善左心室的舒缩性能。     

枳实及其升压有效成分与多巴胺、多巴酚丁胺对心脏功能和血液动力学的对比研究

麻醉犬实验表明枳实及其有效成分辛弗林和N-甲基酪胺与多巴胺、多巴酚丁胺相似,能显著增强多种心肌收缩性和泵血功能的指标:增大左室压变化速率峰值和在共同最高等容收缩压(CPIP)时的心肌收缩成分的缩短速率(V_CE),增加心脏指数(GI),缩短左室从开始收缩到开始射血的时间,降低左室舒张末压。由于在CPIP时的V_CE不受心室后负荷(动脉压)的影响,故可以排除上述指标的增强是由于药物对血压的影响。由于枳实及其有效成分的强心、增加心输出量和收缩血管提高总外周阻力,导致左室压力和动脉血压上升,这是它们抗休克的药理学基础。N-甲基酪胺升高外周阻力的作用比枳实和辛弗林稍弱,但加快心率的作用则较强。这两种成分在作用上是各有特点的。在增加心搏指数等效剂量下,枳实、辛弗林、N-甲基酪胺与大剂量多巴胺增加左室作功指数和射血的张力-时间指数的比值远超过增加心搏指数的百分率,这可能是升压增加左室后负荷造成的。多巴酚丁胺和小剂量多巴胺不同于枳实及其有效成分在于能降低外周血管阻力,降低动脉血压,而不明显增加左室作功指数和射血的张力-时间指数,提示不象枳实那样增加心肌的能量消耗。     

Cardiohemodynamic and respiratory effects of eptazocine, a new analgesic agent, in anesthetized dogs

Cardiohemodynamic and respiratory effects of eptazocine, a new analgesic agent, were studied and compared with those of pentazocine and butorphanol in anesthetized dogs. Eptazocine (1 mg/kg, i.v.) increased the heart rate (HR), left ventricular dP/dt (LVdP/dt) and cardiac output (CO), and scarcely affected the blood pressure (BP), left ventricular end-diastolic pressure (LVEDP), right atrial pressure, pulmonary arterial pressure (PAP) and pulmonary capillary wedge pressure. On the other hand, eptazocine (3 mg/kg, i.v.) decreased BP, LVdP/dt, CO and LVEDP and did not influence the pulmonary circulation. Pentazocine (1 mg/kg and 3 mg/kg, i.v.) increased BP, LVdP/dt and CO, while HR was not altered. Pentazocine also increased PAP. Butorphanol (0.1 mg/kg and 0.3 mg/kg, i.v.) decreased BP, HR and LVdP/dt, while other hemodynamic parameters were not changed. In spontaneously breathing anesthetized dogs, eptazocine (1 mg/kg and 3 mg/kg, i.v.) caused a decrease of respiratory minute volume. The fall in PO2 and pH, and a rise in PCO2 were simultaneously observed in blood gas analysis. These respiratory depressant effects of eptazocine were short-lasting, and they were less potent than those of pentazocine. Butorphanol scarcely affected the respiration. These results suggest that eptazocine has different cardiohemodynamic effects than other analgesics and produces mild respiratory depression.     

苓桂术甘汤对犬急性心肌缺血的影响

目的研究苓桂术甘汤对犬急性心肌缺血、心脏血流动力学及心肌耗氧量的影响。方法采用结扎麻醉犬冠状动脉左前降支中段的方式 ,造成实验性急性心肌缺血病理模型 ,观察药物对心肌缺血、血流动力学及心肌耗氧量各指标的变化 (冠脉流量CBF、心输出量CO、心率HR、左室内压LVP、左室舒张末期压LVEDP、左室内压最大变化速率dp/dtmax等 )。结果苓桂术甘汤 8g/kg显著减少由NBT染色的心肌梗死面积 ,增加CBF ,降低冠脉阻力CVR、LVP、LVEDP、dp/dtmax、HR、氧利用率、耗氧指数、心肌耗氧量 ,与空白对照组及药前值比较差异有显著意义 (P <0 0 5～ 0 0 1 )。同时对血清磷酸激酶 (CPK)、乳酸脱氢酶 (LDH)、谷草转氨酶 (GST)没有明显影响。结论苓桂术甘汤能增加心肌的供血供氧 ,改善心肌缺血状况。     

Effects of intravenous infusion of isosorbide dinitrate (ISDN) on acute experimental congestive heart failure

Experiments were undertaken to examine whether and how intravenous infusion of ISDN ameliorated hemodynamics of anesthetized dogs with congestive heart failure. A model of acute congestive heart failure with markedly high left ventricular end-diastolic pressure (LVEDP) and low cardiac index (CI) was induced by occlusion of the left anterior descending coronary artery (LAD) following 30-min infusion of dextran solution containing propranolol in halothane anesthetized open-chest dogs. Five minutes after occlusion of LAD, intravenous infusion of ISDN (100 and 500 micrograms/kg/min for 5 min) decreased the elevated LVEDP, aortic pressure and systemic vascular resistance, and enhanced the reduced CI. These changes produced by ISDN were significant (P less than 0.05 or P less than 0.01) as compared with values just before infusion of ISDN. ISDN at the same doses slightly reduced LVEDP, but did not increase CI in normal dogs which were not subjected to the coronary occlusion and dextran infusion. These results indicate that intravenous infusion of ISDN reduces both pre- and after-load and increases CI in dogs with heart failure, demonstrating that ISDN is useful for the vasodilator therapy of heart failure.     

强心扩血管药羟苯氨酮对大鼠,猫和狗心脏血流动力学的影响

为了解强心扩血管新药羟苯氨酮( oxyphenamone,9003 )对在体心血管系统的效应,用多导生理仪与电磁流量计测定大鼠,猫与狗的心脏血流动力学参数。结果表明,静注羟苯氨酮引起血压与血管阻力中度下降,心输出量,心肌收缩力与收缩力变化速度,冠状动脉和股动脉血流量明显增加。羟苯氨酮对心率与左室压的影响呈现种系差别,它增加狗的左室收缩压与压力变化速度,降低左室舒张末期压力,小剂量羟苯氨酮(1或3mg·kg^-1)引起狗的心率轻度降低,剂量增到6mg·kg^-1,心率中度加快。羟苯氨酮不影响猫的心率与左室压。大鼠静注羟苯氨酮后引起心率,左室收缩压与压力变化速度降低,左室舒张末期压力无变化。羟苯氨酮对心脏血流动力学的影响有待用病理模型作进一步观察。     

重组人脑钠肽及米力农对麻醉犬血流动力学及肾功能的影响

目的观察重组人脑钠肽(rhBNP)对麻醉犬血流动力学和肾功能的作用。方法给麻醉开胸犬恒速输注rhBNP(采用累积给药方式),或iv米力农后,进行血流动力学测定,并测定尿量、尿钠和血钠含量。结果rhBNP可使MAP,LVSP,LVdP/d_t,PAP,LVEDP,TPR及RVR呈剂量依赖性下降,CO有增加趋势,尿量和尿钠排出量呈剂量依赖性增加。米力农则明显降低MAP,PAP,LVEDP,TPR,RBF及RVR,升高LVSP,LVdP/d_t和CO,加快心率,对尿量、尿钠排出量和血钠无明显影响。结论rhBNP能明显降低心脏前后负荷,改善心脏功能;可舒张肾动脉,有扩张血管和利尿排钠作用。米力农则有正性肌力和频率作用,无利尿利钠作用。     

Cardiovascular effects of the new calcium antagonist isradipine and of diltiazem in anesthetized open-chest dogs

Cardiovascular effects of the new calcium antagonist, isradipine (PN 200-110), were compared with those of diltiazem in anesthetized open-chest dogs. Isradipine 5 micrograms/kg i.v. produced significant decreases in systolic, diastolic and mean aortic blood pressure (AoP) concomitant with a decrease in mean renal blood flow (RBF) and increases in mean vertebral blood flow (VBF), mean coronary blood flow (CBF) and left ventricular dP/dt (LVdP/dt), but almost unchanged heart rate (HR) and left ventricular enddiastolic pressure (LVEDP). Diltiazem 300 micrograms/kg i.v. also produced decreases in AoP and RBF and increases in AoF, VBF and CBF. LVdP/dt and LVEDP were not significantly changed, but HR was decreased by this drug. Duration of increase in AoF, VBF and CBF was significantly longer in isradipine than in diltiazem. The decrease of coronary vascular resistance relative to total peripheral resistance was significantly greater than 1.0 for diltiazem, but not for isradipine. Results indicate that isradipine produces effects on AoP, AoF, VBF, CBF, RBF and LVEDP similar to diltiazem and the drug increases LVdP/dt without a decrease in HR in contrast to diltiazem, and that the effects of isradipine were long sustained when compared with those of diltiazem.     

Differential Inhibitory Effects of Isosorbide Dinitrate and its Mononitrate Metabolites on Platelet Aggregation and Thromboxane Formation

The effects of isosorbide dinitrate (ISDN) and its 2- and 5-mononitrate metabolites (2-ISMN and 5-ISMN) against platelet aggregation and thromboxane release were investigated by analysis of platelet aggregation curves. ISDN, 2-ISMN and 5-ISMN (isosorbide nitrates, ISN) inhibited both ADP- and epinephrine (EPI)-induced platelet aggregation. ISN affected specifically the extent of ADP-induced aggregation and the velocity of EPI-induced effects. 2-ISMN was more potent against platelet aggregation compared to ISDN and 5-ISMN. The isosorbide nitrates were poor inhibitors of both arachidonic acid-induced aggregation and platelet TxB2 release. The differential inhibition by the three isosorbide nitrates of endogenous TxB2 release during ADP-induced aggregation further indicates that 2-ISMN is a significantly more potent platelet inhibitor than either ISDN or 5-ISMN. These studies suggest a role of the metabolites in modulating the pharmacological effects of ISDN on platelet activity.     

Effects of 5-([2-(diethylamino)-ethyl]amino)-3-phenyl-1,2,4-oxadiazole dihydrochloride (DEPO) on cardiac functions and myocardial metabolism of the dog

Effects of 5-([2-(diethylamino)-ethyl]amino)-3-phenyl-1,2,4-oxadiazole (DEPO) on cardiac functions and myocardial metabolism were examined using the heart in vivo and the isolated perfused heart of dogs. In the heart in vivo DEPO i.v. produced dose-dependent decreases in coronary perfusion pressure (PP), heart rate (HR), left ventricular pressure (LVP), dP/dt max of LVP and coronary vascular resistance (VR). DEPO i.c. dose-dependently increased left circumflex coronary flow (LCCF) and decreased PP, LVP and dP/dt max of LVP, but did not change HR. In the isolated perfused heart, DEPO induced a marked increase in coronary blood flow (CBF) and depressed HR and myocardial contractile force. Myocardial oxygen consumption and myocardial redox potential were not significantly changed. DEPO could not modify the effects of isoproterenol, adenosine and reactive hyperaemia on the heart. The results suggest that DEPO may have a coronary vasodilating action and some direct inhibitory actions on the heart.     

慢性间歇性低压低氧对成年和幼年大鼠缺血/再灌注心脏保护作用的比较

目的观察慢性间歇性低压低氧(CIHH)对成年和幼年大鼠心脏缺血/再灌注损伤的保护作用的异同点。方法♂成年和新生Sprague-Dawlay(SD)大鼠随机分为4组:对照28d组(CON28)、对照42d组(CON42)、CIHH处理28d组(CIHH28)和CIHH处理42d组(CIHH42)。间歇性低氧处理组动物于低压氧舱分别接受28d、42d模拟3000米海拔高度(PB=525mmHg,PO2=108.8mmHg)的低压低氧处理,每天5h。对照组动物除了不接受低氧处理外,其它处理均与间歇性低氧组动物相同。应用Langendorff离体心脏灌流技术,给予心脏缺血(停灌30min)/再灌注(复灌60min)处理,记录离体大鼠心脏在不同时期的心功能变化。心功能参数包括左室发展压(left ventricular developing pressure,LVDP)、左室压力最大变化速率(maximum changerate of LVDP,±LVdp/dtmax)、左室舒张末压(left ventricularend di-astolic pressure,LVEDP)、冠脉流量(coronary flow,CF)和心率(heartrate,HR)。结果①对成年大鼠,基础状态和缺血/再灌注状态下CIHH28d组各心功能参数与CON28d组相比差异均无统计学意义。CIHH42d组各心功能参数均好于CON42d组,表现为LVDP、LVEDP、±LVdp/dtmax和CF恢复均增加(P<0.05)。②对幼年大鼠,基础状态下,CIHH大鼠CF较对照大鼠明显增多,其余心功能参数与对照大鼠无差异。CIHH大鼠缺血/再灌注后心脏功能的恢复明显好于对照动物,表现为LVDP、LVEDP、±LVdp/dtmax和CF恢复均增加(P<0.05),且CIHH42d组比CIHH28d组心功能改善更明显。结论CIHH可增强成年和幼年大鼠抗心肌缺血/再灌注损伤的能力,具有明显的心脏保护作用,CIHH42d组保护作用更为明显;CIHH的心脏保护作用有明显的年龄差异,在幼年大鼠更易产生保护作用。     

Beta-adrenergic influence on cardiac dynamics during shock-avoidance in dogs

The role of beta-adrenergic receptors in the mediation of the cardiodynamic effects of a shock-avoidance task was evaluated in conscious dogs with the cardioselective beta-adrenergic antagonist practolol. The animals were chronically instrumented for the measurement of peak rate of change of left ventricular pressure (LV dP/dt), heart rate (HR), cardiac output (CO), systolic (SPB) and diastolic (DBP) blood pressure and total peripheral resistance (TPR), and were each subjected to brief bouts of shock-avoidance with and without practolol pretreatment (2-4 mg/kg). Shock-avoidance evoked reliable increases of LV dP/dt, HR, CO, SBP and DBP, and decreases of TPR. Beta-adrenergic blockade virtually eliminated LV dP/dt increases, attenuated HR and CO increase as well as the vasodilatation, diminished SBP increases in certain animals but did not affect DBP increases. Stable interindividual differences in the magnitude of LV dP/dt and HR increases during shock-avoidance were demonstrated; these differences were abolished by beta blockade. These findings indicate that a beta-adrenergic mechanism accounted for most of the rise of LV dP/dt during avoidance but contributed proportionally less to the elevations of HR and CO. Inter-individual differences in myocardial reactivity were however completely ascribable to beta-adrenergic factors.     

Congestive heart failure model in rabbits: effects of digoxin and a drug containing toad venom.

A low-output-type heart failure model was established in rabbits by protease treatment of the surface of the left ventricular anterior wall. Heart rate, aortic blood flow (AoF), left ventricular pressure (LVP) and maximal rate of rise of LVP (max dP/dt) in this model were maintained at lower levels than in normal rabbits, while left ventricular end-diastolic pressure (LVEDP) and systemic vascular resistance (SVR) were maintained at higher levels, and mean blood pressure (MBP) remained at a normal level. Intraduodenal administration of digoxin and a drug containing toad venom (Kyushin:KY) improved the hemodynamic parameters by increasing the AoF, LVP and max dP/dt and by decreasing the LVEDP and SVR without a significant change in MBP. These results suggest that the beneficial effects of digoxin and KY on this heart failure model originate from their cardiotonic activity.     

CARDIOVASCULAR EFFECTS OF ISOSORBIDE DINITRATE INFUSED INTRAVENOUSLY INTO ANAESTHETIZED DOGS

The cardiohaemodynamic response and the development of tolerance to isosorbide dinitrate (ISDN) were examined in anaesthetized, open-chest dogs. ISDN, infused intravenously (i.v.) for 2 h at a rate of 10 or 30 micrograms/kg per min, decreased systemic blood pressure (systolic, mean and diastolic; SBP), left ventricular (LV) systolic and end-diastolic pressure, LVdP/dt max, pressure-rate product and coronary blood flow. No significant changes in heart rate (HR) and coronary vascular resistance were observed. Intravenous ISDN significantly attenuated the vasodilator effect of bolus intracoronary (i.a.) glyceryl trinitrate (GTN, 1 micrograms), and ISDN (30 micrograms), whereas that of bolus i.a. nicorandil (mononitrate, 20 micrograms) remained unaffected. Just after acute tolerance towards i.a. ISDN was provoked 1 h after starting ISDN infusion (30 micrograms/kg per min, i.v.), the combined infusion of ISDN (i.v.) and nicorandil (30 micrograms/kg per min) was instigated for a further hour. Also, 1 h after the onset of vehicle infusion (i.v.), the combined infusion of vehicle and nicorandil (30 micrograms/kg per min, i.v.) was started. There were essentially no significant differences between the corresponding values concerning the coronary vascular responses obtained from the two combined infusion groups.     

Cardiovascular effects of medorinone in β-adrenoreceptor-blocked and non-blocked anesthetized dogs

The hemodynamic effects of the low K_m cAMP peak III PDE inhibitor medorinone (0.01–0.3 mg/kg, i. v. ) were evaluated in anesthetized dogs in the presence and absence of β-adrenoreceptor blocked. Medorinone increased the peak derivative of left ventricular pressure (+ dP/dt) in non-blocked (all doses) and β-blocked dogs (≥0.03 mg/kg) (2,766±259 and 1,403±262 mm Hg/sec, respectice max. changes). Heart rate (HR) was increased by medorinone in non-blocked (≥0.1 mg/kg) and β-blocked dogs (≥0.03 mg/kg) (77.4±8.9 and 25.5±4.3 beats/min, respective max. changes). In non-blocked dogs only, medorinone (all doses) decreased left ventricular end-diastolic pressure (LVEDP) (7.7±1.7 mm Hg, max. change). Mean arterial pressure (MAP) was similarly decreased by medorinone (<0.03 mg/kg) in β-blocked and non-blocked dogs (max. approx. ?27 mm Hg). Medorinone did not affect cardiac output or renal blood flow. The hemodynamics of medorinone and milrinone (another peak III PDE inhibitor) in non-blocked dogs were similar, except meddorinone was less potent in increasing +dP/dt (2,766±259 vs. 3,747±388, max. changes) and more potent in reducing LVEDP (?7.7±1.7 vs. ?1.8±1.2 mm Hg, max. changes). In conclusion, medorinone similarly reduced MAP, but more effectively decreased preload, increased inotropy and chronotropy in non-blocked than β-blocked anesthetized dogs. Medorinone is more potent in reducing preload, but less potent in enhancing inotropy when compared to milrinone in anesthetized dogs.     

左旋四氢巴马汀对麻醉大鼠血流动力学影响

L-THP 6mg/kg iv仅显著降低麻醉大鼠血压,LVP-过性降低。iv L-THP 18mg/kg在显著降低血压的同时伴有LVP,±(dP/dt)_(max),(dP/dt)P~(-1)降低及HR减慢。但血压下降程度比心室收缩性能下降为大。L-THP依剂量降低DAP,且降低程度大于SAP。表明L-THP能降低外周阻力,大剂量时对心脏收缩性能有抑制作用。     

Absorption and excretion of isosorbide dinitrate and isosorbide-2-mononitrate in dogs

In a crossover design four male dogs were given orally or i.v. [14C]isosorbide dinitrate (ISDN) or [14C]isosorbide-2-mononitrate (2-ISMN) at a dose of 1 mg kg-1 (70-80 microCi). Virtually all of the oral dose was absorbed and all of the radioactivity was excreted in the urine. The profile of serum radioactivity was similar after all drug administrations. ISDN was rapidly denitrated, giving rise to isosorbide-5-mononitrate (5-ISMN) as a major metabolite, and 2-ISMN as a minor metabolite. The apparent elimination half-life from serum of 2-ISMN and 5-ISMN was 2-3 h. More than 50% of the serum radioactivity after [14C]2-ISMN was due to unchanged drug. The apparent volume of distribution of 2-ISMN averaged 8.3 litres. The results show that, in contrast to ISDN, administration of 2-ISMN resulted in relatively high unchanged drug levels in the serum; the disposition of radioactivity after [14C]ISMN was however similar to that after [14C]ISDN. The findings support the concept that the concentrations of ISDN, 2-ISMN and 5-ISMN in the blood are inversely related to the rates of denitration, and that the vascular activity of the nitrates of isosorbide relates to the rates of their dinitration.