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PubMed1975

Reduced myocardial reflow and increased coronary vascular resistance following prolonged myocardial ischemia in the dog.

Studies were performed to determine whether an alteration in coronary vascular resistance and a reduction in the reflow phenomenon occurred in the blood-perfused, heparinized canine heart after various periods of myocaridal ischemia. Regional myocardial blood flow was measured with radioactive microspheres. Proximal left anterior descending coronary artery blood flow was measured with a periarterial flow transducer. Reduced reflow to the ischemic portion of the left ventricle and increased resistance in the left anterior descending coronary artery were present after 120 minutes of myocardial ischemia. The reduction in reflow was specific to the subendocardium of the ischemic area. Saline and isosorbide dinitrate (Isordi) did not prevent the increase in coronary vascular resistance or the significant reduction in reflow to the subendocardial portion of the ischemic area. Hypertonic mannitol given so as to increase serum osmolality 40 mosmoles/kg prevented the increase in coronary vascular resistance and modified the reduction in the reflow phenomenon to the subendocardial portion of the ischemic area. Thus, both an increase in coronary vascular resistance and a significant reduction in reflow to the subendocardial portion of the ischemic area occur in the canine heart after 120 minutes of myocardial ischemia. Moreover, the increase in coronary vascular resistance can be prevented and the reduction in reflow to the subendocardial portion of the ischemic area can be modified by the administration of hypertonic mannitol.

Animals↗
PubMed1981

Hemodynamic effects of molsidomine vasodilatory therapy in acute myocardial infarction.

The hemodynamic effects and duration of action of 4 mg of intravenous molsidomine (M), a new peripheral vasodilator antianginal agent, were evaluated and compared to those of 10 mg sublingual isosorbide dinitrate (ISDN) in 12 patients with uncomplicated acute myocardial infarction (AMI). Both M and ISDN produced marked decreases in mean right atrial pressure (RAP), mean pulmonary capillary wedge pressure (WP), and mean pulmonary arterial pressure. The maximal decreases in RAP (-56%) and WP (-35%) with intravenous M intended to be more pronounced than with sublingual ISDN (RAP-35% and WP-29%). Physiologic modest declines in systemic vascular resistance, cardiac output, and arterial pressure were similar with the both drugs. The duration of action of M was longer (average 5 hours) than that of ISDN (2 hours). No patient experienced hypotension, tachycardia, or other adverse responses following M, suggesting that M is well isolated by patients with normotensive AMI.

Acute Disease↗
PubMed1988

When does nitrate tolerance develop? What dosages and which intervals are necessary to ensure maintained effectiveness?

To address the issues of tolerance development and its circumvention during long-term treatment with nitrates, several controlled studies have been performed. In patients with coronary artery disease, during long-term treatment with isosorbide dinitrate (ISDN) in sustained-release form at dosages of 20 mg t.i.d., 40 mg t.i.d. and 60 mg t.i.d., both the rate of anginal attacks and the ischaemic reaction to exercise were unaffected. After a marked acute anti-ischaemic effect to 40 mg ISDN in nonsustained-release form, during chronic administration of the same dose four times daily, in association with continuously-high nitrate plasma concentrations, similarly, there were no significant effects. On use of nitroglycerin (NTG) transdermal patches delivering 10 mg, 15 mg and 30 mg per 24 hours, respectively, renewed patch application after 24 hours was not met with the same marked response observed after initial application. Clearly attenuated effects could be seen within 8 to 12 hours. These results show that tolerance development is incurred when the incrementation in plasma concentration after a repeated nitrate dose is of relatively limited magnitude with respect to baseline values. The observation of rapid reversibility of nitrate tolerance lead to the concept of interval treatment which on daily use incorporates a sufficiently long period without nitrate administration. On use of a nitrate-free treatment interval employing a regimen of 20 mg ISDN nonsustained-release form twice daily in the morning and at midday, 120 mg ISDN sustained-release form once daily or 50 or 100 mg isosorbide 5-mononitrate once daily, maintained effectiveness has been documented, as it has also been shown for treatment with NTG patches delivering 10 mg per 24 hours on incorporation of a 12-hour patch-free interval. The currently available patch system with discontinuous NTG delivery does not incur a complete loss of action but a considerable attenuation of its effects indicates the need for further refinements. Thus interval treatment guarantees maintenance of nitrate effects, albeit with the limitation that 24-hour therapeutic coverage is not enabled.

Administration, Cutaneous↗
PubMed1996

Nitroprusside inhibits serotonin-induced mitogenesis and tyrosine phosphorylation of smooth muscle cells.

Serotonin (5-hydroxytryptamine, 5-HT) produces hyperplasia and hypertrophy of bovine pulmonary artery smooth muscle cells (SMC) in culture. The growth responses are associated with early elevations of c-myc and actin gene expressions and are blocked by agents that elevate cellular adenosine 3',5'-cyclic monophosphate or inhibit 5-HT transport or tyrosine phosphorylation. A rapid enhancement of tyrosine phosphorylation of a 120-kDa protein (p120) is associated with the 5-HT-induced mitogenesis. In the present studies, sodium nitroprusside (SNP, 10-100 micromol/l), a NO-generating agent, dose dependently inhibited 5-HT-induced thymidine incorporation by SMC. Inhibition of the 5-HT stimulatory effect was also observed with isosorbide dinitrate and nitroglutathione, which are also NO donors. Incubation of cells with 8-bromoguanosine 3',5'-cyclic monophosphate (1 micromol/l) mimicked the antimitogenic action of SNP. The antiproliferative effect of SNP was inhibited by hemoglobin (50 micromol/l) and potentiated by superoxide dismutase (200 U/ml), supporting the role of NO in the process. Enhancement of tyrosine phosphorylation of p120 by 5-HT was prevented by preincubation with SNP or exogenously added guanosine 3',5'-cyclic monophosphate. The data indicate that 5-HT acts as a mitogen for SMC through a signal transduction pathway involving tyrosine phosphorylation. SNP likely prevents the 5-HT-induced mitogenesis of SMC through elevation of intracellular guanosine 3',5'-cyclic monophosphate and inhibition of tyrosine phosphorylation of p120.

Actins↗
PubMed1989

Follow-up the haemodynamic effect of nitroglycerin and determination of the optimal dose using the non-invasive and invasive methods in patients treated at the intensive care unit.

The authors report on observations with nitroglycerin applied in the treatment of acute and chronic left ventricular failure to patients suffering from ischaemic heart disease and acute myocardial infarction. The treatment of 28 patients was discussed in detail, the nitroglycerin products used were: Nitrolingual inj. Nitromint controlled-release tabl., Nitrong tablet and Iso-Mack controlled-release tablet (isosorbide dinitrate). The haemodynamism-influencing effects of nitroglycerin were controlled by the invasive and non-invasive methods. The pulse volume of the left ventricle was estimated by measuring the ejection angle, the filling pressure of the left ventricle by measuring the diastolic pressure of the pulmonary artery. On the basis of their observations the authors attach high importance to the determination of individual nitroglycerin doses of broader spectrum compared to the commonly used doses. By taking into consideration the ejection angle correlating closely with left ventricular pulse volume besides the other characteristic parameters (PCWP, RR, pulse rate, ECG), higher nitroglycerin doses could be used without risk in cases in which the survival of the patient was obviously due to the application of higher doses.

Aged↗
PubMed1987

Effects of nicorandil on rest and effort angina unresponsive to combination therapy with a calcium antagonist and oral nitrate.

The efficacy of nicorandil, a new anti-anginal agent, was evaluated in 11 patients with rest and effort angina not inhibited by combination therapy with a calcium antagonist and an oral nitrate. Electrocardiographic findings during an attack demonstrated ST depression in seven patients, ST elevation in three, and either elevation or depression in two. Coronary angiography in nine patients revealed significant stenosis (greater than or equal to 75%) in eight. Angina persisted in all 11 patients in spite of treatment with 120 to 360 mg/day of diltiazem or 80 mg/day of nifedipine plus 20 to 160 mg/day of isosorbide dinitrate. Three patients were receiving beta-blocker as well; seven were receiving antiplatelet therapy. During combination therapy, patients had between 3.7 and 25 anginal attacks per week (mean +/- SD, 12.2 +/- 6.9). When nicorandil in a dosage of 20 to 40 mg/day was added to the regimen, the mean number of attacks dropped significantly (P less than 0.01) to 1.4 +/- 1.8 times/week. Two patients did not respond to nicorandil. When placebo was substituted for nicorandil in eight of nine responders, the frequency of attacks increased significantly (P less than 0.05) from 0.6 +/- 0.7 to 6.7 +/- 4.8 times/week. Nicorandil did not affect heart rate or blood pressure. These results suggest that nicorandil inhibits rest and effort angina unresponsive to usual doses of calcium antagonist and oral nitrate.

Aged↗
PubMed1982

Contrasting hemodynamic responses in severe heart failure: comparison of captopril and other vasodilator drugs.

Four studies were conducted in 36 patients with severe chronic heart failure to compare the central hemodynamic effects of captopril (CPT) to other vasodilator agents. While CPT produced less marked increases in cardiac output than did hydralazine (n = 14), nitroprusside (n = 15), or prazosin (n = 7), it produced decreases in left ventricular filling pressures similar to nitroprusside and prazosin but more than hydralazine. CPT and isosorbide dinitrate (n = 11) produced similar decreases in systemic vascular resistance and left ventricular filling pressure. However, cardiac output increased less with CPT than with nitrates, because heart rate slowed during CPT therapy. In addition, mean right atrial pressure decreased less with CPT than with nitrates, because CPT had minimal effects on limb venous capacitance and pulmonary arteriolar resistance. Alterations in left ventricular pressure-volume relationships likely contributed to the marked decreases in left ventricular filling pressures seen with CPT. In conclusion, the central hemodynamic effects of CPT differ significantly from other vasodilator drugs used in the treatment of heart failure patients. These effects cannot be characterized simply in terms of "balanced" peripheral arterial and venous vasodilation; CPT exerts highly complex effects on peripheral vessels as well as having actions independent of its peripheral vasodilator effects.

Adult↗
PubMed1993

Plasma cyclic guanosine monophosphate in chronic heart failure: hemodynamic and neurohormonal correlations and response to nitrate therapy.

This study evaluated the relation between plasma cyclic guanosine monophosphate (cGMP) and hemodynamic and neurohormonal parameters in patients with chronic congestive heart failure and assessed the effect of organic nitrate on plasma cGMP levels. Plasma cGMP was fourfold higher in 18 patients with congestive heart failure compared with 15 control subjects (16.7 +/- 9.7 versus 4.0 +/- 1.0 pmol/ml; p < 0.0001) but did not correlate with plasma levels of catecholamines, renin, atrial natriuretic peptide, or with baseline hemodynamic values. The administration of a hemodynamically effective dose of oral isosorbide dinitrate (40 mg) resulted in a transient reduction in plasma cGMP from 16.7 +/- 9.7 pmol/ml at baseline to 13.0 +/- 6.6 pmol/ml at 1 hour (p < 0.05). This change was associated with small and statistically insignificant changes in neurohormonal values and had no relation to any of the hemodynamic changes. We concluded that (1) elevated plasma cGMP in congestive heart failure does not correlate with other neurohormonal or hemodynamic parameters and may be an independent parameter of heart failure, (2) in contrast to previously documented nitrate-mediated increases in intracellular cGMP, nitrate therapy results in a reduction in plasma cGMP, and (3) changes in plasma cGMP cannot serve as a surrogate measurement of changes in intracellular cGMP.

Administration, Oral↗
PubMed1981

[The end-systolic pressure-volume relationship in the assessment of left ventricular function (author's transl)].

This investigation was undertaken to determine whether the left ventricular (LV) end-systolic pressure and end-systolic volume, as measured under clinical conditions, are linearly correlated and whether the slope of the end-systolic pressure-volume relationship (P-Ves) is a meaningful parameter in the assessment of left ventricular function. The studies were performed in twelve patients (eleven with coronary artery disease and one with congestive cardiomyopathy) during which autonomic reflex responses were minimized by propranolol (0.15 mg/kg i.v.) and atropine (1 mg i.v.). Three left ventricular angiograms (at rest, after 10 mg isosorbide dinitrate and during an infusion of 2 mg/min methoxamine) were obtained from which the three respective P-Ves data points were calculated and subjected to linear regression analysis (r greater than or equal to 0.96). The slope k of the linear P-Ves relation correlated most closely with the resting ejection fraction (EF) as an exponential function (r = 0.94). The end-systolic pressure could be interchanged with the peak systolic pressure which is more easily obtained. The theoretical end-systolic volume at end-systolic pressure = 0 (V0) was not related to the resting ejection fraction. Post-extrasystolic potentiation, resulting in an acute inotropic incrementation, shifted the P-Ves toward similar volumes and steepened its slope.

Atropine↗
PubMed1984

Methemoglobin levels produced by organic nitrates in patients with coronary artery disease.

To determine if ordinary doses of nitrates produce a significant increase in methemoglobin, methemoglobin levels were measured in 59 randomly selected patients with coronary artery disease and unstable angina pectoris who were receiving organic nitrate therapy. Patients were taking isosorbide dinitrate, 2% nitroglycerin ointment, or a combination of the two. Patients were subdivided according to whether they were using one (group A) or more than one (group B) organic nitrate preparations. These results were compared with 17 control patients. Mean methemoglobin levels in group B were 1.78 +/- 1.29%, and this differed significantly (P less than 0.05) from both group A mean methemoglobin, 1.13 +/- 0.92%, and controls, 0.99 +/- 0.55%. The proportion of patients with elevated methemoglobin concentration increased from the control to group A to group B. It is concluded that commonly used dosages of nitrates are capable of causing elevations of methemoglobin which are probably not of routine clinical significance. However, these elevations may be of import in certain patient populations such as those with coronary insufficiency or anemia.

Aged↗
PubMed1993

Mechanism of death in heart failure. The Vasodilator-Heart Failure Trials. The V-HeFT VA Cooperative Studies Group.

BACKGROUND: The Vasodilator-Heart Failure Trial (V-HeFT) data base provides information on the mechanism of death of male veterans entered into two trials that evaluated the effect of vasodilator therapy on survival in heart failure. METHODS AND RESULTS: Men aged 18-75 years with heart failure were recruited at 13 Department of Veterans Affairs Medical Centers. In V-HeFT I, 283 of 642 patients (44%) died during follow-up (average, 2.3 years), and in V-HeFT II, 285 of 804 randomized patients (35.5%) died during follow-up (average, 2.5 years). Mechanism of death was established centrally using a standardized classification. In V-HeFT I, 124 of the 283 deaths (43.8%) were sudden with no worsening of symptoms; in V-HeFT II, 104 of the 285 deaths (36.5%) were sudden. An average of 31.5% of the deaths (31.4% and 31.6%, respectively) in the two trials was due to pump failure. The proportion of sudden deaths that occurred without worsening of symptoms was similar in patients with and without ischemic heart failure. Sudden deaths tended to occur earlier and pump failure deaths later in both V-HeFT studies. There was a trend for a lower percentage of cardiac deaths from pump failure and a higher percentage from sudden death in subgroups with higher peak exercise oxygen consumption (VO2), higher ejection fraction, and lower plasma norepinephrine levels. The proportion of deaths that occurred suddenly was similar in placebo, prazosin, and hydralazine plus isosorbide dinitrate treatment groups but was significantly lower in the enalapril treatment group. In V-HeFT I, measures of cardiac function and VO2 predicted pump failure death and sudden death. In V-HeFT II, VO2 and cardiothoracic ratio were independent predictors of all-cause deaths and pump failure deaths; only ejection fraction was an independent predictor of both pump failure and sudden death. CONCLUSION: Although mechanistically distinct terminal events can be identified in patients with heart failure and physiological measurements can provide some insight into the risk of these disparate events, sudden death and pump failure death both appear largely to be linked to the severity of cardiac dysfunction and symptoms. Strategies to identify individuals for selective preventive therapy are not yet practical.

Cause of Death↗
PubMed1987

Beneficial effect of nitrates on myocardial glucose utilization in unstable angina pectoris.

Myocardial uptake of the glucose analog F-18-2-fluoro-2-deoxy-D-glucose (FDG) was assessed by positron emission tomography in 6 normal volunteers, 7 patients with chronic stable angina and 22 patients with unstable angina at rest in fasting conditions. Regional myocardial perfusion was assessed by rubidium-82. The study was repeated a few days later after intravenous infusion of isosorbide dinitrate. FDG uptake was similar in control subjects and patients with stable angina (0.023 +/- 0.032 vs 0.012 +/- 0.008 mol/ml/min, p less than 0.42) but was about 4-fold higher on the average in patients with unstable angina (0.084 +/- 0.047, p less than 0.01). The severity of coronary obstructions in stable and unstable angina patients was similar. The increased uptake involved the whole heart, including areas not distal to critically stenosed vessels; it was not associated with reduced myocardial perfusion and was not related to a recent episode of transient ischemia as assessed by symptoms and by Holter monitoring. After continuous infusion of nitrates, FDG uptake was consistently and significantly reduced toward normal levels both in areas perfused by critically stenosed coronary arteries and by noncritically stenosed vessels.

Adult↗
PubMed1992

Mechanism of nitrate-induced improvement on arterial compliance depends on vascular territory.

The link between arterial caliber and distensibility has been studied extensively, with conflicting results. As have other researchers, we previously showed evidence of an increase in arterial diameter and a decrease in arterial stiffness with use of nitrates at the site of the brachial artery (BA) and the aorta. Whether these results would apply to other large superficial arteries remained to be established. In the present study, by means of an original pulsed ultrasound echo-tracking system based on Doppler shift, we measured internal diastolic diameter and stroke change in diameter of the common carotid artery (CCA), the femoral artery, and the BA in patients with essential hypertension and determined the acute effects of administration of isosorbide dinitrate (ISDN 20 mg). Twenty untreated hypertensive patients entered this randomized, placebo-controlled, double-blind, parallel study. No significant change occurred during placebo. During ISDN therapy, blood pressure (BP) decreased significantly; cross-sectional compliance increased at the site of the CCA, the BA, and the common femoral artery (CFA). The increase in cross-sectional compliance was mainly due to an increase in internal diameter for CCA and to an increase in distensibility coefficient (DC) for BA. The pattern of cross-sectional compliance was intermediate for CFA. During ISDN therapy, the augmentation index of the CCA distension waveform was significantly reduced, whereas no change occurred during placebo, suggesting a reduction in wave reflection by nitrates.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Nitrate therapy without loss of action by correct dosage.

Previous studies carried out with ISDN prove that long lasting, unfluctuating plasma concentrations--e.g. above 300 ng IS-5-N/ml--cause a severe loss of action. This could be cancelled by administration of isosorbide dinitrate (ISDN) according to a regimen in which an interval with considerably reduced nitrate levels is guaranteed. On the other hand a dosage regimen which leads to steady state plasma concentrations which fluctuate between 100 and 300 ng IS-5-N/ml (after 3 times daily 20 mg ISDN) showed no clinically significant loss of efficacy even after 4 weeks of application. Based on these findings a therapy like once daily 120 mg ISDN sustained release which guarantees plasma levels of up to 600 ng IS-5-N/ml (over the active day of the patient) with an interval of nitrate levels down to 100 ng (overnight) could be judged as efficient. As recent studies showed there is no clinically found loss of efficacy after four week application. With regard to a better compliance this regimen seemed to be the optimum.

Coronary Disease↗
PubMed1995

FK409, a new nitric-oxide donor, suppresses smooth muscle proliferation in the rat model of balloon angioplasty.

The effect of FK409, a new nitric-oxide (NO) donor, on neointimal formation of rat carotid arteries following balloon injury was studied. The intimal thickening at 14 days was strongly suppressed by twice daily administration of FK409 at 10 mg/kg from 2 days before to 13 days after injury. The neointima area and neointima/media ratio were decreased by 48.0% (P < 0.01) and 38.5% (P < 0.01), respectively, compared with control. On the other hand, isosorbide dinitrate (ISDN), a classical nitro-vasodilator, did not suppress intimal thickening even at 100 mg/kg twice a day. An in vivo 5-bromo-2'-dedoxyuridine (BrdU) uptake study revealed that FK409 inhibited the proliferative response of smooth muscle cells (SMC) in media at early stage of injury. In fact, the neointimal formation at 14 days was inhibited by the short term administration of FK409 only from the day of injury to 4 days after at 10 mg/kg twice a day. In cultured rat SMC, FK409 (1-10 mumol/l) markedly enhanced intracellular c-GMP and inhibited the proliferation in 10% FBS-containing medium. These results suggest that FK409 suppresses intimal thickening following balloon injury of the rat carotid artery by inhibition of SMC proliferation.

Angioplasty, Balloon↗
PubMed1997

The effect of nitric oxide on uterine and umbilical artery flow velocity waveform in pre-eclampsia.

We compared the flow velocity waveforms of uterine and umbilical arteries in normotensive and pre-eclamptic patients at mid-gestation. In a randomised controlled trial we tested the effects of isosorbide dinitrate (ISDN, nitric oxide donor) patch therapy on the flow velocity waveform of pre-eclamptic patients at mid-gestation. The resistance indices (RI) of human uterine and umbilical arteries were higher in pre-eclamptic patients compared to the normotensive patients. ISDN patch therapy significantly reduced the increased RI values of the umbilical artery in pre-eclamptic patients without any change in systemic blood pressures, but the RI values of the uterine artery were not significantly attenuated. The change of the umbilical artery might be due to the improvement of end-diastolic flow velocity. These results suggest that the feto-placental circulation in pre-eclampsia, perhaps due to the disturbance of the endothelium-dependent vaso-relaxation system, and that ISDN therapy may improve the impaired endothelium dependent nitric oxide system.

Administration, Cutaneous↗
PubMed2002

Organic nitrate tolerance is induced by degradation of some cytochrome P450 isoforms.

The mechanism of nitrate tolerance is poorly defined. We studied the rat P450 (CYP)-catalyzed conversion of organic nitrate to nitric oxide (NO) by purified CYP isoforms and the relationship between P450 expression and nitrate tolerance following continuous infusion of organic nitrates in rats. CYP1A2 effectively formed NO from isosorbide dinitrate and nitroglycerine (NTG). The hypotensive effect of an NTG bolus injection was abolished in rats which had been previously given a continuous 48 h infusion of NTG. Nitrate tolerance was reversible to control levels 2 days after cessation of the continuous infusion. At 48 h after infusion, NTG-induced NO generation of the vessels increased in acetone (a P450 inducer)-pretreated rats, and nitrite and nitrate levels were markedly greater than in normal rats. The appearance and disappearance of P450 isoforms paralleled the conversion of organic nitrates to NO as assessed by immunohistochemistry and Western blotting. Our observations indicate that nitrate tolerance is in large part the result of decreased P450 expression and activity. Interventions that maintain or increase P450 activity may be a useful strategy to provide sustained relief from ischemic conditions in humans.

Animals↗
PubMed2000

Response of the radial artery to three vasodilatory agents.

We examined the response of the radial artery to vasoactive agents (isosorbide dinitrate, ISDN, 1 mg, 3 mg, and 5 mg; verapamil, 1 mg, 3 mg, and 5 mg; and lidocaine, 10 mg, 30 mg, and 50 mg) in 100 consecutive patients admitted for elective coronary angiography. The drug solutions were directly injected into the radial artery from the puncture site. As a result, 5 mg of ISDN increased the diameter of the radial artery by 31% and 28.8% at the proximal and distal sites, respectively. Similarly, 5 mg of verapamil increased it by 9% and 10.8% at the proximal and distal site, respectively. But 10 mg of lidocaine decreased it by -15.6% and -12.1% at the proximal and distal site, respectively. At the doses utilized, ISDN was the most potent vasodilator for the radial artery and lidocaine caused paradoxical vasoconstriction.

Adult↗