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Serotonin-induced vasoconstriction in the perfused canine femoral artery can be blocked in vivo by ketanserin.

Serotonin, applied to helical strips of larger vessels such as coronary arteries, acts as a potent vasoconstrictor in vitro. In contrast, in vivo serotonin causes a remarkable decrease in total peripheral resistance. To differentiate the influence of serotonin on resistances of large and small vessels, experiments were done in nine anesthetized dogs. The left iliacal artery was cannulated and blood flow into the femoral artery was kept constant by a roller pump. Mean proximal femoral artery pressure and mean dorsal pedal artery pressure were measured. Pressure gradient (delta P), resistances between proximal femoral artery and dorsal pedal artery (R1), dorsal pedal artery and right atrium (R2), as well as total peripheral resistance were calculated during systemic infusion of 50 micrograms/kg X min serotonin. Serotonin caused a significant increase in delta P and R1 and a decrease in R2 and total peripheral resistance. Pretreatment with 100 micrograms/kg ketanserin abolished the significant change in delta P and R1, whereas the decrease in R2 and total peripheral resistance was not affected. Additional experiments with prazosin showed that alpha-receptors are obviously not involved in the responses observed. Isosorbide dinitrate, which was infused to differentiate passive and active narrowing of vessels, showed a serotoninlike decrease in mean dorsal pedal artery pressure but no change in either delta P or R1. The 5--HT2-serotonergic antagonist ketanserin blocked serotonin-induced constriction of large vessels in vivo but not the dilation of small arteries.

Animals↗

Ovariectomy aggravates hypersensitivity reactions to paclitaxel in rats.

The incidence of hypersensitivity reactions is still a matter of serious concern during chemotherapy with paclitaxel, particularly in patients with ovarian cancer. We recently reported that intravenous injection of paclitaxel causes acute lung injury characterized by vascular hyperpermeability, edema and respiratory dysfunction in rats. In the present study, we investigated the influence of ovariectomy on the paclitaxel-induced acute lung injury in rats. Ovariectomy worsened paclitaxel-induced acute lung injury, which was reversed by 17beta-estradiol. The mRNA expression for endothelial nitric oxide synthase was reduced in lungs of ovariectomized rats. To determine the role for nitric oxide, we examined the effects of several agents that modulate nitric oxide concentration on the pulmonary response to paclitaxel. In ovary-intact rats, a nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester exaggerated paclitaxel-induced acute lung injury, while nitric oxide donors such as sodium nitroprusside and isosorbide dinitrate attenuated the lung injury. Sodium nitroprusside was also effective in alleviating the paclitaxel-induced acute lung injury in ovariectomized rats. These findings suggest that ovariectomy enhances the susceptibility to paclitaxel hypersensitivity, in which decrease in estrogen and subsequent reduction in nitric oxide synthesis may be involved.

Animals↗

[Drug therapy of angina pectoris. Are the possibilities exploited well enough?].

A retrospective comparative study of the use of antianginal drugs in 1987 and 1992/93 has been carried out in unselected series of patients admitted for angiographic evaluation. Compared with the patients in 1987 the patients in 1992/93 were treated with approximately 50% of the doses of beta-blockers and isosorbide dinitrate. There was also a considerable reduction of the proportion of patients who received doses of beta-blockers of a similar level as used in large multicentre studies showing improved survival after myocardial infarction. The explanation of this change in therapy may be due, at least partly, to a general fear of side-effects.

Adrenergic beta-Antagonists↗

Efficacy of Terminalia arjuna in chronic stable angina: a double-blind, placebo-controlled, crossover study comparing Terminalia arjuna with isosorbide mononitrate.

BACKGROUND: Terminalia arjuna, an Indian medicinal plant, has been reported to have beneficial effects in patients with ischemic heart disease in a number of small, open studies. The need for a double-blind, randomized, placebo-controlled study with adequate sample size has long been felt. The bark extract (IPC-53) contains acids (arjunic acid, terminic acid), glycosides (arjunetin arjunosides I-IV), strong antioxidants (flavones, tannins, oligomeric proanthocyanidins), minerals. etc. and exhibits antifailure and anti-ischemic properties. METHODS AND RESULTS: Fifty-eight males with chronic stable angina (NYHA class II-III) with evidence of provocable ischemia on treadmill exercise test received Terminalia arjuna (500 mg 8 hourly), isosorbide mononitrate (40 mg/daily) or a matching placebo for one week each, separated by a wash-out period of at least three days in a randomized, double-blind, crossover design. They underwent clinical, biochemical and treadmill exercise evaluation at the end of each therapy which were compared during the three therapy periods. Terminalia arjuna therapy was associated with significant decrease in the frequency of angina and need for isosorbide dinitrate (5.69+/-6.91 mg/week v. 18.22+/-9.29 mg/week during placebo therapy, p<0.005). The treadmill exercise test parameters improved significantly during therapy with Terminalia arjuna compared to those with placebo. The total duration of exercise increased (6.14+/-2.51 min v. 4.76+/-2.38 min, p<0.005), maximal ST depression during the longest equivalent stages of submaximal exercise decreased (1.41+/-0.55 mm v. 2.21+/-0.56 mm, p<0.005), time to recovery decreased (6.49+/-2.37 min v. 9.27+/-3.39 min, p<0.005) and higher double products were achieved (25.75+/-4.81x10(3) v. 23.11+/-4.83x10(3), p<0.005) during Terminalia arjuna therapy. Similar improvements in clinical and treadmill exercise test parameters were observed with isosorbide mononitrate compared to placebo therapy. No significant differences were observed in clinical or treadmill exercise test parameters when Terminalia arjuna and isosorbide mononitrate therapies were compared. No significant untoward effects were reported during Terminalia arjuna therapy. CONCLUSIONS: Terminalia arjuna bark extract, 500 mg 8 hourly, given to patients with stable angina with provocable ischemia on treadmill exercise, led to improvement in clinical and treadmill exercise parameters as compared to placebo therapy. These benefits were similar to those observed with isosorbide mononitrate (40 mg/day) therapy and the extract was well tolerated. Limitations of this study include applicability of the results to only men with chronic stable angina but not necessarily to women, as they were not studied.

Adult↗

The alpha-1 adrenergic blocking agent urapidil counteracts postrotational atherectomy "elastic recoil" where nitrates have failed.

Calcium antagonist pretreatment and intracoronary high doses of nitrates (9 mg of isosorbide dinitrate) do not counteract coronary vasoconstriction occurring after rotational atherectomy. In 30 patients undergoing Rotablator atherectomy, intracoronary injection of the alpha 1-sympathetic blocker urapidil abolished or prevented significant vasoconstriction occurring 15 minutes after the procedure despite repeated injections of nitrates.

Adrenergic alpha-Antagonists↗

Pharmacology of nitroglycerin and long-acting nitrates.

Organic nitrates are available in a remarkably diverse variety of formulations, including sublingual, buccal and oral tablets, capsules, topical creams, ointments, patches, tapes, inhalable sprays and intravenous solutions. Although not all of these formulations are available in the United States, the array of drugs and dosages approved for use is extensive. It is only by weighing the pharmacologic properties of these agents against the patient's clinical status and needs that a concise and appropriate treatment regimen may be derived. Numerous recent studies have confirmed the protracted efficacy of the organic nitrates in the treatment of patients with angina pectoris and congestive heart failure (CHF) as evidenced by improvements in cardiac hemodynamics and desired clinical parameters. It is appropriate that the patient's dosage of nitrates be administered with a formulation most likely to be both clinically effective and well tolerated. The use of nitroglycerin and isosorbide dinitrate in the acute and chronic treatment of CHF will be discussed in the context of their unique pharmacologic and pharmacokinetic properties. A rationale for the most efficacious use of these agents will be presented. Tolerance phenomena and adverse effects (i.e., headache) will also be discussed from the perspective of their significance in chronic nitrate therapy.

Absorption↗

Prinzmetal's angina with documented coronary artery spasm. Treatment and follow-up.

Eighteen patients with Prinzmetal's angina were studied angiographically and 17 were followed for an average of 27 months. The were 12 men and six women, with a mean age of 46.3 years. The mean duration of symptoms before clinical diagnosis was 4.1 weeks. Four had had a previous myocardial infarction. Six patients had spontaneous cardiac arrests within 48 hours of diagnosis and hospital admission. At coronary arteriography, 10 patients had significant coronary artery disease; two of these had coronary artery spasm. The remaining eight patients had normal cornary arteries with significant coronary artery spasm at arteriography. Angiographic mitral valve prolapse was found in eight patients; seven of these had inferior ST segment elevation with pain. Six of the 10 patients with significant coronary artery disease had aortocoronary bypasses performed with good results. Ten of the remaining 11 patients who were treated medically had their symptoms controlled with oral isosorbide dinitrate alone or in combination with propranolol, nifedipine or perhexiline but propranolol may have an adverse effect. Though the initial clinical course in untreated patients was unfavourable, progress after starting treatment was good, with no further cardiac arrests, myocardial infarctions, or deaths.

Angina Pectoris↗

Influence of long-acting nitrate therapy on the risk of reinfarction, sudden death, and total mortality in survivors of acute myocardial infarction.

The effects of 20 variables that might influence postmyocardial infarction prognosis were assessed retrospectively in 139 patients followed up for an average of 11 months after discharge from San Francisco General Hospital following an acute myocardial infarction. When these variables were analyzed with the use of multivariate techniques, the presence of complex ventricular ectopy was the variable most highly predictive of the mortality rate, followed by age and failure to receive long-acting nitrates, principally isosorbide dinitrate (ISDN). Whereas 23 of 90 patients (25.6%) not receiving ISDN died, only 5 of the 49 patients (10%) receiving ISDN died (p less than 0.05). Although total mortality was statistically significantly greater among patients receiving antiarrhythmic drugs or digitalis than among patients not receiving these agents, these relationships did not persist when subjected to multivariate analysis.

Age Factors↗

Drug interactions with medical plastics.

Knowledge about drug interactions with plastic materials used in medical and surgical practice is at an elementary stage. Information that has appeared so far on the sorption of drugs to intravenous fluid containers, delivery sets, syringes, or other plastic apparatus has highlighted that polyvinyl chloride (PVC) is the major offender in this respect. Fortunately, in only a few cases is this sorption phenomenon and loss of drug from fluid likely to present a clinical hazard; in most instances, methods are available to prevent or overcome the problem, providing it is recognized. Current information suggests that the following drugs may exhibit clinically significant sorption to plastic materials: insulin, glyceryl trinitrate (nitroglycerin), diazepam, chlormethiazole, vitamin A acetate, isosorbide dinitrate, and a miscellaneous group of drugs including some phenothiazines, warfarin sodium, hydralazine hydrochloride, and thiopentone sodium. In addition, chloroquine binds strongly to glass and to cellulose acetate, but seemingly not to plastics. Brief details of these interactions and their management are given, together with some preliminary information and warnings on drug interactions (e.g., epinephrine, rifampicin) with hydrophilic contact lenses. The latter interactions may cause irreversible coloration of the lenses.

Adsorption↗

[Isotope study of the effects of a nitrate derivative on pulmonary blood volume. Application in the treatment of cardiogenic pulmonary edema].

Isotopic study of pulmonary and ventricular blood volumes after the ingestion of 5 mg of isosorbide dinitrate showed that cardio-pulmonary blood volume decreased by 380 ml without any change in total circulating blood volume. The demonstration of this effective "internal venesection" explains the fall in capillary pressure seen after the administration of nitrate derivatives. It justifies their use in the treatment of acute pulmonary oedema or refractory cardiac failure and explains the results observed.

Aged↗

The effect of prenylamine and organic nitrates on the bioenergetics of bovine catecholamine storage vesicles.

We have compared the cardioprotective agents prenylamine and glyceryl trinitrate (GTN) with respect to their effects on the bioenergetics of catecholamine storage vesicles. Chromaffin granule ghosts, which have a well preserved ability to actively transport and store catecholamines, were used as a model for adrenergic synaptic vesicles due to their functional similarity. Prenylamine, which partially and reversibly deplete the endogenous stores of noradrenaline in adrenergic nerves and ganglia, was found to inhibit the generation of the transmembrane proton electrochemical gradient driven by a H(+)-ATPase, mainly by acting as an uncoupler of this ATPase. The inhibition of the energy dependent dopamine uptake (and noradrenaline biosynthesis) by prenylamine could be accounted for by its effect on the bioenergetics of the storage vesicles. The organic nitrates glyceryl trinitrate and isosorbide dinitrate also partly inhibited the catecholamine uptake in parallel with their effects on the proton electrochemical gradient. It is concluded that GTN is a weak catecholamine depletor. Experiments with 3-morpholinosydnonimin-hydrochloride, a source of nitric oxide (NO), opens up the possibility that the mechanism of inhibition of the bioenergetics of chromaffin granule ghosts by GTN is mediated by NO.

Animals↗

Clinical experience with Imdur in angina pectoris. A review.

Imdur contains isosorbide-5-mononitrate (IS-5-MN) in a controlled-release (Durules) formulation. It has a significant anti-anginal effect when taken once daily at a dose of 60 mg. This anti-anginal effect persists during long-term treatment without the development of tolerance; once-daily treatment produces a plasma nitrate profile that is high enough to give anti-anginal protection during the daytime, but low enough during the latter part of the dosage interval to avoid the development of tolerance. Evidence shows that once-daily Imdur is equivalent in efficacy to plain tablets of IS-5-MN and isosorbide dinitrate taken three times daily at the same total daily dosage (60 mg), and to the calcium antagonist diltiazem (60 mg three times daily). In addition, the anti-anginal protection provided by Imdur in combination with beta-blocker treatment is superior to that achieved with beta-blocker treatment alone. In long-term studies Imdur has been shown to be well tolerated.

Adrenergic beta-Antagonists↗

[Myocardial revascularization in the developing phase of myocardial infarction using intracoronary thrombolytic therapy].

The author's experience on intracoronary thrombolysis on 71 patients that underwent coronary angiography in the first six hours of myocardial infarction is presented. The coronary artery responsible for the infarction was totally occluded in 66 cases and presented a subtotal occlusion in the remaining 5 cases. The protocol included the intracoronary injection of 2 mg isosorbide dinitrate and 78.000-385.000 U of streptokinase. An early reperfusion occurred in 66% of the patients, without mortality in the acute phase. ST-segment returned to normal in 41 of the 47 reperfused cases, but a Q wave developed in 42 cases. Hospital mortality was 6,4%, and the reocclusion rate was 17%.

Adult↗

Short and long-acting oral nitrates for stable angina pectoris.

Nitroglycerin (NTG) spray and sublingual tablets rapidly relieve an established attack of angina, and their infrequent use is not associated with the development of tolerance. Although, following a suitable nitrate-free interval, the first dose of oral, long-acting nitrates produces significant hemodynamic effects, increases angina free walking, and decreases exercise-induced ischemia, during continued long-term therapy tolerance limits their usefulness. Appropriate dosing regimens of controlled-release formulations of isosorbide dinitrate (ISDN) and controlled-release NTG during long-term therapy have not been established. Use of immediate-release formulation of 15-120 mg of ISDN in a qid regimen lead to a marked reduction in the size and duration of antianginal effects compared to the initial dose. Asymmetric tid therapy with 30 mg of ISDN (7 a.m., 1 p.m., and 6 p.m.) is also associated with the development of partial tolerance and appears to provide antianginal prophylaxis for only a period of 6 hours each day. Asymmetric bid therapy with ISDN at 7 a.m. and noon may give sustained effect but is supported by only a single, small study that did not examine effectiveness after the noon dose in long-term use. Isosorbide-5-mononitrate (IS-5-MN) has been the subject of more recent studies than other nitrates because of attempts to bring a number of products into the U.S. market. IS-5-MN in qid, tid, and standard bid (8 a.m. and 8 p.m.) dosing regimens produce tolerance. Asymmetric regimens of immediate-release IS-5-MN (10 and 20 mg) given bid (once in the morning and again 7 hours later) decrease the development of tolerance compared to symmetric regimens and produce an increased exercise duration after each dose of the day; the 20 mg bid dosing is more effective. Similarly, once-daily 120 and 240 mg controlled-release IS-5-MN does not produce tolerance and gives a sustained increase in daytime exercise duration. Both asymmetric bid immediate-release and once-daily controlled-release IS-5-MN preparations do not produce deterioration in exercise performance prior to the administration of the medication in the morning (i.e., no zero-hour effect). Further studies are needed to establish useful dosing regimens for ISDN, for controlled-release ISDN, and for controlled-release nitroglycerin. None of the dosing regimens of any oral, long-acting nitrate (including IS-5-MN) provide 24 hour antianginal and antiischemic effects.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Oral↗

Combined vasodilator therapy in the treatment of chronic heart failure.

Treatment of resistant congestive cardiac faiure by vasodilators is now well accepted. Twelve such patients were started on Isosorbide Dinitrate and Hydralazine therapy and monitored for 24 hours. Oral treatment was then continued indefinitely. This group responded well to combined therapy and four had their regimes altered in the light of haemodynamic observations. It was then concluded that this type of treatment can be tailored to the individual patient to produce the best effects on preload and afterload.

Blood Pressure↗

The significance of some noninvasive methods in the objective evaluation of treatment of patients with coronary artery disease.

A measurement of STI and Bcg was used to provide an objective evaluation of the results of isosorbide dinitrate treatment of 120 patients suffering from coronary artery disease. Normalization of STI and Bcg in patients reporting subjective improvement following treatment was observed in a greater number of cases than the number with ECG normalization. Therefore, it can be concluded that after effective treatment measurement of STI AND Bcg provides a more sensitive means of objective evaluation than ECG.

Adult↗

Insulin resistance relates to acetylcholine-induced microvascular vasoconstriction in a patient with vasospastic angina: potential implication of causalities between hyperinsulinemia and coronary microcirculation failure.

Coronary vasomotor response to acetylcholine infusion was studied in a 69-year-old currently smoking man with enhanced insulin response to oral glucose load. Coronary angiogram showed no significant stenoses. Immediately after 20 microg acetylcholine infusion in the right coronary artery, angiographic no-flow, ischemic electrocardiographic changes, and anginal pain developed in the absence of epicardial coronary obstruction. While intracoronary infusion of isosorbide dinitrate was only partially effective, intracoronary infusion of nicorandil, an agent known to improve coronary microcirculation, completely resolved these changes. This is the first case reported so far suggesting that enhanced insulin response may be associated with acetylcholine-induced microvascular vasoconstriction. Microvascular vasoconstriction must be considered when a patient with insulin resistance presents with chest pain.

Acetylcholine↗

Is post-infarction angina related to poor residual left ventricular function?

To investigate the relationship between left ventricular function and presence and type of myocardial ischaemia in the post-acute phase of myocardial infarction (MI) 313 patients admitted consecutively to our Center of Rehabilitation were studied. In all subjects a good quality two-dimensional echocardiogram, 24-h ambulatory electrocardiogram and in 308 of them a symptom-limited exercise test were performed. Clinical observation was for 3 months since MI occurrence. Transient episodes of post-MI ischaemia were observed in 164 patients (52%). No differences in left ventricular asynergy or ejection fraction were noted among patients with and without post-MI ischaemia as a whole, nor in subsets identified on the basis of occurrence of pain or ischaemia characteristics (at rest or exercise-induced). Episodes of left ventricular failure occurred more frequently in patients with silent, myocardial ischaemia at rest. Sublingual isosorbide dinitrate (5 mg), administered to 20 patients, did not differently change asynergy and ejection fraction in patients with and without documented post-MI ischaemia. In conclusion, extent of asynergy and degree of left ventricular dysfunction at rest seem to be: unrelated to the risk of post-MI ischaemia occurrence; related to the infarct size and not to the presence of stunned myocardium.

Aged↗