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PubMed2002

Dual effect of local application of nitric oxide donors in a model of incision pain in rats.

The effects of local application of a cream containing nitric oxide (NO) donors, S-nitroso-N-acetylpenicillamine (SNAP) or isosorbide dinitrate were studied in a rat model of incision pain. An incision was made in the plantar aspect of a hind paw and the cream was applied inside the surgical wound. SNAP (1-10%) or isosorbide (2.5-5%) reduced the incision allodynia as measured with von Frey filaments. Higher concentrations produced a smaller or no effect, but SNAP (30%) intensified the allodynia. Allodynia was also intensified by SNAP (5% or 30%) in rats pretreated with intraplantar 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one (ODQ, 4 microg), a guanylate cyclase inhibitor. The effect of isosorbide (5%) was prevented by ODQ. The cream containing SNAP released 10- to 20-fold more nitrite than did isosorbide from a macrophage culture. We conclude that local application of drugs generating a low NO concentration reduces incision pain through activation of guanylate cyclase. Drugs generating high NO concentrations, however, intensify pain via a guanylate cyclase-independent mechanism.

Animals↗
PubMed1997

Purification, properties, and sequence of glycerol trinitrate reductase from Agrobacterium radiobacter.

Glycerol trinitrate (GTN) reductase, which enables Agrobacterium radiobacter to utilize GTN and related explosives as sources of nitrogen for growth, was purified and characterized, and its gene was cloned and sequenced. The enzyme was a 39-kDa monomeric protein which catalyzed the NADH-dependent reductive scission of GTN (Km = 23 microM) to glycerol dinitrates (mainly the 1,3-isomer) with a pH optimum of 6.5, a temperature optimum of 35 degrees C, and no dependence on metal ions for activity. It was also active on pentaerythritol tetranitrate (PETN), on isosorbide dinitrate, and, very weakly, on ethyleneglycol dinitrate, but it was inactive on isopropyl nitrate, hexahydro-1,3,5-trinitro-1,3,5-triazine, 2,4,6-trinitrotoluene, ammonium ions, nitrate, or nitrite. The amino acid sequence deduced from the DNA sequence was homologous (42 to 51% identity and 61 to 69% similarity) to those of PETN reductase from Enterobacter cloacae, N-ethylmaleimide reductase from Escherichia coli, morphinone reductase from Pseudomonas putida, and old yellow enzyme from Saccharomyces cerevisiae, placing the GTN reductase in the alpha/beta barrel flavoprotein group of proteins. GTN reductase and PETN reductase were very similar in many respects except in their distinct preferences for NADH and NADPH cofactors, respectively.

Amino Acid Sequence↗
PubMed1997

Smooth muscle cell expression of type I cyclic GMP-dependent protein kinase is suppressed by continuous exposure to nitrovasodilators, theophylline, cyclic GMP, and cyclic AMP.

A key component of the nitric oxide-cyclic guanosine monophosphate (cGMP) pathway in smooth muscle cells (SMC) is the type I GMP-dependent protein kinase (PK-G I). Activation of PK-G I mediates the reduction of cytoplasmic calcium concentrations and vasorelaxation. In this manuscript, we demonstrate that continuous exposure of SMC in culture to the nitrovasodilators S-nitroso-N-acetylpenicillamine (SNAP) or sodium nitroprusside (SNP) results in approximately 75% suppression of PK-G I mRNA by 48 h. PK-G I mRNA and protein were also suppressed by continuous exposure to cGMP analogues 8-bromo- and 8-(4-chlorophenylthio) guanosine-3,5-monophosphate or the cAMP analogue dibutyryl cAMP. These results suggest that activation of one or both of the cyclic nucleotide-dependent protein kinases mediates PK-G I mRNA suppression. Using isoform-specific cDNA probes, only the PK-G I alpha was detected in SMC, either at baseline or after suppression, while PK-G I beta was not detected, indicating that isoform switch was not contributing to the gene regulation. Using the transcription inhibitor actinomycin D, the PK-G I mRNA half-life in bovine SMC was observed to be 5 h. The half-life was not affected by the addition of SNAP to actinomycin D, indicating no effect on PK-G I mRNA stability. Nuclear runoff studies indicated a suppression of PK-G I gene transcription by SNAP. PK-G I suppression was also observed in vivo in rats given isosorbide dinitrate in the drinking water, with a dose-dependent suppression of PK-G I protein in the aorta. PK-G I antigen in whole rat lung extract was also suppressed by administration of isosorbide or theophylline in the drinking water. These data may contribute to our understanding of nitrovasodilator resistance, a phenomenon resulting from continuous exposure to nitroglycerin or other nitrovasodilators.

Animals↗
PubMed1997

Quantitative determination of pentaerythrityl tetranitrate and its metabolites in human plasma by gas chromatography/mass spectrometry.

Up to now, there has been no data available on the pharmacokinetics of pentaerythrityl tetranitrate (PETN, CAS 78-11-5) and its metabolites, pentaerythrityl-trinitrate (PE-tri-N), pentaerythrityl-dinitrate (PE-di-N), pentaerythrityl-mononitrate (PE-mono-N) in human plasma. Therefore, in order to determine PETN and its metabolites in plasma sensitive and highly selective GC/MS methods had to be developed and validated. PETN and its metabolite PE-tri-N were validated in the concentration range 50 pg/ml to 10 ng/ml. Isosorbide dinitrate (ISDN) was used as the internal standard and the analytes were extracted with dichloromethane from the plasma. The mass spectrometric tests were carried out using chemical ionization in the negative mode (NlCl) with the application of ammonia as a reagent gas. The nitrate ion m/z 62 was determined in the analytes and internal standard. The accuracy of the mean of the quality control samples during the three days (between days) was between 100 and 110% (PETN), as well as 90 and 106% (PE-tri-N). After an oral application of 100 mg PETN in a pilot study, unchanged PETN and PE-tri-N was measured in plasma. Both metabolites PE-di-N and PE-mono-N were validated at the concentration range of 0.25 ng/ml to 25 ng/ml plasma. After extraction, these analytes were derivatized with BSTFA (N,O-bis[trimethylsilyl]trifluoro-acetamide). The applied internal standard was isosorbide-5-mononitrate (IS-5-MN). The mass spectrometric tests were carried out in the same manner as for PETN and PE-tri-N with chemical ionization in the NlCl mode. The detected masses were m/z 324 for PE-di-N, m/z 351 for PE-mono-N and m/z 217 for IS-5-MN. The accuracy of the mean of the quality control samples during 5 days were between 104 and 107% (PE-di-N) and 102 and 106% (PE-mono-N). The maximum concentration of these analytes in the subject samples were on the average all over 5 ng/ml plasma after the oral administration of 100 mg PETN.

Calibration↗
PubMed1993

New approaches in the pharmacologic treatment of portal hypertension.

To alleviate the risk of variceal bleeding, the portal pressure gradient--usually evaluated as the hepatic venous pressure gradient (HVPG)--must be reduced to < or = 12 mmHg. Although beta-blocking agents are accepted therapy for preventing first or subsequent bleeding episodes, propranolol therapy decreases final HVPG to < or = 12 mmHg in only 12% of patients, while only 24% of patients have a > or = 20% reduction in HVPG and nearly 40% show no reduction in HVPG. This has stimulated research on alternative or additional treatments. Nitrates such as isosorbide dinitrate reduce portal pressure by decreasing resistance to portal and collateral blood flow and by promoting reflex splanchnic vasoconstriction. However, while nitrates are effective in the acute situation, tolerance leading to refractoriness develops over the long term unless they are combined with diuretics or other agents in the treatment of portal hypertension. Propranolol and isosorbide-5-mononitrate combined cause a substantially greater reduction in HVPG than monotherapy with either drug in both acute and long-term use. Presumably concomitant isosorbide-5-mononitrate administration opposes the increase in portal resistance induced by propranolol. Spironolactone, which has been shown to lower HVPG in patients with cirrhosis, produces a reduction in plasma volume that attenuates the increased cardiac output associated with cirrhosis and triggers vasoactive mechanisms that decrease splanchnic blood flow. Potentially, spironolactone may maintain and enhance the decrease in portal pressure achieved by nitrates or propranolol. Triple therapy with a beta-blocker, a nitrate and spironolactone may be feasible.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1994

Costs and effectiveness of angiotensin converting enzyme inhibition in patients with congestive heart failure.

BACKGROUND: Chronic heart failure is associated with a poor prognosis and reduced survival rates. The addition of vasodilator drug therapy to conventional therapy for congestive heart failure has resulted in improved survival. METHODS: Adopting a societal viewpoint, we designed a decision analytic model to analyze the costs and effectiveness of three therapies available for the treatment of congestive heart failure: standard therapy (digoxin and diuretic therapy) plus (1) no vasodilator agents, (2) hydralazine hydrochloride-isosorbide dinitrate combination, and (3) enalapril. In addition, we performed sensitivity analyses to determine which model variables were influential in determining incremental cost-effectiveness ratios (cost of drug, cost of hospitalization, efficacy of agents, etc). We used data from three major randomized controlled trials to estimate treatment efficacy, mortality rates, and hospitalization rates. RESULTS: An additional year of life gained by a patient receiving hydralazine-isosorbide combination therapy compared with standard therapy required an additional expense (incremental cost-effectiveness ratio) of $5600. Compared with the hydralazine-isosorbide combination therapy, the incremental cost-effectiveness ratio for enalapril therapy was $9700 per year of life saved. These results were insensitive to wide variations in our baseline assumptions. CONCLUSIONS: The cost per year of life saved by vasodilator therapy is much lower than that of other accepted medical therapies. Although the cost per year of life saved for hydralazine-isosorbide combination therapy is lower than that for enalapril therapy, enalapril therapy saves more lives, and the incremental cost of enalapril therapy is justified by the added benefits.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

Myocardial ischemia induced by topical use of 5-fluorouracil.

An 85-year-old woman, with known stable angina pectoris, was prescribed 5-fluorouracil cream to treat a small basal cell carcinoma on the forehead. Half an hour after application the patient developed her typical ischemic pain which persisted for 2 hours. Rechallenge, during hospitalization, resulted in recurrence of symptoms that were effectively controlled with sublingual isosorbide dinitrate. Prophylactic therapy with nitroglycerin patch enabled further use of the 5-fluorouracil cream for the next month.

Administration, Topical↗
PubMed2004

[Therapy with NO donors-antiatherogenic and antioxidant actions].

Nitric acid esters such as glyceryl trinitrate were introduced into therapy more than a century ago and are still widely used for the treatment of myocardial ischemia and its main symptom angina pectoris. The basic mechanisms responsible for the vasodilatory and anti-ischemic action of organic nitrates involve bioactivation of, and nitric oxide (NO) release from, these compounds which have therefore been termed NO donors. The organic nitrate pentaerythritol tetranitrate (PETN) is known to possess antioxidant properties that are thought to be the underlying cause for its specific pharmacological profile. In contrast to other long-acting nitrates, PETN induces tolerance- free vasodilation in humans and was reported to prevent endothelial dysfunction as well as atherogenesis in cholesterol- fed rabbits. However, the exact nature of the vasoprotective signaling pathways triggered by PETN has remained obscure. The present study demonstrates that the active PETN metabolite PETriN stimulates protein expression of the antioxidant defense protein heme oxygenase-1 (HO-1; Figures 1 and 2). Additionally, PETriN enhanced the enzymatic activity of HO-1 measured as formation of the HO-1 metabolites bilirubin (Figure 3) and carbon monoxide (Figure 4) in lysates from endothelial cells. HO-1 induction subsequently led to a marked increase in protein expression of a second antioxidant protein, ferritin, via the HO-1-dependent release of free iron from endogenous heme sources (Figures 1 and 5). Pretreatment of endothelial cells with PETriN was followed by increased cellular resistance to oxidant injury mediated by hydrogen peroxide (Figure 6). Endothelial protection by PETriN was mimicked by exogenous bilirubin which led to an almost complete reversal of hydrogen peroxide-induced toxicity (Figure 8). Increased HO-1 and ferritin expression as well as endothelial protection occurred at micromolar concentrations of PETriN which are well within the range of plasma or tissue levels that can be expected during oral therapy. The capacity to protect the endothelium in vitro may translate into and explain the previously observed antiatherogenic actions of PETN in vivo. In this study, another long-acting nitrate, isosorbide dinitrate (ISDN), did not protect endothelial cells from oxidant damage (Figure 6). The absence of significant cytoprotection in the presence of ISDN was paralleled by a lack of HO-1 and ferritin stimulatory capacity (Figures 2 and 5). ISDN had no significant effect on carbon monoxide release or bilirubin formation (Figures 3 and 4). These observations are in agreement with results demonstrating small or nondetectable amounts of NO released from ISDN and its active metabolite isosorbide mononitrate (ISMN) measured as cyclic GMP formation in RFL-6 reporter cells (Figure 7). Interestingly and in contrast to PETN, isosorbide nitrates are known to induce tolerance to their cardiovascular effects, presumably via oxidant stress. Moreover, in earlier investigations aimed at assessing the antiatherogenic potential of nitrates, PETN but not isosorbide nitrates prevented plaque formation and endothelial dysfunction in animal models of atherosclerosis. Thus, the ability to activate HO-1 induction and associated antioxidant pathways apparently distinguishes PETN from other long-acting nitrates and may explain their different patterns of action in vivo (Figure 9).

Animals↗
PubMed1991

[Drug treatment of myocardial ischemia].

Nitrates are the basic medication of patients suffering from coronary heart disease. Frequently they are combined with calcium-antagonists or beta-receptor-blocking agents. The dose of 20 mg non-retarded dinitrates or mononitrates three times a day have the same effect as retarded nitrates once a day but of a higher dose (60-120 mg). The meaning of this drug has increased because of new results on the mechanism of action: nitric oxide is able to substitute the missing EDRF in the injured intima and leads to dilatation of the stenosis. This mechanism is the basis for the antianginal effect. Already minimal doses (0.025 mg nitroglycerine i.v. 1.25 mg isosorbide dinitrate oral) are effective independent of the dilatation of peripheral venous and arterial vessels. The antiaggregatory effect decrease thrombus formation in patients with unstable angina and the risk of infarction and produce a kind of rinsing effect in the stenosis. The size of infarction becomes smaller, the expansion of the ventricle is less and the prognosis improved. Concerning the calcium-antagonists dihydropiridine-preparations, verapamil and diltiazem have to be separated. Arterial vasodilatation of nifedipine may increase heart rate during exercise and rarely coronary steel phaenonemen. In contrast verapamil (3 x 120 mg) and gallopamil (3 x 50 mg) have strong antianginal effects and reduce the ischemic reaction during exercise about 50%. Heart rate is reduced during physical exercise, similar to the beta-receptor-blocking agents. AV-blocks are rare. Obstipation is more frequent with verapamil than with gallopamil. Verapamil decreases the infarct size and improves the prognosis after infarction in patients without left ventricular failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1990

Dissociation of platelet activation and spontaneous myocardial ischemia in unstable angina.

A dynamic thrombotic process, coronary spasm or both can be responsible for recurrent episodes of transient reduction of coronary blood flow in unstable angina. We have investigated the temporal relationship between episodic platelet activation, as detected by increased urinary excretion of 11-dehydro-TXB2, and spontaneous myocardial ischemia, assessed by continuous electrocardiographic monitoring and recording in 21 patients with unstable angina pectoris. In order to validate measurements of metabolite excretion as a reflection of intracoronary platelet activation, we have also performed repeated urine sampling from 8 patients undergoing PTCA and from 6 patients with peripheral vascular disease. The latter showed a 16% coefficient of variation in 3 consecutive 8-h urine samples. 11-dehydro-TXB2 increased significantly, by up to 15-fold, in the 2.5- to 5.0-h urine collection encompassing PTCA and decreased by greater than 50% during the following 2-h period. Patients with unstable angina were characterized by episodic increases (greater than 2 SD of controls) in metabolite excretion, in successive 6-8 h specimens. Paired measurements of 11-dehydro-TXB2 and 2,3-dinor-TXB2 in 15 urine samples did not reveal evidence of altered metabolic disposition of endogenously released TXB2. A total of 125 ECG ischemic episodes were recorded, of which 64% asymptomatic. We have compared these biochemical and ECG changes in patients randomized to i.v. low-dose aspirin or i.v. isosorbide dinitrate and oral diltiazem. Twenty-five of 56 (i.e. 45%) urine samples obtained in aspirin-free periods showed increased metabolite excretion as compared to 15 of 88 (i.e. 17%) samples collected during aspirin.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1981

[Hourly distribution of episodes of angina at rest. Effect of medical treatment].

Aim of the study was to evaluate whether frequency of myocardial ischemic attacks at rest (IA) had any identifiable distribution during 24-hour periods. Two ECG leads were continuously recorded by an Oxford 4-24 tape recorder for a total of 148 days in 10 patients admitted to CCU because of frequent spontaneous anginal attacks. During 48 days, in absence of therapy, 682 IA were recorded (2.03 per patient per day). They showed a symmetrical bell-shaped distribution curve in the 24 hour periods with a peak occurring at 5 a.m. and 43% of IA from 0 to 6 a.m. Only 25% of IA was symptomatic with the lowest values (10%) between 2 and 6 a.m. Distribution of IA was independent from their distinctive electrocardiographic feature [ST (71%) or T changes]. During 100 days with therapy [Verapamil and/or Isosorbide dinitrate ointment) a marked reduction of episodes was observed (0.64 per patient per day), while their distribution, the incidence of different electrocardiographic patterns and percentage of symptomatic IA remained unchanged. Attenuated incidence, but inalterated distribution of IA with therapy suggest its possible effect on the threshold response of coronary smooth muscle to vasoconstrictor stimuli rather than its primary effect on pathogenetic factors.

Adult↗
PubMed2006

Coronary artery spasm and the polymorphisms of the endothelial nitric oxide synthase gene.

BACKGROUND: Coronary artery spasm plays an important role in the pathogenesis of vasospastic angina, and contributes to the development of several acute coronary syndromes. Endothelial nitric oxide synthase (ecNOS) catalyzes the synthesis of nitric oxide, which regulates vascular tone, and may be related to coronary vasospasm. The present study investigated whether coronary spasm is related to particular polymorphisms of the ecNOS gene. METHODS AND RESULTS: Spasm provocation by serial infusions of acetylcholine was performed on 165 patients who were clinically suspected of having angina. In both study patients and healthy controls (n=400), genomic polymorphisms of the ecNOS gene were determined by using polymerase chain reaction. Quantitative luminal diameter measurements of the 3 major coronary arteries were initially obtained before and after acetylcholine injection, and then after isosorbide dinitrate injection, by using a computer-assisted analysis system. Logistic multiple regression analysis identified the a/a or a/b genotype in intron 4 of ecNOS (NOS4a: p=0.0431, odds ratio (OR) 2.43) and diabetes mellitus (p=0.0060, OR 4.88) as significant predictors of coronary spasm. In the patients with NOS4a, both the induced and spontaneous contractions were augmented. CONCLUSION: The present study results indicated that NOS4a could be a good marker for coronary artery spasm.

Acetylcholine↗
PubMed1999

Topical vasoactive cream in the treatment of erectile failure: a prospective, randomized placebo-controlled trial.

OBJECTIVE: To repeat a previous study on the use of a topical treatment for erectile failure using a vasoactive cream. PATIENTS AND METHODS: Fourteen patients with erectile failure who had previously responded to intracorporeal injection therapy were enrolled in a randomized placebo-controlled trial. They were given two topical applications, comprising either a cream containing aminophylline, isosorbide dinitrate and co-dergocrine mesylate, or a placebo cream of similar appearance containing no pharmacologically active ingredients. Each patient received 16 applications, eight of the active cream and eight placebo. The creams were applied alternatively on successive occasions and the results recorded. RESULTS: The active cream, applied on 77 occasions, resulted in three good and 13 partial erections. The placebo cream, applied on 76 occasions, yielded four good and 13 partial erections. CONCLUSIONS: We were unable to reproduce the successful results reported by others; in the present study the active cream performed no better than placebo.

Adult↗
PubMed1992

Agreement and reproducibility of the estimates of cardiovascular function by impedance cardiography and M-mode echocardiography in healthy subjects.

The reproducibility and agreement of the estimates of stroke volume (SV), cardiac output (CO) and total peripheral resistance (TPR) by transthoracic impedance cardiography (ZCG) and M-mode echocardiography (ECHO) were analyzed before and after the placebo-controlled administration of ascending doses of isosorbide dinitrate and nicorandil in 12 healthy subjects. There was no biostatistical agreement between the two methods in estimating cardiovascular function either before or after dosing (ZCG estimated substantially larger SV, CO and lower TPR). But, ZCG and ECHO estimated about similar overall treatment related changes (across treatments and periods) and reached substantially better agreement when the values were expressed as ratio of the baseline before dosing. Such improvement did not occur when the data were expressed as arithmetic difference from baseline. In spite of the improvement of agreement by expressing the data as ratio of baseline, the coefficients of reproducibility between the two methods (circa 25% of baseline) remained too large to judge the methods interchangeable.

Adult↗
PubMed1988

The vasorelaxant effects of milrinone and other vasodilators are attenuated by ouabain.

The purpose of this study was to investigate the effect of ouabain pretreatment (1 microM) on relaxation induced by milrinone and other reference vasorelaxants in guinea pig aorta. Pretreatment with ouabain for 1 h significantly reduced the threshold concentration and increased the vasoconstrictor potency of phenylephrine. Relaxation by milrinone of aortic rings contracted by phenylephrine or by an equieffective concentration of phenylephrine in the presence of ouabain was significantly attenuated in the presence of ouabain. The effect of all other vasorelaxants tested, which included isosorbide dinitrate, hydralazine, sodium nitroprusside, forskolin, HA 1004, isoproterenol and verapamil, were also significantly reduced in the presence of ouabain. The vasorelaxant effects of milrinone and verapamil were also evaluated in K+-contracted guinea pig aorta. In contrast to results obtained with phenylephrine-contracted vessels, milrinone and verapamil were equipotent as vasorelaxants in K+-contracted vessels in the presence or absence of ouabain. The results show that ouabain not only potentiates the effect of the vasoconstrictor phenylephrine, but also reduces the potency of drugs that cause vasorelaxation in phenylephrine-contracted tissues, regardless of the mechanism of action of the vasorelaxant. These data may have clinical relevance to the concomitant use of vasodilators and digitalis in the treatment of congestive heart failure.

Animals↗
PubMed1990

[Effect of vasodilator agents on the character and incidence of cardiac arrhythmia in chronic heart failure].

In 50 patients with chronic congestive heart failure (CCHF, III or IV class), aged 62.8 +/- 9.1 years, who were treated with digoxin (Dx) and furosemide (F) (investigation A), continuous 24-hour ecg registration was performed according to Holter. Next, this treatment was extended by two-week administration of nifedipine (N) or isosorbide dinitrate (S) (investigation B), followed by one-month addition of captopril (Cp) (investigation C). During the last two weeks Dx, F, N or Dx, F, S were administered with Cp being withdrawn (investigation D). At the end of each stage of the treatment ecg registration was repeated according to Holter. At the same time, during the investigation A there were performed determinations of blood serum sodium, potassium and digoxin concentrations, two-dimensional echocardiography and evaluation of submaximal exercise tolerance. In 96 per cent of patients with CCHF, treated with Dx and F, cardiac rhythm disturbances were found. In 53.3 per cent life-threatening ventricular arrhythmias occurred, including unstable ventricular tachycardia in 11.1 per cent of patients. Addition of N or S to the classical treatment did not decrease either patient number or amounts of cardiac rhythm disturbances in individual classes according to Lown. Also Cp did not affect numbers of patients with cardiac rhythm disturbances, but it decreased numbers of patients with life-threatening ventricular arrhythmias from 53.3 per cent to 28.9 per cent (from 24/45 to 13/45). At the same time, Cp significantly decreased numbers of ventricular arrhythmias in class 3 and 4a (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Patterns of coronary artery stenosis vasomotion: observed versus "predicted" stenosis reactivity in patients with chronic stable angina.

BACKGROUND: Patterns of constriction and dilatation of angiographically normal coronary artery segments and coronary stenoses, in response to vasoactive stimuli, remain speculative. METHODS: We compared the vasomotor response of angiographically normal and stenotic coronary segments and assessed the effects of stenosis location and morphology on coronary stenosis vasomotion in 52 patients with chronic stable angina (40 men and 12 women) who underwent intracoronary ergonovine or isosorbide dinitrate administration or both. Changes in coronary diameter in response to nitrate and ergonovine were assessed by computed arteriography. The "predicted" change in stenosis diameter was calculated according to the "geometric theory" (based on the vasomotor response of angiographically normal segments adjacent to the lesion and on stenosis severity). Coronary diameter was assessed at baseline and after nitrate administration in 58 stenoses (34 concentric and 24 eccentric), of which 40 were located proximally and 18 distally, and also after ergonovine administration (23 stenoses: 14 proximal and 9 distal, 14 concentric and 9 eccentric). RESULTS: Significant (> or = 10% lumen diameter change) vasoconstriction was observed after ergonovine administration in 14 of the 23 stenoses (61%), and significant vasodilation was noted after nitrate administration in 29 of 58 stenoses (50%). A larger proportion of distal (89%) and eccentric (89%) compared with proximal (43%) and concentric (43%) stenoses showed a greater than 10% vasoconstriction after ergonovine administration (P < 0.05). Vasodilatation after nitrate administration was also observed in a larger proportion of distal (78%) and eccentric (67%) than in proximal (38%) and concentric (38%) stenoses (P < 0.05). On average, the "observed" changes in coronary diameter in response to nitrate and ergonovine administration were of significantly less magnitude than those "predicted" by the geometric theory in both proximal and distal stenoses and in concentric and eccentric stenoses. In only 17% of stenoses were observed and predicted vasoconstriction similar. CONCLUSIONS: Our results suggest that in patients with chronic stable angina, calculations based on the "geometric theory" cannot predict the actual vasomotor response of a stenosis. Factors other than severity, such as baseline coronary tone, stenosis location, and stenosis morphology, appear to modulate stenosis vasomotion in vivo.

Adult↗
PubMed2001

Treatment of congestive heart failure: guidelines for the primary care physician and the heart failure specialist.

During the past 10 years, the philosophy of heart failure treatment has evolved from symptom control to a combined prevention and symptom-management strategy. Recent clinical trials have proved that early detection can delay progression. Treatment of asymptomatic left ventricular dysfunction is as important as treatment of symptomatic disease. The purpose of this review is to simplify recent guidelines for pharmacological management of chronic systolic heart failure for the primary care physician and the heart failure specialist. Early recognition and prevention therapies, combined with lifestyle modification, are essential in the treatment of heart failure. Therapy with angiotensin-converting enzyme inhibitors, beta-blockers, and diuretics is now standard. Digoxin is added to improve clinical symptoms, especially in patients with atrial fibrillation. Aldosterone antagonists may be recommended in select patients with stable New York Heart Association class III or IV heart failure. If angiotensin-converting enzyme inhibitors are not tolerated, angiotensin receptor blockers, hydralazine hydrochloride, and isosorbide dinitrate are recommended. The data on antiarrhythmic and anticoagulation therapies are inconclusive.

Adrenergic beta-Antagonists↗