cyclic-gmp and Angina-Pectoris

Topics: Angina Pectoris; Coronary Circulation; Coronary Disease; Cyclic GMP; Cytochrome P-450 Enzyme System; Humans; Muscle, Smooth, Vascular; Nitrates; Nitric Oxide

The organic nitrates exert the same pharmacological actions. They differ in potency and in pharmacokinetics. They are more potent as dilators of veins than of arteries/arterioles and more potent as dilators of large arteries than of arterioles. This hemodynamic profile decreases heart work mainly by preload reduction but to some extent also by afterload reduction. The coronary flow is relatively improved and a redistribution to the ischemic myocardium takes place. The nitrates may facilitate the dissociation of oxygen from oxyhemoglobin and also may cause a more efficient energy metabolism. The basal mechanisms of action involve-SH groups and consecutively cyclic GMP. Glyceryl trinitrate is denitrated faster by the liver than is isosorbide dinitrate. The first pass metabolism is easily circumvented by sublingual and dermal application. Oral administration requires large dosages. Metabolites may contribute to the pharmacological activity. Plasma concentrations cannot be used to predict clinical effects of the nitrates.

Topics: Angina Pectoris; Animals; Arterioles; Coronary Circulation; Coronary Vessels; Cyclic AMP; Cyclic GMP; Drug Tolerance; Humans; Inactivation, Metabolic; Isosorbide Dinitrate; Liver; Muscle, Smooth, Vascular; Myocardium; Nitrates; Nitroglycerin; Oxyhemoglobins; Vasodilation; Venous Pressure

We tested the hypothesis that asymmetric dimethylarginine (ADMA) levels could be elevated and influence endothelin-1 and nitric oxide release and action in patients with cardiac syndrome X (CSX). In addition, we evaluated whether an intravenous infusion of L-arginine would improve endothelial function in these subjects.. Nine patients with CSX and 14 control subjects underwent a continuous infusion of L-arginine (0.125 g/min) or saline for 120 minutes. Sixty minutes after L-arginine or saline infusions, an intravenous insulin bolus (0.1 U/kg) combined with a euglycemic clamp was performed. Basal ADMA and endothelin-1 levels were higher in patients with CSX than in controls. At the end of the first hour of infusion, compared with saline, L-arginine infusion increased basal forearm blood flow, nitrite and nitrate (NOx), and forearm cGMP release and decreased endothelin-1. After insulin bolus, during saline, insulin-induced NOx, endothelin-1, and forearm cGMP release was almost abolished. Conversely, L-arginine restored a physiological profile of all endothelial variables compared with control subjects. In control subjects, compared with saline infusion, L-arginine infusion did not modify any parameter. ADMA levels were positively correlated with basal endothelin-1 levels and negatively correlated with insulin-induced incremental levels of NOx and forearm cGMP release.. Plasma ADMA levels are increased in patients with CSX, and they are correlated with increases in endothelin-1 and reductions in insulin-induced increments in plasma NOx and cGMP, effects that are reversed by intravenous L-arginine. These data suggest that increased ADMA levels play a role in the abnormal vascular reactivity that is observed in patients with CSX.

Topics: Angina Pectoris; Arginine; Blood Pressure; Coronary Angiography; Cyclic GMP; Endothelin-1; Endothelium, Vascular; Female; Forearm; Humans; Infusions, Intravenous; Insulin; Male; Middle Aged; Nitric Oxide; Regional Blood Flow; Syndrome

To examine whether the prophylactic antianginal agent perhexiline potentiates platelet responsiveness to nitric oxide (NO) in patients with stable angina pectoris (SAP) and acute coronary syndromes (ACS: unstable angina pectoris or non-Q-wave myocardial infarction).. Blood samples were obtained from patients before and after initiation of treatment with perhexiline. ADP-induced platelet aggregation and its inhibition by the NO donor sodium nitroprusside (SNP) were determined via impedance aggregometry in whole blood (WB) and platelet-rich plasma (PRP). Intraplatelet cGMP content was assayed by RIA, and superoxide (O(2)(-)) level by lucigenin-derived chemiluminescence. In patients with ACS not receiving perhexiline (n=12), platelet responsiveness to SNP did not vary significantly over the first 3 days post admission to hospital. Therapy with perhexiline for 3 days was associated with increases in SNP-induced inhibition of aggregation from 29+/-2% to 43+/-4% (n=50,P <0.001) in WB and from 20+/-5% to 42+/-7% (n=12, P<0.01) in PRP. Resolution of symptomatic ischaemia (n=39) was associated with significantly greater (P<0.01) increases than non-resolution (n=11). Similar increases in SNP responsiveness (P<0.001) occurred following institution of perhexiline therapy in patients with SAP (n=30), associated with a 85% decrease in anginal frequency. Treatment with perhexiline potentiated the cGMP-elevating effects of SNP in platelets (n=9,P =0.03). Although perhexiline did not alter whole blood O(2)(-) concentration ex vivo, it inhibited (P<0.01) O(2)(-) release from neutrophils in vitro.. Perhexiline potentiates platelet responsiveness to NO both in SAP and ACS patients; in the latter group this improvement was predictive of resolution of ischaemic symptoms. The predominant mechanism of perhexiline effect is an increase in platelet cGMP responsiveness. Perhexiline also may reduce the potential for NO clearance by neutrophil-derived O(2)(-).

Topics: Aged; Angina Pectoris; Blood Platelets; Cardiovascular Agents; Coronary Disease; Cyclic GMP; Female; Humans; Male; Neutrophils; Nitric Oxide; Nitric Oxide Donors; Nitroprusside; Perhexiline; Platelet Aggregation; Superoxides

We compared isosorbidedinitrate (ISDN) and 3-morpholinosydnonimine (SIN-1) as dilators of epicardial coronary arteries and inhibitors of ex vivo platelet aggregation in 23 patients referred for diagnostic coronary arteriography. After completion of the diagnostic study, the patient received graded intravenous (i.v.) infusions (0.5, 1.0, and 1.5 micrograms/kg/min) of either SIN-1 (n = 11) or ISDN (n = 12). Diameters of left anterior descending (LAD) and left ramus circumflex (RCX) coronary arteries were assessed by quantitative digital coronary arteriography before and 5 min after each infusion was started. SIN-1 required an infusion rate of 1.0 micrograms/kg/min to cause dilatation of proximal and middle segments of LAD and RCX. The highest infusion rate caused a modest decrease in mean arterial blood pressure (MAP). In these aspects, SIN-1 was equivalent to ISDN. In addition, blood was collected immediately before treatment and after infusion of the highest dose of ISDN or SIN-1. The sensitivity of platelet-rich plasma (PRP) to ADP and the thromboxane A2 (TXA2) mimetic U-46619 was determined in an aggregometer. The lesser responses to threshold concentrations of ADP and U-46619 and the slight shift in both concentration-response curves indicated that platelets of SIN-1-treated patients were slightly less sensitive to both stimuli as compared with platelets of ISDN-treated subjects. These ex vivo results suggest that SIN-1 may be superior to ISDN as an inhibitor of platelet activation.

Topics: Angina Pectoris; Blood Pressure; Coronary Vessels; Cyclic AMP; Cyclic GMP; Double-Blind Method; Female; Humans; Infusions, Intravenous; Isosorbide Dinitrate; Male; Middle Aged; Molsidomine; Platelet Aggregation; Platelet Aggregation Inhibitors; Vasodilator Agents

Nitric oxide (NO) and atrial natriuretic peptide (ANP) relax vascular smooth muscle increasing levels of cyclic guanosine 3':5' monophosphate (cGMP). Nitrovasodilators act as exogenous nitric oxide donors. The aim of this study was to ascertain the response of cGMP to exercise without medication and after the administration of 20 mg of isosorbide-5-mononitrate (IS-5-MN) in coronary patients (n = 8) and healthy control subjects (n = 9). A third group of 10 normal volunteers was studied to test plasma cGMP response to second exercise test without IS-5-MN administration. Plasma cGMP increased significantly in both patients (P < 0.02) and controls (P < 0.01) after the first ergometry. After IS-5-MN administration, plasma cGMP did not increase either before or after exercise. In normal volunteers without IS-5-MN plasma cGMP increased significantly after first (P < 0.004) and second (P < 0.0008) exercise test. In conclusion, plasma cGMP increases during exercise. Administration of IS-5-MN does not raise plasma cGMP and neither does performance of further exercise after its administration.

Topics: Angina Pectoris; Coronary Disease; Cyclic GMP; Exercise; Exercise Test; Female; Humans; Isosorbide Dinitrate; Male; Middle Aged; Vasodilator Agents

Most patients with vasospastic angina who have no significant organic coronary arterial stenosis are well controlled by medical therapy and the prognosis is almost satisfactory. Calcium channel (Ca) blockers are used as the first choice and effective agents for vasospastic angina pectoris. However, they do not always work well. Some uncontrolled coronary vasospasms would happen to cause prolonged occlusion of coronary artery resulting in myocardial infarction, life-threatening arrhythmias and sudden death. Therefore, it is very important to pay attention to such a refractory coronary spasm and choose the most effective agent out of Ca blockers for the treatment of each patient with vasospastic angina attacks. This study was designed to evaluate the anti-vasospastic efficacy of benidipine, a long acting dihydropyridine (DHP) Ca blocker, in patients with other Ca blockers-resistant angina.. Patients treated with diltiazem but not enough to control angina attacks were enrolled in the present study. Treatment with diltiazem (CAS 33286-22-5, 42399-41-7) was changed to treatment with benidipine (CAS 91599-74-5) and the parameters such as angina frequency, duration, blood pressure, heart rate, electrocardiogram and hematological parameters (serum NO(x), plasma cGMP) were measured and compared.. Fifteen patients with vasospastic angina were enrolled. After switching from diltiazem to benidipine, angina attacks were completely disappeared in six patients. Although the frequency was not decreased, the average duration of attacks was shorter than before in three patients. Four patients did not improve and two patients obviously worsened. In the improved nine patients, serum nitrite/nitrate (NO(x)) levels showed a significant increase from 37.6 +/- 15.3 to 54.5 +/- 26.7 pmol/L (p < 0.05) and cGMP levels subsequently elevated from 2.2 +/- 0.8 to 2.5 +/- 0.6 micromol/L (p = 0.05) after benidipine therapy started. Adverse effects such as hypotension and bradycardia were not observed.. This study suggests that benidipine may be helpful in Japanese patients with vasospastic or variant angina pectoris, if diltiazem was not successful.

Topics: Aged; Angina Pectoris; Blood Pressure; Calcium Channel Blockers; Coronary Vasospasm; Cyclic GMP; Dihydropyridines; Diltiazem; Female; Heart Rate; Humans; Male; Middle Aged; Nitric Oxide; Treatment Failure; Treatment Outcome; Vasodilator Agents

A single and local administration of L-arginine after balloon angioplasty enhances nitric oxide (NO) generation and inhibits lesion formation in animals.. The present study assessed the effect of increasing NO to inhibit restenosis after percutaneous transluminal coronary angioplasty (PTCA) in humans by local and systemic administration of L-arginine, a precursor of NO in humans.. L-arginine was administered to 34 consecutive patients with angina pectoris or old myocardial infarction via a cardiac catheter (500 mg/4 min) before PTCA, and via a peripheral vein (30 g/4 hr, for 5 days) after PTCA. Patients were treated between December 1998 and December 2000. Plasma concentrations of L-arginine, NO (as nitrite + nitrate) and cyclic guanosine monophosphate (cGMP) were measured before and after L-arginine administration. The control group consisted of 90 patients who underwent PTCA successfully without L-arginine administration in the period between July 1996 and November 1998. Baseline clinical and angiographic characteristics were compared between the two groups. All patients were followed by coronary angiography for 3 months after PTCA. Quantitative coronary angiography and restenosis rate were studied.. Baseline clinical and angiographic characteristics were not different between the two study groups. Despite a significant elevation in plasma L-arginine concentration after L-arginine administration, NO and cGMP did not increase significantly. After PTCA, the difference in restenosis rates between L-arginine and control subjects (34% vs 44%) was not significantly different.. Short-term administration of high dose L-arginine did not significantly change the restenosis rate after PTCA.

Topics: Aged; Angina Pectoris; Angioplasty, Balloon, Coronary; Arginine; Coronary Restenosis; Cyclic GMP; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Myocardial Infarction; Nitric Oxide

This paper aims to demonstrate that there is currently sufficient evidence to suggest that endothelin-1 (ET-1) may play a role in angina and be associated with myocardial ischaemia. In order to demonstrate the potential role of ET-1 in angina, this paper examines three main factors: (i) that endothelin-1 can cause the pathophysiological states associated with myocardial ischaemia and angina; (ii) that ET-1 is over-expressed in humans and in animal models of myocardial ischaemia, which is associated with angina; and (iii) that modification of the ET-1 system is associated with an improvement in myocardial ischaemia and angina.

Topics: Angina Pectoris; Animals; Cardiovascular Diseases; Cyclic GMP; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Humans; Myocardial Ischemia

It has been shown that there is the supersensitivity of the dilator effect of nitrovasodilators in the coronary arteries of patients with coronary spastic angina. This study was aimed to elucidate its mechanism(s) by examination of dilator response of spastic coronary arteries to atrial natriuretic peptide (ANP), which is known to dilate arteries by the same final common pathway through cyclic guanosine monophosphate (cGMP) as nitrovasodilators. Effects of infusion of nitroglycerin and ANP on epicardial coronary diameter of left coronary arteries were thus examined by quantitative coronary angiography in 20 patients with coronary spastic angina, who had spasm in left coronary arteries, and in 27 control subjects. Dilator response of coronary diameter to intracoronary infusion of ANP (0.5 microgram/kg) was found to be comparable between spastic coronary arteries and control arteries, whereas dilator response to nitroglycerin (250 micrograms) was enhanced in the spastic arteries compared with control arteries. The results indicate that spastic coronary arteries exhibit supersensitive dilator response to nitroglycerin but not to ANP. There is a possibility that dilator response to cGMP may be comparable between spastic and control coronary arteries and that soluble guanylate cyclase activity and/or conversion of nitric oxide bio-activity from nitroglycerin may be enhanced in spastic coronary arteries.

Topics: Adult; Aged; Angina Pectoris; Atrial Natriuretic Factor; Biological Availability; Coronary Angiography; Coronary Vasospasm; Coronary Vessels; Cyclic GMP; Diltiazem; Female; Guanylate Cyclase; Humans; Injections, Intra-Arterial; Male; Middle Aged; Nitric Oxide; Nitroglycerin; Vasodilator Agents

Isosorbide dinitrate (ISDN) has an inhibitory effect on platelet aggregation through the generation of nitric oxide (NO). We examined the effect of ISDN on whole blood aggregation using an impedance aggregometer. Blood samples were obtained from 16 patients with acute myocardial infarction and 4 patients with angina pectoris before and after an intravenous administration of ISDN during coronary arteriography. Whole blood obtained from normal healthy donors was used for an in vitro study. Whole blood aggregation after administration of ISDN was significantly inhibited compared to that before administration (36.1 +/- 8.3 vs 43.7 +/- 8.4 omega, p < 0.001), and cyclic guanine monophosphate (c-GMP) concentration increased (5.56 +/- 2.0 vs 5.14 +/- 1.86 p mol/ml, p < 0.05). The inhibitory effect of ISDN was also observed in the in vitro study, in which the effective concentration of ISDN corresponded to the blood level of ISDN (> or = 10(-7) mol) in the clinical setting. The inhibitory effect of ISDN was diminished by the addition of methylene blue or NG-monomethyl-L-arginine monoacetate in the exo vivo and in vitro studies. The concentration of c-GMP was increased by the addition of ISDN to platelets and white blood cell suspended plasma compared to the control (1.93 +/- 0.50 vs 1.77 +/- 0.42 p mol/ml, p < 0.05), but there was no significant difference when ISDN was added to platelet-rich plasma. These results suggest that ISDN inhibits whole blood aggregation through NO generation and white blood cells are important in the mechanism of ISDN action.

Topics: Angina Pectoris; Blood; Cell Aggregation; Cyclic GMP; Female; Humans; In Vitro Techniques; Isosorbide Dinitrate; Leukocytes; Male; Methylene Blue; Middle Aged; Myocardial Infarction; omega-N-Methylarginine; Platelet Aggregation; Platelet Aggregation Inhibitors; Vasodilator Agents

Platelet hyperactivity plays an important role in the pathogenesis of cardio-vascular diseases. In patients with stable angina pectoris, we have recently demonstrated that nitroglycerin suppressed the increased platelet aggregability. The anti-aggregating effect of NTG and other nitrovasodilators is mediated by platelet guanylate cyclase, which generates cyclic GMP (cGMP) in response to nitric oxide (NO) liberated from the nitrovasodilator molecule. In the current study we utilised a more "direct" NO donor, sodium nitroprusside (SNP), to examine reversal of ADP-induced platelet aggregation in comparison with intraplatelet cGMP elevation in platelets from normal subjects (n = 22) and patients with stable angina pectoris (n = 23). Concentrations of SNP associated with 50% reversal of aggregation were 2.7 +/- 0.4 x 10(-7) mol/L with normal subjects and 4.5 +/- 0.5 x 10(-6) mol/L with patients (P < 0.01). SNP produced a concentration-dependent elevation of intraplatelet cGMP content: with 10(-4) mol/L SNP this was 17-fold for normals and 5-fold for patients (P < 0.01). An increase in cAMP content was seen only with 10(-4) mol/L SNP, and was 157 +/- 11% of baseline in platelets from normal subjects and 138 +/- 14% in patients. There was a strong interrelationship between cGMP-stimulating and anti-aggregating effects of SNP. The decrease in cGMP responsiveness to SNP was not related to a dysfunction of platelet guanylate cyclase; neither basal nor SNP-stimulated activity of the enzyme varied significantly between normal subjects and patients. Lipophilic derivatives of cGMP (db-cGMP) and cAMP (db-cAMP) caused reversal of aggregation; there was a nonsignificant trend towards decreased responsiveness of platelets from patients to both db-cGMP and db-cAMP. The observed decrease in responsiveness of platelets from angina patients to anti-aggregating effects of the exogenous NO donor, SNP, can therefore be attributed to suppressed cGMP accumulation. These results imply reduced platelet sensitivity to endogenous NO (endothelium-derived relaxing factor): this might contribute to platelet hyperaggregability observed in angina pectoris.

Topics: Adult; Aged; Angina Pectoris; Blood Platelets; Bucladesine; Cyclic AMP; Cyclic GMP; Dibutyryl Cyclic GMP; Female; Guanylate Cyclase; Humans; Male; Middle Aged; Nitric Oxide; Nitroprusside; Platelet Aggregation

Endothelin-1 and cyclic guanosine monophosphate (c-GMP) peripheral vein plasma levels increase during coronary angioplasty, but the reason for this increase has not been elucidated. The purpose of this study was to investigate whether these changes are related to myocardial ischaemia, or to mechanical artery injury induced during the procedure. Thirty-two patients with stable angina pectoris and a single lesion were studied. They were aged 56 +/- 8 and were undergoing balloon angioplasty. Eight arteries were totally occluded and 24 were partially occluded. Blood samples were drawn from a peripheral vein after coronary artery engagement with the guiding catheter (baseline), after the first balloon inflation, immediately after the end of the procedure, and 4 h later. In the total occlusion group endothelin-1 increased by 7% (P ns), whereas in the partial occlusion group it increased by 45% after the procedure (P < 0.001). c-GMP in the partial occlusion group increased by 41% (P < 0.001) after the procedure whereas in the total occlusion group it increased by 5% (P ns). Thus, the increase in endothelin-1 and c-GMP peripheral vein plasma levels after coronary angioplasty is related to myocardial ischaemia rather than to mechanical artery injury.

Topics: Adult; Aged; Angina Pectoris; Angioplasty, Balloon, Coronary; Atrial Natriuretic Factor; Coronary Disease; Coronary Vessels; Cyclic GMP; Diagnosis, Differential; Endothelins; Female; Humans; Male; Middle Aged; Myocardial Ischemia

In rat aortic rings, isoproterenol (ISO) 10(-9)-3 x 10(-6)M relaxed the contraction induced by phenylephrine (PE) 3 x 10(-7)M. Pretreatment with nicorandil 3 x 10(-7) and 3 x 10(-6) M potentiated the relaxation induced by ISO. Nicorandil 3 x 10(-6) M also potentiated the relaxations induced by forskolin 3 x 10(-9) - 10(-6) M and dibutylyl-cyclic AMP 3 x 10(-6) - 3 x 10(-4) M. Nitroglycerin (NTG) 10(-8) M, but not cromakalim 3 x 10(-8) M, also potentiated the ISO relaxation. Pretreatment with glyburide 10(-6) M or apamin 10(-6) M did not affect the potentiating action of nicorandil 3 x 10(-6) M. Pretreatment with methylene blue (MB) 10(-6) M, but not with NG-monomethyl-L-arginine (NMMA), however, markedly inhibited the potentiating effect of nicorandil. Removal of endothelium impaired the relaxation induced by ISO but did not inhibit the potentiating effect of nicorandil. In addition, in the presence of MCl-154 (10(-7) M), which itself potentiated ISO-induced relaxation, nicorandil 3 x 10(-6) M did not further potentiate the relaxing response to ISO. Furthermore, nicorandil 3 x 10(-6) M potentiated the increase in the tissue level of cyclic AMP caused by ISO 3 x 10(-7) M, whereas the nicorandil-induced increase in cyclic GMP levels were not affected by ISO. These results suggest that the potentiating effect of nicorandil on the relaxation induced by ISO is most likely due to inhibition of phosphodiesterase III (PDE III) by increased cyclic GMP levels.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Angina Pectoris; Animals; Aorta; Cyclic AMP; Cyclic GMP; Drug Synergism; In Vitro Techniques; Isoproterenol; Male; Muscle Relaxation; Muscle, Smooth, Vascular; Niacinamide; Nicorandil; Rats; Rats, Wistar; Vasodilator Agents

The effects of nitroglycerin (NTG) on platelet aggregation are controversial. Most in vitro investigations suggest that NTG suppresses platelet aggregation only at suprapharmacologic concentrations. We investigated various aspects of the antiaggregating effects of NTG in both normal individuals and in patients with stable angina pectoris not treated with nitrates. Platelets from patients exhibited hyperresponsiveness to ADP as an inductor of aggregation. Sublingual administration to patients of NTG (300 micrograms) decreased platelet aggregability; ADP concentrations inducing 50% aggregation were 3.3 +/- 0.3 microM after NTG versus 2.1 +/- 0.1 microM before NTG (p < 0.01). Consistent with previous findings, NTG was a weak inhibitor of platelet aggregation in vitro when added before induction of aggregation. When added after the beginning of aggregation, however, NTG induced both inhibition of developing aggregation and marked disaggregation at concentrations > or = 10(-8) M NTG; concentration associated with 50% reversal of aggregation was 1.4 +/- 0.3 x 10(-6) M. Therefore, antiplatelet effects of NTG in vitro are demonstrable in low, clinically achievable concentrations; previously reported effects of NTG have been underestimated owing to suboptimum experimental conditions. Platelets from patients with angina pectoris were 100-fold less responsive to the cyclic GMP-increasing and disaggregating effects of NTG in vitro, which, together with increased aggregability, could imply reduced platelet sensitivity to endogenous sources of nitric oxide (NO) in vivo. The observed antiplatelet effects of NTG raise the question of its potential utility to reduce the risk of thrombotic complications in patients with ischemic heart disease.

Topics: Adenosine Diphosphate; Adult; Aged; Angina Pectoris; Blood Platelets; Cyclic GMP; Female; Humans; In Vitro Techniques; Male; Middle Aged; Nitroglycerin; Platelet Aggregation Inhibitors

Plasma levels of cyclic nucleotides were determined by radioimmunoassay in patients with (1) angina-like chest pain and normal coronary arteries (suspected spasm angina), (2) exercise-induced angina, and (3) heart diseases other than angina pectoris, as well as in (4) normal subjects. The concentration of cyclic GMP in plasma was significantly lower (by at least three-fold) in patients with suspected spasm angina, as compared with the other groups. No statistically significant difference in the plasma levels of cAMP was observed between the different patient groups. The low cGMP levels in plasma from patients with angina-like chest pain and normal coronary arteries might be an indication of a defect in the vasculature, making it more sensitive to contractile stimuli.

Topics: Adult; Angina Pectoris; Coronary Angiography; Coronary Disease; Coronary Vasospasm; Cyclic AMP; Cyclic GMP; Female; Humans; Male; Middle Aged

Various dosing strategies to determine therapeutic effects of nitroglycerin (NTG) preparations are reviewed. The importance of individual patient titration in establishing an effective NTG dosage is emphasized by reviewing a nitroglycerin ointment study and a crossover study. Studies reporting the development of hemodynamic attenuation ("tolerance") with longterm nitrate therapy are also discussed. The results of these and other studies suggest that the magnitude of the hemodynamic response to NTG or isosorbide dinitrate diminishes over time, with acute or first-dose effects far exceeding those obtained during long-term therapy. However, patients on long-term therapy continue to respond to sublingual NTG, which suggests that this phenomenon is not true NTG tolerance. The effect of a nitrate-free interval as a mechanism for avoiding hemodynamic attenuation of NTG therapy is reviewed. The results of 4 studies discussed found that intermittent nitrate protocols were not associated with the attenuated hemodynamic effect observed during chronic therapy. Two possible mechanisms for the vasodilatory effects of nitroglycerin are discussed. The first relates to the production of cyclic guanosine monophosphate in the smooth muscle cells of arteries and veins; the second to the synthesis of prostaglandin I2 by vascular endothelial cells. A mechanism by which nitrate receptors could be manipulated to increase vascular responsiveness is theorized, as well as a means by which a nitrate-free interval might avoid the development of hemodynamic attenuation in terms of cellular mechanisms and receptors.

Topics: Acetylcysteine; Administration, Oral; Administration, Topical; Angina Pectoris; Angina, Unstable; Animals; Blood Vessels; Cheek; Cyclic GMP; Drug Administration Schedule; Drug Tolerance; Electrocardiography; Endothelium; Exercise Test; Hemodynamics; Humans; Infusions, Parenteral; Isosorbide Dinitrate; Nitroglycerin; Prostaglandins; Vascular Resistance

Topics: Angina Pectoris; Autonomic Nervous System; Catecholamines; Cyclic AMP; Cyclic GMP; Hemodynamics; Humans; Male; Middle Aged; Pilocarpine

Developing myocardial infarction is shown to be accompanied by raised plasma cAMP and cGMP levels which peak within the first few hours of the disease. Two patterns of changes were noted in the content of cyclic nucleotides: cAMP increase prevailing (a more typical pattern) and cGMP increase prevailing. Primary ventricular fibrillation was recorded in some patients belonging to the latter group. The development of cardiac failure is accompanied by a more stable rise of plasma cAMP.

Topics: Adult; Aged; Angina Pectoris; Coronary Disease; Cyclic AMP; Cyclic GMP; Female; Heart Failure; Humans; Male; Middle Aged; Myocardial Infarction; Time Factors