pituitrin and Angina-Pectoris

Novel fluoroprostacyclin analogs (1a-f) have been synthesized and pharmacologically evaluated. Compounds 1a-c given intravenously or orally showed potent and long-lasting anti-anginal activities in an animal model.

Topics: Administration, Oral; Angina Pectoris; Animals; Blood Pressure; Dose-Response Relationship, Drug; Drug Evaluation; Electrocardiography; Epoprostenol; Fluorine; Guinea Pigs; Heart; Iloprost; Injections, Intravenous; Platelet Aggregation; Rats; Stereoisomerism; Structure-Activity Relationship; Vasopressins

Topics: Adenine Nucleotides; Angina Pectoris; Angiotensin II; Animals; Atrial Function; Blood Pressure; Coronary Disease; Coronary Vessels; Epinephrine; Histamine; Humans; Myocardium; Nitrates; Nitrites; Norepinephrine; Oxygen Consumption; Peptides; Piperazines; Prenylamine; Propranolol; Regional Blood Flow; Serotonin; Vasodilator Agents; Vasopressins; Verapamil

Angina occurs due to imbalance between heart oxygen demand and supply and is associated with serious morbidity and mortality. Here, the possible antianginal effect of Mentha longifolia extract was studied in experimental model of angina. Aerial parts of M. longifolia were extracted, standardized, and given to rats three days before angina. Heart hemodynamics and conductivity were recorded by microtip catheter and surface electrodes. M. longifolia extract significantly alleviated the sustained decline in cardiac contractility after vasopressin exposure. However, M. longifolia did not affect the impaired cardiac dilation after vasopressin. Heart rate was significantly decreased after vasopressin exposure in rats treated with M. longifolia compared with untreated animals. In addition, M. longifolia produced more increase in systolic and diastolic durations after vasopressin exposure compared with untreated animals. Moreover, the plant extract alleviated the ST height changes during vasopressin injection. M. longifolia extract alleviates impaired cardiac function associated with angina through decreasing heart work. PRACTICAL APPLICATIONS: The present study is the first to study the effect of M. longifolia in an experimental model of angina. M. longifolia alleviated the impaired cardiac contractility associated with angina exposure. The antianginal effect of M. longifolia could be through reducing cardiac load. This can be concluded from the decrease in heart rate and the systolic and diastolic cycles elongation after exposure to vasopressin in animals pretreated with M. longifolia. This helps in reducing the associated cardiac ischemia upon exposure to vasopressin as indicated by ST change. This could provide new directions in the management of the serious angina disease.

Topics: Angina Pectoris; Animals; Blood Pressure; Heart; Heart Rate; Humans; Male; Mentha; Myocardial Contraction; Plant Extracts; Plant Leaves; Rats; Rats, Wistar; Vasopressins

We assessed the anti-anginal effects of cilnidipine in comparison with those of nicardipine and nifedipine (1 and 10 µg/kg, n = 6 for each drug) or vehicle (n = 6) by using the vasopressin-induced angina model of rats. The administration of vasopressin (0.5 IU/kg, i.v.) to the rats depressed the S-wave level of the electrocardiogram reflecting the presence of subendocardial ischemia, whereas it significantly increased the mean blood pressure, resulting in the decrease of the heart rate and the prolongation of the PR interval possibly through a reflex-mediated increase in vagal tone. Cilnidipine suppressed the vasopressin-induced depression of the S-wave level in a dose-related manner, which was not observed by nicardipine or nifedipine. In addition, the low dose of cilnidipine hardly affected the vasopressin-induced pressor response, but it attenuated the negative dromotropic effect, suggesting N-type Ca

Topics: Angina Pectoris; Animals; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Coronary Vasospasm; Coronary Vessels; Dihydropyridines; Disease Models, Animal; Dose-Response Relationship, Drug; Electrocardiography; Heart Rate; Male; Nicardipine; Nifedipine; Rats; Time Factors; Vasoconstriction; Vasodilator Agents; Vasopressins

The antianginal effects of lercanidipine, a newly synthesized 1,4-dihydropyridine derivative calcium channel antagonist, were evaluated in experimental angina model rats and the effects were compared with those of nifedipine, benidipine and amlodipine. In the vasopressin-induced angina model, intravenous administration of lercanidipine dose-dependently suppressed vasopressin-induced ST-depression. Amlodipine barely suppressed it, while benidipine, at the same dose, completely suppressed it. Nifedipine had a potency between that of amlodipine and benidipine. Oral administration of lercanidipine showed similar effects to the intravenous administration test on ST change. High doses of amlodipine, benidipine and nifedipine suppressed ST-depression by almost 100%. In the methacholine-induced angina model, lercanidipine suppressed the ST elevation dose dependently. Amlodipine barely suppressed it, while benidipine at 30 microg/kg effected almost total suppression. Nifedipine had a potency between that of amlodipine and benidipine. Intraduodenal administration of lercanidipine also suppressed the ST-elevation dose dependently. Nifedipine, benidipine and amlodipine at 10 mg/kg all markedly suppressed the elevation. Lercanidipine was more potent than the other calcium channel antagonists tested. In conclusion, it was explicitly demonstrated that lercanidipine exerts potent protective effects on the ischemic electrocardiography (ECG) changes in a variety of putative angina pectoris models in rats. An antispasmolytic coronary vasodilating action may be involved in the mechanism. It is expected that lercanidipine will be useful as an antianginal agent.

Topics: Angina Pectoris; Animals; Dihydropyridines; Disease Models, Animal; Male; Methacholine Chloride; Rats; Rats, Sprague-Dawley; Vasodilator Agents; Vasopressins

We examined the involvement of endogenous vasopressin and platelet-activating factor (PAF) in the pathogenesis of two types of experimental angina in urethane-anaesthetised male Wistar rats. In the first model, epinephrine (10 microg kg(-1)) was injected into the tail vein, followed at the development of the maximum blood pressure response, i.e., 30 s later, by phentolamine (15 mg kg(-1)). In the second model, the vasopressin V1 receptor agonist ornithine-vasopressin (ornipressin; 0.5 IU kg(-1), i.v.) was administered. The heart rate, mean arterial blood pressure and surface electrocardiogram (ECG, standard lead II) were registered simultaneously. As a measure of myocardial ischaemia, at 1 min after phentolamine or ornipressin administration, we found significant ST-segment depression, lasting for more than 10 or 5 min, respectively. Pretreatment (15 min, s.c.) with the vasopressin V1 receptor antagonist Mca1,Tyr(Me)2AVP (the Manning peptide; 0.02-0.2 microg kg(-1)) or the platelet-activating factor receptor antagonist ginkgolide B (BN 52021; 0.25-2.5 mg kg(-1)) alone caused a dose-dependent reduction of the ST-segment depression. Concurrent administration of the two antagonists in their threshold doses (0.02 microg kg(-1) and 0.25 mg kg(-1)) also attenuated the ST-segment depression in both models. Neither antagonist affected the blood pressure or heart rate changes throughout the studies. Our results suggest that endogenous vasopressin and platelet-activating factor interact synergistically in provoking myocardial ischaemia in vivo in experimental angina in the rat.

Topics: Angina Pectoris; Animals; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Blood Pressure; Diterpenes; Dose-Response Relationship, Drug; Drug Interactions; Electrocardiography; Epinephrine; Ginkgolides; Heart Rate; Hormone Antagonists; Injections, Intravenous; Lactones; Male; Myocardial Ischemia; Ornipressin; Phentolamine; Platelet Activating Factor; Rats; Rats, Wistar; Receptors, Vasopressin; Time Factors; Vasoconstrictor Agents; Vasopressins

The effects of SMP-300, an orally active, potent, and selective Na+/H+ exchange inhibitor, were evaluated and compared with those of nifedipine, propranolol, and nicorandil on three experimental angina models and on myocardial infarction in rats. SMP-300 (0.1-1 mg/kg, p.o.) reduced isoproterenol-induced ST segment depression in a dose-dependent manner. Its maximal effect was comparable to that reported for propranolol and greater than that of nifedipine. SMP-300 (0.3-1 mg/kg) reduced vasopressin-induced ST segment depression in a dose-dependent manner, and its maximal effect was comparable to those of nifedipine and nicorandil. SMP-300 (0.3-1 mg/kg, p.o.) and propranolol (100 mg/kg, p.o.) inhibited coronary artery occlusion-induced T-wave elevation, but nifedipine (3 mg/kg, p.o.) did not. SMP-300 (1 mg/kg, p.o.) reduced myocardial infarct size after 40 min of coronary artery occlusion followed by 24 h of reperfusion, but nifedipine (3 mg/kg, p.o.) or propranolol (100 mg/kg, p.o.) did not. This study provides support for the future use of a Na+/H+ exchange inhibitor as an anti-anginal drug with a novel mode of action.

Topics: Administration, Oral; Angina Pectoris; Animals; Azocines; Coronary Disease; Electrocardiography; Isoproterenol; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Nicorandil; Nifedipine; Propranolol; Pyrroles; Rats; Rats, Sprague-Dawley; Rats, Wistar; Sodium-Hydrogen Exchangers; Vasodilator Agents; Vasopressins

We studied the antiischemic properties of fasudil, a Rho-kinase inhibitor, in conscious rabbits with coronary vasospasm induced by vasopressin and endothelin. Pretreatment with fasudil (0.3 and 3 mg/kg) attenuated the maximum elevation of the T-wave elicited by endothelin. Pretreatment with fasudil inhibited the T-wave elevation elicited by vasopressin. Fasudil and hydroxy fasudil, an active metabolite of fasudil, relaxed the endothelin-, U-46619-, 5-hydroxytryptamine- or histamine-induced contraction in swine coronary arterial strips. Fasudil and hydroxy fasudil significantly prevented the reduction in coronary flow by vasopressin in the Langendorff perfused rat heart. Fasudil was effective in protecting the heart against vasopressin and endothelin-induced myocardial ischemic change in conscious rabbits, and this beneficial effect can be attributed to its action of ameliorating the severe contraction of arteries. The inhibition of Rho-kinase may have implications for the development of novel therapeutic strategies for vasospastic angina in patients.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Angina Pectoris; Animals; Coronary Vasospasm; Disease Models, Animal; Dose-Response Relationship, Drug; Electrocardiography; Endothelins; Histamine; In Vitro Techniques; Intracellular Signaling Peptides and Proteins; Male; Protein Serine-Threonine Kinases; Rabbits; Rats; Rats, Wistar; rho-Associated Kinases; Swine; Time Factors; Vasodilation; Vasodilator Agents; Vasopressins

We evaluated the effects of SMP-300 (N-(aminoiminomethyl)-11-chloro-5,6,7,8-tetrahydro-8-oxo-4H-pyrrolo[3,2,1-kl][1]benzazocine-2-carboxamide monomethanesulfonate monohydrate), a newly synthesized compound, on Na+/H+ exchange activity in rat cardiomyocytes and on other ion transporters, channels and receptors. We also investigated the protective effects of SMP-300 in isolated ischemic rat hearts and rat isoproterenol- or vasopressin-induced experimental angina models. SMP-300 concentration-dependently inhibited recovery from acidosis in rat myocytes, and its IC50 for Na+/H+ exchange was 6 nM. In comparison, its IC50s for Na+/Ca2+ exchange and for the Na+ channel were >1000 nM, and those for other channels or receptors tested were >10,000 nM. In rat isolated perfused hearts, SMP-300 (10(-8)-10(-7) M), administered only at preischemia and not during reperfusion, significantly improved the postischemic recovery of cardiac function. SMP-300 (0.03-0.3 mg/kg, i.v.) or 5-(N-ethyl-N-isopropyl)-amiloride (1 mg/kg, i.v.) prevented the isoproterenol-induced ST-segment depression in the ECG of anesthetized rats, in a dose-dependent manner. SMP-300 (0.1 mg/kg, i.v.) and 5-(N-ethyl-N-isopropyl)-amiloride (1 mg/kg, i.v.) also inhibited the vasopressin-induced ST-segment depression in the ECG of anesthetized rats. This is the first report presenting the protective effect of Na+/H+ exchange inhibitors on isoproterenol- or vasopressin-induced ECG changes in rats, providing the future perspective of SMP-300, a potent Na+/H+ exchange inhibitor, as an anti-anginal drug.

Topics: Amiloride; Angina Pectoris; Animals; Azocines; Blood Pressure; Disease Models, Animal; Electrocardiography; Heart; Heart Rate; Isoproterenol; Male; Myocardial Ischemia; Myocardium; Neuroprotective Agents; Pyrroles; Rats; Rats, Sprague-Dawley; Sodium-Hydrogen Exchangers; Vasopressins

The effects of ranolazine (CAS 95635-55-5, KEG-1295), a novel antianginal drug, on the ST-segment changes induced by coronary ligation, epinephrine, and vasopressin were examined following oral or intraduodenal administration. In anesthetized dogs, intraduodenal administration of KEG-1295 (10, 30, or 50 mg/kg) or atenolol (10 mg/kg) significantly attenuated the ST-T wave elevation induced by 2-min coronary ligation imposed during electrical heart pacing (200 beats/min). This antianginal effect of KEG-1295 persisted for 3 h without any changes in hemodynamic parameters, while that of atenolol was accompanied by more or less maintained decreases in diastolic blood pressure, heart rate, and the maximum first derivative of left ventricular pressure. In anesthetized rats, oral administration of KEG-1295 (10, 30, or 50 mg/kg) attenuated the ST-T wave elevation induced by epinephrine (0.3 microgram/kg i.v.) in a dose-dependent manner, although KEG-1295 (10 or 30 mg/kg p.o.) failed to attenuate the ST-segment depression induced by vasopressin (0.2 IU/kg i.v.). These findings suggest that, taken orally, KEG-1295 may exert potent protective effects against angina pectoris, except that caused by vasospasm. Further, KEG-1295 may be categorized as a new type of antianginal agent, without any primary hemodynamic effects.

Topics: Acetanilides; Administration, Oral; Adrenergic beta-Antagonists; Anesthesia; Angina Pectoris; Animals; Atenolol; Dogs; Duodenum; Electrocardiography; Epinephrine; Female; Intubation, Gastrointestinal; Male; Myocardial Ischemia; Piperazines; Ranolazine; Rats; Rats, Wistar; Vasoconstrictor Agents; Vasopressins

A relationship was examined between blood vasopressin levels and the fibrinolytic system in 35 patients with angina pectoris (16 with vasospastic angina (VA) and 19 with exercise-induced angina) who had undergone vein occlusion testing. There was a positive correlation between the post-testing vasopressin levels and the activity of tissue plasminogen activator inhibitor (TPAI) (r = 0.54) which was more high in patients with VA (r = 0.61). Only did the patients with VA show a direct relationship between the vasopressin concentrations and the activity of tissue plasminogen activator (TPA) (r = 0.63), the concentration of fibrinogen-fibrin degradation products (FFDP) (r = 0.88). Thirteen patients having higher vasopressin levels (over 3.4 ng/ml) displayed a greater TPAI activity than did the patients with vasopressin levels of at least 3.4 ng/ml (26.2 +/- 4.9 and 15.0 +/- 1.42 IU/ml, respectively; p less than 0.05). There was a direct relationship between the vasopressin levels and the activity of TPA (r = 0.65), the concentration of FFDP (r = 0.78) in patients having a vasopressin level of above 3.4 ng/ml. The findings are in agreement with the concept that endogenous vasopressin is involved in the regulation of the blood fibrinolytic system.

Topics: Adult; Angina Pectoris; Female; Fibrin Fibrinogen Degradation Products; Fibrinolysis; Humans; Male; Tissue Plasminogen Activator; Vasopressins

Antianginal effects of (+/-)-(R*)-2,6-dimethyl-4-(m-nitrophenyl)- 1,4-dihydropyridine-3,5-dicarboxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049) in various experimental angina-pectoris models (anesthetized rats, spontaneously hypertensive rats (SHR] were compared with those of nifedipine, propranolol and hydralazine. Furthermore, the effects of these drugs on the pressure-rate product were evaluated. 1. Vasopressin test (SHR): The administration of KW-3049 at 10 micrograms/kg (i.v.) developed an inhibitory effect comparable to that of nifedipine at 200 micrograms/kg (i.v.) against the ischemic ECG changes caused by the intravenous administration of vasopressin at 1 U/kg. The effects of KW-3049 at 3 and 10 mg/kg (p.o.) lasted for 8 h or more. 2. Coronary occlusion test (rat): The rise of T-wave of epicardial ECG following ligation of coronary artery was inhibited by the administration of KW-3049 at doses of 30 and 100 micrograms/kg i.v. Nifedipine at dose of 200 micrograms/kg i.v. was slightly effective. 3. Isoproterenol (isoprenaline) test (rat): The fall of ST in ECG by the continuous infusion of isoprenaline (10 micrograms/kg/min) was almost completely prevented by propranolol (500 micrograms/kg i.v.). Also, KW-3049 (200 micrograms/kg i.v.) and nifedipine (200 micrograms/kg i.v.) significantly inhibited the decline of ST, in which the former was more effective than the latter. 4. Anoxia test (SHR): The fall of ST and rise of T-wave of ECG, induced by stopping artificial respiration of gallamine-immobilized SHR, were suppressed by the administration of KW-3049 at doses of 10 and 30 micrograms/kg i.v.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angina Pectoris; Animals; Blood Pressure; Calcium Channel Blockers; Coronary Circulation; Electrocardiography; Heart Rate; Hydralazine; Isoproterenol; Male; Nifedipine; Propranolol; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Vasopressins

Topics: Angina Pectoris; Animals; Beverages; Coronary Vasospasm; Plants, Medicinal; Rats; Vasopressins

Earlier we have shown in the dog model mimicking angina on effort a delayed antiischaemic effect of PgI2 and its stable analogue 7-oxo-PgI2-Na, appearing only when the drug induced marked vasodilatation was over [1]. In the present experiments we could show that the protective effect appears at a time when the blood pressure returned to normal and in addition the marked platelet aggregation inhibitory effect has also faded away. In the rat 7-oxo-PgI2 could substantially diminish vasopressine induced T-wave elevation in the ECG if given 2 hours before administration of vasopressin. In addition it could moderate the vasopressin induced metabolic changes appearing as diminution of the myocardial CP and ATP-level and increase of the myocardial lactate content. A similar metabolic protection was found in the heart of rats pretreated with 7-oxo-PgI2 2 hours before taking myocardial samples and exposing them for 1 minute to ischaemia by incubation in Ringer solution. It is concluded that a direct metabolic and hemodynamic effect could be at least partly responsible for the late antiischaemic effect of 7-oxo-PgI2. This effect was also present in the early phase of experimental myocardial infarction in conscious rats if animals were pretreated with 7-oxo-PgI2 2 hours before occlusion. However treatment did not increase survival rate and failed to reduce the incidence and severity of arrhythmias.

Topics: Adenine Nucleotides; Angina Pectoris; Animals; Disease Models, Animal; Dogs; Epoprostenol; Female; Heart; Lactates; Male; Myocardial Infarction; Myocardium; Phosphocreatine; Rats; Rats, Inbred Strains; Vasopressins

Topics: Adenosine Diphosphate; Administration, Oral; Alprostadil; Angina Pectoris; Animals; Collagen; Drug Evaluation, Preclinical; Guinea Pigs; Heart; Humans; Platelet Aggregation; Prostaglandins E; Prostaglandins E, Synthetic; Rats; Structure-Activity Relationship; Vasodilation; Vasopressins

Topics: Angina Pectoris; Animals; Coronary Vessels; Electrocardiography; Hypoxia; Isoproterenol; Male; Methods; Rabbits; Sympatholytics; Vasodilator Agents; Vasopressins

Topics: Angina Pectoris; Coronary Disease; Digoxin; Electrocardiography; Hydrochlorothiazide; Hypercholesterolemia; Hypertension; Metaraminol; Nitroglycerin; Shock; Shock, Cardiogenic; Vasopressins; Warfarin

Ergometrine usually depresses the S-T segment as in coronary insufficiency, when injected intravenously in rabbits with experimental coronary atherosclerosis and in patients with effort angina, but not in normal animals and man. To explain this difference, we carried out Langendorff perfusion studies in 32 normal and 29 atherosclerotic isolated rabbit hearts. Preliminary tests with ergometrine were done to ensure that advanced coronary atherosclerosis had developed in the rabbits fed a cholesterol diet; pathological examination of the heart after perfusion confirmed the result of the final test with ergometrine. Before drugs were perfused, the basal rate of coronary flow was greater, the heart rate was slower and the contractile amplitude was smaller in the atherosclerotic than in the normal hearts; nitroglycerin markedly increased flow in both normal and atherosclerotic groups. Ergometrine consistently caused a reduction in contractile amplitude with negligible changes in heart rate in both normal and atherosclerotic hearts. On coronary flow, however, the effects of ergometrine differed significantly in these groups; in doses of between 0.2 and 0.4 mg., the average decrease in flow was 8% in normal and 22% in atherosclerotic hearts. The effect was more variable in normal hearts and an increase in flow sometimes occurred. The difference in the response of normal and atherosclerotic hearts was particularly striking when ergometrine was given during recovery from a reduction of coronary flow which had been induced by vasopressin. Ergometrine then uniformly increased flow in the normal, but usually had the opposite effect in the atherosclerotic heart. In normal and atherosclerotic hearts, cardiac effects of vasopressin were similar. Tachyphylaxis to vasopressin, but not to ergometrine, was observed.

Topics: Angina Pectoris; Animals; Arginine Vasopressin; Cardiovascular Agents; Cholesterol, Dietary; Ergonovine; Ergot Alkaloids; Heart; Humans; Male; Oxytocics; Perfusion; Rabbits; Vasopressins