pituitrin and Myocardial-Ischemia

Topics: Arrhythmias, Cardiac; Atrial Fibrillation; Catecholamines; Drug Therapy, Combination; Humans; Length of Stay; Myocardial Ischemia; Randomized Controlled Trials as Topic; Renal Replacement Therapy; Shock, Septic; Stroke; Treatment Outcome; Vasoconstrictor Agents; Vasopressins

Cardiac troponins are sensitive and specific biomarkers of myocardial necrosis. We evaluated troponin, CK, and ECG abnormalities in patients with septic shock and compared the effect of vasopressin (VP) versus norepinephrine (NE) on troponin, CK, and ECGs.. This was a prospective substudy of a randomized trial. Adults with septic shock randomly received, blinded, a low-dose infusion of VP (0.01 to 0.03 U/min) or NE (5 to 15 μg/min) in addition to open-label vasopressors, titrated to maintain a mean blood pressure of 65 to 75 mm Hg. Troponin I/T, CK, and CK-MB were measured, and 12-lead ECGs were recorded before study drug, and 6 hours, 2 days, and 4 days after study-drug initiation. Two physician readers, blinded to patient data and drug, independently interpreted ECGs.. We enrolled 121 patients (median age, 63.9 years (interquartile range (IQR), 51.1 to 75.3), mean APACHE II 28.6 (SD 7.7)): 65 in the VP group and 56 in the NE group. At the four time points, 26%, 36%, 32%, and 21% of patients had troponin elevations, respectively. Baseline characteristics and outcomes were similar between patients with positive versus negative troponin levels. Troponin and CK levels and rates of ischemic ECG changes were similar in the VP and the NE groups. In multivariable analysis, only APACHE II was associated with 28-day mortality (OR, 1.07; 95% CI, 1.01 to 1.14; P=0.033).. Troponin elevation is common in adults with septic shock. We observed no significant differences in troponin, CK, and ECGs in patients treated with vasopressin and norepinephrine. Troponin elevation was not an independent predictor of mortality.. Controlled-trials.com ISRCTN94845869.

Topics: Adult; Aged; Biomarkers; Double-Blind Method; Electrocardiography; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Norepinephrine; Prospective Studies; Shock, Septic; Troponin T; Vasopressins

As part of a large pragmatic study, the authors investigated heart rate, blood pressure, dysrhythmic and ischemic responses to lidocaine 2% with a combination vasoconstrictor (noradrenaline 1:50,000 and vasopressin 0.25 IU/mL), and midazolam sedation in a medically compromised population. There were anesthesia-induced physiological changes to both hemodynamics and the electrocardiogram. The use of midazolam significantly ameliorated the sympathoadrenal response to stress, and the greatest hemodynamic and electrocardiographic changes were observed during surgery.

Topics: Anesthesia, Dental; Anesthetics, Local; Arrhythmias, Cardiac; Blood Pressure; Conscious Sedation; Electrocardiography; Epinephrine; Female; Follow-Up Studies; Heart Diseases; Heart Rate; Hemodynamics; Humans; Hypnotics and Sedatives; Lidocaine; Male; Midazolam; Middle Aged; Myocardial Ischemia; Oral Surgical Procedures; Single-Blind Method; Statistics as Topic; Statistics, Nonparametric; Stress, Physiological; Vasoconstrictor Agents; Vasopressins

Intravenous tetramethylpyrazine has been widely used in China as a complementary and/or alternative medicine to treat patients with ischemic heart disease. We assessed the anti-anginal effect of tetramethylpyrazine (10 mg/kg, intravenously (i.v.), n=6) in comparison with that of its vehicle, saline (1 mL/kg, i.v., n=6), using vasopressin-induced angina model rats. First, Donryu rats were anesthetized with pentobarbital sodium (60 mg/kg, intraperitoneally (i.p.)), and the surface lead I electrocardiogram was continuously monitored. Administration of vasopressin (0.5 IU/kg, i.v.) to the rats depressed the S-wave level of the electrocardiogram, indicating the onset of subendocardial ischemia. However, pretreatment with tetramethylpyrazine suppressed the vasopressin-induced depression of the S-wave level, which was not observed following pretreatment with its vehicle alone (saline), suggesting that tetramethylpyrazine ameliorated the vasopressin-induced subendocardial ischemia in vivo. These results may provide experimental evidence for the empirically known clinical efficacy of tetramethylpyrazine against ischemic heart disease, and could provide clues to better understanding its in vivo mechanism of action.

Topics: Animals; Blood Pressure; Cardiotonic Agents; Disease Models, Animal; Heart Rate; Male; Myocardial Ischemia; Pyrazines; Rats; Vasoconstrictor Agents; Vasodilator Agents; Vasopressins

One of the rationales for the use of vasopressin in septic shock has been its potential cardioprotective mechanisms. Lower heart rates, higher arterial pressures, and fewer norepinephrine doses during vasopressin therapy were hypothesized to protect the heart from myocardial ischemia. In a prospective sub-study of the VASST (Vasopressin in Septic Shock Trial) project, Mehta and colleagues specifically evaluated this hypothesis but failed to find lower cardiac biomarkers or fewer ischemic electrocardiogram changes in patients receiving vasopressin compared with subjects receiving norepinephrine alone. After recent evidence of a lacking survival benefit, the present study results further challenge the future role of vasopressin as a vasopressor in septic shock.

Topics: Female; Humans; Male; Myocardial Ischemia; Norepinephrine; Shock, Septic; Vasopressins

We investigated the gender differences in heme-oxygenase (HO) enzyme, which produces endogenous vascular protective carbon monoxide (CO). We studied (1) the activity and expression of HO enzymes in the left ventricle (LV) and aorta, (2) basal increase in basal blood pressure provoked by arginine vasopressine (AVP) in vivo, (3) the heart perfusion induced by AVP, (4) the ST segment depression provoked by adrenaline and 30 seconds later phentolamine, and (5) the aorta ring contraction induced by AVP in female and male Wistar rats. We found that HO activity and the expression of HO-1 and HO-2 were increased in female rat aorta and LV. We demonstrated that the basal blood pressure and administration of AVP provoked blood pressure response are increased in the males; the female myocardium was less sensitive towards angina. Both differences could be aggravated by the inhibition of HO. The aorta rings were more susceptible towards vasoconstriction by AVP in males; isolated heart perfusion decrease was higher in males. The HO inhibition aggravated the heart perfusion in both sexes. In conclusion, the increased HO activity and expression in females might play a role in the sexual dimorphism of cardiovascular ischemia susceptibility during the reproductive age.

Topics: Animals; Aorta; Blood Pressure; Disease Susceptibility; Female; Heart Ventricles; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; In Vitro Techniques; Male; Metalloporphyrins; Myocardial Contraction; Myocardial Ischemia; Perfusion; Protoporphyrins; Rats; Rats, Wistar; Sex Characteristics; Ultrasonography; Vasopressins

The reliability of electrocardiogram interpretation to diagnose myocardial ischemia in critically ill patients is unclear. In adults with septic shock, we assessed intra- and inter-rater agreement of electrocardiogram interpretation, and the effect of knowledge of troponin values on these interpretations.. Prospective substudy of a randomized trial of vasopressin vs. norepinephrine in septic shock.. Nine Canadian intensive care units.. Adults with septic shock requiring at least 5 μg/min of norepinephrine for 6 hrs.. Twelve-lead electrocardiograms were recorded before study drug, and 6 hrs, 2 days, and 4 days after study drug initiation.. Two physician readers, blinded to patient data and group, independently interpreted electrocardiograms on three occasions (first two readings were blinded to patient data; third reading was unblinded to troponin). To calibrate and refine definitions, both readers initially reviewed 25 trial electrocardiograms representing normal to abnormal. Cohen's Kappa and the φ statistic were used to analyze intra- and inter-rater agreement.. One hundred twenty-one patients (62.2 ± 16.5 yrs, Acute Physiology and Chronic Health Evaluation II 28.6 ± 7.7) had 373 electrocardiograms. Blinded to troponin, readers 1 and 2 interpreted 46.4% and 30.0% of electrocardiograms as normal, and 15.3% and 12.3% as ischemic, respectively. Intrarater agreement was moderate for overall ischemia (κ 0.54 and 0.58), moderate/good for "normal" (κ 0.69 and 0.55), fair to good for specific signs of ischemia (ST elevation, T inversion, and Q waves, reader 1 κ 0.40 to 0.69; reader 2 κ 0.56 to 0.70); and good/very good for atrial arrhythmias (κ 0.84 and 0.79) and bundle branch block (κ 0.88 and 0.79). Inter-rater agreement was fair for ischemia (κ 0.29), moderate for ST elevation (κ 0.48), T inversion (κ 0.52), and Q waves (κ 0.44), good for bundle branch block (κ 0.78), and very good for atrial arrhythmias (κ 0.83). Inter-rater agreement for ischemia improved from fair to moderate (κ 0.52, p = .028) when unblinded to troponin.. In patients with septic shock, inter-rater agreement of electrocardiogram interpretation for myocardial ischemia was fair, and improved with troponin knowledge.

Topics: Biomarkers; Electrocardiography; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Norepinephrine; Observer Variation; Prospective Studies; Shock, Septic; Time Factors; Troponin; Vasoconstrictor Agents; Vasopressins

Echinocystic acid (EA), a pentacyclic triterpene, was isolated and identified from the fruits of Gleditsia sinensis Lam. The protective effects of EA were evaluated in rat models with acute myocardial ischemia induced by isoproterenol and vasopressin. In the electrocardiogram of anesthetized rats, EA prevented the ST-segment depression induced by isoproterenol or vasopressin in a dose-dependently manner. Furthermore, the mRNA expression of Bcl-2 was analyzed by RT-PCR. EA shows an elevation of Bcl-2 mRNA level in infarcted tissue induced by isoproterenol in rats. These results demonstrated for the first time EA has a cardioprotective effect and may be a natural drug.

Topics: Adrenergic beta-Agonists; Animals; Drug Evaluation, Preclinical; Female; Gleditsia; Isoproterenol; Male; Molecular Structure; Myocardial Ischemia; Oleanolic Acid; Phytotherapy; Plant Extracts; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Vasoconstrictor Agents; Vasopressins

A patient with a giant ovarian tumor weighing about 7 kg was successfully removed by operation. However, her ECG demonstrated ischemic changes after the operation. We report a case of ischemic heart disease due to persistent diuresis after giant ovarian tumor resection. A 75-year-old, 56.5 kg, 143.5 cm woman was admitted to our hospital for ovarian tumor resection. The preoperative ECG showed normal sinus rhythm and no ischemic changes. Both general anesthesia and epidural anesthesia were planed. An epidural catheter was inserted at T12-L1. Anesthesia was induced with propofol 100 mg, fentanyl 100 microg and vecuronium 8 mg under 100% oxygen inhalation. General anesthesia was maintained with sevoflurane while epidural anesthesia was achieved using 0.375% ropivacaine 6 ml. During the operation, blood pressure was 90-110/70-80 mmHg, with SaO2, 100% and heart rate, 70-80 beats x min(-1). The content of tumor was suctioned for 30 minutes. Surgery was successfully finished without any other incidence. After extubation, her ECG changed to atrial fibrillation from normal sinus rhythm and showed ST-T depression. And then her systolic blood pressure became 80 mmHg or below, but we found continued diuresis at about 10 ml x kg(-1) x hr(-1) for over 2 hr. The total of 7 unit vasopressin was intermittently given for vasoconstriction and antidiuresis. Her hemodynamic was immediately restored, and ECG turned to normal ST-T. The patient had uneventful postoperative recovery.

Topics: Aged; Anesthesia, Epidural; Anesthesia, General; Antidiuretic Agents; Atrial Fibrillation; Diuresis; Electrocardiography; Female; Humans; Myocardial Ischemia; Ovarian Neoplasms; Postoperative Complications; Treatment Outcome; Urination Disorders; 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

Small-dose IV vasopressin infusion may be beneficial in acute brain injury patients with unstable hemodynamics who are refractory to fluid resuscitation and catecholamine vasopressors.

Topics: Brain Injuries; Catecholamines; Humans; Hypotension; Male; Middle Aged; Myocardial Ischemia; Pulmonary Edema; Resuscitation; Vasoconstrictor Agents; Vasopressins

It has been reported that the administration of vasopressin induces myocardial ischaemia in rats, which causes electrocardiographic ST segment alterations according to many authors. But rat electrocardiogram (ECG) lacks ST segment. Consequently it appears important to study the effects of vasopressin in rabbits, which show ST segment present in the ECG. Since cardiac necrosis markers are released in the plasma of humans with myocardial infarction, as well as in a variety of experimental models of myocardial necrosis, it is possible that the same may occur in rabbits with myocardial ischaemia induced by vasopressin. The main aim of this study was to investigate whether the administration of vasopressin causes the appearance of specific myocardial necrosis markers, such as cardiac troponin I, myoglobin or creatine kinase MB (CK MB) in rabbits in the presence or absence of modified ECG profile, and to also verify whether these markers are associated with the alterations in some coagulation parameters, that are known to be induced by vasopressin. As the effects of vasopressin are counteracted by nitric oxide (NO), another aim was to verify whether vasopressin also affects plasma NO levels and whether the administration of a NO donor can reverse these effects. Vasopressin was administered to rabbits and caused ischaemic alterations such as electrocardiographic changes, and significantly increased the levels of plasma cardiac necrosis markers (c-troponin I, myoglobin and CK MB). It also elevated diastolic blood pressure (BP), lowered heart rate (HR), increased procoagulation activity, and lowered plasma NO levels. The appearance of heart necrosis, demonstrated by plasma cardiac necrosis markers in the animals receiving vasopressin, was attributed to a drug-induced increase in vasoconstriction and coagulation activity. The intense vasoconstriction and thrombosis may lead to endothelium necrosis and a consequent drop in NO production. The administration of the NO donor nitroglycerin (NG) in the vasopressin treated animals restored NO values, and was capable of preventing the appearance of the plasma cardiac necrosis markers and altered coagulation values. The protective activity of NG was attributed to NO release, which lowers BP values and counteracts coagulation activity in vasopressin-treated animals. The described procedure may also be proposed for the study of early ischaemic myocardial lesions and the screening of NO donors preventing myocardial damage.

Topics: Animals; Biomarkers; Creatine Kinase; Creatine Kinase, MB Form; Electrocardiography; Fibrinogen; Isoenzymes; Male; Myocardial Ischemia; Myocardium; Myoglobin; Necrosis; Nitric Oxide; Nitric Oxide Donors; Nitroglycerin; Partial Thromboplastin Time; Prothrombin Time; Rabbits; Troponin I; Vasopressins

A case of transient myocardial ischemia following subendometrial vasopressin infiltration in intractable intra-operative postpartum bleeding due to placenta accreta is described. In our experience, the rate of this side effect is one in 14 patients (rate of 7.1%). We believe that the benefits of the treatment outweigh the risks, since the uterus was saved in all 14 patients. Nevertheless, this case emphasises that extreme precaution is needed with subendometrial vasopressin infiltration. It should be emphasised that the needle must not be within a blood vessel because intravascular injection of vasopressin solution can precipitate acute arterial hypertension, bradycardia and even death. We suggest that local vasopressin infiltration into the placental site is indicated in cases of intractable bleeding at cesarean section after other conventional obstetric and pharmacological maneuvers have failed.

Topics: Blood Loss, Surgical; Cesarean Section; Female; Hemostatics; Humans; Myocardial Ischemia; Placenta Accreta; Pregnancy; Uterine Hemorrhage; 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

Substance P receptor-like immunoreactive (SPR-LI) structures and changes following intravenous injection of vasopressin in the medullary visceral zone (MVZ) of the rat were studied by using immunohistochemical methods. In normal control rats the distribution of SPR-LI structure in MVZ generally matched with that of immunostaining against substance P (SP-LI) except in some areas. SPR-LI neurons and dendrites differed in size and shape in different areas of MVZ. Their dendrites could be classified into three types, i.e, wool-shaped, smooth and varicose. Some SPR-LI neurons were also positive for tyrosine hydroxylase-like immunoreactivity (TH-LI) . After administration of vasopressin SPR-LI structures became denser, especially at levels of pyramidal decussation (PYX) and area postrema (AP). The dendrites of motor dorsal nucleus of X (NMDX) in the dorsal part of MVZ appeared thin and straight in morphology instead of curl and thick outlooks. These results implicate that some SPR-LI neurons might be involved in the modulation of the cardiovascular stress induced by vasopressin.

Topics: Acute Disease; Animals; Immunohistochemistry; Injections, Intravenous; Male; Medulla Oblongata; Myocardial Ischemia; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1; Tyrosine 3-Monooxygenase; Vasopressins

Inhibitors of nitric oxide (NO) synthesis have been used in the treatment of septic and endotoxic shock. However, several studies question the beneficial effect of inhibiting NO production in sepsis and endotoxemia. We have investigated the effect of inhibition of NO synthesis after endotoxemia in the isolated perfused rat heart. In hearts from endotoxin-treated animals, coronary flow was elevated 64% and oxygen consumption was elevated 20% compared with control hearts. NADH fluorescence imaging was used as an indicator of regional hypoperfusion. A homogeneous low-surface NADH fluorescence, indicative of adequate tissue perfusion, was observed in both control and endotoxin-treated hearts. The increase in coronary flow and oxygen consumption could only partially be prevented by pretreatment of the animals with dexamethasone. Addition of N omega-nitro-L-arginine (NNLA), an inhibitor of NO synthesis, to the perfusion medium eliminated differences in coronary flow and oxygen consumption between normal and endotoxin-treated hearts. However, NADH surface fluorescence images of endotoxin-treated hearts after NNLA revealed areas of high fluorescence, indicating local ischemia, whereas the control hearts remained without signs of ischemia. The ischemic areas were present at various perfusion pressures and disappeared after the infusion of L-arginine, the natural precursor of NO, or the exogenous NO donor sodium nitroprusside. Methylene blue (MB), an inhibitor of soluble guanylate cyclase, the effector enzyme of NO, also eliminated differences in coronary flow and produced similar areas of local myocardial ischemia in endotoxin-treated hearts but not in control hearts.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amino Acid Oxidoreductases; Animals; Arginine; Coronary Circulation; Dexamethasone; Endotoxins; Male; Methylene Blue; Myocardial Ischemia; NAD; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Oxygen Consumption; Rats; Rats, Wistar; Sepsis; Vasopressins

The anti-ischemic effects of a new, selective and potent cyclic 3',5'-guanosine monophosphate-specific phosphodiesterase (phosphodiesterase type V) inhibitor, sodium 1-[6-chloro-4-(3,4-methylenedioxybenzyl)aminoquinazolin-2-yl ]piperidine-4- carboxylate (E4021), in a vasopressin-induced guinea pig anginal model were examined and compared with those of coronary vasodilators with a guanylate cyclase-activating action. An intravenous injection of vasopressin (0.2 IU/kg) into anesthetized guinea pigs produced ST segment elevation on the electrocardiogram (an index of myocardial ischemia) of 0.28 +/- 0.02 mV (n = 10) from the baseline within 30 s. E4021 administered intravenously at doses of 0.03 and 0.1 mg/kg, 5 min before the injection of vasopressin, significantly inhibited the ST segment elevation to 0.15 +/- 0.03 mV (n = 6, P < 0.01) and 0.17 +/- 0.02 mV (n = 6, P < 0.01), respectively. Three guanylate cyclase activators, isosorbide dinitrate (0.1 mg/kg), nicorandil (0.1 mg/kg), and FK409 (0.3 mg/kg), also significantly reduced the ST segment elevation to 0.18 +/- 0.03, 0.11 +/- 0.02 and 0.17 +/- 0.02 mV, respectively. In a second experiment, E4021 was administered intraduodenally 30 min before the injection of vasopressin to examine its oral effectiveness. Intraduodenal E4021, at doses of 1.0 and 3.0 mg/kg, also significantly inhibited the ST segment elevation to 0.16 +/- 0.02 mV (n = 6, P < 0.01) and 0.13 +/- 0.02 mV (n = 6, P < 0.01), respectively. It is concluded that the potent phosphodiesterase type V inhibitor, E4021, administered intravenously or intraduodenally, ameliorated myocardial ischemia similarly to guanylate cyclase activators. Thus, E4021 may be an orally effective drug in the treatment of angina pectoris.

Topics: Animals; Drug Interactions; Electrocardiography; Guinea Pigs; Injections, Intravenous; Isosorbide Dinitrate; Male; Myocardial Ischemia; Niacinamide; Nicorandil; Nitro Compounds; Phosphodiesterase Inhibitors; Piperidines; Quinazolines; Vasodilator Agents; Vasopressins

1. The preventive effects of monatepil, a new calcium antagonist with alpha 1-adrenoceptor blocking activity, on ischaemic electrocardiographic changes in rat models of vasospastic angina were evaluated and compared with those of the existing calcium antagonists (diltiazem, verapamil, nicardipine and nifedipine). 2. In order to assess the contribution of the alpha 1-adrenoceptor blocking action of monatepil to its anti-vasospastic action, the anti-ST depression effect of prazosin, an alpha 1-adrenoceptor blocker, was also examined. 3. Monatepil given orally (3-30 mg/kg) inhibited vasopressin (0.2 IU/kg, i.v.)-induced ST depression which is considered to indicate ischaemic electrocardiographic changes in a vasospastic angina. This effect of monatepil was more potent and long-lasting than that of diltiazem, and was similar to that of verapamil and nicardipine. At a dose of 30 mg/kg, monatepil produced a significant inhibition, even at 7 h after administration. 4. Monatepil given intravenously (0.3 mg/kg) exerted a significant inhibitory effect on methacholine (16 micrograms/kg, intracoronary arterial administration; i.c.a.)-induced ST elevation which seems to be caused by coronary vasospasm. This effect was more potent or equipotent to those of the existing calcium antagonists. 5. These results indicate that monatepil produces the preventive effect on the drug-induced ischaemic electrocardiographic changes in rats and suggest that monatepil may have potential for the treatment of vasospastic angina.

Topics: Administration, Oral; Animals; Blood Pressure; Calcium Channel Blockers; Coronary Vasospasm; Dibenzothiepins; Electrocardiography; Heart Rate; Injections, Intravenous; Male; Methacholine Chloride; Myocardial Ischemia; Piperazines; Prazosin; Rats; Rats, Sprague-Dawley; Rats, Wistar; Vasopressins

Topics: Aged; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Humans; Infusions, Intravenous; Male; Myocardial Ischemia; Nitroglycerin; Torsades de Pointes; Vasopressins

Synthetic oxytocin (Syntocinon) can be shown to reduce or abolish ST-T changes induced experimentally by hypoxaemia alone, by hypoxaemia and ergometrine, by vasopressin, and by a new procedure involving injection of small doses of picrotoxin into the lateral cerebral ventricle. Ventricular fibrillation induced by picrotoxin can also be reversed by oxytocin. These effects suggest a probable metabolic action of oxytocin against cardiac anoxic changes, and its possible therapeutic usefulness as an antagonist of myocardial ischaemia. It is speculated that this might be a physiological action of the hormone.

Topics: Animals; Arginine Vasopressin; Electrocardiography; Ergonovine; Hypoxia; Myocardial Ischemia; Oxytocics; Oxytocin; Rabbits; Vasopressins