A study of the actions of histamine on the isolated rat heart

1. The effects of histamine on cardiac force, heart rate and coronary perfusion pressure were studied in the isolated rat heart, using the Langendorff perfused heart preparation. 2. Single injections of histamine induced dose-dependent decreases in contractile amplitude, heart rate and coronary perfusion pressure. 3. Perfusions of metiamide (above 1 × 10^-4 M) had a depressant effect on contractile force and heart rate, whereas diphenhydramine (4 × 10^-6 M) reduced only the heart rate. Both agents caused a fall in coronary perfusion pressure. 4. The negative inotropic and chronotropic effects of histamine on the isolated rat heart were not significantly influenced by either metiamide or diphenhydramine, or a combination of these drugs. However, the fall in coronary perfusion pressure induced by injections of histamine was significantly antagonized by metiamide or diphenhydramine. 5. These results suggest that the effects of histamine on the isolated rat heart may not be due entirely to stimulation of H₁- or H₂-receptors on the cardiac muscle cells. Evidence is presented for the existence of histamine H₁- and H₂-receptors in the coronary vessels.     

GABA and Glutamate Receptors as Therapeutic Targets in Neurodegenerative Disorders*

Abstract: The amiloride derivatives, 2′,3′-benzobenzamil (BB), 3′,4′-dichlorobenzamil (DCB), and 5-(N-4-chlorobenzyl)-2′,4′-dimethylbenzamil (CBDB) are known as inhibitors of the Na⁺/Ca²⁺ exchange. This kind of drug action was recently suggested to be a new inotropic mechanism. In guinea-pig myocardium, we have studied the inotropic and the accompanying electrophysiological effects of the three compounds in order to assess their selectivity of action. In left atria and in papillary muscle, force of contraction increased with DCB and CBDB (atria only) at a high concentration (5 × 10^-5 ? 10^-4 mol/l) and after long exposure time, whereas BB produced a negative inotropic effect. In the isolated perfused Langendorff heart, the amiloride derivatives tested decreased spontaneous heart rate and force of contraction and prolonged the duration of contraction. In isolated cardiac myocytes, sodium current, calcium current and the delayed rectifier were reduced by concentrations of BB, DCB and CBDB similar to the IC₅₀ values reported for the inhibition of the Na⁺/Ca²⁺ exchange. Our results demonstrate that the amiloride derivatives have multiple sites of action. It is concluded that more specific modulators of the Na⁺/Ca²⁺ exchange are required in order to define their contribution to the regulation of contractile activation of the heart.     

Prostaglandins and CGRP release from cardiac sensory nerves

Summary (1) The possible influence of Prostaglandins (PG) E₁ and I₂ as well as ischaemia, ouabain and bradykinin on the outflow of calcitonin gene-related peptide (CGRP)- and neuropeptide Y (NPY)-like immunoreactivity (LI) from the guinea-pig heart was studied in vitro. (2) Exposure to PGE₁ (10^–5 M), but not PGI₂ (10^–5 M), induced an increased outflow, suggesting release of CGRP-LI. PGE₁ simultaneously increased the contractile force and heart rate while no effects were observed on perfusate volume or outflow of NPY-LI. PGI₂ had no effect on contractile parameters or coronary flow. In separate experiments on capsaicin-pretreated animals, the stimulatory effects of PGE₁ on heart rate and contractile force remained unchanged while no increased CGRP-LI outflow was detectable. (3) Ouabain, bradykinin and reperfusion after total stop-flow ischaemia was associated with an indomethacin-resistant increase in perfusate levels of CGRP-LI but not of NPY-LI. While ouabain markedly increased the contractile force, exposure to bradykinin or ischaemia did not induce any clear-cut changes in contractile force or heart rate. (4) Capsaicin-exposure evoked a markedly increased outflow of CGRP-LI but not of NPY-LI in combination with an increase in heart rate and a decrease in contractile force. Repeated administration of capsaicin induced tachyphylaxis. The stimulatory effects of capsaicin on CGRP-LI outflow and heart rate, but not the negative inotropic effect, did not occur in capsaicin-pretreated animals. (5) It is concluded that PGE₁, but not PGI₂, can activate cardiac capsaicin-sensitive fibres as revealed by increased outflow of CGRP-LI. The cardiostimulatory effects induced by PGE₁ are not related to CGRP release, however. A possible prostaglandin link in the CGRP-LI released by ouabain, bradykinin or ischaemia seems unlikely. Send offprint requests to: A. Franco-Cereceda at the above address     

The effects of amrinone and glucagon on verapamil-induced myocardial depression in a rat isolated heart model

• 1.1. We measured the ability of glucagon and amrinone, used alone and in combination, to improve the myocardial function in a rat isolated heart model of calcium channel blocker (CCB) cardiotoxicity.
• 2.2. Verapamil 10⁻⁴ mol consistently decreased heart rate and cardiac contractile force in our Langendorff rat isolated heart preparations. Glucagon increased the heart rate in a dose-dependent fashion. Amrinone increased the heart rate only at the 1 × 10⁻³ mol concentration, and had no significant effect on cardiac contractility.
• 3.3. A positive linear correlation was found between the glucagon concentration and the percent recovery of baseline contractile force.
• 4.4. Although complete reversal of verapamil-induced myocardial depression occurred at glucagon concentrations of >3 × 10⁻⁶ mol, amrinone produced only 23.8±3.6% recovery from baseline at its highest concentration (4×10⁻³mol).
• 5.5. When glucagon and amrinone were administered together, there was no additional increase over glucagon alone in the increase in contractile force.
• 6.6. Glucagon, and not amrinone, is an appropriate agent, capable of reversing verapamil-induced myocardial toxicity in this rat isolated heart model. In vivo studies should be performed to assess whether this may be a reliable therapy in clinical cases.

     

NO EFFECT OF ATRIAL NATRIURETIC FACTOR ON CARDIAC RATE, FORCE AND TRANSMITTER RELEASE

1. The effects of atrial natriuretic factor (ANF, 1-300 nmol/l) on cardiac rate, force and neurotransmitter release were examined in guinea-pig isolated heart preparations. 2. Synthetic ANF had little effect on the contractile force of electrically driven papillary muscle regardless of the presence or absence of isoprenaline. 3. The pulse period of spontaneously beating right atria was not affected by ANF. Neither the positive nor negative chronotropic effect of isoprenaline or bethanechol respectively were changed in the presence of ANF. 4. ANF did not affect the release of neurotransmitter from the nerve endings in the isolated atrium. 5. ANF was confirmed to relax isolated aortic rings precontracted with either noradrenaline (ANF, IC₅₀= 3 nmol/l, s.e.m. = 0.2, n= 5) or potassium (ANF, IC₅₀= 24 nmol/l, s.e.m. = 0.2, n= 5). 6. These results demonstrate that ANF within doses effective for vasorelaxation has no appreciable effect on myocardial function or neutrotransmitter release in the heart.     

Cardiotonic effect of <Emphasis Type="Italic">Apocynum venetum</Emphasis> L. extracts on isolated guinea pig atrium

The effects on guinea-pig heart muscle of extracts of Apocynum venetum L. leaf, root, stem, old stem and Venetron—a polyphenol-rich extract of leaves—were studied by recording the mechanical activity and heart rate of isolated right atria. Cymarin—a cardiac glycoside—was also determined in A. venetum extracts by LC–MS/MS analysis. All extracts examined here showed a weak cardiotonic effect, i.e., induced a contractile response of the isolated atria and increased the pulse at a concentration of 1 mg/mL, which was not inhibited by propranolol (1 μM)—a β-adrenoceptor blocker. The cymarin content in extracts of A. venetum was ranked as follows: old stem >> stem > root > leaf >> Venetron. Since the cardiotonic effects of A. venetum extracts did not reflect the cymarin content, a possible mechanism other than that of cardiac glycosides was investigated. The inhibitory effects on phosphodiesterase 3 (PDE3) were studied in a cell-free enzyme assay; all extracts of various parts of A. venetum inhibited PDE purified from human platelets. These results suggest that PDE3 inhibition may contribute to the cardiotonic effects of A. venetum extracts.     

Positive inotropic effects of the calcium channel activator Bay K 8644 on guinea-pig and human isolated myocardium

Summary 1. The positive inotropic effects of the dihydropyridine calcium activator Bay K 8644 were studied in guinea-pig isolated contracting myocardium and human papillary muscle strips obtained from patients undergoing mitral valve replacement or cardiac transplantation. 2. Bay K 8644 produced a slowly developing, concentration-dependent positive inotropic response in all cardiac tissues studied. In guinea-pig papillary muscle, the increase in force of contraction was half-maximal at 3.9 × 10^–8 mol/l and the maximal inotropic effect was comparable to that obtained with ouabain, dobutamine or calcium. The guinea-pig left atrium (EC₅₀, 2.1 × 10^–7 mol/l) was fivefold less sensitive than the papillary muscle. 3. The maximal inotropic response to dihydroouabain was significantly increased after preincubation with Bay K 8644 (1 × 10^–6 mol/l) in papillary muscles from both guinea-pig and human. In guinea-pig papillary muscles, the maximal inotropic response to dobutamine was not changed by preincubation with Bay K 8644 whereas in human papillary muscle strips, Bay K 8644 increased the inotropic response to dobutamine. 4. Bay K 8644 increased force of contraction (EC₅₀, 4 × 10^–8 mol/l) in human papillary muscle strips from patients undergoing mitral valve replacement. However, the maximal inotropic response to Bay K 8644 was reduced to 32 ± 4.4% that of calcium (15 mmol/l) measured in the same muscle strips. 5. A further reduction in maximal inotropic response to Bay K 8644 to 13 ± 1.2% that of calcium (15 mmol/l) with no change in potency was measured in human papillary muscle strips taken from terminally failing hearts of cardiac transplant recipients. 6. There was a significant correlation between the preoperative left ventricular ejection fraction and the maximal inotropic response to Bay K 8644 in isolated human papillary muscle strips. 7. These results suggest that Bay K 8644 affects excitation-contraction coupling of cardiac muscle so as to increase the maximal inotropic effect of the digitalis glycosides. Further, the inotropic response of human myocardial tissue to calcium channel activator Bay K 8644 may be reduced in states of pathological heart function.The human heart papillary muscles were provided by Prof. E. Kreuzer, Prof. B. Kemkes, Dr. C. Weinhold and their colleagues, Herzchirurgische Klinik der Universität, Klinikum Grosshadern, D-8000 München 70, Federal Republic of Germany Send offprint requests to E. Erdmann     

Inotropic and Chronotropic Effects of 4-(4′-n-Butylaniline)-7,8-dimethoxy-5H-pyrimido[5,4–b]indole in Guinea-pig Atria

Cardiotonic effect of 4-(4′-n-butylaniline)-7,8-dimethoxy-5H-pyrimido[5,4-b)]indole (B₁₁) was investigated in isolated cardiac tissue preparations. The action of this agent on force of contraction, beating frequency and cyclic nucleotide phosphodiesterase (PDE) activity was studied. Amrinone was used for comparison. B₁₁ produced concentration-dependent (5 × 10^?6-1 × 10^?4m) positive inotropic and positive chronotropic responses in guinea-pig atrial tissues. The potency of B₁₁ was greater than that of amrinone. The cardiotonic effects of B₁₁ were not modified by β-adrenoceptor blockade. Carbachol inhibited the positive inotropic effect of B₁₁. The activity of B₁₁ was increased in desensitized left atrial tissues. B₁₁ inhibited the activities of PDE isoenzymes (type I, II, IV and V) from dog heart ventricle and PDE type IV from guinea-pig heart ventricle nonselectively. It is concluded that B₁₁ possesses potent positive inotropic activity in guinea-pig atria, and the effect is probably mediated by a non-selective inhibition of PDE activity.     

Effect of a novel partial adenosine A1 receptor agonist VCP102 in reducing ischemic damage in the mouse heart

Investigations into the use of A₁ adenosine receptor (A₁AR) agonists in reducing post‐ischemic damage to the heart have been of significant interest to cardiovascular research. The present study examined the cardioprotective effects of the partial A₁AR agonist, N⁶‐[4‐[1,1,3,3‐tetramethylisoindolin‐2‐yloxyl‐5amido]ethyl]phenyl]adenosine (VCP102) and the full A₁AR agonist, N⁶‐cyclopentyl adenosine (CPA), in murine isolated hearts perfused in Langendorff mode. Following 30‐min ischemia, hearts were treated with the A₁AR agonists during early reperfusion for 15 min (IR protocol). Significant increases in left ventricular developed pressure (LVDP) and contractility (dP/dt_max) were observed at the final reperfusion values for VCP102 (100 nM)‐treated hearts, as compared with the control tissues (P<0.05). EDP values in VCP102‐treated hearts were also lower than control tissues (P<0.05). The A₁AR antagonist, 8‐cyclopentyl‐1,3‐dipropylxanthine (DPCPX, 10 nM) and the A₃AR antagonist 3‐ethyl‐5‐benzyl‐2‐methyl‐4‐pheylethynyl‐6‐phenyl‐1,4‐(±)‐diphydropyridine‐3,5‐dicarboxylate (MRS1191, 200 nM) attenuated the protective actions of 15 min VCP102 during IR (P<0.05). An improvement in functional recovery was not observed with CPA (100 nM, P>0.05). Infarct size was also significantly reduced in VCP102‐ or CPA‐treated hearts as compared with control tissues (P<0.05). DPCPX and MRS1191 attenuated VCP102‐induced decreases in infarct size (P<0.05), but did not alter the responses to CPA (P>0.05). Significant reductions in cardiac troponin I release and expression of the pro‐apoptotic zymogen caspase‐3 were observed in both treatment groups (P<0.05). In summary, both A₁ARs and A₃ARs may play a role in mediating cardioprotection and improving functional recovery in the IR heart with VCP102. Furthermore, treatment with the partial agonist appeared to confer improved functional cardiac protection when compared with CPA. Drug Dev Res 68:529–537, 2007. © 2008 Wiley‐Liss, Inc.     

Pre- and Postjunctional Effects of Diadenosine Polyphosphates in the Guinea-pig Vas Deferens

The pre- and postjunctional activities of a number of diadenosine polyphosphates were examined in the guinea-pig isolated vas deferens at the level of the membrane-potential, using a modified sucrose-gap technique. P¹,P³-Di(adenosine 5′)triphosphate (Ap₃A), P¹,P⁴-di(adenosine 5′)tetraphosphate (Ap₄A) and P¹,P⁵-di(adenosine 5′)pentaphosphate (Ap₅ A) all caused concentration-dependent depolarization of the smooth muscle membrane. The potency order was: Ap₅A > Ap₄A. Ap₃A. P¹, P²-Di(adenosine 5′)pyrophosphate (Ap₂A) did not evoke depolarization even at the highest concentration tested (1 mM). All the dinucleotides caused a reduction in the amplitude of evoked excitatory junction potentials (e.j.ps). The potency order was: Ap₅A = Ap₄A > Ap₃A > Ap₂A. The depolarizations evoked by the dinucleotides were markedly reduced by the selective P_2X-purinoceptor antagonist, pyridoxalphosphate-6-azophenyl-2′,4′-disulphonic acid (PPADS, 10 μM), as was the amplitude of the fully facilitated e.j.p. The inhibition of the e.j.p. evoked by Ap₃A and Ap₂A was reduced by the P₁-purinoceptor antagonist, 8-p-sulphophenyltheophylline (8-pSPT, 50 μM), but that evoked by Ap₅A and Ap₄A was not. Thus, Ap₃A, Ap₄A and Ap₅ A evoke depolarization of the guinea-pig vas deferens via P_2X-purinoceptors, and additionally Ap₂A and Ap₃A exert a prejunctional effect via P₁-purinoceptors. The prejunctional activity of Ap₄A and Ap₅A is mediated via an undefined purinoceptor, which is neither P₁ nor P_2X.     

Midazolams cardiac depressant effects and their lack of reversal by flumazenil in isolated rabbit hearts.

Midazolam is known to cause a dose-dependent increase and decrease in the contractile force of the myocardium. Whether flumazenil can reverse these effects of midazolam remains unclear. In this study, we determined the cardiac effects of midazolam and the counter effect of flumazenil on midazolam-induced myocardial depression in isolated rabbit hearts. Rabbit hearts were isolated and perfused using the Langendorff technique, and left ventricle pressure and heart rate were measured by a pressure transducer in the left ventricle. One set of hearts were perfused with increasing concentrations of midazolam for 10 min, another set were perfused with concomitant midazolam and flumazenil. Concentrations of 5, 10, 20 and 50 microM midazolam decreased left ventricle pressure significantly (P < 0.01, P < 0.05, P < 0.01, P < 0.01, respectively). Heart rates decreased with concentrations of 10, 20 and 50 microM midazolam (P < 0.01, P < 0.01, P < 0.05, respectively). Flumazenil had no effect on the midazolam-induced decrease in left ventricle pressure and heart rate. Midazolam decreased the cardiac contractile force and heart rate of isolated rabbit hearts in a concentration-dependent manner. The failure of flumazenil to reverse these effects suggest that this cardiac depressant effect of midazolam is not mediated through peripheral benzodiazepine receptors.     

Some biochemical aspects of the potential benefit of associating MD780515 with tricyclic antidepressants

In the rat, suitable oral doses of tricyclic antidepressants (amitriptyline 20 mg kg^?1, imipramine, desipramine 2·5 mg kg^?1) are able to antagonize the increase of cardiac levels of intravenous tyramine after a pharmacologically active dose (3·5 mg kg^?1 orally) of a reversible and specific type A MAO inhibitor, MD780515 (3-[4-(3-cyanophenyl-methoxy)phenyl]-5-(methoxymethyl)-2-oxazolidinone). MD780515, in oral doses up to 35 mg kg^?1, does not alter the liver microsomal drug metabolizing enzymes in the rat. Therefore, when given with tricyclic antidepressants, it should not interfere with their metabolism.     

CARDIAC INTERACTION BETWEEN PARATHYROID HORMONE, β-ADRENOCEPTOR AGENTS, AND VERAPAMIL IN THE GUINEA-PIG IN VITRO

1. The present study examines the modulation, by parathyroid hormone, of the changes in myocardial contractile force induced by isoprenaline, propranolol isomers, verapamil, and nadolol. 2. Cardiac contractile force was estimated by the use of guinea-pig isolated auricles. Synthetic bovine 1-34 parathyroid hormone (sPTH) alone did not modify contractile force; conversely, sPTH significantly inhibited the cardiode-pressant effect of l-propranolol, d, l-propranolol, d-propranolol, and verapamil. These results suggested an action of sPTH independent of β-adrenoceptors. Against an hypothesis of a single, non-β-adrenoceptor mechanism of sPTH action on the heart are the following observations: (i) when β-adrenoceptors were blocked with nadolol, sPTH no longer inhibited the cardiodepressant effect of propranolol, (ii) sPTH reduced the inotropic effects of isoprenaline. Our conclusion, therefore, is that sPTH probably affects cardiac muscle contraction by at least two mechanisms, one of which involves non-adrenergic transmembrane calcium flux and the second β-adrenoceptors. 3. When these studies were extended into the clinical pharmacological field, it was found that plasma ultrafiltrates from severely hyperparathyroid patients in chronic renal failure inhibited like sPTH the cardiodepressant action of propranolol. No such effect was seen with ultrafiltrates from parathyroidectomized patients. Accordingly, high PTH levels may inhibit the action of cardiotropic drugs administered to hyperparathyroid patients, and may be one factor in the cardiomyopathy seen in such patients.     

CP-96,345, a non-peptide antagonist of substance P. III. Cardiovascular effects in mammals unrelated to actions on substance P receptors

Summary The cardiovascular effects of CP-96,345, a non-peptide antagonist of substance P, were analyzed in vivo and in vitro. In the anaesthetized rat, the i.v. injection of 3 µmolkg^–1 of CP-96,345 induced a fall in mean arterial blood pressure and a reduction in heart rate. Similar effects were obtained with the enantiomer CP-96,344 ((2R,3R)-cis-isomer of CP-96,345) which does not interact with substance P receptors. Both enantiomers, at a concentration of 10 gM, decreased the beating frequency of the isolated atria and of the isolated perfused heart of the guinea-pig to a similar extent, and caused transient coronary dilatation. CP-96,345 (10 µM) decreased the spontaneous sinus rate, prolonged the atrioventricularnodal conduction interval and the His-bundle conduction interval of the perfused guinea-pig heart. The intraventricular spread of conduction was markedly inhibited. During programmed stimulation 10 min after the beginning of the drug application, the effective refractory periods evaluated by stimulation with premature beats, as well as rate dependent effective refractory periods, of the atrioventricular node, of the atrial and of the ventricular myocardium, were prolonged. Sinus node recovery time was also prolonged. It was concluded that these cardiac effects of CP-96,345 were not caused by an action of the compound on substance P receptors. Send offprint requests to F. Lembeck at the above address     

Effects of lisinopril on cardiac contractility and ionic currents

1. The effects of lisinopril, an angiotensin-converting enzyme inhibitor, were studied on cardiac contractile force, action potential characteristics and membrane ionic currents.2. In guinea-pig atria, lisinopril (0.001–1 μM) exerted a negative inotropic effect which was accompanied by a shortening of the time to peak tension and time for total contraction. However, it did not modify atrial rate or the characteristics of the ventricular action potentials recorded either in normally polarized or in depolarized papillary muscles.3. In isolated guinea-pig ventricular myocytes, lisinopril had no effect on the inward L-type Ca²⁺ (I_Ca,L), the inward rectifier (I_K1) or the delayed rectifier K⁺ currents (I_K), but abolished the stimulation-dependent facilitation of the I_Ca,L. Furthermore, it did not alter a cloned human cardiac K⁺ current (hKv1.5) expressed in a mouse L cell line (Ltk⁻).4. The absence of negative inotropic effects in patients with congestive heart failure can be explained by the potent arterial vasodilator action of lisinopril which reduced left ventricular afterload overriding the expected direct cardiodepressant effects of the drug.     

Antimuscarinic properties of vamicamide,a novel compound for the treatment of pollakiuria

The antimuscarinic profile of vamicamide, a novel compound for the treatment of pollakiuria, was investigated in both in vitro and in vivo preparations. Vamicamide (10 nM–10 μM) inhibited the contractile response of isolated guinea-pig detrusor muscle to transmural electrical stimulation. In isolated guinea-pig detrusor muscle, vamicamide also inhibited contractile response to carbachol with an IC₅₀ value of 0.71 μM, whereas it had little or no effect on detrusor contractions induced by KCl, BaCl₂, or α, β-methylene ATP. In binding studies with dog membrane preparations, the dissociation constant (Ki) of vamicamide against tritiated N-methylscopolamine ([³H]NMS) binding was 172 ± 8 nM for the urinary bladder, which was lower (P < 0.01) than those for the heart (322 ± 31 nM), stomach (317 ± 29 nM), and salivary gland (321 ± 32 nM). The Ki value for the cerebral cortex (95 ± 4 nM) tended to be lower than that for the urinary bladder. In binding studies with cloned human muscarinic receptor subtypes (m1–m3), the dissociation constant (Ki) of vamicamide against [³H]NMS binding was 89.0 ± 3.5 nM for the m3 receptor subtype, which was lower than those for the m1 (235 ± 5 nM, P < 0.05) and m2 (593 ± 49 nM, P < 0.01) receptor subtypes. In anesthetized dogs, vamicamide (3.2–100 μg/kg; 11–336 nmol/kg, iv) inhibited the carbachol-induced contractile responses of the urinary bladder with an ID₅₀ value of 16.1 μg/kg (54 nmol/kg), the stomach with a value of 31.3 μg/kg (105 nmol/kg), the descending colon with a value of 10.1 μg/kg (34 nmol/kg), and secretory response of the salivary gland to carbachol with a value of 43.3 μg/kg (146 nmol/kg); the inhibitory effects of the compound on the stomach and salivary gland were weaker (P < 0.01) than that on the urinary bladder. Furthermore, duration of the action of vamicamide was longer on the urinary bladder and descending colon than those on the stomach and salivary gland. These results suggest that vamicamide has a selective binding affinity to the muscarinic m3 receptor subtype and exhibits greater and longer inhibitory action on the urinary bladder than the other organs examined. © Wiley-Liss, Inc.     

The effect of the tricyclic antidepressant drug,nortriptyline on left ventricular ejection fraction and left ventricular volumes

Eight patients with major depression but otherwise healthy underwent radionuclide cardiography before and during nortriptyline treatment. The second examination was performed when the nortriptyline plasma concentration was within the therapeutic range (60–150 g·l^–1). Heart rate, arterial blood pressure, left ventricular ejection fraction, left ventricular volumes, systolic pressure-volume ratio, and cardiac output were determined. Heart rate increased in mean by 13% (P<0.05). All other variables were unchanged. We conclude that nortriptyline in therapeutic doses produces no major adverse effect on left ventricular function. Routine radionuclide cardiography might be a suitable method to detect among those treated with tricyclic antidepressants the occasional susceptible patient. This may particularly apply to patients with known heart disease and to elderly patients.     

Frequency-force relationship in guinea-pig ventricular myocardium as influenced by magnesium

Summary o li]1.|In guinea-pig papillary muscle, the characteristic relation between force of contraction and frequency is changed by the withdrawal of magnesium from the incubation medium. In magnesium-free solution, reduction of contraction frequency below 0.1 Hz leads to an increase in force of contraction which reaches its maximum at a frequency of 0.00166 Hz (i.e., one contraction every 10 min).After magnesium withdrawal, the frequency-force relationship in guinea-pig ventricular muscle resembles that of guinea-pig atrial muscle in magnesium-containing solution. li]2.|The increase by magnesium withdrawal in contractile force of guinea-pig papillary muscles contracting at low frequencies is the result of an increase in contraction velocity. The time to peak force is shortened and the relaxation time is prolonged. li]3.|After obtaining steady-state values of contractile force at 1 Hz contraction frequency, stimulation was terminated and the time course of changes in the inherent contractile activity of the muscle was determined by eliciting single contractions at time intervals of between 0.5 and 10 min duration.After cessation of stimulation, the contractile activity declines exponentially in solution containing 1.2 mM Mg²⁺; in magnesium-free solution an initial decline is followed by a slowly developing increase. This rise in contractile activity is reduced at 3.2 mM Ca²⁺ by the presence of 0.075 mM Mg²⁺ and is prevented by 0.3 mM Mg²⁺. li]4.|The increase in contractile activity obtained in the papillary muscle during rest by magnesium withdrawal depends in its magnitude on [Ca²⁺]₀. li]5.|The rested-state contractile activity of ventricular muscle in magnesium-free solution is reduced by 75% with the first and by 90% with the second contraction after onset of 1 Hz stimulation. li]6.|Possible mechanisms are discussed by which Mg²⁺ inhibits the development of rested-state contractile activity in the guinea-pig ventricular myocardium.     

Effect of adrenochrome on calcium accumulation by heart mitochondria

The effects of adrenochrome (1–100 μg/ml or 5.6 × 10^?6 to 5.6 × 10^?4 M) on calcium binding, calcium uptake, and ATPase activities of rat heart mitochondria were investigated. Depression, by adrenochrome, of mitochondrial calcium binding and uptake was observed under in vitro conditions, whereas mitochondrial ATPase activity was not altered appreciably. The inhibitory effect of adrenochrome on calcium uptake activity was independent of the pH of the incubation medium, but it was dependent upon the dose of drug and the time of incubation. High concentrations of calcium in the incubation medium antagonized the adrenochrome-induced depression. The inhibition of mitochondrial calcium uptake by adrenochrome was of a mixed type. Furthermore, the depressed calcium uptake activity was observed after washing adrenochrome-treated mitochondria with buffer. Significant decreases in calcium accumulating activities were also seen in mitochondria isolated from hearts perfused with various concentrations of adrenochrome (5–50 μg/ml) for 10 min, or with 50 μg/ml adrenochrome for various time periods. Contractile force of the perfused rat heart with various concentrations of adrenochrome (5–50, μg/ml) decreased in a dose-dependent manner. It is suggested that the cardiac contractile failure and myocardial cell necrosis induced by adrenochrome may partly be due to its inhibitory effect on the calcium accumulating ability of mitochondria.     

多沙唑嗪以及阿夫唑嗪对映体对小鼠离体心房心率和收缩力的影响

目的分析多沙唑嗪以及阿夫唑嗪的光学异构体及其外消旋体与药物调节小鼠离体心房心率和心肌收缩力效应的关系。方法制备小鼠离体左心房和离体右心房标本,观察消旋多沙唑嗪[(±)DOX]、左旋多沙唑嗪[(-)DOX]、右旋多沙唑嗪[(+)DOX]、消旋阿夫唑嗪[(±)ALF]、左旋阿夫唑嗪[(-)ALF]以及右旋阿夫唑嗪[(+)ALF]对小鼠离体右心房心率及左心房心肌收缩力的影响。结果 (+)DOX组的16例标本中,加入30μmol·L-1药物后,5例(31.3%)发生停搏;(±)DOX组、(-)DOX组各有1例发生停搏;其他各组标本未出现停搏反应。(+)DOX和(±)DOX各浓度均减慢小鼠右心房心率(P<0.01),并具有浓度依赖关系;(+)DOX减慢心率的作用强于同浓度(±)DOX(P<0.01)。10和30μmol·L-1浓度的(-)DOX减慢心率(P<0.01),其作用弱于同浓度(+)DOX(P<0.01)。(-)ALF、(+)ALF及(±)ALF在10和30μmol·L-1浓度时均轻度减慢小鼠右心房心率(P<0.05)。在小鼠离体左心房标本,(+)DOX(10和30μmol·L-1)抑制心肌收缩力(P<0.05);而(-)DOX(3～30μmol·L-1)增强心肌收缩力(P<0.05),其增强作用强于同浓度(±)DOX(P<0.05)。(±)ALF及其对映体(3～30μmol·L-1)对小鼠离体左心房心肌收缩力无影响。结论 DOX对小鼠离体心房的心率和心肌收缩力具有明显的影响,高浓度尚可诱发心脏停博反应;DOX的手性结构对其上述活性具有明显的影响。相反,ALF仅影响小鼠心率,ALF的手性结构对其心脏效应无明显影响。