Does guanabenz have a non-specific effect on spontaneous contractions of isolated guinea pig atria?

Guanabenz was found to produce a concentration-dependent depression of the isometric contractility of the isolated, spontaneously beating atria of the guinea-pig. It also depressed the atrial rate of the isolated, spontaneously beating atria of the guinea-pig. The effect of the increasing concentrations of guanabenz on the heart rate was weaker than its effect on the isometric contraction. A time-dependent depression of both the isometric contraction and of the atrial rate after the addition of a single dose of guanabenz was also found up to 10th min. Guanabenz did not change the maximal driving (following) frequency of the atria. Aminophylline partially, isoprenaline almost completely and calcium completely antagonized the negative inotropic action of guanabenz. They, however, did not antagonize the negative chronotropic action of guanabenz. It seems, regardless of what the precise mechanism(s) of action of guanabenz may be (probably nonspecific on the isolated guinea-pig atria), that all these substances (aminophylline, isoprenaline and calcium) restore the contractility of the isolated atria by compensating the calcium balance which has been previously changed by guanabenz.     

Changes in sensitivity to histamine of guinea pig cardiac muscles during postnatal development

Histamine stimulates the heart by interacting with cardiac histamine receptors. We investigated the postnatal changes in histamine sensitivity with spontaneously beating right atria and electrically driven left atria and right ventricular papillary muscles from 0-, 5-, and 10-day-old and adult guinea pigs. The positive chronotropic response to histamine in right atria was antagonized by cimetidine but not by chlorpheniramine at any age. Chlorpheniramine did not antagonize the positive inotropic effect of histamine and 2-(2-pyridyl)ethylamine in the immature left atria but it blocked the positive inotropic effect in the adult; cimetidine had no effect. The positive inotropic effect of histamine in right ventricular muscles was not affected by chlorpheniramine in immature right ventricular muscles but was antagonized in the adult. These results suggest that, in immature left atria and right ventricular muscles, there is no H1-receptor system mediating the positive inotropic effect of histamine and that, as age advances, this system begins to mediate the positive inotropic effect. In immature left atria, non-H1 and non-H2 receptors exist and mediate the positive inotropic effect of histamine.     

Activation of muscarinic K<Superscript>+</Superscript> channels by arecaidine propargyl ester in isolated guinea-pig atrial myocytes

Summary Arecaidine propargyl ester (APE) was developed as a potential candidate compound for the treatment of Alzheimer’s disease. APE has been shown to have cardiovascular effects. APE produces negative chronotropic and inotropic effects in isolated atria. However, the ionic mechanisms underlying the cardiovascular effects of APE in guinea-pig atria are unclear. The aims of this study were: (1) to examine the shortening effect of APE on action potential duration (APD) and to compare the difference in potency between APE and muscarine in isolated single guinea-pig atrial myocytes by using the current clamp method, (2) to examine by using patch clamp techniques the ionic mechanisms underlying the cardiac effects of APE, and (3) to determine whether the cardiac effects caused by APE affect the usefulness of APE as a potential candidate for the treatment of Alzheimer’s disease. The APE significantly reduced the APD in guinea-pig atria and produced no direct effect on ventricular myocytes. APE is approximately 20 times as potent as muscarine in shortening the APD. Attenuation of the APD was consistently accompanied by a hyperpolarization of the resting membrane potential in a concentration-dependent manner. The APE activated muscarinic K⁺ channels and increased potassium conductance in guinea-pig atrial myocytes. In the cell-attached configuration, the APE contained in the pipette increased the channel-opening probability and decreased the closed-state time interval. The proposal that APE can be used as a potential remedy for the treatment of Alzheimer’s disease should be taken into consideration the undesirable cardiovascular side effects that APE causes at lower concentrations.     

Pharmacological profile of a new peptidic gastrin antagonist

Boc-Trp-Met-Asp-NH2 was described as the smallest peptidic fragment which presented gastric antisecretory activity. Some pharmacological aspects of a peptide analogue, Boc-Trp-Leu-Asp-NH2 (Boc-WLD-NH2), were studied on the main biological functions of gastrin. This compound was found to inhibit the binding of gastrin to isolated gastric fundic mucosal cells (IC50 50 microM). On pentagastrin-induced gastric acid secretion in the rat, a dose-dependent inhibition was observed with an ID50 of 55 mumol/kg when pentagastrin (1 microgram/kg per h) was continuously infused and with an ID50 of 7.8 mumol/kg when pentagastrin (1 microgram/kg) was bolus i.v. injected. Similar inhibition was observed on acid secretion induced by pentagastrin in the isolated rat gastric mucosa (IC50 100 microM), whereas the tripeptide had no effect when acid output was triggered by histamine. A dose-dependent inhibition with the tripeptide was shown on pentagastrin induced guinea-pig ileum contractions (IC50 31 microM). The compound had no activity on histamine-stimulated guinea-pig atria (histamine H2-receptor). These results suggest some evidence for a selective antigastrin activity.     

Endothelin is a positive inotropic agent in human and rat heart in vitro

We have investigated the response to endothelin of isolated atrial and ventricular trabeculae from failing human hearts obtained at transplant. Results indicate that endothelin exerts a significant positive inotropic effect on human atrial and ventricular tissue, with increases in developed tension of 74.6 +/- 14.1% (+/- SEM) and 9.9 +/- 4.0%, respectively. Further studies on rat cardiac muscle demonstrate that the greater inotropic effect on atrial than ventricular muscle is also exhibited by the rat heart in vitro, with 39.9 +/- 10.7% and 17.1 +/- 5.9% increases in developed tension for atria and papillary muscle, respectively. Studies in rat atria also provide no evidence for an effect of endothelin on the frequency of spontaneous contractions. These results suggest that the potential exists for regulation of cardiac function in humans and rats by endothelial-derived factors such as endothelin, possibly via augmentation of atrial systole.     

Direct actions of prostaglandins E1, A1, and F2α on myocardial contraction

The inotropic and chronotropic actions of prostaglandin (PG) types PGE₁, PGA₁, and PGF_2α were studied in isolated guinea pig right and left atria, and papillary muscles; rabbit atria; and toad ventricular strips in order to more completely define the cardiac contractile properties of PG. All three prostaglandins, in muscle bath concentrations of 10μg/ml, exerted positive inotropic and chronotropic actions on guinea pig atrium. These contractile effects were persistent after removal of PG from the muscle bath and appeared to limit the relative response to a subsequent dose of PG. The inotropic action of PGE₁ was present over a wide range of bath calcium concentrations (1.1 to 4.4 mM/L). Beta adrenergic receptor blockade, histamine blockade, and pretreatment with reserpine failed to significantly affect the inotropic actions of PG. Norepinephrine and histamine produced more potent inotropic and chronotropic effects on guinea pig atria than did PG and these contractile effects did not exhibit persistence or tachyphylaxis. The prostaglandins did not significantly affect dose response curves for norepinephrine inotropic and chronotropic actions. The prostaglandins had no effect on the force or frequency of contraction in rabbit atria. PGE₁ exerted a positive inotropic effect on toad ventricular myocardium whereas PGA₁ had no effect and PGF_2α had a negative inotropic action.     

Cardiovascular effects of atrial natriuretic extract in the whole animal

Atrial tissue extract (AE) and ventricular tissue extract cause identical decreases in total peripheral resistance when they are injected i.v. into anesthetized rats. However, only AE causes significant hypotension because of cardiac inhibition. This involves both bradycardia and failure of stroke volume to increase appropriately. The observations cannot be explained by direct action of AE on myocytes, but are more likely to be the result of interactions with cardiovascular reflex mechanisms. Excitation of chemosensitive cardiac receptors with vagal afferents appears to be an important afferent mechanism. The efferent limb for the negative chronotropic response resides partly in the vagus nerves and partly in cardiac sympathetic nerves. The negative inotropic response of AE was not altered by vagotomy, spinal section, atropine, or propranolol. These results suggest that atrial peptides may cause the release of a negatively inotropic substance from a site that is not yet identified.     

Effects of 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (platelet activating factor) on cardiac function in perfused guinea-pig heart

The direct cardiac action of 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (PAF) was studied in isolated perfused guinea-pig heart preparations. PAF produced a fall in left ventricular pressure, decreases in the rate of rise of the left ventricular pressure (dp/dt) and coronary flow, but had no effect on heart rate. These results indicate that PAF is a cardiodepressant with inotropic selectivity and this effect on heart is blocked by CV-3988, a specific PAF antagonist.     

Effect of vanadate on cardiac contraction and adenylate cyclase.

Vanadate produces a positive inotropic effect on ventricular muscle from rat, rabbit, guinea pig and cat; a positive inotropic effect on the atria of rat and rabbit, but a negative inotropic effect on the atria of guinea pig and cat. The effects of vanadate are completely reversible and occur in a concentration range of 10^?5M to 10^?3M. In this same concentration range, vanadate also causes a marked activation of cardiac adenylate cyclase suggesting that the positive inotropic action might be due in part to an elevation of cyclic AMP levels. The effects of vanadate are not influenced by alprenolol, cimetidine, or mepyramine, indicating a lack of involvement of β-adrenergic or histamine H₂ and H₁ receptors.     

垂体后叶素和加压素对离体心肌的直接作用

本实验采用大鼠离体右心房和右心室肌条模型,观察了垂体后叶素和加压素对右心房和右心室肌的直接作用。结果表明:垂体后叶素对右心房的自主性收缩频率和幅度及右心室肌的收缩幅度均有剂量依赖性抑制作用;加压素对右心房和右心室肌收缩幅度也有剂量依赖性抑制作用,但对右心房自主节律无影响;催产素对右心房的收缩频率和幅度则均无影响。加压素V_1、V_2受体拮抗剂d(CH_2)_5Tyr(Me)AVP和d(CH_2)_5(D-Ile~2,Ile~4,Ala(NH_2)~9)AVP对垂体后叶素的负性变力作用具有不同程度的阻断作用,但对垂体后叶素的负性变时作用无阻断作用。以上结果提示,垂体后叶素的负性变力作用主要是由加压素产生的,加压素对心肌有直接的负性变力作用;垂体后叶素的负性变时作用可能是非加压素和催产素成分的作用结果。     

Effects of nicardipine on the spontaneous beat of isolated atria of guinea pigs

Nicardipine was found to produce a concentration-dependent depression of the isometric contraction of the isolated, spontaneously beating atria of the guinea-pig. It also depressed the atrial rate of the isolated, spontaneously beating atria of the guinea-pig. The effect of the increasing concentrations of nicardipine on the heart rate was negligibly weaker than its effect on the isometric contraction. A time-dependent depression of the isometric contraction and the atrial rate after the addition of a single dose of nicardipine was also found up to the 10th min. Calcium almost completely, isoprenaline completely and aminophylline partially antagonized the depressive action of nicardipine on the isometric contractility of the atria. Only isoprenaline antagonized the negative chronotropic action of higher doses of nicardipine. It is possible that these substances restore the contractility by compensating the calcium balance, previously changed by nicardipine, or by producing an increase in the intracellular cAMP content (isoprenaline and aminophylline).     

Temperature-dependent inotropic action of A23187 on guinea-pig ventricular muscles

The effects of the Ca2+ ionophore, A23187, on the contraction and membrane action potential of the isolated guinea-pig papillary muscle were examined at various temperatures (30-16 degrees C) and compared to those of isoprenaline and a high calcium medium. A23187 caused a marked positive inotropic effect with a significant prolongation of the action potential duration at an early repolarization phase but not a late repolarization phase at normal temperature (30 degrees C). Such an inotropic effect was completely abolished at low temperature (16 degrees C) where a marked positive inotropic effect of isoprenaline (5 X 10(-8) M) and a high calcium medium (6.2 mM) still remained. These results suggest that the cardiac responsiveness to A23187 was sensitive to a low temperature at which a membrane lipid phase transition may occur.     

Callipeltin A, a cyclic depsipeptide inhibitor of the cardiac sodium-calcium exchanger and positive inotropic agent

Callipeltin A, a cyclic depsipeptide from the New Caledonian Lithistida sponge Callipelta sp., is a macrocyclic lactone containing four amino acids in the L configuration, Ala, Leu, Thr (2 residues); one (Arg) in the D configuration; two N-methyl amino acids, N-MeAla and N-MeGln; a methoxy tyrosine, a 3, 4-dimethyl-l-glutamine; and a 4-amino-7-guanidino-2,3 dihydroxypentanoic acid (AGDHE), formally derived from L-Arg. In cardiac sarcolemmal vesicles Callipeltin A induces a powerful (IC(50) = 0.85 microM) and selective inhibition of the Na(+)/Ca(2+) exchanger. In electrically driven guinea-pig atria, at concentrations ranging between 0.7 and 2.5 microM, Callipeltin A induces a positive inotropic effect, which at the highest concentrations is accompanied by a rise in resting tension. It is suggested that the positive inotropic effect is linked to the inhibition of the Na(+)/Ca(2+) exchanger and that Callipeltin A may be an useful tool to study the role of the cardiac Na(+)/Ca(2+) exchanger in physiological and pathological conditions.     

Calcium as a counteractive agent to streptomycin induced respiratory depression: an in vivo electrophysiological observation.

Effect of streptomycin on respiratory function in cats was studied. It was observed that streptomycin at a dose of 40 mg/kg body weight intravenously (i.v.) caused respiratory failure or streptomycin induced respiratory depression (SIRD). This respiratory failure is not linked with Herring-Breuer stretch receptors because the effect remained unaltered in artificially ventilated cats. The involvement of central structures in SIRD can be discarded since intracarotid and intraventricular administration of streptomycin failed to produce any change in respiration. Studies on monosynaptic reflex, dorsal and ventral root activities of spinal phrenic and intercostal nerves, and on fusimotor and alpha-motor neuron activities of spinal intercostal and phrenic nerves in decerebrated cats indicated clearly that respiratory depression is not only due to blockade at neuromuscular junction but due to functional depression at the level of muscle receptors and spinal cord motor neurons. The respiratory depression induced by streptomycin was more or less completely reversed when calcium was administered intravenously from external source. It is speculated that streptomycin induced respiratory depression may be mediated through calcium inhibition which can be treated with external calcium in conjunction with artificial respiration.     

The cardiac effects of parathyroid hormone in the tiger frog, Rana tigrina

1. The cardiac effects of the N-terminal (1-34) peptide fragment of bovine parathyroid hormone [bPTH-(1-34)] on isolated atria were examined in the frog, Rana tigrina. 2. bPTH-(1-34) produced dose-related inotropic response but no chronotropic response. This inotropic response varied at different times of the year. 3. The inotropic effect of bPTH-(1-34) was attenuated in the presence of verapamil and imidazole. 4. The mechanism of action of bPTH-(1-34) is probably a stimulation of calcium influx directly or indirectly via cAMP production.     

Isolation of a cardiotonic glycoprotein,striatoxin, from the venom of the marine snail Conus striatus

Striatoxin, a powerful cardiotonic glycoprotein has been isolated from the venom of the marine snail Conus striatus, monitored by the inotropic action on the guinea-pig left atria. The molecular weight was estimated to be 25,000 by gel filtration. The purified glycoprotein is electrophoretically homogeneous. The toxin at concentrations above 10^?7 g/ml has a long-lasting inotropic action, which was abolished by tetrodotoxin (10^?6 M). The minimum lethal dose in the fish Rhodeus ocellatus smithi was 1 μg/g body weight. A possible biological role of striatoxin in C. striatus is briefly discussed.     

Dissociation of cyclic GMP from the negative inotropic action of carbachol in guinea pig atria.

The relationship between the negative inotropic action of carbachol and its ability to elevate cyclic GMP was determined in isolated paced guinea pig atria. A clear dissociation was observed between that concentration of carbachol which depressed contractility and that which elevated tissue cyclic GMP content. Doses as low as 0.03 micronM caused a negative inotropic effect while cyclic GMP was not elevated until concentrations nearly 100-fold higher were used. Thus a correlation between tissue cyclic GMP content and the negative inotropic action of carbachol was not found to exist in guinea pig atria.     

Differential regulation of SR calcium transporters by thyroid hormone in rat atria and ventricles

Thyroid hormone exerts positive inotropic effects on the heart mediated in part by its regulation of calcium transporter proteins, including sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2), phospholamban (PLB), and Na(+)/Ca(2+) exchanger (NCX). To further understand the potential cardiac chamber-specific effects of thyroid hormone action, we compared the triiodo-L-thyronine (T(3)) responsiveness of calcium transporter proteins in atrial versus ventricular tissues. Rats were rendered hypothyroid by ingestion of propylthiouracil, and a subgroup of animals was treated with T(3) for 7 days (7 microg/day by constant infusion). Atrial and left ventricular (LV) tissue homogenates were analyzed for expression of SERCA2, PLB, and NCX proteins by Western blot analysis. SERCA2 protein significantly decreased by 50% in hypothyroid LV and was normalized by T(3) treatment. In contrast, SERCA2 protein in atria was unaltered in the hypothyroid state. PLB protein expression significantly increased by 1.6- and 5-fold in the hypothyroid LV and atria, respectively, and returned to euthyroid levels with T(3) treatment. Expression of NCX protein showed a greater response to T(3) treatment in atria tissue than in ventricular tissue. Sarcoplasmic reticulum calcium cycling is determined in part by the ratio of SERCA2 to PLB. This ratio was sixfold higher in the atria compared with LV, suggesting that PLB may play a minor role in the regulation of SERCA2 function in normal atria. We conclude that calcium transporter proteins are responsive to thyroid hormone in a chamber-specific manner, with atria showing a greater change in protein content in response to T(3). The differential effect on atria may account for the occurrence of atrial rather than ventricular arrhythmias in response to even mild degrees of thyrotoxicosis.