Ventricular Contractile Force Research Articles

Different Chronotropic and Inotropic Effects of EMD 57033 and EMD 53998, Ca2+ Sensitizers, on Isolated, Blood-Perfused Dog Heart Preparations

To investigate whether a Ca2+ sensitizer increases sinus rate, we studied the effects of racemic thiadiazinone, EMD 53998 (a Ca2+ sensitizer with phosphodiesterase inhibitory action) and its (+)-enantiomer EMD 57033 (a relatively pure Ca2+ sensitizer) on isolated, blood-perfused spontaneously beating right atria and paced left ventricles of the dogs. EMD 53998 increased sinus rate dose-dependently, but EMD 57033 did not. Both substances increased atrial and ventricular contractile force. Propranolol did not affect the responses to each substance. These results suggest that the Ca2+ sensitizing action induced by EMD 57033 does not affect pacemaker currents directly.

Chronotropic and inotropic effects of terikalant on isolated, blood-perfused atrial and ventricular preparations of dogs.

We investigated the effects of terikalant, which blocks inward rectifier K+ current, on the sinus rate, atrial and ventricular contractile force in the isolated, blood-perfused right atrial and left ventricular preparations of dogs, and the effects of terikalant on the negative cardiac responses to acetylcholine, adenosine or pinacidil (an ATP-sensitive K+ channel opener) and on the positive cardiac responses to norepinephrine. Terikalant (1-100 nmol) decreased sinus rate and briefly and slightly increased atrial contractile force in isolated atria. However, terikalant did not increase ventricular contractile force in isolated ventricles. Neither propranolol nor atropine inhibited the positive inotropic and negative chronotropic responses to terikalant, respectively. Terikalant (10 or 30 nmol) did not significantly affect the negative cardiac responses to acetylcholine, adenosine nor pinacidil and the positive responses to norepinephrine. These results suggest that terikalant decreases sinus rate with a small changes in myocardial contractile force and does not affect the cardiac responses to muscarinic and adenosine receptor agonists, ATP-sensitive K+ channel openers nor beta-adrenoceptor agonists in the dog heart.

PACAP-38 activates parasympathetic nerves in isolated, blood-perfused dog atria

A pituitary adenylate cyclase-activating polypeptide (PACAP) activates PACAP and vasoactive intestinal peptide (VIP) receptors. We investigated the effects of PACAP-38 on the sinus rate and atrial contractile force in isolated, blood-perfused dog heart preparations and the stimulation by PACAP-38 of the parasympathetic nerve fibers. PACAP-38 (3–1000 pmol) caused positive and/or negative chronotropic responses and it dose dependently increased atrial and ventricular contractile force. The positive cardiac responses to PACAP-38 unlike those to VIP were much less than the positive responses to norepinephrine. Atropine inhibited the negative chronotropic responses to PACAP-38 and augmented the positive chronotropic and inotropic responses. Physostigmine potentiated the negative cardiac responses to PACAP-38 and acetylcholine. After physostigmine treatment, additionally, tetrodotoxin blocked the negative cardiac responses to PACAP-38 and intracardiac parasympathetic nerve stimulation. Propranolol did not inhibit the positive cardiac responses to PACAP-38 in atropine-treated atria. PACAP-(6–38) (1 and 3 nmol), an antagonist of PACAP-38, did not affect the cardiac responses to 100 pmol of PACAP-38. These results suggest that (1) PACAP-38 directly increases sinus rate and atrial contractile force and (2) PACAP-38 activates parasympathetic nerves and causes negative chronotropic and inotropic responses in the dog heart.

Inhibition by bertosamil of cardiac responses to pinacidil or Bay k 8644 in isolated dog atria and ventricles

We investigated the effects of a novel bradycardic agent, bertosamil (3-isobutyl-7-isopropyl-9,9-pentamethylene-3,7-diazabicyclo[3.3.1]nonane sesquihydrogenfumarate), on the sinus rate and atrial contractile force and the left ventricular contractile force in isolated, blood-perfused dog hearts and the blocking effects of bertosamil on the chronotropic and inotropic responses to pinacidil and Bay k 8644 (methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-piridine-5-carboxylate). Bertosamil (0.1–100 nmol) caused transient positive, followed by continuous negative, chronotropic responses and positive inotropic responses in atria, and increased the left ventricular contractile force. Neither propranolol nor atropine affected the cardiac responses to bertosamil. Bertosamil (3–100 nmol) dose dependently attenuated the negative chronotropic and inotropic responses to pinacidil but not to acetylcholine. Bertosamil at a high dose attenuated the positive cardiac responses to Bay k 8644, norepinephrine and isoproterenol. These results suggest that bertosamil inhibits negative cardiac responses mediated by an ATP-sensitive K + channel but not an acetylcholine muscarinic receptor and, at a high dose, attenuates the L-type Ca 2+ channel-mediated positive cardiac responses in isolated dog hearts.

Effects of potassium channel blockers on the action potentials and contractility of the rat right ventricle

1. 1. The effects of several potassium channel blockers on the action potentials and contractile force of the electrically driven rat right ventricle have been determined. 2. 2. Glibenclamide, which blocks the ATP-sensitive potassium channels, had no effect on the ventricular action potentials or contractile force responses. 3. 3. 4-Aminopyridine, which blocks the Na +-activated potassium channels in ventricles, at 0.3-3 mM increased the amplitude and prolonged the action potentials, and also augmented the force responses to cardiac stimulation and to isoprenaline. 4. 4. Clofilium, a selective blocker of the delayed outward rectifying potassium channel, at 0.1 and 0.3 μM prolonged the action potentials. At 0.1 μM, clofilium augmented the cardiac stimulation responses and, at 0.3 μM, clofilium augmented the maximal responses to isoprenaline. At 1 and 3 μM, clofilium had a lesser ability to prolong action potentials and did not alter force responses. 5. 5. Procaine blocks the Na +-activated and the delayed outward rectifying potassium channels and, at higher concentrations, sodium channels. Procaine, at 30 μM, prolonged the action potentials and augmented the force responses to isoprenaline, presumably by blocking potassium channels. Procaine, at 1 mM, had no effect on action potentials but reduced the maximal force responses to isoprenaline, probably by blocking sodium channels. 6. 6. Tetraethylammonium blocks the inward rectifying and delayed outward rectifying potassium channels. Tetraethylammonium, at 1 and 3 mM, prolonged the action potentials and augmented all of the force responses; these effects are likely to be predominantly due to blocking the outward rectifying potassium channel. Thus, in the presence of procaine, the effects of tetraethylammonium are predominantly due to the additional blockade of the inward rectifying potassium channel and there were no effects. 7. 7. None of the potassium channel blockers at any of the concentrations tested had arrhythmogenic effects alone or in the presence of isoprenaline. 8. 8. In summary, this study has shown that blockade of the Na +-activated and the delayed outward rectifying, but not the ATP-sensitive or inward rectifying, potassium channel is associated with pro. longation of the action potentials, augments the contractile force responses, and is not arrhythmogenic on the rat right ventricle. New drugs that block the Na +-activated or delayed outward rectifying potassium channel may have potential as positive inotropes in the treatment of heart failure.

Calcium-antagonists abolish the protective effect of atrial ANP on ventricular contractile force

P2Y receptor pharmacology is hampered by a lack of subtype selective antagonists. However, a recent study evaluated series of compounds, structurally related to the dye reactive blue 2, for their antagonist selectivity at P2X vs. P2Y receptors. Acid blue 129, acid blue 80, acid blue 25 and acid violet 34 were found to be the most potent of the antagonists studied, at P2Y receptors [Naunyn Schmiedeberg's Arch. Pharmacol. 357 (1998) 111]. In this study, we have determined the ability of these four agents to selectively antagonize inositol phosphate turnover mediated by P2Y1 and P2Y2 receptors that are natively expressed in bovine aortic endothelial (BAE) cells. Acid blue 129, acid blue 80, and acid violet 34 shifted the dose–response curve of the P2Y1 agonist 2-methylthio adenosine trisphosphate (2MeSATP) to the right. Acid blue 129 and acid blue 80 were also very weak antagonists of the P2Y2 agonist uridine 5′-triphosphate (UTP). At 30 and 100 μM, acid violet 34 failed to have any significant effect on the dose–response to UTP. However, at 10 μM, acid violet 34 enhanced the UTP responses. Acid blue 80, acid blue 129 and acid violet 34 are P2Y vs. P2X selective, but show poor selectivity between P2Y1 and P2Y2 receptors and are therefore of limited use in the field of P2Y receptor pharmacology. Furthermore, contrary to previous reports, acid blue 25 is not a P2Y-selective antagonist.

Effect of Calcium Entry Blocking Agents (Nifedipine and Verapamil) on Myocardial Recovery during Reperfusion.

A comparative study on isolated guinea pig hearts was carried out to determine the effect of calcium entry blocking agents: nifedipine- and verapamil-added reperfusion solutions on myocardial recovery after global ischemia. After 20 min of normothermic ischemia, three groups of solutions were used for reperfusion (10 animals each): (1) Nifedipine-added (10--8 mmol L(minus sign1)) Krebs--Henseleit solution; (2) verapamil-added (10--8 mmol L(minus sign)) Krebs-Henseleit solution; (3) Krebs--Henseleit solution. Postischemic myocardial functions (ventricular contractile force and heart work) and enzyme activities were compared with their preischemic values. The addition of calcium entry blocking agents does not have any significant advantage over control solutions in myocardial recovery.

Pinacidil attenuates positive inotropic but not chronotropic responses to norepinephrine in isolated dog atrial and ventricular preparations.

We investigated whether pinacidil, a K+ATP channel opener like acetylcholine and adenosine, attenuated the positive chronotropic and inotropic responses to norepinephrine in isolated, blood-perfused dog atrial and ventricular preparations. Pinacidil (0.01-0.3 mumol) decreased atrial and ventricular contractile force to a much greater extent than sinus rate in a dose-related manner. Pinacidil dose-dependently attenuated increases in atrial and ventricular forces induced by norepinephrine but not increases in sinus rate. Pinacidil similarly attenuated the positive atrial and ventricular inotropic responses to Bay k 8644 and CaCl2. The pinacidil doses producing a fifty percent decrease (ED50) of the atrial and ventricular contractile force were not significantly different from the respective pinacidil doses producing a fifty percent inhibition (ID50) of the positive inotropic responses to norepinephrine, Bay k 8644 and CaCl2. Ouabain (5 and 15 nmol) did not affect the decreases in atrial and ventricular contractile force in response to pinacidil. These results suggest that the K+ATP-channel activator pinacidil, unlike acetylcholine or adenosine, functionally attenuates increases in ventricular and atrial contractile force in the responses to norepinephrine and other cardiotonics due to shortening of the action potential duration induced by K+ATP-channel activation in the dog heart.

The effects of thyroid hormones on the heart following global ischemia. A clinical and experimental study.

Cardiopulmonary bypass is associated with a reduction in plasma thyroid hormone concentrations in patients undergoing cardiac surgery. However, studies of the effects of cardiopulmonary bypass on thyroid function are limited and many studies report conflicting data concerning only the period of cardiopulmonary bypass. In this study, we tried to clinically determine the effects of cardiopulmonary bypass on concentrations of thyroid hormones by comprehensive thyroid function tests in 10 patients before and after surgery, and observed the benefits of triiodothyronine supplementation after global ischemia on myocardial function experimentally in guinea pigs. In patients undergoing surgery, concentrations of total triiodothyronine and free triiodothyronine decreased progressively on the institution of cardiopulmonary bypass and remained below normal levels until 24 hours postoperatively. In the guinea pig hearts studied in a Langendorf perfusion apparatus, T3 supplementation enhanced percentage recovery of ventricular contractile force, heart work and heart rate with respect to other groups receiving no T3 supplementation or T3 supplementation without any ischemic interval.

Effect of allopurinol on myocardial recovery during reperfusion

A comparative study on isolated guinea pig hearts was carried out to determine the effect of allopurinol added to reperfusion solution on myocardial recovery after global ischaemia. After 20 min of normothermic ischaemia two groups of solutions (1-Krebs Solution 2-Krebs Solution + Allopurinol 1 mmol l-1) were used for reperfusion (10 animals in each group). Post-ischaemic myocardial functions (ventricular contractile force and heart work) and enzyme activities (CK-MB, LD) were compared with their preischemic values. Addition of allopurinol 1 mmol l-1 to reperfusion solution improved post-ischaemic myocardial functions and decreased myocardial injury.

Analysis of systemic and pulmonary vascular responses to PACAP and VIP: role of adrenal catecholamines.

Systemic and pulmonary vascular responses to pituitary adenylate cyclase-activating polypeptide (PACAP), a novel peptide with 68% sequence homology to vasoactive intestinal peptide (VIP), were investigated in the anesthetized cat. Intravenous injections of PACAP in doses of 0.1-3.0 nmol/kg produced decreases in arterial pressure (AP) at low doses and biphasic changes (decreases followed by increases) at higher doses, which were accompanied by increases in central venous pressure (CVP) and cardiac output (CO), and decreases and biphasic changes in systemic vascular resistance (SVR). In contrast, VIP in doses of 0.1-3.0 nmol/kg produced only dose-dependent decreases in AP and SVR and produced little change in CVP and CO. PACAP produced increased pulmonary arterial pressure (PAP), left atrial pressure (LAP), and increases in pulmonary vascular resistance (PVR). PACAP increased heart rate (HR) and right ventricular contractile force (RVCF), while VIP had no effect. Increases in AP and SVR in response to PACAP were changed to decreases following the administration of phentolamine or after adrenalectomy. Under constant flow conditions, PACAP and VIP produced dose-dependent decreases in lobar arterial pressure when tone was elevated, with PACAP being threefold more potent than VIP. Meclofenamate and nitro-L-arginine methyl ester (L-NAME) had no effect on pulmonary responses to the peptides. PACAP produced dose-dependent biphasic changes in hindquarters perfusion pressure, whereas VIP produced only decreases that were unchanged by indomethacin, L-NAME, and glibenclamide. Phentolamine and adrenalectomy eliminated the hindquarters pressor response to PACAP and D-Phe2-VIP, a VIP antagonist, reduced responses to VIP but not to PACAP. These data suggest that responses to PACAP and VIP are mediated by distinct receptors and that pressor responses to PACAP are due to the release of catecholamines from the adrenal gland.

Correlation of contractile dysfunction and abnormal tissue energy metabolism during hypoperfusion with norepinephrine in isolated rat hearts: Differences between normal and diabetic hearts

The relationship of myocardial high-energy phosphate depletion and lactate accumulation with contractile dysfunctions was investigated in streptozotocin-diabetic (DM) and normal rat hearts. The isolated hearts were perfused with 10 −6 m norepinephrine (NE) at various low-flow rates (0.4–6 ml/min/g heart wt) for 1 h. Left ventricular pressure (LVP) and contractile force (CF) were monitored, through a water-filled balloon in LV and through a hook attached to the apex, respectively. In DM hearts resting CF (diastolic tension) increased, when the perfusion flow rate was reduced below 6 ml and reached a maximum at a flow rate of less than 3 ml. The large increase in LV stiffness correlated with an elevation in diastolic LVP. In normal hearts these parameters were elevated at a flow rate below 1 ml. A flow-dependent decrease in developed CF was more prominent in DM than in normal hearts, while developed LVP and perfusion pressure were slightly higher in DM hearts with a marked increase in the LV stiffness. A flow-dependent decrease in high-energy phosphates and increases in inorganic phosphate and lactate were more prominent in the inner than in the outer layer of LV free wall in both groups. The change of ATP in the inner layer was greater, while increases of lactate in both layers were smaller in DM hearts. Changes in mechanical parameters correlated well with the ATP decrease and lactate increase in the inner layer in both groups. The correlation curves, however, were not coincidental: at the same low ATP and high lactate level, the LV stiffness was higher in DM hearts. Results indicate that DM hearts are more susceptible to flow-reduction with NE and depletion of total ATP in their tissue, and easily suffer from increased LV stiffness. This cannot be explained by the rate of decrease in total ATP and lactate accumulation alone.

The stretched ventricle

The hypothesis that nonischemic distention of the arrested, flaccid ventricle causes myocardial creep and reduces ventricular contractile force was tested in 16 sheep. Left ventricular volume was calculated from ultrasonic dimension transducers spanning left ventricular major and minor axes and left ventricular wall thickness. Changes in left ventricular volume were plotted against left ventricular pressure, with and without temporary occlusion of both venae cavae before and after nonischemic distention of the continuously perfused, flaccid nonbeating left ventricle arrested with oxygenated, normothermic blood-potassium perfusate. During 12 minutes of cardiac arrest, an apical balloon progressively distended the left ventricle to a peak pressure of 40 mm Hg in 11 sheep using a protocol designed to prevent subendocardial ischemia or mechanical injury. Coronary sinus lactate measurements and myocardial distribution of microspheres confirmed the absence of ischemia in 16 animals. In five control sheep the balloon was inserted but not inflated. Left ventricular volume at zero pressure increased from 5.9 +/- 3.5 to 9.5 +/- 4.4 ml (p < 0.05) after balloon inflation and did not change in the control animals. After maximum distention of the balloon, static left ventricular volumes at identical pressures were significantly greater. After passive distention, the slope of the end-systolic pressure-volume relationship, a measure of contractility, decreased significantly (p < 0.05) from 7.1 +/- 2.8 to 3.5 +/- 1.8 mm Hg/ml and did not change in the control group. Passive distention ("stretching") of the nonischemic flaccid left ventricle thus causes myocardial creep and reduces ventricular contractility.

Cardiovascular actions of OPC-18790: a novel positive inotropic agent with little chronotropic action.

OPC-18790 [(+/-)-6-[3-(3,4-dimethoxybenzylamino)-2-hydroxypropoxy]- 2(1H)-quinolinone], a novel positive inotropic agent, was investigated in several in vitro and in vivo experiments to elucidate its cardiovascular effects and its mechanism of action. In isolated blood-perfused dog heart preparations, OPC-18790 increased contractile force at 10 to 1,000 nmol i.a.; increased coronary arterial blood flow at 30 to 1,000 nmol; and decreased sinus rate slightly at 1,000 nmol. Atrio-ventricular nodal conduction was slightly facilitated with OPC-18790 (10 to 1,000 nmol), whereas ventricular automaticity tended to decrease. OPC-18790 (10(-6) to 10(-4) M) increased contractile force in isolated ventricular muscles of dogs, cats, rabbits and guinea pigs but not rats. OPC-18790 increased left ventricular contractile force dose-dependently in anesthetized open-chest dogs and in conscious dogs with slight or no changes in heart rate and blood pressure. The positive inotropic effect of OPC-18790 was not affected by beta-blockade. OPC-18790 (10(-5) to 10(-4) M) prolonged the duration of action potential in guinea pig papillary muscles. Na+, K(+)-ATPase was not inhibited, but peak-III phosphodiesterase (low Km cyclic AMP specific fraction, inhibited by cyclic GMP) was inhibited by OPC-18790 (IC50 = 0.41 x 10(-6) M) in dog myocardium. However, such an inhibitory action of phosphodiesterase can hardly be reconciled with the lack of a positive chronotropic effect shown by OPC-18790. Thus, these results suggest that OPC-18790 may have an additional mechanism. The cardiovascular effects revealed by this study suggest that OPC-18790 may exert a beneficial effect in the treatment of congestive heart failure.

Cardiac effects of vecuronium and its interaction with autonomic nervous system in isolated perfused canine hearts.

The chronotropic and inotropic effects of vecuronium bromide and its interaction with the autonomic nervous system were investigated in the isolated, cross-circulated right atrial and left ventricular preparations of the dog. Vecuronium, injected into the external jugular vein of the support dog, induced dose-dependent decreases in heart rate and arterial blood pressure, and increased atrial contractile force with no change in sinus rate in isolated atrial preparations. Vecuronium (1-3,000 micrograms), injected into the sinus node artery of the isolated atrium, induced dose-dependent increases in atrial contractile force with small increases in sinus rate. Vecuronium also increased the ventricular contractile force in a dose-dependent manner. The positive inotropic effect was attenuated in part by propranolol, but not by either tetrodotoxin or imipramine. Vecuronium inhibited in a dose-related manner the negative chronotropic and inotropic responses to parasympathetic nerve stimulation and carbachol (CCh) and the negative followed by positive cardiac responses to nicotine, but did not attenuate the positive responses to sympathetic nerve stimulation. The ID50s for the responses to parasympathetic stimulation, CCh, and nicotine were not significantly different. Vecuronium enhanced the positive chronotropic and inotropic responses to sympathetic nerve stimulation, tyramine, norepinephrine, and isoproterenol. These results indicate that (a) vecuronium causes the positive inotropic responses mediated by nonadrenergic mechanisms and beta-adrenoceptors, (b) vecuronium blocks ganglionic and presynaptic nicotinic and postsynaptic muscarinic receptor-mediated responses similarly, and (c) vecuronium enhances beta-adrenoceptor-mediated responses in the dog heart.

The anaphylatoxins C3a and C5a are vasodilators in the canine coronary vasculaturein vitro andin vivo

The effect of complement fragments on coronary blood flow in vivo and the contraction of coronary arteries in vitro was determined. In pentobarbital anesthetized dogs, intraarterial bolus injection of C3a and C5a, zymosan-activated serum and methylcholine in the coronary vascular bed caused transient and dose-dependent increases in coronary blood flow. Similar increases were obtained with 25 micrograms of C3a (104 +/- 13%, n = 5) and 0.1 microgram of methylcholine (102 +/- 4%, n = 3). Smaller increases in blood flow were elicited by 25 micrograms of C5a (41 +/- 18%, n = 4) and 0.2 ml of zymosan-activated serum (48 +/- 5%, n = 4). None of these responses were associated with significant changes in left ventricular contractile force measured with a strain gauge, arterial blood pressure, and heart rate. C3a dilated the coronary vascular bed in conscious dogs with an activity equal to or greater than that observed in anesthetized dogs. Isolated canine coronary arteries that were precontracted with serotonin relaxed in response to C3a, whether or not the endothelium was intact. Overall these data suggest that physiologically high doses of anaphylactic complement fragments vasodilate the canine coronary circulation.

Adverse Interaction Between Bupivacaine and Halothane on Ventricular Contractile Force and Intraventricular Conduction in the Dog

Regional anesthesia with bupivacaine in pediatric patients is often accompanied by light levels of halothane general anesthesia. To determine the potential cardiotoxicity of these two drugs when used together, we defined the interaction between moderate plasma bupivacaine concentrations (1270-1760 ng/mL) and halothane (end-tidal concentrations, 0.5%-1.0%) on ventricular contractility and conduction in 22 closed-chest dogs anesthetized with chloralose. Bupivacaine alone (1-mg/kg intravenous bolus plus a 0.1-mg.kg-1.min-1 constant rate infusion) resulted in significant increases in ventricular conduction time (VCT) and effective refractory period (VERP) and nonsignificant decreases in dP/dtmax and blood pressure. The addition of halothane resulted in hypotension and in progressively increasing plasma bupivacaine levels secondary to reduced hepatic clearance, which led to further dose-related significant increases in VCT and VERP and to significant decreases in dP/dtmax and blood pressure. In other dogs given halothane but in which bupivacaine levels were held constant (1400 ng/mL), VCT remained constant and VERP lengthened slightly, whereas dP/dtmax decreased. We conclude that the combination of bupivacaine and halothane can cause adverse effects on ventricular contractility and intraventricular conduction.

Effects of Tetrodotoxin and Imipramine on the Cardiac Responses to Nicotine in Isolated, Blood-Perfused Canine Heart Preparations

The effects of nicotine on the sinus rate and atrial or left ventricular contractile force were investigated in the isolated, blood-perfused dog right atrium and left ventricle. Nicotine (3-300 nmol) in the right atrium induced dose-dependent negative followed by positive chronotropic and inotropic responses, whereas nicotine caused only a positive inotropic response in the left ventricle. The negative responses to nicotine were blocked by atropine, hexamethonium (C6), and tetrodotoxin (TTX). The positive effects of nicotine were abolished by propranolol and C6. TTX significantly inhibited the positive responses to nicotine by about 50% in the atrial preparation and totally suppressed them in the left ventricle. Imipramine inhibited the positive cardiac responses to nicotine and tyramine, but potentiated the responses to noradrenaline (NA) in atrial and ventricular preparations. These results suggest that (a) nicotine induces negative and positive cardiac effects mediated by parasympathetic ganglionic nicotinic receptors and presynaptic nicotinic receptors of the postganglionic sympathetic nerves, respectively, in the dog heart; (b) there are few parasympathetic ganglionic cells in the dog left ventricle; (c) the positive cardiac responses to nicotine are caused by both TTX-sensitive and TTX-insensitive NA release mechanisms; and (d) imipramine inhibits the positive cardiac responses to nicotine at the presynaptic nicotinic receptor sites of the postganglionic sympathetic nerves.

Analysis of pulmonary and systemic vascular responses to cromakalim, an activator of K+ATP channels

Cardiovascular and pulmonary responses to cromakalim, a member of a novel class of antihypertensive agents that open ATP-sensitive K+ (K+ATP) channels, were investigated in the anesthetized cat. Intravenous injections of cromakalim in doses of 30-300 micrograms/kg decreased arterial pressure (AP), pulmonary arterial pressure (PAP), and increased cardiac output (CO), while producing small changes in right and left atrial pressures. Pulmonary and systemic vascular resistances were decreased and vasodilator responses to cromakalim were blocked by glybenclamide, a K+ATP channel-blocking agent. The low dose of cromakalim caused a reflex increase in heart rate (HR) and right ventricular contractile force (RVCF), whereas the high dose decreased HR and RVCF. Under constant-flow conditions the K+ATP channel opener caused dose-dependent decreases in hindquarters perfusion pressure, and when tone was elevated in the pulmonary vascular bed, dose-dependent decreases in pulmonary lobar arterial perfusion pressure. Hindquarters and pulmonary lobar vasodilator responses to cromakalim were inhibited in a specific manner by glybenclamide. The present data show that cromakalim has significant vasodilator activity in both the systemic and pulmonary vascular beds and suggest that responses to this agent result from activation of glybenclamide-sensitive K+ATP channels. These data show that cromakalim can cause substantial decreases in systemic and pulmonary vascular resistance in a dose that has little effect on RVCF.

Effects of histamine H1- and H2-receptor antagonists on cardiovascular function during systemic anaphylaxis in guinea pigs

The heart is a target organ of anaphylaxis. In isolated perfused hearts, an anaphylactic reaction is characterized by arrhythmias, coronary constriction and severe impairment of ventricular contractile force. Various mediators such as PAF, thromboxane A2 and leukotrienes are responsible for anaphylactic coronary constriction and negative inotropic effects. The cardiac effects of anaphylactic histamine release are related to the stimulation of two antagonistic receptor types. Histamine induces atrioventricular conduction delay and constriction of the epicardial coronary vessels via H1-receptor stimulation. H2-receptors, however, mediate coronary vasodilation and an increase in heart rate and myocardial contractility. It may therefore be concluded that administration of histamine H2-receptor antagonists is disadvantageous. During anaphylactic states, the cardiodepressive effects of the other mediators of anaphylaxis are unmasked, resulting in a sustained coronary constriction and impairment of myocardial contractility. To verify this speculation, we investigated the effects of H1- and H2-receptor antagonists on cardiovascular function of guinea pigs during systemic anaphylaxis. In guinea pigs, sensitization was produced by subcutaneous application of ovalbumin. Fourteen days after sensitization, the effects of an intravenous infusion of ovalbumin were tested in the anesthetized artificially ventilated guinea pigs. The renewed administration of the antigen induced severe cardiac dysfunction. Within a few minutes, cardiac output markedly decreased and left ventricular end-diastolic pressure increased significantly, indicating left ventricular pump failure. In the same time range, ECG recordings uniformly showed signs of acute myocardial ischemia. In addition, arrhythmias occurred in terms of an atrioventricular block.(ABSTRACT TRUNCATED AT 400 WORDS)