Tachycardia In Rats Research Articles

Turn Up the HETE on Septic Shock.

Septic shock is life-threatening organ dysfunction due to a dysregulated response to infection. It is a leading cause of death caused by the excessive release of cytokines and inflammatory mediators in response to bacterial endotoxins. It produces hypotension refractory to vasoconstrictors leading to tissue hypoperfusion and multiple organ failure. Despite intensive investigation, there still are no specific pharmacologic treatments. Current therapy relies on supportive care, including antibiotics, fluid resuscitation, corticosteroids, and pressor agents. This commentary summarizes little-known previous observations that inhibition of vascular 20-hydroxyeicosatetraenoic acid (20-HETE) by nitric oxide plays a key role in sepsis. It also highlights the new and exciting current report by Tunctan et al (2022) in this issue of Journal of Cardiovascular Pharmacology that administration of a 20-HETE mimetic can prevent lipopolysaccharide-induced vascular hyporeactivity, hypotension, and tachycardia in rats by activating the recently discovered GPR75/20-HETE receptor. Overall, these results provide a compelling case for initiating 20-HETE clinical trials to prevent hypotension, multiple organ failure, and death in septic shock.

Acute ozone exposure can cause cardiotoxicity: Mitochondria play an important role in mediating myocardial apoptosis

ObjectiveTo clarify the cardiotoxicity induced by acute exposure to different concentrations of ozone in both gender rats and explore the underlying mechanisms. MethodsA total of 240 rats were randomly sorted into 6 groups with equal numbers of male and female rats in each group. The rats were subjected to ozone inhalation at concentrations of 0, 0.12, 0.5, 1.0, 2.0 and 4.0 ppm, respectively, for 6 h. After ozone exposure, function indicators, myocardial injury indexes and risk factors of cardiovascular disease in blood were assayed. ResultsHigh ozone exposure resulted in sustained ventricular tachycardia in male and female rats. Myocardial apoptosis in male rats started from 1.0 ppm ozone, and that in female rats started from 2.0 ppm ozone (p < 0.05). Caspase-9 increased significantly from 0.12 ppm ozone (p < 0.01) in both gender rats, while caspase-3 was initially activated at 0.5 ppm ozone. From 1.0 ppm ozone, mitochondrial cristae and myofilaments dissolved. The ratio of Bcl-2/Bax decreased significantly from 0.12 ppm and MRCC-IV decreased significantly from 2.0 ppm by ozone. ConclusionAcute ozone exposure can cause paroxysmal ventricular tachycardia in rats. Moreover, the changes of inflammatory factors in the heart tissues of female and male rats after ozone exposure were greater than those of oxidative stress. This study reported for the first time that 6 h ozone exposure does not cause acute cardiomyocyte necrosis, but promotes cardiomyocyte apoptosis in a mitochondrial-dependent manner. Ozone could regulate caspases-3 dependent cardiomyocyte apoptosis by affecting the balance between caspase-9 and XIAP.

Blockade of 5-HT2 receptors with sarpogrelate uncovers 5-HT7 receptors inhibiting the tachycardic sympathetic drive in pithed rats.

Our group has previously shown in pithed rats that the cardiac sympathetic drive, which produces tachycardic responses, is inhibited by 5-HT via the activation of prejunctional 5-HT1B/1D/5 receptors. Interestingly, when 5-HT2 receptors are chronically blocked with sarpogrelate, the additional role of cardiac sympatho-inhibitory 5-HT1F receptors is unmasked. Although 5-HT2 receptors mediate tachycardia in rats, and the chronic blockade of 5-HT2 receptors unmasked 5-HT7 receptors mediating cardiac vagal inhibition, the role of 5-HT7 receptors in the modulation of the cardiac sympathetic tone remains virtually unexplored. On this basis, male Wistar rats were pretreated during 14days with sarpogrelate (a 5-HT2 receptor antagonist) in drinking water (30mg/kg/day; sarpogrelate-pretreated group) or equivalent volumes of drinking water (control group). Subsequently, the rats were pithed to produce increases in heart rate by either electrical preganglionic spinal (C7 -T1 ) stimulation of the cardiac sympathetic drive or iv administration of exogenous noradrenaline. The iv continuous infusion of AS-19 (a 5-HT7 receptor agonist; 10µg/kg/min) (i) inhibited the tachycardic responses to sympathetic stimulation, but not those to exogenous noradrenaline only in sarpogrelate-pretreated rats. This inhibition was completely reversed by SB258719 (a selective 5-HT7 receptor antagonist; 1mg/kg, iv) or glibenclamide (an ATP-sensitive K+ channel blocker; 20mg/kg, iv). These results suggest that chronic 5-HT2 receptor blockade uncovers a cardiac sympatho-inhibitory mechanism mediated by 5-HT7 receptors, involving a hyperpolarization due to the opening of ATP-sensitive K+ channels. Thus, these findings support the role of 5-HT7 receptors in the modulation of the cardiac sympathetic neurotransmission.

247 - Cardiac Grafts Engineered from Human iPSC Ventricular-Pure or Heterogeneous Cardiomyocytes Display Synchronous and Spontaneous Contraction and Reduced Ventricular Tachycardia in Rats with Chronic Heart Failure

Background: Twenty six million people worldwide are diagnosed with chronic heart failure (CHF). With only 5000 heart transplants performed annually, the prognosis for these individuals is poor and new therapeutic options are needed. Previously we have described a cardiac engineered graft comprised of human induced pluripotent stem cell (iPSC) derived cardiomyocytes co-cultured with fibroblasts in a bio-absorbable mesh. While this work is exciting, few studies to date have examined comparatively the therapeutic benefits of different cardiac populations. In the present study we engineered grafts generated with either hiPSC derived heterogeneous cardiac myocytes (hetCMs) or ventricular pure myocyte (VMs) populations to compare functional outcomes in a rat model of CHF. Methods: Cardiac grafts were generated with hetCMs or VMs (Axiogenesis) by co-culture into a 3D bioabsorbable mesh with human dermal fibroblasts. The hetCMs contain 60% ventricular, 40% atrial and nodal-like cardiomyocytes. The VMs contain 90% ventricular and 10% atrial cardiomyocytes. Grafts were evaluated in culture out to 6 days. Adult male Sprague-Dawley rats underwent permanent left coronary artery ligation and were randomized to Sham, CHF or graft treatment. Hemodynamic pressure measurements were performed at 6 weeks post-ligation with Millar solid state micromanometer pressure catheters. Ventricular tachycardia (VT) induction studies were performed at study endpoint (3 weeks after implant) to evaluate VT susceptibility using methods developed in the laboratory. Results: Both HetCM and VM generated cardiac grafts displayed synchronous and spontaneous contractions after 48 hrs in culture and maintained an average contraction rate of 67 ± 6 (hetCM) and 71 ± 9 (VM) beats per minute (n = 10 per group). Implantation of HetCM and VM grafts statistically (P < .05) improved EDP 45% vs 14% and resulted in decreased susceptibility of VT induction 54% vs 65% respectively (n = 10). Conclusion: Cardiac grafts engineered with hetCMs or VMs and implanted in a rat CHF model can lower LV EDP in-vivo while decreasing susceptibility of induced VT. This approach raises the possibility that iPSC derived engineered grafts may be used as a treatment for VT in patients with CHF.

Abstract 344: Cardiac Grafts Engineered From Human Induced Pluripotent Stem Cell Ventricular Pure or Heterogeneous Cardiomyocytes Display Synchronous and Spontaneous Contraction and Reduce Ventricular Tachycardia in Rats with Chronic Heart Failure

Background: Twenty six million people worldwide are diagnosed with chronic heart failure (CHF). With only 5000 heart transplants performed annually, the prognosis for the remaining individuals is poor and new therapeutic options are needed. Previously we have described a cardiac engineered graft comprised of human induced pluripotent stem cell (iPSC) derived cardiomyocytes co-cultured with fibroblasts in a bio-absorbable mesh. Few studies to date have examined comparatively the therapeutic benefits of different cardiac populations. In the present study we engineered grafts generated with either hiPSC derived heterogeneous cardiac myocytes (hetCMs) or ventricular pure myocyte (VMs) populations to compare functional outcomes in a rat model of CHF. Methods: Cardiac grafts were generated with hetCMs or VMs (Axiogenesis) by co-culture into a 3D bioabsorbable mesh with human dermal fibroblasts. The hetCMs contain 60% ventricular, 40% atrial and nodal-like cardiomyocytes. The VMs contain 90% ventricular and 10% atrial cardiomyocytes. Grafts were evaluated in culture out to 6 days. Adult male Sprague-Dawley rats underwent permanent left coronary artery ligation and were randomized to Sham, CHF or graft treatment. Hemodynamic pressure measurements were performed at 6 weeks post-ligation with Millar solid state micromanometer pressure catheters. Ventricular tachycardia (VT) induction studies were performed at study endpoint (3 weeks after implant) to evaluate VT susceptibility using methods developed in the laboratory. Results: Both HetCM and VM generated cardiac grafts displayed synchronous and spontaneous contractions after 48hrs in culture and maintained an average contraction rate of 67±6 (hetCM) and 71±9 (VM) beats per minute (n=10 per group). Implantation of HetCM and VM grafts lowered (p&lt;0.05) EDP 45% and 14% (n=10) and resulted in decreased susceptibility of VT induction 54% and 65%, respectively (n=4). Conclusion: Cardiac grafts engineered with hetCMs or VMs and implanted in a rat CHF model can lower LV EDP in-vivo while decreasing susceptibility of induced VT. This approach raises the possibility that iPSC derived engineered grafts may be used as a treatment for VT in patients with CHF.

Effects of zacopride, a moderate IK1 channel agonist, on triggered arrhythmia and contractility in human ventricular myocardium

Ventricular tachycardia is the leading cause of sudden arrhythmic death in the U.S. Recently, the moderate IK1 channel activator, zacopride, was shown to suppress triggered ventricular tachycardia in rats. Nonetheless, concerns were raised about the possibility of pro-arrhythmic activity after IK1 channel stimulation based on the promising anti-arrhythmic strategy of IK1 blockade in other animal models. Therefore, the goal of the current study was to investigate the ex-vivo effects of zacopride on triggered arrhythmia and contractility in ventricular human myocardium in order to validate data that was solely obtained from animal models. Application of 100nmol/L isoproterenol and 0.5mmol/L caffeine led to triggered arrhythmia in isolated cardiac muscles from non-failing and end-stage failing hearts. However, the occurrence of arrhythmia in muscles of non-failing hearts was markedly higher than those of end-stage failing hearts. Interestingly, zacopride eliminated the ex-vivo triggered arrhythmia in these muscles of non-failing and failing hearts in a concentration-dependent manner, with an effective IC50 in the range of 28–40μmol/L. Conversely, in the absence of isoproterenol/caffeine, zacopride led to a negative inotropic effect in a concentration-dependent manner. Reduced cardiac contraction was clearly observed at high zacopride concentration of 200μmol/L, along with the occurrence of contractile alternans in muscles of non-failing and failing hearts. Zacopride shows promising antiarrhythmic effects against triggered arrhythmia in human ventricular myocardium. However, in the absence of Ca2+ overload/arrhythmia, zacopride, albeit at high concentrations, decreases the force of contraction and increases the likelihood of occurrence of contractile alternans, which may predispose the heart to contractile dysfunction and/or arrhythmia. Overall, our results represent a key step in translating this drug from the benchtop to the bedside in the research area.

Salusins in Hypertension and Related Cardiovascular Diseases.

The salusins are bioactive peptides with hemodynamic effects. They play a role in hypertension, atherogenesis and cardiovascular diseases. In this review we focus on new actions, which are related to the regulation of blood pressure. Decrease in salusin-̛ and the increase in salusin-̜ concentrations are known to contribute to the development of the metabolic syndrome and atherosclerosis. Microinjections of salusin-̜. in the paraventricular nucleus (PVN) increases the plasma argininevasopressin (AVP) and norepinephrine levels, which contribute to hypertension. It also increases the AVP release from the rostral ventrolateral medulla (RVLM) via the projection from PVN to RVLM. Increased activity of the RVLM neurons is transmitted to the intermediolateral nucleus (IML) cell column of the spinal cord, where peripheral sympathetic nerves to the heart, arterioles and kidneys are activated, thus increasing blood pressure. Microinjection of salusin-̜ into the RVLM increased renal sympathetic nerve activity, median arterial pressure (MAP) and heart rate (HR). There was no significant effect on the AVP level in the RVLM and plasma. Microinjection of salusin-̜. in the nucleus tractus solitarii (NTS) produces a dose dependent hypotension and bradycardia. Intravenous injection of salusin-̜. significant increased MAP, but did not have a meaningful outcome on HR. Nevertheless, intravenous injection of a very high dose of salusin-̜. caused instantaneous decrease in both MAP and HR. Salusin-̜. overexpression provoked severe and prolonged hypertension accompanied by tachycardia in rats. It is clear that more research needs to be done to evaluate the function of salusin-̜ in the mechanism of essential hypertension, atherosclerosis, and the metabolic syndrome.

Repeated amygdala-kindled seizures induce ictal rebound tachycardia in rats

It is thought that cardiovascular changes may contribute to sudden death in patients with epilepsy. To examine cardiovascular alterations that occur during epileptogenesis, we measured the heart rate of rats submitted to the electrical amygdala kindling model. Heart rate was recorded before, during, and after the induced seizures. Resting heart rate was increased in stages 1, 3, and 5 as compared with the unstimulated control condition. In the initial one third of the seizures, we observed bradycardia, which increased in intensity with increasing stage and was blocked by injecting methyl atropine. During stage 5 seizures, a rebound tachycardia was observed that also increased in intensity with increasing number of seizures. This study demonstrated the influence of seizure frequency on cardiac autonomic modulation, providing a basis for discussion of potential mechanisms that cause patients with epilepsy to die suddenly.

The dorsomedial hypothalamus (DMH) plays a strain-dependent role in vascular responses to cocaine but not cold stress in conscious rats

s / Autonomic Neuroscience: Basic and Clinical 163 (2011) 1–133 56 P.039 The dorsomedial hypothalamus (DMH) plays a strain-dependent role in vascular responses to cocaine but not cold stress in conscious rats M.M. Knuepfer, M. Busauskas (St. Louis University School of Medicine Pharmacol. & Physiol. Science, USA) We demonstrated that cocaine or cold water stress (CWS) elicits systemic vasoconstriction in Brown-Norway (BN) rats but an increase in cardiac output in Dahl salt sensitive (DSS) rats. Since the DMH plays an important role in stress responsiveness, we sought to determine the role of the DMH to these disparate stressors on regional vascular hemodynamics. We hypothesized that inhibition of the DMH would attenuate greater hindquarters vasoconstriction to either stress in BN compared to DSS rats. BN and DSS rats were instrumented for determination of arterial pressure, heart rate, andwith pulsed Doppler flowprobes on the superiormesenteric and abdominal aorta. Bilateral guide cannulaswere implanted above the DMH. After recovery, we observed that cocaine (5 mg/kg, iv) elicited greater hindquarters andmesenteric vasoconstriction and greater bradycardia in BN rats compared toDSS rats. In contrast, CWS (1 cm deep for 1 min) elicited tachycardia in all rats and greater increases in mesenteric resistance in BN rats but hindquarters vasodilation that was greater in BN compared to DSS rats. Therefore, visceral and skeletalmuscle vascular responses differed between strains and stressors. We examined the dependence of these responses on the DMH with bilateral microinjections of muscimol (80 pmol in 100 nl) in theDMH.Muscimol attenuated thegreaterhindquarters andmesenteric vasoconstriction and tachycardia in BN rats without affecting responses in DSS rats in response to cocaine. Responses to CWSwere unaffected by muscimol except that tachycardia was selectively reduced in BN rats. Kainate (10 pmol) in the DMH elicited a similar response pattern as CWS. These studies demonstrate that the DMH plays a strainand stimulus-dependent role in mediating hemodynamic responses to stress. Our data suggest that there are significant variations in central neural pathways mediating stress that vary in different rat strains.

High-Resolution Optical Mapping of Ventricular Tachycardia in Rats with Chronic Myocardial Infarction

Ventricular tachycardia (VT) is a common cause of mortality in post-myocardial infarction (MI) patients, even in the current era of coronary revascularization treatment. We report a reproducible VT model in rats with chronic MI induced by ischemia-reperfusion and describe its electrophysiological characteristics using high-resolution optical mapping. An MI was generated by left anterior descending coronary ligation (25 minutes) followed by reperfusion in 20 rats. Electrophysiology study and optical mapping were performed 5 weeks later using a Langendorff-perfused preparation and compared to normal rats. The conduction velocity of the MI border zone was decreased to 53% of the normal areas remote from the infarct (0.37 +/- 0.16 m/sec vs 0.70 +/- 0.09 m/sec, P < 0.0001). The rate of VT inducibility in MI rats was significantly greater than in normal control rats (70% vs 0%, P = 0.00002). VT circuits involving the infarct area were identified with optical mapping in 83% MI rats. In addition, fixed and functional conduction block were observed in the infarct border zone. This ischemia-reperfusion MI rat model is a reliable VT model, which simulates clinical revascularization treatment. High-resolution optical mapping in this model is useful to study the mechanism of VT and evaluate the effects of therapies.

D-ribose improves cardiac contractility and hemodynamics, and reduces expression of c- fos in the hippocampus during sustained slow ventricular tachycardia in rats

Background Moderate hypotension during hemodynamically stable ventricular tachycardia (VT), leads to cerebral ischemia. Supplementation of d-ribose has been shown to improve cardiac metabolism. We hypothesized that cerebral ischemia during slow VT may lead to the expression of immediate early genes related to neurodegeneration. This expression may be prevented by d-ribose substitution. Methods Slow VT was induced over 20 min by external left ventricular pacing after infusion of physiologic saline or d-ribose (450 mg/kg) in 44 rats. Different coloured microspheres were used for tissue blood flow measurements. Histochemistry of c- fos in cerebral tissue sections was performed. Results With the onset of VT, the mean arterial pressure (MAP) significantly dropped in both groups. However, the MAP in the d-ribose group was significantly higher ( p < 0.05) than in the control group (111 ± 21 mm Hg vs. 80 ± 40 mm Hg). The rate pressure product (RPP) during VT was significantly higher in the d-ribose group than in the control group (75,000 vs. 59,000, p < 0.05). The occurrence of lethal VT was significantly higher in the control group and could be prevented by d-ribose. A stable activation of c- fos was observed in the control group. This ischemic stress response of the brain could not be seen after d-ribose infusion. Conclusion d-ribose improves hemodynamic parameters, cardiac contractility and prevents the activation of pro-apoptotic c- fos, demonstrating a neuroprotective effect of d-ribose during slow VT.

Dorsomedial hypothalamic sites where disinhibition evokes tachycardia correlate with location of raphe-projecting neurons.

Disinhibition of neurons in the region of the dorsomedial hypothalamus (DMH) elicits sympathetically mediated tachycardia in rats through activation of the brain stem raphe pallidus (RP), and this same mechanism appears to be largely responsible for the increases in heart rate (HR) seen in air jet stress in this species. Neurons projecting to the RP from the DMH are said to be concentrated in a specific subregion, the dorsal hypothalamic area (DA). Here, we examined the hypothesis that the location of RP-projecting neurons in the DA correspond to the sites at which microinjection of bicuculline methiodide (BMI) evokes the greatest increases in HR. To determine the distribution of RP-projecting neurons in the DA, cholera toxin B was injected in the RP in four rats. A consistent pattern of retrograde labeling was seen in every rat. In the hypothalamus, RP-projecting neurons were most heavily concentrated midway between the mammillothalamic tract and the dorsal tip of the third ventricle dorsal to the dorsomedial hypothalamic nucleus approximately 3.30 mm caudal to bregma. In a second series of experiments, the HR response to microinjections of BMI (2 pmol/5 nl; n = 76) was mapped at sites in the DA and surrounding areas in 22 urethane-anesthetized rats. All injection sites were located from 2.56 to 4.16 mm posterior to bregma, and the microinjections that evoked the largest increase in HR (i.e., >100 beats/min in some instances) were located in a region where RP-projecting neurons were most densely concentrated. Thus RP-projecting neurons in the DA may mediate DMH-induced tachycardia and thus play a role in stress-induced cardiac stimulation.

Arterial baroreflex deficit induced organ damage in sinoaortic denervated rats.

To verify the independent role of the arterial baroreceptor dysfunction involved in target-organ damage in hypertension, sinoaortic denervated (SAD) rats were used as a model of arterial baroreflex (ABR) deficit. SAD, isolated aortic-denervated (AD), and isolated sinus-denervated (SD) rats were instrumented to record blood pressure (BP), heart rate (HR), BP variability (BPV), HR variability (HRV), ABR function control of heart period (ABR-HP), and BP (ABR-BP). Vascular maximum contractile/relaxant function was determined and organ damage was estimated by observation of morphologic changes. Short-term (postoperative 1 week) SAD caused hypertension and tachycardia in rats. Eighteen weeks after operation, BP and HR values in SAD and SD rats were not different from those in sham-operated rats, but AD rats were hypertensive compared with control group. Although 24-h mean BP values of long-term SAD rats were not different from those of sham-operated rats, 24-h BPV of SAD rats was significantly higher than that of sham-operated rats. Arterial baroreflex function in short-term SAD rats was significantly less than in sham-operated rats, whereas in long-term SAD rats, ABR-HP and ABR-BP were higher than those in short-term SAD rats, but were still significantly lower than those in control groups. At postoperative 18 weeks, baroreflex function in SAD and AD rats was significantly less than function in SD and control groups. SBPmax after phenylephrine and DBPmin after nitroprusside were significantly higher in SAD, AD, and SD rats than in control rats. Baroreflex function was negatively correlated to DBPmin and SBPmax in all denervated rats (n = 44). Some morphologic changes were found 18 weeks after denervation in heart, kidney, and small artery in SAD, AD, and SD rats. Baroreflex function in all denervated rats was negatively related to 24-h BPV values. In contrast, 24-h BPV values in SAD, AD, and SD rats were positively related to organ-damage score. A negative correlation between ABR function and end-organ damage score was found. Arterial baroreflex deficit played an independent and important role in organ-damage in SAD rats with significantly elevated 24-h BPV.

Pharmacological characterisation of cannabinoid CB 1 receptors in the rat and mouse

The role of cannabinoid CB 1 receptors in sympathetic neurotransmission was characterised in nerve-mediated responses of isolated right atria, vasa deferentia and small mesenteric resistance arteries using the cannabinoid CB 1 receptor agonists Δ 9-tetrahydrocannabinol, CP 55,940 and anandamide and the cannabinoid CB 1-selective antagonist SR 141716A. In the mouse vas deferens, the twitch response was completely inhibited by each of the putative cannabinoid receptor agonists with pIC 50 values of CP 55,940, 9.2±0.1; Δ 9-tetrahydrocannabinol, 8.4±0.1; anandamide, 7.1±0.1. SR 141716A 10–100 nM was a competitive antagonist of all three agonists with a p K B value of 8.4–8.6, consistent with an interaction at the cannabinoid CB 1 receptor. In the rat vas deferens CP 55,940 (0.01–10 μM) inhibited the contractions to a significant extent (88.5±0.5% at 10 μM; pIC 50 of 7.1±0.1) while Δ 9-tetrahydrocannabinol and anandamide (both up to 10 μM) were inactive. CP 55,940 exhibited low potency in rat compared with mouse vas deferens and the rat concentration–response curve was not competitively antagonised by SR 141716A (100 nM) or SR 144528 (10 nM–10 μM), suggesting an interaction at a receptor(s) distinct from cannabinoid CB 1 or CB 2. Sympathetic nerve-induced tachycardia in rat and mouse atria, and rat mesenteric artery smooth muscle contractile responses to perivascular nerve stimulation, were not inhibited by Δ 9-tetrahydrocannabinol, CP 55,940 or anandamide up to 1 μM. These data indicate that cannabinoid CB 1 receptor activation inhibits sympathetic neurotransmission only in the mouse vas deferens and thus point to species and regional differences in cannabinoid CB 1 receptor involvement in pre-synaptic inhibition of sympathetic neurotransmission and CP 55,940 may have inhibitory actions in rat vas deferens unrelated to cannabinoid receptor activity.

Positive inotropic action of NMDA receptor antagonist (+)-MK801 in rat heart.

(+)-MK801, a noncompetitive NMDA receptor antagonist, was reported to exhibit anticonvulsive and neuroprotective activities during the postischemic period. Intravenous administration of (+)-MK801 produced tachycardia in rats, but bradycardia in pigs. We examined the mechanical and electrophysiological effects of (+)-MK801 on rat cardiac tissues. (+)-MK801 dose-dependently increased (3-100 microM) twitch tension in rat atria and ventricular strips. The spontaneous beating rate in rat right atria, however, was dose-dependently decreased by (+)-MK801. The inotropic effect of (+)-MK801 was affected neither by alpha(1)-antagonist (1 microM prazosin) nor by beta(1)-adrenoceptor antagonist (3 microM atenolol), but significantly by a transient outward K(+) channel blocker (3 mM 4-aminopyridine). (+)-MK801 did not cause any significant change of intracellular cAMP content. Electrophysiological study in rat ventricular cells revealed that (+)-MK801 concentration-dependently prolonged the action potential duration with a concomitant decrease in the maximum rate of the action potential upstroke (V(max)) and an increase in the recovery time constant of V(max). Voltage clamp study showed that (+)-MK801 (3 microM) reduced inward Na(+) current (I(Na)), along with a slowing of its recovery from inactivation and a slight negative shift of its voltage-dependent steady-state inactivation curves. At a much higher concentration (30 microM), (+)-MK801 slightly reduced the amplitude of L-type calcium inward current (I(Ca)), although the voltage dependence of its steady-state inactivation was unaffected. For the potassium currents in rat ventricular cells, 3 microM of (+)-MK801 reduced the peak transient outward current (I(to)), steady-state outward current (I(ss)) and inward current through K(1) channels. The inhibition of I(to) was associated with a prominent negative shift in the voltage dependence of its steady-state inactivation curve. The outward current through K(1) channels was unaffected. These results indicate that (+)-MK801 may be a strong I(Na) and I(to) blocker with some I(Ca) blocking activity. The inhibition of I(to) and other K(+) efflux would prolong action potential duration, produce positive inotropic action and contribute to the negative chronotropic effect of (+)-MK801.

Positive Inotropic Action of NMDA Receptor Antagonist (+)-MK801 in Rat Heart

(+)-MK801, a noncompetitive NMDA receptor antagonist, was reported to exhibit anticonvulsive and neuroprotective activities during the postischemic period. Intravenous administration of (+)-MK801 produced tachycardia in rats, but bradycardia in pigs. We examined the mechanical and electrophysiological effects of (+)-MK801 on rat cardiac tissues. (+)-MK801 dose-dependently increased (3–100 μM) twitch tension in rat atria and ventricular strips. The spontaneous beating rate in rat right atria, however, was dose-dependently decreased by (+)-MK801. The inotropic effect of (+)-MK801 was affected neither by α₁-antagonist (1 μM prazosin) nor by β₁-adrenoceptor antagonist (3 μM atenolol), but significantly by a transient outward K⁺ channel blocker (3 mM 4-aminopyridine). (+)-MK801 did not cause any significant change of intracellular cAMP content. Electrophysiological study in rat ventricular cells revealed that (+)-MK801 concentration-dependently prolonged the action potential duration with a concomitant decrease in the maximum rate of the action potential upstroke (V_max) and an increase in the recovery time constant of V_max. Voltage clamp study showed that (+)-MK801 (3 μM) reduced inward Na⁺ current (I_Na), along with a slowing of its recovery from inactivation and a slight negative shift of its voltage-dependent steady-state inactivation curves. At a much higher concentration (30 μM), (+)-MK801 slightly reduced the amplitude of L-type calcium inward current (I_Ca), although the voltage dependence of its steady-state inactivation was unaffected. For the potassium currents in rat ventricular cells, 3 μM of (+)-MK801 reduced the peak transient outward current (I_to), steady-state outward current (I_ss) and inward current through K₁ channels. The inhibition of I_to was associated with a prominent negative shift in the voltage dependence of its steady-state inactivation curve. The outward current through K₁ channels was unaffected. These results indicate that (+)-MK801 may be a strong I_Na and I_to blocker with some I_Ca blocking activity. The inhibition of I_to and other K⁺ efflux would prolong action potential duration, produce positive inotropic action and contribute to the negative chronotropic effect of (+)-MK801.

Effects of Saiko-ka-ryukotsu-borei-to, a Japanese Kampo Medicine, on Tachycardia and Central Nervous System Stimulation Induced by Theophylline in Rats and Mice

Effects of Saiko-ka-ryukotsu-borei-to (SRBT) on theophylline-induced tachycardia in anesthetized rats and theophylline-induced locomotion and convulsions in mice were examined. An intraduodenal administration of SRBT (1 g/kg) prevented theophylline (5 mg/kg, i.v.)-induced tachycardia in rats. SRBT also attenuated an increase in arterial blood pressure with a slow reduction in heart rate of rats treated with theophylline, with no influence on the plasma level of theophylline. However, SRBT did not change the beating rate of right atrium isolated from rats in the absence or presence of theophylline or isoproterenol. The locomotor activity of theophylline in mice was reduced by the treatment with SRBT. Furthermore, the latency of convulsions in mice induced by administration of theophylline at a higher dose (240 mg/kg, i.p.) was prolonged by treatment with SRBT (1 g/kg, p.o.) and seven out of fifteen mice were saved from death due to convulsions. These results suggest that theophylline-induced tachycardia and central nervous stimulation are suppressed by SRBT and that SRBT may reduce the undesirable actions of theophylline on the cardiovascular and central nervous systems.

Cardiovascular Pharmacology of SKP-450, a New Potassium Channel Activator, and Its Major Metabolites SKP-818 and SKP-310

The cardiovascular effects of SKP-450, a newly synthesized potassium channel activator, and its two major metabolites SKP-818 and SKP-310 were evaluated on isolated rat aorta and in freely moving rats and anesthetized beagle dogs. The rank order of potency in relaxing rat aorta precontracted with norepinephrine was SKP-450>SKP-818>lemakalim>SKP-310 (EC₅₀: 0.12, 0.55, 0.71 and 5.89 µmol/l, respectively). In rats, SKP-450, SKP-818 and lemakalim (3–100 µg/kg, i.v.) induced a dose-dependent decrease in mean arterial pressure (MAP; ED₂₀: 9.8, 11.7 and 22.4 µg/kg, respectively) followed by reflex tachycardia. In dogs, SKP-818 and SKP-310 (0.3–1,000 µg/kg, i.v.) had quite similar hemodynamic profiles to SKP-450 but with a smaller potency. SKP-450, SKP-818 and SKP-310 dose-relatedly decreased MAP (ED₂₀: 2.6, 4.2 and 588.8 µg/kg, respectively). They slightly increased left ventricular positive dP/dt_max with a transient decrease at the highest dose, while inducing a dose-related decrease in rate-pressure product, tension time index and systolic time. SKP-450, SKP-818 and SKP-310 induced a marked dose-dependent increase in coronary blood flow (E_max: 172.8, 257.9 and 178.7%, respectively) with less effects on blood flow through other arteries. Glybenclamide antagonized all the hemodynamic effects of SKP-450 in rats and dogs, whereas propranolol antagonized its reflex tachycardia in rats. These results indicate that SKP-450 is a potent coronary and peripheral vasodilator in rats and dogs activating ATP-sensitive potassium channels and that SKP-818 and SKP-310 exert a similar hemodynamic profile to the parent compound with equi- and weaker potency, respectively.

Comparison of cardiac Troponin T and cardiac Troponin I concentrations in peripheral blood during orciprenaline induced tachycardia in rats

In this study we addressed the question of whether the measurement of the cardiac structure protein cardiac Toponin I (cTnI) in serum is also able to detect marked myocardial cell damage in rats like cardiac Troponin T (cTnT). To answer this question 5 male rats and 5 female rats were injected with orciprenaline to induce myocardial cell damage. Further 5 animals of each sex received physiological saline as control. We could demonstrate that troponin I was rised significantly 6 hours after injection in serum as well as cTnT. 24 hours after injection cTnI was elevated on a lower significance level compared to cTnT. All values returned to normal 96 hours after the injection. We conclude that cTnI was also able to detect a marked myocardial cell damage in rats but we could show that cTnI was elevated on a lower significance level compared to cTnT. Furthermore we found that a cTnI increase to at least 4.1 ng/ml is necessary to detect marked myocardial cell injury in this rat tachycardia model.

Vibrio vulnificus hemolysin dilates rat thoracic aorta by activating guanylate cyclase

Hemolysin produced by Vibrio vulniflcus caused hypotension and tachycardia in rats and dilated rat thoracic aorta. Hemolysin-induced vasodilatation of the aorta was not affected by Nω-nitro-L-arginine methyl ester and aminoguanidine, NO synthase inhibitors, whereas the vasodilatation was inhibited by LY 83,583, a guanylate cyclase inhibitor. Hemolysin elevated cGMP levels, and the elevation was abolished by LY 83,583. These results suggest that V. vulnificus hemolysin activates guanylate cyclase independently of NO synthase, and the subsequent increase in cGMP levels results in vasodilatation.