Negative Chronotropic Action Research Articles

Ayurvedic preparation of Zingiber officinale Roscoe: effects on cardiac and on smooth muscle parameters

The rhizome of the Zingiber officinale Roscoe, a biennial herb growing in South Asia, is commonly known as ginger. Ginger is used in clinical disorders, such as constipation, dyspepsia, diarrhoea, nausea and vomiting and its use is also recommended by the traditional medicine for cardiopathy, high blood pressure, palpitations and as a vasodilator to improve the circulation. The decoction of ginger rhizome is widely used in Ayurvedic medicine. In this papery by high-performance liquid chromatography, we have seen that its main phytomarkers were 6-gingerol, 8-gingerol and 6-shogaol and we report the effects of the decoction of ginger rhizome on cardiovascular parameters and on vascular and intestinal smooth muscle. In our experimental models, the decoction of ginger shows weak negative inotropic and chronotropic intrinsic activities but a significant intrinsic activity on smooth muscle with a potency on ileum is greater than on aorta: EC50 = 0.66 mg/mL versus EC50 = 1.45 mg/mL.

Neuropeptide Y (NPY) inhibits spontaneous contraction of the mouse atrium by possible activation of the NPY1 receptor.

Neuropeptide Y (NPY) causes various central and peripheral actions through activation of G-protein-coupled NPY receptors. Although a species-dependent difference in cardiac actions of NPY has been reported, the responses to NPY have not been examined in mice, widely used experimental animals. This study aimed to clarify the responses to NPY and the receptor subtype involved in the responses in mouse atrium. Neuropeptide Y caused negative inotropic and negative chronotropic actions in spontaneous beating right atria. Negative inotropic actions were more marked than negative chronotropic actions. Therefore, negative inotropic actions were studied in detail for evaluation of the NPY-induced cardiac actions in mouse atrium. Neuropeptide Y-induced negative inotropic actions were not affected by atropine but were abolished in the atria from pertussis toxin-treated mice. In isolated atrial preparations from reserpine-treated mice, NPY-induced negative inotropic actions were significantly attenuated. [Leu31, Pro34]-NPY, but not peptide YY, was effective in decreasing spontaneous contraction in atrial preparations. Although Y1 , Y2 , Y4 and Y5 receptor mRNAs were expressed almost equally in the brain, NPY1 receptor mRNA was dominantly expressed in the atrium. In conclusion, NPY caused negative inotropic and chronotropic actions through activation of the Y1 receptor in the mouse atrium. A high expression level of Y1 mRNA in the atrium suggests a functional role of NPY in the regulation of mouse cardiac contraction.

Experimental evaluation of effects of a pyrimidine derivative 4CPTP on cardiovascular system

Aim: To study the effects of pyrimidine derivative 4CPTP on cardiovascular system. Material and methods: Ionotropic and chronotropic effects of 4CPTP were studied using rabbit heart and frogs heart in situ preparation. Dogs blood pressure preparation was used to assess the effects of 4CPTP on blood pressure. Results: The test compound, like phenobarbitone produced dose dependent decrease in heart rate and amplitude of contractions of rabbit and frog heart and decrease in blood pressure in dogs. Conclusions: 4 CPTP possesses negative ionotropic and negative chronotropic action along with hypotensive action in animal models.

Roselle Polyphenols Exert Potent Negative Inotropic Effects via Modulation of Intracellular Calcium Regulatory Channels in Isolated Rat Heart.

Roselle (Hibiscus sabdariffa Linn.) calyces have demonstrated propitious cardioprotective effects in animal and clinical studies; however, little is known about its action on cardiac mechanical function. This study was undertaken to investigate direct action of roselle polyphenols (RP) on cardiac function in Langendorff-perfused rat hearts. We utilized RP extract which consists of 12 flavonoids and seven phenolic acids (as shown by HPLC profiling) and has a safe concentration range between 125 and 500μg/ml in this study. Direct perfusion of RP in concentration-dependent manner lowered systolic function of the heart as shown by lowered LVDP and dP/dt max, suggesting a negative inotropic effect. RP also reduced heart rate (negative chronotropic action) while simultaneously increasing maximal velocity of relaxation (positive lusitropic action). Conversely, RP perfusion increased coronary pressure, an indicator for improvement in coronary blood flow. Inotropic responses elicited by pharmacological agonists for L-type Ca2+ channel [(±)-Bay K 8644], ryanodine receptor (4-chloro-m-cresol), β-adrenergic receptor (isoproterenol) and SERCA blocker (thapsigargin) were all abolished by RP. In conclusion, RP elicits negative inotropic, negative chronotropic and positive lusitropic responses by possibly modulating calcium entry, release and reuptake in the heart. Our findings have shown the potential use of RP as a therapeutic agent to treat conditions like arrhythmia.

Tissue thyroid hormones and thyronamines.

It has been known for a long time that changes in cardiac function are a major component of the clinical presentation of thyroid disease. Increased heart rate and hyperdynamic circulation are hallmarks of hyperthyroidism, while bradycardia and decreased contractility characterize hypothyroidism. Recent findings have provided novel insights in the physiology and pathophysiology of heart regulation by thyroid hormones. In this review, we summarize the present knowledge on thyroxine (T4) transport and metabolism and on the biochemical pathways leading to genomic and non-genomic effects produced by 3,5,3'-triiodothyronine (T3) and by its active metabolites, particularly 3,5-diiodothyronine (T2) and 3-iodothyronamine (T1AM). On this basis, specific issues of special interest for cardiology are discussed, namely (1) relevance of the regulation of proteins involved in the control of calcium homeostasis and in pacemaker cell activity, due to non-genomic as well as to classical genomic effects; (2) stimulation of fatty acid oxidation by T2 and T1AM, the latter also causing a negative inotropic and chronotropic action at micromolar concentrations; (3) induction of D3 deiodinase in heart failure, potentially causing selective cardiac hypothyroidism, whose clinical implications are still controversial; and (4) cardioprotective effect of T1AM, possibly occurring at physiological concentrations, and relevance of T3 and of thyroid hormone receptor α1 in post-infarction repair.

Coronary Heart Disease at the Patient With Metabolic Syndrome: Strategy of Antianginal Therapy

Fist-line drugs in ischemic heart disease are -adrenoblockers. However there are cases when comorbidities limit possibilities of their use. In metabolic syndrome some representatives of this class unfavorably affect insulin sensitivity, carbohydrate and lipid metabolism. Alternative is to use ivabradine - selective inhibitor of If receptors with negative chronotropic activity. Ivabradine is metabolically neutral, has no negative inotropic effect, no influence on atrioventricular conduction and arterial pressure.

Circulatory effect of TCS-80, a new imidazoline compound, in rats.

Synthesis and hypotensive properties of centrally acting imidazoline agents: 1-[(imidazolidin-2-yl)imino]-1H-indazole (Marsanidine) and 7-chloro-1-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-1H-indazole (TCS-80) were tested in rats. We have recently synthesized two novel Marsanidine analogues which decrease blood pressure and heart rate in rats: 1-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-1H-indole (TCS-54), and 7-chloro-1-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-1H-indole (TCS-213). Among all these analogues, compound TCS-80 exhibits the highest affinity to I1-imidazoline receptors and the lowest α2/I1 selectivity ratio. The observed cardiovascular effects of the compounds might be mediated through α2-adrenergic and I1-imidazoline receptors and subsequent decrease of the symphathetic nerve activity. The present studies were performed to determine whether α2-adrenergic and/or I1-imidazoline receptors are involved in the decrease of blood pressure and heart rate induced by Marsanidine, TCS-54, TCS-80, and TCS-213 in rats. Anesthetized rats were infused iv with the tested compounds and selective α2-adrenoceptor antagonist, RX821002, or nonselective α2-adrenergic/I1-imidazoline receptor antagonist, Efaroxan. The mean arterial blood pressure and heart rate were monitored directly and continuously throughout the experiment. Efaroxan inhibited the hypotensive effect of TCS-80 stronger than RX821002. The degree of inhibition of the hypotensive effect of the remaining compounds was similar for both antagonists. The presence of Efaroxan and RX821002 diminished the heart rate decrease induced by all compounds administration, though the influence on the maximal chronotropic effect was attenuated significantly in the TCS-80 and TCS-213 treated animals only. Our results indicate that hypotensive and negative chronotropic activities of all tested compounds are mediated by both the α2-adrenergic and I1-imidazoline receptors. Moreover, the circulatory effect of TCS-80 might be mediated to relatively higher degree by the I1-imidazoline receptors than by the α2-adrenergic ones.

In vitro chronotropic effects of Erythrina senegalensis DC (Fabaceae) aqueous extract on mouse heart slice and pluripotent stem cell-derived cardiomyocytes

Ethnopharmacological relevanceErythrina senegalensis DC (Fabaceae) bark is commonly used in sub-Saharan traditional medicine for the treatment of many diseases including gastrointestinal disorders and cardiovascular diseases. In this study, we investigated the effect of the aqueous extract of the stem bark of Erythrina senegalensis on the contractile properties of mouse ventricular slices and human induced pluripotent stem (hiPS) cell-derived cardiomyocytes. We also investigated the cytotoxic effect of the extract on mouse embryonic stem (ES) cells differentiating into cardiomyocytes (CMs). Materials and methodsWe used well-established electrophysiological technologies to assess the effect of Erythrina senegalensis aqueous extract (ESAE) on the beating activity of mouse ventricular slices, mouse ES and hiPS cell-derived CMs. To study the cytotoxic effect of our extract, differentiating mouse ES cells were exposed to different concentrations of ESAE. EB morphology was assessed by microscopy at different stages of differentiation whereas cell viability was measured by flow cytometry, fluorometry and immunocytochemistry. The electrical activity of CMs and heart slices were respectively captured by the patch clamp technique and microelectrode array (MEA) method following ESAE acute exposure. ResultsOur findings revealed that ESAE exhibits a biphasic chronotropic activity on mouse ventricular slices with an initial low dose (0.001 and 0.01µg/mL) decrease in beating activity followed by a corresponding significant increase in chronotropic activity at higher doses above 10µg/mL. The muscarinic receptor blocker, atropine abolished the negative chronotropic activity of ESAE, while propranolol successfully blocked its positive chronotropic activity. ESAE showed a significant dose-dependent positive chronotropic activity on hiPS cell-derived CMs. Also, though not significantly, ESAE decreased cell viability and increased total caspase-3/7 activity of mouse ES cells in a concentration-dependent manner. ConclusionErythrina senegalensis aqueous extract exhibits a biphasic chronotropic effect on mouse heart and a positive chronotropic activity on hiPS cell-derived CMs, suggesting a possible mechanism through muscarinic and β-adrenergic receptor pathways. Also, ESAE is not cytotoxic on mouse ES cells at concentrations up to 100µg/mL.

Cardiac and Vascular Synergic Protective Effect of Olea europea L. Leaves and Hibiscus sabdariffa L. Flower Extracts.

This study was aimed at investigating the cardiovascular effects of an Olea europea L. leaf extract (OEE), of a Hibiscus sabdariffa L. flower extract (HSE), and of their 13 : 2 w/w mixture in order to assess their cardiac and vascular activity. Both extracts were fully characterized in their bioactive compounds by HPLC-MS/MS analysis. The study was performed using primary vascular endothelial cells (HUVECs) to investigate the antioxidant and cytoprotective effect of the extracts and their mixture and isolated guinea-pig left and right atria and aorta to evaluate the inotropic and chronotropic activities and vasorelaxant properties. In cultured HUVECs, OEE and HSE reduced intracellular reactive oxygen species formation and improved cell viability, following oxidative stress in dose-dependent manner. OEE and HSE exerted negative inotropic and vasorelaxant effects without any chronotropic property. Interestingly, the mixture exerted higher cytoprotective effects and antioxidant activities. Moreover, the mixture exerted an inotropic effect similar to each single extract, while it revealed an intrinsic negative chronotropic activity different from the single extract; its relaxant activity was higher than that of each single extract. In conclusion OEE and HSE mixture has a good potential for pharmaceutical and nutraceutical application, thanks to the synergistic effects of the single phytochemicals.

Ionic mechanisms underlying the negative chronotropic action of propofol on sinoatrial node automaticity in guinea pig heart.

Propofol is a widely used intravenous anaesthetic agent, but has undesirable cardiac side effects, including bradyarrhythmia and its severe form asystole. This study examined the ionic and cellular mechanisms underlying propofol-induced bradycardia. Sinoatrial node cells, isolated from guinea pig hearts, were current- and voltage-clamped to record action potentials and major ionic currents involved in their spontaneous activity, such as the hyperpolarization-activated cation current (If ), T-type and L-type Ca(2+) currents (ICa,T and ICa,L , respectively) and the rapidly and slowly activating delayed rectifier K(+) currents (IKr and IK s , respectively). ECGs were recorded from Langendorff-perfused, isolated guinea pig hearts. Propofol (≥5 μM) reversibly decreased the firing rate of spontaneous action potentials and their diastolic depolarization rate. Propofol impaired If activation by shifting the voltage-dependent activation to more hyperpolarized potentials (≥1 μM), slowing the activation kinetics (≥3 μM) and decreasing the maximal conductance (≥10 μM). Propofol decreased ICa,T (≥3 μM) and ICa,L (≥1 μM). Propofol suppressed IKs (≥3 μM), but had a minimal effect on IKr . Furthermore, propofol (≥5 μM) decreased heart rates in Langendorff-perfused hearts. The sinoatrial node cell model reasonably well reproduced the negative chronotropic action of propofol. Micromolar concentrations of propofol suppressed the slow diastolic depolarization and firing rate of sinoatrial node action potentials by impairing If activation and reducing ICa,T , ICa,L and IKs . These observations suggest that the direct inhibitory effect of propofol on sinoatrial node automaticity, mediated via multiple channel inhibition, underlies the propofol-induced bradycardia observed in clinical settings.

Direct Negative Chronotropic Action of Desflurane on Sinoatrial Node Pacemaker Activity in the Guinea Pig Heart

Desflurane inhalation is associated with sympathetic activation and concomitant increase in heart rate in humans and experimental animals. There is, however, little information concerning the direct effects of desflurane on electrical activity of sinoatrial node pacemaker cells that determines the intrinsic heart rate. Whole-cell patch-clamp experiments were conducted on guinea pig sinoatrial node pacemaker cells to record spontaneous action potentials and ionic currents contributing to sinoatrial node automaticity, namely, hyperpolarization-activated cation current (If), T-type and L-type Ca currents (ICa,T and ICa,L, respectively), Na/Ca exchange current (INCX), and rapidly and slowly activating delayed rectifier K currents (IKr and IKs, respectively). Electrocardiograms were recorded from ex vivo Langendorff-perfused hearts and in vivo hearts. Desflurane at 6 and 12% decreased spontaneous firing rate of sinoatrial node action potentials by 15.9% (n = 11) and 27.6% (n = 10), respectively, which was associated with 20.4% and 42.5% reductions in diastolic depolarization rate, respectively. Desflurane inhibited If, ICa,T, ICa,L, INCX, and IKs but had little effect on IKr. The negative chronotropic action of desflurane was reasonably well reproduced in sinoatrial node computer model. Desflurane reduced the heart rate in Langendorff-perfused hearts. High concentration (12%) of desflurane inhalation was associated with transient tachycardia, which was totally abolished by pretreatment with the β-adrenergic blocker propranolol. Desflurane has a direct negative chronotropic action on sinoatrial node pacemaking activity, which is mediated by its inhibitory action on multiple ionic currents. This direct inhibitory action of desflurane on sinoatrial node automaticity seems to be counteracted by sympathetic activation associated with desflurane inhalation in vivo.

Remifentanil Has a Minimal Direct Effect on Sinoatrial Node Pacemaker Activity in the Guinea Pig Heart

Whereas remifentanil administration is associated with severe bradycardia, it has yet to be fully investigated whether the negative chronotropic action of remifentanil is mediated by its direct action on sinoatrial (SA) node pacemaker activity in the heart versus indirect results of enhanced vagal activity. We examined the effects of remifentanil and fentanyl on the spontaneous action potentials of guinea pig SA node cells at concentrations of 5, 10, 100, and 1000 nM using the amphotericin B-perforated whole-cell patch-clamp technique. Isolated guinea pig hearts were perfused in a Langendorff mode with 5, 10, 100, and 1000 nM remifentanil. The spontaneous firing rate and diastolic depolarization rate (DDR) of the SA node action potentials were 189.1 ± 14.8 /min and 74.1 ± 2.9 mV/s (n = 8), respectively, under control conditions, and were not significantly affected by exposure to 5 nM (P = 1.0 for both spontaneous firing rate and DDR; n = 6), 10 nM (P = 0.62 for spontaneous firing rate, P = 0.99 for DDR; n = 6), or 100 nM (P = 0.23 for spontaneous firing rate, P = 0.38 for DDR; n = 6) remifentanil. However, 1000 nM remifentanil modestly but significantly decreased the spontaneous firing rate (P = 0.0087) and DDR (P = 0.0072, n = 6). Remifentanil did not affect the heart rate of isolated Langendorff-perfused guinea pig hearts at concentrations of 5 nM (P = 0.98), 10 nM (P = 0.35), or 100 nM (P = 0.24) but significantly reduced the heart rate at 1000 nM (P < 0.0001). Fentanyl did not affect the spontaneous firing rate and DDR at concentrations of 5 nM (P = 1.0 for both spontaneous firing rate and DDR) and 10 nM (P = 0.62 for spontaneous firing rate, P = 0.79 for DDR), but it significantly reduced both at 100 nM (P = 0.00038 for spontaneous firing rate, P = 0.0080 for DDR) and 1000 nM (P < 0.0001 for both spontaneous firing rate and DDR). Clinically relevant concentrations (nanomolar order concentrations) of remifentanil do not produce significant direct effects on intrinsic cardiac automaticity; thus, suggesting that remifentanil-induced bradycardia in the clinical setting is independent of its direct cardiac effects.

A ganglionic stimulant, 1,1-dimethyl-4-phenylpiperazinium, caused both cholinergic and adrenergic responses in the isolated mouse atrium

An isolated atrial preparation of the mouse is useful for analyzing the actions of drugs on the myocardium, autonomic neurons and endocardial endothelium. The aim of the present study was to examine the functions of intrinsic neurons of the atrium using a ganglionic stimulant, 1,1-dimethyl-4-phenylpiperazinium (DMPP). DMPP (1–100μM) caused a negative chronotropic action followed by a positive chronotropic action in spontaneously beating right atria and also caused biphasic inotropic actions consisting of initial inhibition followed by potentiation of electrical field stimulation (EFS)-induced contraction in the left atria. Inotropic actions in the left atria induced by DMPP were characterized using some autonomic drugs and M2 and/or M3 muscarinic receptor knockout (M2R-KO, M3R-KO and M2M3R-KO) mice. Atropine and hexamethonium decreased the initial negative inotropic actions of DMPP. In the atria from pertussis toxin-treated, M2R-KO and M2/M3R-KO mice, the negative inotropic actions were abolished. On the other hand, the following positive inotropic actions were decreased by hexamethonium, atropine and atenolol. In the atria from reserpine-treated mice, positive inotropic actions were also decreased. The positive inotropic action induced by DMPP was almost the same in M2R-KO mice but was reduced in both M3R-KO mice and M2/M3R-KO mice. In conclusion, DMPP caused biphasic inotropic/chronotropic actions in the mouse atrium through activation of intrinsic cholinergic and adrenergic neurons. M2 and M3 muscarinic receptors and β1-adrenoceptor are thought to be involved in these actions.

Negative Inotropic and Chronotropic Effects of Phenolic Fraction from &lt;i&gt;Cynodon dactylon&lt;/i&gt; (linn) on Isolated Perfused Frog Heart

Cynodon dactylon (L.) Pers belongs to the family Poaceae is a grass native to North Africa, Asia and Australia and southern Europe. The phenolic fraction of Cynodon dactylon (Linn) (CDP) was evaluated for its cardio-protective activity using isolated frog´s heart perfusion method. The negative inotropic and chronotropic activities were recorded using kymograph. The CDP produced negative inotropic and chronotropic actions on isolated frog heart. The pharmacological effect was selectively inhibited by atropine indicating that these might have been mediated through muscarinic receptor.© 2012 JSR Publications. ISSN: 2070-0237 (Print); 2070-0245 (Online). All rights reserved.doi: http://dx.doi.org/10.3329/jsr.v4i3.8549 J. Sci. Res. 4 (3), 657-663 (2012)

Possible Mechanism of Action of the Hypotensive Effect of Peperomia pellucida and Interactions between Human Cytochrome P450 Enzymes

Background: Peperomia pellucida is used as a medicinal plant and as an antihypertensive remedy. We investigated the possible mechanism of this action and its impact on cytochrome P450 (CYP) enzyme activity. Methods: Mean arterial pressure and heart rate were recorded via cannulation of the carotid artery on anaesthetized, normotensive Sprague-Dawley rats following intravenous administration of Peperomia pellucida aqueous (10-30 mg/ kg) plant extract (PPAE). Recordings of the contractile activity of the aortic rings to the extract (1.9-8.6 mg/ml) were done using standard organ bath techniques. Impact on CYP3A4 and CYP2D6 enzyme activities was investigated using human liver and heterologously expressed microsomes. Results: We observed a dose-dependent reduction in systolic, diastolic, MAP and HR. Pre-treatment with atropine (2 mg/kg) and propranolol (1 mg/kg) but not mepyramine (2 mg/kg) significantly (p<0.05) reduced the hypotensive and negative chronotropic activities caused by the extract, while L-NAME (5 mg/kg) completely abolished it. PPAE significantly (p<0.05) relaxed the phenylephrine (10 -9 -10 -4 M) and KCl- induced contractions and displayed moderate inhibition of CYP3A4 enzyme activity with IC50 values of 0.466 ± 0.126 mg/mL and 0.153 ± 0.054 mg/mL, respectively using heterogenously expressed CYP3A4 and human liver microsomes (HLMs) Conclusion: Results suggest dose-dependent hypotensive, bradycardic and vasorelaxant effects of PPAE are mediated through Nitric oxide-dependent mechanisms. The impact on CYPs enzyme activities indicate unlikely adverse drug effect when Peperomia pellucida is consumed with other medications reliant on CYP3A4 metabolism.

Electrophysiological effects of hydrogen sulfide on human atrial fibers.

It has been reported that endogenous or exogenous hydrogen sulfide (H(2)S) exerts physiological effects in the vertebrate cardiovascular system. We have also demonstrated that H(2)S acts as an important regulator of electrophysiological properties in guinea pig papillary muscles and on pacemaker cells in sinoatrial nodes of rabbits. This study was to observe the electrophysiological effects of H(2)S on human atrial fibers. Human atrial samples were collected during cardiac surgery. Parameters of action potential in human atrial specialized fibers were recorded using a standard intracellular microelectrode technique. NaHS (H(2)S donor) (50, 100 and 200 µmol/L) decreased the amplitude of action potential (APA), maximal rate of depolarization (V(max)), velocity of diastolic (phase 4) depolarization (VDD) and rate of pacemaker firing (RPF), and shortened the duration of 90% repolarization (APD(90)) in a concentration-dependent manner. ATP-sensitive K(+) (K(ATP)) channel blocker glibenclamide (Gli, 20 µmol/L) partially blocked the effects of NaHS (100 µmol/L) on human atrial fiber cells. The L-type Ca(2+) channel agonist Bay K8644 (0.5 µmol/L) also partially blocked the effects of NaHS (100 µmol/L). An inhibitor of cystathionine γ-lyase (CSE), DL-propargylglycine (PPG, 200 µmol/L), increased APA, V(max), VDD and RPF, and prolonged APD(90). H(2)S exerts a negative chronotropic action and accelerates the repolarization of human atrial specialized fibers, possibly as a result of increases in potassium efflux through the opening of K(ATP) channels and a concomitant decrease in calcium influx. Endogenous H(2)S may be generated by CSE and act as an important regulator of electrophysiological properties in human atrial fibers.

Supersensitivity of isolated atria from diabetic rats to adenosine and methacholine: modulation by pertussis toxin.

The chronotropic response of isolated right atria obtained from rats made diabetic 14-15 weeks previously by streptozotocin, was compared with age-matched controls. Diabetic rat atria are significantly more sensitive to the negative chronotropic actions of adenosine and of methacholine. Pretreating both control and diabetic rats with 2.5 mg kg-1 pertussis toxin attenuated the negative chronotropic effects of methacholine and adenosine on isolated atria, although diabetic atria still displayed a significantly greater sensitivity to these agonists (P less than 0.05-0.001). The negative chronotropic effects of methacholine and adenosine on both control and diabetic atria were abolished following pretreatment with higher doses of pertussis toxin (10 mg kg-1). These results suggest that pertussis toxin-sensitive G proteins may be involved in the supersensitivity of diabetic hearts to methacholine and adenosine.

Effect of Pinacidil on the Electrophysiological Properties in Guinea-pig Papillary Muscle and Rabbit Sino-atrial Node

The electrophysiological effect of the antihypertensive drug pinacidil has been examined in preparations of guinea-pig papillary muscle and rabbit sino-atrial node using a standard microelectrode method. In papillary muscle preparations, pinacidil (greater than 30 microM) shortened the action potential duration (APD), whereas it did not affect the maximum rate of rise (Vmax). Pinacidil (greater than 1 microM) also decreased APD of slow action potentials evoked by high K+ (27 mM) solution containing 0.2 mM Ba2+. At 30 microM, the drug reduced the Vmax of slow action potentials. In the spontaneously beating sino-atrial node, pinacidil (greater than 30 microM) shortened APD. At 100 microM, it also decreased the heart rate, Vmax, action potential amplitude and the rate of diastolic depolarization. It is concluded that pinacidil modifies the electrical activity of myocardial cells probably due to an increase in the potassium conductance although in high concentrations the compound might also reduce Ca2+ influx through the cell membrane, which would contribute to an obvious negative chronotropic action.

Comparative Effects of Azelnidipine and Amlodipine on Myocardial Function and Mortality After Ischemia/Reperfusion in Dogs

Effects of azelnidipine were examined and compared with those of amlodipine on stunned myocardium in dogs. The left anterior descending (LAD) coronary artery was ligated for 20 min and subsequently released for 60 min. A vehicle, azelnidipine (0.3 mg/kg), or amlodipine (0.3 or 1 mg/kg) was injected intravenously 20 min before LAD ligation. The heart rate increased after a depressor response in the presence of amlodipine, while it decreased despite a decrease in arterial pressures in the presence of azelnidipine. After reperfusion, the coronary flow (CF) significantly increased in the presence of azelnidipine, but did not change with amlodipine after reperfusion. A positive inotropic effect was observed after treatment with both calcium antagonists. Ischemia significantly decreased the percentage of segment shortening (%SS) in all groups. Treatment with both calcium antagonists significantly increased %SS after reperfusion, although high-energy phosphate levels did not improve in the presence of calcium antagonists 60 min after reperfusion. Mortality with azelnidipine was significantly lower than that with 0.3 mg/kg amlodipine immediately after reperfusion. In conclusion, improvement in myocardial stunning after pretreatment with azelnidipine is associated with an increase in CF after reperfusion. The negative chronotropic action may have contributed to decreased mortality due to reperfusion arrhythmias. Azelnidipine is more beneficial than amlodipine and may provide an additional advantage to patients with angina and hypertension.

ChemInform Abstract: Synthesis of Oxypropanolamine Derivatives of 3,4-Dihydro-2H-1,4-benzoxazine, β-Adrenergic Affinity, Inotropic, Chronotropic and Coronary Vasodilating Activities.

Aseries of oxypropanolamine derivatives of 3,4-dihydro-2H-1,4-benzoxazine were synthesized and evaluated for inotropic, chronotropic and coronary vasodilating activities in the canine heart, affinity to β1-adrenergic receptor in turkey erythrocytes and affinity to the β2-adrenergic receptor in the rat lung. Among these compounds, 4-acetyl-6-(3-tert-butylamino-2-hydroxy)propoxy-3,4-dihydro-2H-1,4-benzoxazine showed 2.1-fold more potent affinity to the β1 receptor than propranolol and 7-(3-tert-butylamino-2-hydroxy)propoxy-N-butyryl-3,4-dihydro-2H-1,4-benzoxazine showed 2.5-fold more potent affinity to the β2 receptor and furthermore 4 386-fold more potent selectivity to the β2 receptor than propranolol. In addition, 4-acetyl-6-[3-(3,4-dimethoxybenzyl)amino-2-hydroxy]propoxy-3,4-dihydro-2H-1,4-benzoxazine showed 1.1-fold more potent affinity to the β1 receptor than propranolol and also 1 147-fold more potent selectivity to the β1 receptor. With a few exceptions, negative inotropic and chronotropic actions of these compounds were dependent on the size of the 4-substituent obeying the order: unsubstituted < acetyl < propanoyl < butanoyl, while the benzoyl substituent conferred even stronger negative actions in the 6-oxypropanolamine derivatives. Neither negative inotropic and chronotropic actions related with affinity to β1-adrenoceptor nor coronary vasodilator action related with affinity to β2-adrenoceptor were observed. 4-acetyl-7-[3-(3,4-dimethoxybenzyl)amino-2-hydroxy]propoxy-3,4-dihydro-2H-1,4-benzoxazine exerted potent positive inotropic, chronotropic and coronary vasodilating actions. The inotropic and chronotropic actions of the latter compound may be attributed to the release of intrinsic catecholamines, as concluded by the absence of β1-adrenoceptor affinity and disappearance of activity in the presence of a β-blocker.