Aging alters the force-frequency relationship and toxicity of oxidative stress in rabbit heart

Adult (6 months) and senescent (greater than 5 years) rabbit atria were studied under conditions known to increase cytoplasmic calcium (increased frequency of contraction and oxidative stress). At a contraction frequency of 1/sec, cardiac relaxation (90% relaxation time) was similar in senescent and adult atria but at a frequency of 2 or 3/sec, relaxation was significantly slower in senescent preparations (P less than 0.05). Additional experiments indicated that H2O2 (500 microM), a powerful oxidant, increased resting force and decreased developed force (DF) much more rapidly in senescent than adult atria; the maximum decrease in DF, however, was less in senescent preparations (adult = 81 +/- 6% and senescent = 42 +/- 27% of pre-H2O2 values; P less than 0.05). Age-related differences in effects of H2O2 did not result simply from a decreased ability of senescent hearts to detoxify an oxidative stress by the glutathione pathway. Both basal glutathione (GSH) concentrations and the H2O2-mediated decreases in GSH were similar in adult and senescent ventricular preparations, as were activities of glutathione peroxidase and glutathione reductase. These observations suggest that interventions known to increase cytoplasmic calcium can amplify age-related impairments of cardiac relaxation through mechanisms that may be independent of the glutathione pathway.     

Myocardial contractility in chickens (Gallus gallus): analysis of systolic time intervals

The avian cardiovascular system is of special interest because avian hearts are relatively larger than mammalian hearts, and activation of ventricular myocardium in birds has a "flash" pattern. Systolic time intervals and indices of myocardial contractility were examined in anaesthetized open-chest chickens by polycardiography, including synchronous recordings of electrocardiogram, phonocardiogram, and apex cardiogram. The asynchronous contraction time, isometric contraction time, pre-ejection period and ejection time were 26 +/- 3 (Mean +/- SD), 21 +/- 9, 47 +/- 12, and 83 +/- 23 ms, respectively, for heart rates of 260 +/- 57 bpm. The myocardial tension index, isometric contraction index and the pre-ejection period/ejection time ratio were 0.39 +/- 0.11, 0.42 +/- 0.10, and 0.54 +/- 0.14, respectively. A "flash" pattern of ventricular myocardial depolarization causes more rapid excitation and as a consequence shorter asynchronous contraction time of relatively larger chicken hearts compared with rabbit hearts. Inverse relation (P < 0.05) of the asynchronous contraction time to the heart rate in chickens is probably associated with the specific activation pattern of avian ventricles. Establishment of the values of systolic time intervals will facilitate a better understanding of cardiac function in birds. The obtained results are discussed in comparison with the rabbit. The indices calculated from the systolic time intervals show disadvantageous contractile function of chicken heart compared to rabbit heart.     

Heart rate dynamics in iNOS knockout mice

Nitric oxide has both an inhibitory and excitatory role in the regulation of pre-ganglionic sympathetic neurons, involving the iNOS and nNOS systems respectively. The aim of the present study was to examine cardiovascular autonomic activity in iNOS knockout mice using spectral analysis of heart rate variability (HRV), and to determine the role of iNOS in altered HRV in endotoxaemia. Electrocardiograms were recorded in anaesthetised mice, and the R-R intervals digitized for spectral analysis of HRV and cardiac rhythm regularity using sample entropy analysis. The basal heart rate was higher in iNOS knockout mice compared with controls (465+/-8 vs 415+/-13 beat/min P<0.05), with a significant increase in the low frequency power of HRV spectra in iNOS knockout mice compared with controls (49.4+/-4.3 vs 33.8+/-5.6 normalized units, P<0.05), consistent with increased cardiac sympathetic activity. Endotoxaemia is known to decrease HRV, but the role of iNOS is unknown. LPS (20 mg/kg i.p) increased basal heart rate in both wild type and iNOS knockout mice, but caused a depression of HRV and sample entropy in both groups. Studies in isolated beating atria showed that the changes of HRV under basal or post-LPS conditions disappeared in vitro, suggesting that the autonomic system is responsible for altered HRV. We conclude that disruption of iNOS gene leads to an increase in the low frequency power of HRV consistent with increased cardiac sympathetic activity. These data also demonstrate that LPS-induced decrease of HRV is independent of iNOS.     

Myosin light chain phosphorylation and evidence for latchbridge formation in norepinephrine stimulated canine veins

The role of 20000 dalton myosin light chain phosphorylation in mediating venous smooth muscle contraction was studied in isolated preparations of canine jugular and femoral vein. One min 10(-5) M norepinephrine-induced contraction was accompanied by significant increases in phosphorylation (jugular - 21 to 46%; femoral - 19 to 54%) which were reversed within 10 min after agonist washout. During 40 min stimulation, phosphorylation and isometric force redevelopment rates declined to near basal levels while force was maintained. These findings implicate light chain phosphorylation as a prerequisite for initial tension development by crossbridge cycling in venous smooth muscle. However, long term tension can be maintained through a process similar to the latchbridge state in tracheal and arterial smooth muscle.     

BDNF modulates heart contraction force and long-term homeostasis through truncated TrkB.T1 receptor activation

Brain-derived neurotrophic factor (BDNF) is critical for mammalian development and plasticity of neuronal circuitries affecting memory, mood, anxiety, pain sensitivity, and energy homeostasis. Here we report a novel unexpected role of BDNF in regulating the cardiac contraction force independent of the nervous system innervation. This function is mediated by the truncated TrkB.T1 receptor expressed in cardiomyocytes. Loss of TrkB.T1 in these cells impairs calcium signaling and causes cardiomyopathy. TrkB.T1 is activated by BDNF produced by cardiomyocytes, suggesting an autocrine/paracrine loop. These findings unveil a novel signaling mechanism in the heart that is activated by BDNF and provide evidence for a global role of this neurotrophin in the homeostasis of the organism by signaling through different TrkB receptor isoforms.     

Autonomic innervation of the circular and longitudinal layers in swine myometrium.

Experiments were conducted on uteri excised from 44 gilts to clarify the autonomic innervation of the longitudinal (LM) and circular muscle (CM) layers of the myometrium. Functionally and biochemically, the two layers differed markedly in their reaction to transmitters. On transmural nerve stimulation (TMS) of isolated LM strips, relaxation was elicited and spontaneous contraction was inhibited in proportion to the electrical frequency imparted. Although the relaxation was accompanied by preliminary contraction in half the LM preparations tested, the relaxation phase predominated in all the LM strips. Relaxation was sensitive to carteolol (beta-blocker) and to guanethidine (adrenergic neuron blocker), whereas the contractile response in LM was sensitive to phentolamine (alpha-adrenergic antagonist). In the CM strips, contraction resulted from TMS, and though not responsive to hexamethonium, the contractions were enhanced by neostigmine and abolished by atropine. The amount of norepinephrine (NE) and the intensity of dopamine beta-hydroxylase activity were about 2.5 times greater in LM than in CM. Conversely, choline acetyltransferase activity, associated exclusively with cholinergic nerves, was about 8 times more intense in the CM. In line with the TMS responses, alpha-receptor-mediated contractions initiated by NE were enabled exclusively in the LM. Furthermore, beta-receptor-mediated inhibition elicited by isoproterenol was also paramount in the LM. We conclude that there are layer-specific variations in the functional innervation of the myometrium of the nulliparous pig uterus such that CM layer is primarily endowed with cholinergic innervation and the LM layer with adrenergic innervation.     

Effect of ciguatoxins on the cardiocirculatory system

The aim of the present review was to collect the main observations reported until now concerning the cardio-circulatory effects of polyether toxins, called ciguatoxins, which are involved in an endemic intoxication named ciguatera found in tropical and subtropical countries. Ciguatera is caused by the ingestion of fishes contaminated with the dinoflagellate Gamberdiscus toxicus. Due to both tropical fish exportation destined for food and tourism, the disease has now spread out to temperate areas. Several toxins have been isolated and purified from different fish species living in different geographical areas. They are classified into three main groups by the nature of certain cycles of their carbon skeleton. Clinical reports show evidence that ciguatera intoxication affect both electrocardiograms and blood pressure. In most cases, ciguateric intoxication mainly evoked bradycardia, hypotension, and the alteration of S-T segment in the electrocardiogram. Isolated and purified ciguatoxins strongly altered the morphology of cardiac tissue inducing swelling of the cells and alterations of cellular organelles. These toxins impair the conduction of cardiac nerves and increase the opening probability of Na+ channels in intracardiac ganglions. Depending on the concentration applied, the substances exerted either a fast positive inotropic effect or a negative inotropic effect on the contraction of mammalian atrial and ventricular cardiac muscle. These effects were attributed to a release of noradrenaline and acetylcholine from neural terminals of the autonomic nervous system present in cardiac tissue. They also exert a slow delayed inotropic effect on the contraction which has been attributed to a direct effect of the toxins on tetrodotoxin-sensitive voltage-dependent Na+ channels of cardiac membranes. Ciguatoxins depolarized the membrane of mammalian atrial and ventricular preparations and shifted the threshold of sodium current activation to more negative membrane potentials. In conclusion, the inotropic effects of ciguatoxins on cardiac tissues mainly depend on the toxin concentration sensitivity of autonomic nerve terminals, which released noradrenaline and/or acetylcholine, while the ciguatoxin-induced increase of the sodium influx could be involved in the cardiac cell swelling which coincides with reports in which ciguatoxins induced a mannitol-inhibited swelling of the Node of Ranvier.     

Developmental increase in the inotropic and cyclic AMP response to isoproterenol in embryonic and newly hatched chicks

The cyclic adenosine 3',5'-monophosphate (cyclic AMP) levels of ventricles isolated from 15- to 20-day-old chick embryos and 0- to 3-day-old hatched chicks were compared to clarify the mechanism underlying the change in sensitivity to isoproterenol during perinatal developmental stages when the functional sympathetic innervation has been completely achieved. Isoproterenol produced a positive inotropic effect on ventricles isolated from both embryonic and hatched chicks, but the ventricles from the hatched chicks were more sensitive. At both developmental stages sotalol was an equipotent antagonist of isoproterenol. 3-Isobutyl-1-methylxanthine (IBMX) produced an increment in the contractile force of the ventricles at both stages, but the ventricles from the hatched chicks responded to lower doses of IBMX. The reactivity to isoproterenol in increasing cyclic AMP level was significantly higher in the hatched ventricles than in the embryonic ventricles. The results suggest that the different sensitivities to isoproterenol between embryonic and newly hatched chick ventricles may be due to some changes in the process for cyclic AMP production.     

Essential Role of the m2R-RGS6-IKACh Pathway in Controlling Intrinsic Heart Rate Variability

Normal heart function requires generation of a regular rhythm by sinoatrial pacemaker cells and the alteration of this spontaneous heart rate by the autonomic input to match physiological demand. However, the molecular mechanisms that ensure consistent periodicity of cardiac contractions and fine tuning of this process by autonomic system are not completely understood.Here we examined the contribution of the m₂R-I_KACh intracellular signaling pathway, which mediates the negative chronotropic effect of parasympathetic stimulation, to the regulation of the cardiac pacemaking rhythm. Using isolated heart preparations and single-cell recordings we show that the m₂R-I_KACh signaling pathway controls the excitability and firing pattern of the sinoatrial cardiomyocytes and determines variability of cardiac rhythm in a manner independent from the autonomic input. Ablation of the major regulator of this pathway, Rgs6, in mice results in irregular cardiac rhythmicity and increases susceptibility to atrial fibrillation. We further identify several human subjects with variants in the RGS6 gene and show that the loss of function in RGS6 correlates with increased heart rate variability. These findings identify the essential role of the m₂R-I_KACh signaling pathway in the regulation of cardiac sinus rhythm and implicate RGS6 in arrhythmia pathogenesis.     

Contractile properties of the axolotl ventricle at 17 and 21 °C

Mammalian cardiac muscle exhibits a number of intrinsic response systems which adjust function to changing conditions. These include the Frank–Starling response and the slow force response which are activated upon myocardial stretch, and the force–frequency response, which is evident upon changes in cardiac frequency. In this study we have examined the effect of myocardial stretch and changes in pacing frequency on isolated ventricular muscle preparations from the ectothermic amphibian, the axolotl (Ambystoma mexicanum). We preformed these studies at two physiologically relevant temperatures 17 °C and 21 °C. We found that increasing the length of the muscle increased active force via the Frank–Starling response at both temperatures, which is consistent with cardiac muscle preparations in other vertebrates. We found no evidence for the slow force response at either temperature suggesting that in axolotl, unlike mammals but similar to fish, the slow force response is not associated with the Frank–Starling response. Increasing contraction frequency caused a decrease in active force across all frequencies tested (0.5−2.0 Hz)—a monophasic negative force–frequency response, independent of temperature.     

迷走神经对心室功能的调控机制研究进展

自主神经系统由交感神经系统和副交感神经系统（迷走神经）组成,二者相互拮抗,对哺乳动物心脏的功能调控具有重要的作用。副交感（迷走）神经对心房可产生变时、变传导和变力作用,但是对心室的支配及对心室的调控作用还不清楚。一直以来都存在一个误解,认为交感神经支配心脏的各个部位而副交感神经仅支配心脏的室上性组织,对心室没有支配。近年来的研究显示在一些哺乳动物的心脏上,胆碱能神经在心室也有分布,且对左心室的功能有重要的调控作用。本文从解剖及组织化学、分子生物学和功能学三个方面阐述迷走神经对心室的支配及调控证据,并对心章收缩功能的迷走神经（毒蕈碱）调控及其信号转导途径进行综述。     

Functional innervation of the myometrium of Myotis lucifugus, the little brown bat

Myometria of pregnant and nonpregnant Myotis lucifugus were studied in vitro by using electrical field stimulation as well as autonomic agonists and antagonists to determine whether functional responses corresponded with structural evidence showing abundant adrenergic and sparse cholinergic innervation, which uniquely does not disappear during pregnancy. Field stimulation (70 V, 0.6 ms, 5.0-s pulse train, 2.5 - 60 Hz) of myometria from nonpregnant (hibernating) bats produced graded responses consisting of an initial alpha-adrenergic contraction and a subsequent beta-adrenergic relaxation phase. Responses were sensitive to both the nerve poison tetrodotoxin and the adrenergic antagonist guanethidine, demonstrating that they resulted from stimulation of intrinsic adrenergic nerves. Field stimulation responses were unaffected by atropine indicating that there was no functional cholinergic innervation, even though carbachol-induced contraction showed that muscarinic receptors were present. In contrast, functional innervation of cervical tissue was cholinergic and nonadrenergic-non-cholinergic, but not adrenergic. At the beginning of active gestation, some myometrial preparations exhibited little of no response to field stimulation. However, as uterine size increased, the biphasic response to field stimulation was enhanced, particularly the inhibitory (beta-adrenergic) phase. Moreover, the contractile phases, though reduced, was not abolished by alpha-adrenergic antagonists. The residual contractile response was also tetrodotoxin-resistant, suggesting that the myometrium was sensitive to direct electrical stimulation. Near the end of pregnancy, myometrial tissue became nonresponsive to both field stimulation and autonomic agonists, suggesting an absence of available receptor sites on muscle cells.     

Effects of chronic endothelin-1 stimulation on cardiac myocyte contractile function

Endothelin-1 (ET-1) has acute positive inotropic effects, but consequences of chronically increased ET-1 on contractile function of cardiac myocytes are largely unknown. In the present study, effects of long-term treatment with ET-1 (10 nM) for 5 days on both force development [force of contraction (FOC)] and kinetics of contraction were determined in heart tissue reconstituted from rat cardiac cells. Isometric force was measured in response to cumulative concentrations of Ca(2+) and isoprenaline. ET-1 augmented basal FOC by 64 +/- 11% (P < 0.05), which was associated with a significantly blunted contractile response to Ca(2+) and isoprenaline. Moreover, ET-1 significantly prolonged relaxation (62 +/- 3 vs. 53 +/- 2 ms). Selective ET(A) (BQ-123) and ET(B) receptor blockade (BQ-788) demonstrated that effects of ET-1 on contractile function were mediated through the ET(A) receptor subtype. Effects of ET-1 were prevented by cotreatment with either Ro31-8425, a PKC inhibitor, or dimethylamiloride, an inhibitor of the Na(+)/H(+) exchanger. In contrast to long-term ET-1 treatment, no changes in contractile parameters were observed after ET-1 treatment for 3 h before force measurement. These data suggest that chronic ET-1 stimulation has dual effects on contractility: improvement of basal force but impairment of twitch kinetics and inotropic responsiveness to beta-adrenoceptor stimulation. The signaling pathways involved include ET(A) receptors, PKC, and the Na(+)/H(+) exchanger. The present in vitro findings raise the possibility that ET-1 may exert both adaptive and maladaptive effects in the failing myocardium in which local accumulation of ET-1 is present.     

Regulation of glucose transport in Ca2+-tolerant myocytes from adult rat heart

Calcium-tolerant cardiac myocytes were isolated from adult rat ventricles and sarcolemmal glucose transport was assessed by measuring linear initial uptake rates of the nonmetabolized glucose analog 3-O-methyl-D-glucose in the presence and absence of Ca2+ in the incubation medium. (1) Agents which are known to increase internal Na+ and thus stimulate Ca2+ influx via Na+-Ca2+ exchange stimulated 3-methylglucose transport in the presence of external Ca2+. These include low-Na+ medium, 10(-6) M ouabain and K+-free medium, cyanide and the sodium ionophore, monensin. Hyperosmolarity stimulated transport also in the absence of Ca2+, consistent with release of Ca2+ from internal stores. Transport was decreased in a hypo-osmolar medium and with 10(-9) M ouabain, a concentration which stimulates the Na+ pump. (2) The calcium ionophore A23187 increased basal 3-methylglucose transport but opposed stimulation of transport by insulin. (3) Insulin-stimulated transport was antagonized by palmitate and this effect was reversed by 2-bromostearate, an inhibitor of fatty acid oxidation. These results are identical in all respects to those obtained in intact cardiac and skeletal muscle preparations, confirming that hexose transport in muscle shows Ca2+ dependence and indicating that isolated cardiac myocytes are suitable for the study of this phenomenon.     

迷走神经功能调节与心肌缺血保护

心血管系统的生理活动受自主神经系统(autonomic nervous system,ANS)调节.已有研究表明,自主神经功能紊乱,尤其是迷走神经功能低下,与心血管疾病(cardiovascular disease,CVD)的发生、发展及预后密切相关.本文结合国内外研究现状,就本研究室在迷走神经对心脏不同部位的调控及其对心肌的保护作用机制方面的研究成果进行阐述.通过收缩功能检测及标准玻璃微电极细胞内记录技术,发现迷走神经递质--乙酰胆碱对哺乳动物心室肌有直接作用,可抑制细胞收缩力及动作电位时程;通过组织化学染色及分子生物学方法进一步证明心室有毒蕈碱受体分布;通过膜片钳技术显示在部分动物心室肌上存在乙酰胆碱激活的内向整流钾通道(acetylcholine-activated potassium channel,KACh),并且其电流(IK·ACh)和心房肌一样具有衰减现象.前期研究证明心房肌IK·ACh的衰减与毒蕈碱受体、G蛋白或钾通道磷酸化有关;而心室肌的IK·ACh还有待于进一步研究.我们建立了相关动物模型,结合心率变异性分析等自主神经评价方法,探讨ANS在健康和疾病状态下的变化情况,证明了迷走神经对心脏调节的增龄性改变及代偿效应.通过提高迷走张力(乙酰胆碱缺血预/后适应、有氧运动、β受体阻断剂),研究改善自主神经平衡对缺血心肌的保护作用以及胆碱能抗炎通路防御缺血,再灌注诱导的炎症损伤机制.综合评价心脏自主神经调节,改善交感和迷走张力平衡,将为CVD防治的基础研究提供重要的理论依据.     

Time to task failure and muscle activation vary with load type for a submaximal fatiguing contraction with the lower leg.

The purpose was to compare the time to failure and muscle activation patterns for a sustained isometric submaximal contraction with the dorsiflexor muscles when the foot was restrained to a force transducer (force task) compared with supporting an equivalent inertial load and unrestrained (position task). Fifteen men and women (mean+/-SD; 21.1+/-1.4 yr) performed the force and position tasks at 20% maximal voluntary contraction force until task failure. Maximal voluntary contraction force performed before the force and position tasks was similar (333+/-71 vs. 334+/-65 N), but the time to task failure was briefer for the position task (10.0+/-6.2 vs. 21.3+/-17.8 min, P<0.05). The rate of increase in agonist root-mean-square electromyogram (EMG), EMG bursting activity, rating of perceived exertion, fluctuations in motor output, mean arterial pressure, and heart rate during the fatiguing contraction was greater for the position task. EMG activity of the vastus lateralis (lower leg stabilizer) and medial gastrocnemius (antagonist) increased more rapidly during the position task, but coactivation ratios (agonist vs. antagonist) were similar during the two tasks. Thus the difference in time to failure for the two tasks with the dorsiflexor muscles involved a greater level of neural activity and rate of motor unit recruitment during the position task, but did not involve a difference in coactivation. These findings have implications for rehabilitation and ergonomics in minimizing fatigue during prolonged activation of the dorsiflexor muscles.     

The parasympathetic nervous system: its role during torpor in the fat-tailed dunnart (Sminthopsis crassicaudata)

This study investigated the effect of parasympathetic inhibition on the cardio-ventilatory interaction during torpor in the fat-tailed dunnart (Sminthopsis crassicaudata). Studies on the influence of the autonomic nervous system on cardiac function during torpor have focused on deep hibernation in eutherians. S. crassicaudata was used as a representative of the Metatheria that exhibits shallow, daily torpor as a comparison for the patterns of cardiac function found in other mammalian heterotherms. During torpor, parasympathetic inhibition removed the cardio-ventilatory interaction, eliminated heart rate variability and increased the overall heart rate; these are responses that have been shown to be typical of eutherian hibernators under the same conditions. Similarly, there was evidence to suggest that as the bout of torpor progressed, the variation in instantaneous heart rate decreased as a result of the progressive removal of parasympathetic tone. It has been suggested that the ability to enter a "steady state" during torpor, which is characterised by a regular heart rate, is limited to deep hibernators. On the basis of this, and the results of previous physiological studies, it was proposed that there is little evidence to suggest that there is any physiological difference between shallow, daily torpor and deep hibernation.     

Atrial myocardium is the predominant inotropic target of adrenomedullin in the human heart

Adrenomedullin (ADM) is an endogenous peptide with favorable hemodynamic effects in vivo. In this study, we characterized the direct functional effects of ADM in isolated preparations from human atria and ventricles. In electrically stimulated human nonfailing right atrial trabeculae, ADM (0.0001-1 micromol/l) increased force of contraction in a concentration-dependent manner, with a maximal increase by 35 +/- 8% (at 1 micromol/l; P < 0.05). The positive inotropic effect was accompanied by a disproportionate increase in calcium transients assessed by aequorin light emission [by 76 +/- 20%; force/light ratio (DeltaF/DeltaL) 0.58 +/- 0.15]. In contrast, elevation of extracellular calcium (from 2.5 to 3.2 mmol/l) proportionally increased force and aequorin light emission (DeltaF/DeltaL 1.0 +/- 0.1; P < 0.05 vs. ADM). Consistent with a cAMP-dependent mechanism, ADM (1 micromol/l) increased atrial cAMP levels by 90 +/- 12%, and its inotropic effects could be blocked by the protein kinase A (PKA) inhibitor H-89. ADM also exerted positive inotropic effects in failing atrial myocardium and in nonfailing and failing ventricular myocardium. The inotropic response was significantly weaker in ventricular vs. atrial myocardium and in failing vs. nonfailing myocardium. In conclusion, ADM exerts Ca(2+)-dependent positive inotropic effects in human atrial and less-pronounced effects in ventricular myocardium. The inotropic effects are related to increased cAMP levels and stimulation of PKA. In heart failure, the responsiveness to ADM is reduced in atria and ventricles.     

Human isolated bronchial muscle preparations from asthmatic patients: effects of indomethacin and contractile agonists

Airway reactivity to histamine was determined in a group of non-asthmatic and asthmatic patients prior to thoracotomy. The latter group was more reactive to histamine provocation than the former (PC40: 28.40 +/- 6.27 mg/ml and 1.15 +/- 0.19 mg/ml, respectively). Subsequent to the surgical intervention, isolated human bronchial muscle preparations were obtained from both groups (15 non-asthmatic and 5 asthmatic subjects). Histamine concentration-effect curves were generated both in the absence and in the presence of indomethacin (1.7 microM; 30 min). Neither the basal tone nor the histamine response and sensitivity of the preparations were altered by the antiinflammatory drug. In bronchial preparations from one asthmatic subject, indomethacin significantly reduced the prostaglandin production during histamine contraction. Prostaglandin E2 and F2 alpha contracted isolated human bronchial muscle preparations from these asthmatic individuals. These data suggest that endogenous prostaglandins may not regulate the contractile response to histamine in vitro.     

cAMP and in vitro inotropic actions of secretin and VIP in rat papillary muscle.

Secretin and VIP stimulate cardiac adenylyl cyclase activity and exert a positive inotropic action in several mammalian species. This study examined positive inotropic activity and cAMP levels in rat papillary muscle. Isoproterenol and secretin increased contractions by 150+/-31% and 129+/-27%, respectively. VIP increased contraction by 30+/-21% only at 10 microM. Isoproterenol significantly increased cAMP levels by 82%, whereas increases by secretin (58%) and VIP (56%) were not significant. These results are consistent with reports that secretin and VIP stimulate cardiac adenylyl cyclase in the rat, but suggest that cAMP tissue levels cannot totally explain the positive inotropic responses to secretin and VIP.