Indian red scorpion venom modulates spontaneous activity of rat right atria through the involvement of cholinergic and adrenergic systems.

The effect of Indian red scorpion (Mesobuthus tamulus concanesis, Pocock; MBT) venom was investigated on isolated rat right atrial preparations. MBT venom (0.001-3.0 micrograms/ml) exhibited a peculiar concentration-response pattern with respect to rate. The venom concentrations between 0.001-0.01 microgram/ml increased the atrial rate (phase I), followed by a relative decrease with 0.03-0.3 microgram/ml (phase II), and then an abrupt increase with 0.6-3.0 micrograms/ml (phase III). On the other hand, the force was unaltered by venom at phases I and II, while an increase was seen at phase III (3.0 micrograms/ml). Propranolol (0.1 microM) completely blocked the cardiostimulant action of venom at phase III. Further, this stimulant action of venom was absent in atria obtained from reserpinized animals. Pretreatment with atropine (0.3 microM), produced tachycardia at concentrations 0.1-0.3 microgram/ml of venom. But, hexamethonium (30 microM) had no influence on the venom (0.1 microgram/ml)-induced alterations in rate. However, MBT venom increased the acetylcholinesterase (AChE) activity (2-3 fold) in a concentration-dependent manner. Tetrodotoxin (2 microM), did not block the increase in rate produced by 0.01 microgram/ml of venom. Results suggest that, MBT venom-induced alterations of cardiac rhythmicity are mediated through cholinergic as well as adrenergic mechanisms depending upon the concentrations. The modulation of atrial rate at very low concentrations may be due to the direct action of venom on the atrium.     

薯蓣皂苷对大鼠心肌收缩与钠-钙交换体的影响

目的：观察薯蓣皂苷（Dio）对大鼠心肌收缩作用以及胞内Ca²⁺浓度的影响,并初步探讨其作用机制与Na⁺-Ca²⁺交换体（NCX）的关系。方法：采用Langendorff逆行主动脉灌流法对大鼠离体心脏进行灌流,利用压力感受器插管法测定左心室相关心功能参数,记录及其在应用NCX选择性抑制剂SEA0400情况下对左心室收缩压（LVSP）、左心室舒张末期压（LVEDP）、左心室内压最大上升/下降速率（±dp/dt_max）以及心率（HR）的影响;利用激光共聚焦显微观察薯蓣皂苷及SEA0400对大鼠心肌细胞H9c2细胞内Ca²⁺浓度的影响。结果：离体心脏灌流结果显示,1 μmol/L Dio可显著增加LVSP,增加约19.7%（P<0.01）;增加左室内压最大上升速率（+dp/dt_max）,增加约9.6%;激光共聚焦测定Ca²⁺荧光强度实验结果显示：1 μmol/L Dio可使H9c2细胞中Ca²⁺相对荧光强度增加（P<0.01）;而在SEA0400存在的情况下,1 μmol/L的Dio使细胞内Ca²⁺相对荧光强度变为（17.09±0.63）,给予Dio后差异有显著性（P<0.01）。在细胞液中无Ca²⁺或无Na⁺时,给予1 μmol/L的Dio使Ca²⁺相对荧光强度减小,与给予1 μmol/L的Dio差异有显著性（P<0.01）。结论：Dio可增加左心室收缩压和最大上升速率,表现正性肌力作用;Dio可使细胞内Ca²⁺浓度增加,其作用机制与增加Na⁺内流,促进NCX反向转运有关。     

Plasma and atrial levels of atrial natriuretic peptide (ANP) in pulmonary hypertensive rats

Immunoreactive atrial natriuretic peptide (IR-ANP) was measured in plasma and atrium of normal and monocrotaline induced pulmonary hypertensive rats (PH rats). In these animals, there was right ventricular hypertrophy and right ventricular systolic pressure was elevated. Fourteen days after a single dose of monocrotaline (40 mg/kg), plasma IR-ANP concentrations were significantly elevated (964.3 +/- 63.0 pg/ml vs. 521.0 +/- 81.9 pg/ml in controls, p less than 0.001). Tissue levels of IR-ANP in the right atrium in PH rats was significantly lower than those in the controls (45.1 +/- 3.9 ng/mg vs. 240.5 +/- 10.4 ng/mg, p less than 0.001), while there was no significant difference in tissue levels of atrial IR-ANP in the left atrium between the two groups. Thus, development of pulmonary hypertension led to an increase in release of ANP from the right atrium.     

Compensatory recovery of vagal control of hemodynamics after unilateral vagotomy

This study investigated whether each part of the heart is evenly innervated by the left or right vagus and observed the mechanism of compensatory recovery after unilateral cervical vagotomy. HR, BP, LVSP and +/-dp/dt max all decreased one week after left vagotomy, whereas only BP and -dp/dt max decreased one week after right vagotomy. Western blot analyses revealed that the expression of M(2) receptors in the left atrium and left ventricle was upregulated after subacute (1 week) left/right vagotomy. However, significantly more cholinesterase-positive nerves in LV and RV were seen one week after unilateral vagotomy compared to the sham-operated group. In addition, baroreflex sensitivity was increased after subacute right vagotomy. The decreasing effects of ACh (0.5 microg/kg) on LVSP and +/-dp/dt max (but not on HR and BP) were facilitated by subacute unilateral vagotomy. Our present experiments indicate that 1) the working myocardium is innervated bilaterally by the vagus, 2) ventricular contractility is influenced more by denervation of the left than the right vagus and 3) up-regulation of M(2) muscarinic receptors in the left heart, increase of cholinergic nerves, and high baroreflex sensitivity could be involved in the mechanism of compensatory hemodynamic recovery via contralateral vagus overactivity, thereby amplifying contralateral vagal activity and decreasing cardiac contractility.     

Decreased content in left atrium and increased plasma concentration of atrial natriuretic polypeptide in spontaneously hypertensive rats (SHR) and SHR stroke-prone

The atrial contents and concentrations, and the plasma concentrations of atrial natriuretic polypeptide (ANP) in spontaneously hypertensive rats (SHR) and SHR stroke-prone (SHRSP) were measured and compared with those of age-matched Wistar Kyoto rats (WKY) using a specific radioimmunoassay (RIA) for alpha-rat ANP (alpha-rANP). The contents of alpha-rANP-LI in the atria of SHR (19.0 +/- 0.9 micrograms, mean +/- SEM) and SHRSP (19.3 +/- 0.6 micrograms) were significantly lower than that of WKY (22.8 +/- 1.4 micrograms) (p less than 0.05). The atrial concentration of alpha-rANP-LI was also significantly lower in SHR (248.2 +/- 11.3 ng/mg, p less than 0.05) and tended to be lower in SHRSP (272.2 +/- 12.4 ng/mg) than that of WKY (300.0 +/- 14.2 ng/mg). Furthermore, the concentrations in the left auricles of SHR and SHRSP were significantly lower than that of WKY (p less than 0.01 and p less than 0.05, respectively). In contrast, no significant difference was observed in the alpha-rANP-LI concentrations in the right auricles of WKY, SHR and SHRSP. Gel filtration studies coupled with RIA showed that gel filtration profiles of the extracts from the right and left auricles of WKY, SHR and SHRSP were essentially identical. The plasma alpha-rANP-LI levels in SHR (260 +/- 34 pg/ml) and SHRSP (319 +/- 19 pg/ml) were significantly higher than that in WKY (170 +/- 17 pg/ml) (p less than 0.05 and p less than 0.01, respectively). These results suggest that the secretion of ANP from the heart is increased in SHR and SHRSP compared with WKY.     

Ciprofloxacin in the prevention and treatment of surgical infections]

A clinico-laboratory study on ciprofloxacin made by Bayer (Germany) was applied to patients with extended posttraumatic wounds and performed with the aim of preventing postoperative purulent complications in patients operated on the organs of the gastrointestinal tract. In the both groups ciprofloxacin was administered orally in doses of 500 and 1000 mg and intravenously in a dose of 200 mg. The results of the assay on ciprofloxacin sensitivity of the isolates from the wound excretion and urine showed that they were more sensitive to ciprofloxacin than to aminoglycosides and cephalosporins. 15 minutes after the intravenous administration the serum concentration of ciprofloxacin amounted to 7.5 +/- 0.9 micrograms/ml and in 6 hours it was equal to 0.45 +/- 0.45 micrograms/ml, the mean concentrations of ciprofloxacin being attained in the bile (8.7 +/- +/- 3.9 micrograms/ml), gallbladder wall (5.5 +/- 3.8 micrograms/g), liver (0.73 micrograms/g), muscles (1.93 micrograms/g) and tendon (0.15 microgram/g). After the oral administration in a dose of 500 mg ciprofloxacin was detected in the blood serum in an amount of 2.0 +/- 0.7 micrograms/ml in 1 hour and in an amount of 0.9 +/- 0.13 micrograms/ml in 6 hours. After the drug oral administration in a dose of 1000 mg the maximum concentrations were: 6.34 +/- 4.2 micrograms/ml on the average and 2.1 +/- 0.8 micrograms/ml in 6 hours (0.4 micrograms/g in the muscles, 1.4 micrograms/g in the skin and 0.34 micrograms/g in the bones). The study showed that ciprofloxacin was a highly efficient antimicrobial agent in the treatment of the complicated wound infections and the prophylaxis of the purulent complications during the postoperative period in the patients operated on gastrointestinal organs.     

The effects of certain vasodilating prostaglandins on the coronary and hindlimb vascular beds of the conscious sheep

Vasodilating prostaglandins were injected, in bolus doses, into the lower abdominal aorta or left circumflex coronary artery (LCCA) of conscious sheep. Local blood flow, mean arterial pressure (MAP), heart rate (HR) and ECG were monitored continuously. 6-Keto PGF1 alpha had no effect on either vascular bed in doses up to 100 micrograms. PGE2 was more potent than PGI2 in dilating hindlimb vasculature and PGE2 induced a more persistent hyperaemia whereas PGD2 elicited a biphasic response (constriction-dilation). PGE1, PGE2, PGD2 and PGI2 all produced dose-dependent vasodilation, the order of potency being PGD2 greater than PGI2 greater than PGE1 greater than or equal to PGE2. The effect of PGI2 was more transient and PGE1 and PGD2 caused small but consistent decreases in MAP and HR, respectively.     

Cardiac response to submaximal exercise in dogs susceptible to sudden cardiac death

The hemodynamic response to submaximal exercise was investigated in 38 mongrel dogs with healed anterior wall myocardial infarctions. The dogs were chronically instrumented to measure heart rate (HR), left ventricular pressure (LVP), LVP rate of change, and coronary blood flow. A 2 min coronary occlusion was initiated during the last minute of an exercise stress test and continued for 1 min after cessation of exercise. Nineteen dogs had ventricular fibrillation (susceptible) while 19 animals did not (resistant) during this test. The cardiac response to submaximal exercise was markedly different between the two groups. The susceptible dogs exhibited a significantly higher HR and left ventricular end-diastolic pressure (LVEDP) but a significantly lower left ventricular systolic pressure (LVSP) in response to exercise than did the resistant animals. (For example, response to 6.4 kph at 8% grade; HR, susceptible 201.4 +/- 5.1 beats/min vs. resistant 176.2 +/- 5.6 beats/min; LVEDP, susceptible 19.4 +/- 1.1 mmHg vs. resistant 12.3 +/- 1.7 mmHg; LVSP, susceptible 136.9 +/- 7.9 mmHg vs. resistant 154.6 +/- 9.8 mmHg.) beta-Adrenergic receptor blockade with propranolol reduced the difference noted in the HR response but exacerbated the LVP differences (response to 6.4 kph at 8% grade; HR, susceptible 163.4 +/- 4.7 mmHg vs. resistant 150.3 +/- 6.4 mmHg; LVEDP susceptible 28.4 +/- 2.1 mmHg vs. resistant 19.6 +/- 3.0 mmHg; LVSP, susceptible 122.2 +/- 8.1 mmHg vs. resistant 142.8 +/- 10.7 mmHg). These data indicate that the animals particularly vulnerable to ventricular fibrillation also exhibit a greater degree of left ventricular dysfunction and an increased sympathetic efferent activity.     

降钙素基因相关肽对不同程度冠脉狭窄时的心脏功能的影响

本实验观察了冠脉内注射降钙素基因相关肽（ＣＧＲＰ０．３μｇ／ｋｇ）对正常及不同程度冠脉狭窄犬的心功能的影响。结果表明正常犬冠脉内注射ＣＧＲＰ后,平均动脉压（ＭＡＰ）下降１．２ｋＰａ（Ｐ＜０．０５）,同时,心率（ＨＲ）、心输出量（ＣＯ）、左室收缩压峰值（ＬＶＳＰ）均不同程度增加;左室舒张末压（ＬＶＥＤＰ）轻度降低。在中度狭窄３０ｍｉｎ后,冠脉内注射ＣＧＲＰ对ＨＲ、ＭＡＰ无明显影响;而重度狭窄后注射ＣＧＲＰ,ＭＡＰ由狭窄时降低逐渐增高,ＨＲ由增快而变慢。ＣＯ、ＬＶＳＰ均显著增高,ＬＶＥＤＰ降低,此作用较冠脉狭窄前更为明显。提示ＣＧＲＰ扩张冠脉动脉,增加冠脉血流量和心排血量,增强心肌收缩力,对缺血心脏功能有保护作用。     

Spontaneous baroreflex control of cardiac output during dynamic exercise, muscle metaboreflex activation, and heart failure

We have previously shown that spontaneous baroreflex-induced changes in heart rate (HR) do not always translate into changes in cardiac output (CO) at rest. We have also shown that heart failure (HF) decreases this linkage between changes in HR and CO. Whether dynamic exercise and muscle metaboreflex activation (via imposed reductions in hindlimb blood flow) further alter this translation in normal and HF conditions is unknown. We examined these questions using conscious, chronically instrumented dogs before and after pacing-induced HF during mild and moderate dynamic exercise with and without muscle metaboreflex activation. We measured left ventricular systolic pressure (LVSP), CO, and HR and analyzed the spontaneous HR-LVSP and CO-LVSP relationships. In normal animals, mild exercise significantly decreased HR-LVSP (-3.08 +/- 0.5 vs. -5.14 +/- 0.6 beats.min(-1).mmHg(-1); P < 0.05) and CO-LVSP (-134.74 +/- 24.5 vs. -208.6 +/- 22.2 ml.min(-1).mmHg(-1); P < 0.05). Moderate exercise further decreased both and, in addition, significantly reduced HR-CO translation (25.9 +/- 2.8% vs. 52.3 +/- 4.2%; P < 0.05). Muscle metaboreflex activation at both workloads decreased HR-LVSP, whereas it had no significant effect on CO-LVSP and the HR-CO translation. HF significantly decreased HR-LVSP, CO-LVSP, and the HR-CO translation in all situations. We conclude that spontaneous baroreflex HR responses do not always cause changes in CO during exercise. Moreover, muscle metaboreflex activation during mild and moderate dynamic exercise reduces this coupling. In addition, in HF the HR-CO translation also significantly decreases during both workloads and decreases even further with muscle metaboreflex activation.     

Modulation of mouse cardiac function in vivo by eNOS and ANP

To study the role of endothelial nitric oxide synthase (eNOS) in cardiac function, we compared eNOS expression, contractility, and relaxation in the left ventricles of wild-type and eNOS-deficient mice. eNOS immunostaining is localized to the macro- and microvascular endothelium throughout the myocardium in wild-type mice and is absent in eNOS-/- mice. Whereas blood pressure is elevated in eNOS-/- mice, baseline cardiac contractility (dP/dt(max)) is similar in wild-type and eNOS-/- mice (9,673 +/- 2, 447 and 9,928 +/- 1,566 mmHg/s, respectively). The beta-adrenergic agonist isoproterenol (Iso) at doses of >/=1 ng causes enhanced increases in dP/dt(max) in eNOS-/- mice compared with wild-type controls in vivo (P < 0.01) as well as in Langendorff isolated heart preparations (P < 0.02). beta-Adrenergic receptor binding (B(max)) is not significantly different in the two groups of animals (B(max) = 41.4 +/- 9.4 and 36.1 +/- 5.1 fmol/mg for wild-type and eNOS-/-). Iso-stimulated ventricular relaxation is also enhanced in the eNOS-/- mice, as measured by dP/dt(min) in the isolated heart. However, baseline ventricular relaxation is normal in eNOS-/- mice (tau = 5.2 +/- 1.0 and 5.6 +/- 1.5 ms for wild-type and eNOS-/-, respectively), whereas it is impaired in wild-type mice after NOS inhibition (tau = 8.3 +/- 2.4 ms). cGMP levels in the left ventricle are unaffected by eNOS gene deletion (wild-type: 3.1 +/- 0.8 pmol/mg, eNOS-/-: 3.1 +/- 0.6 pmol/mg), leading us to examine the level of another physiological regulator of cGMP. Atrial natriuretic peptide (ANP) expression is markedly upregulated in the eNOS-/- mice, and exogenous ANP restores ventricular relaxation in wild-type mice treated with NOS inhibitors. These results suggest that eNOS attenuates both inotropic and lusitropic responses to beta-adrenergic stimulation, and it also appears to regulate baseline ventricular relaxation in conjunction with ANP.     

Effects of streptozotocin-induced diabetes on action potentials in the sinoatrial node compared with other regions of the rat heart

In vivo biotelemetry studies have demonstrated that heart rate (HR) is progressively and rapidly reduced after administration of streptozotocin (STZ) and that the reduction in HR can be partially normalized with insulin replacement. Reductions in HR have also been reported in isolated perfused heart and superfused right atrial preparations suggesting that intrinsic defects in the heart are at least partly responsible for the bradycardia. The regional effects of STZ-induced diabetes mellitus (DM) on action potentials (APs) in the sinoatrial node (SAN), right and left atria and ventricles have been compared in the spontaneously beating Langendorff perfused rat heart 10–12 weeks after treatment. HR was significantly reduced in STZ-induced diabetic rat heart (174 ± 9 BPM) compared to controls (241 ± 12 BPM). The duration of AP repolarization at 50% and 70% from peak AP was significantly prolonged in SAN, right atrium and right ventricle from STZ-induced diabetic rat compared to age-matched controls. In the SAN AP duration (APD) at 50% and 70% were 51.7 ± 2.2 and 59.5 ± 2.3 ms in diabetic rat heart compared to 45.2 ± 1.7 and 50.0 ± 1.6 ms in controls, respectively. In contrast APD at 50% and 70% were not significantly altered in the left atrium and left ventricle. Regional defects in the expression and/or electrophysiology of SAN ion channels, and in particular those involved in AP repolarization, might underlie heart rhythm disturbances in the STZ-induced DM rat.     

家兔Bezold—Jarisch反射的血流动力学效应

在40只麻醉兔,观察经冠脉内注射尼古丁诱发Bezold-Jarisch反射时的血流动力学变化。反射效应表现为心率减慢、动脉血压和左心室收缩压降低以及左心室内压微分值减小。切断两侧窦神经和减压神经后,上述效应增强;两侧迷走神经切断后,多数动物反射效应消失。 冠脉内注射尼古丁后,心输出量和总外周阻力均下降。人工起搏心脏以防止心率减慢时,对上述效应无明显影响。动物阿托品化并切除两侧星状神经节后,心率减慢基本消失,但动脉血压降低的程度并无明显变化。结果提示,Bezold-Jarisch反射时所表现的动脉血压降低,可归因于心输出量减少和总外周阻力降低,而以后者为主。     

Hemodynamic basis for cocaine-induced pulmonary edema in dogs.

We tested the hypothesis that cocaine-induced impairment of left ventricular function results in cardiogenic pulmonary edema. Mongrel dogs, anesthetized with alpha-chloralose, were injected with two doses of cocaine (5 mg/kg iv) 27 min apart. Cocaine produced transient decreases in aortic and left ventricular systolic pressures that were followed by increases exceeding control. As aortic pressure recovered, left ventricular end-diastolic, left atrial (Pla), pulmonary arterial (Ppa), and central venous pressures rose. Cardiac output and stroke volume were reduced when measured 4-5 min after cocaine administration. Peak Ppa and Pla were 31 +/- 5 (SE) mmHg (range 17-51 mmHg) and 26 +/- 5 mmHg (range 12-47 mmHg), respectively. Increases in extravascular lung water content (4.10 to 6.24 g H2O/g dry lung wt) developed in four animals in which Pla exceeded 30 mmHg. Analysis of left ventricular function curves revealed that cocaine depressed the inotropic state of the left ventricle. Cocaine-induced changes in hemodynamics spontaneously recovered and could be elicited again by the second dose of the drug. Our results show that cocaine-induced pulmonary hypertension, associated with decreased left ventricular function, produces pulmonary edema if pulmonary vascular pressures rise sufficiently.     

Cardiovascular effects of matrine isolated from the Chinese herb Shan-dou-gen

Matrine, a pure compound isolated from the Chinese herb Shan-don-Gen (Sophora subprostrata), was studied for its effects on the cardiovascular system of the rat. Intravenous injections of matrine at doses from 5 mg to 20 mg/kg body weight exhibited dose-dependent hypotensive and bradycardiac effects. These effects lasted only 1 to 3 min. In the isolated atria and ventricle preparations, matrine at doses from 50 micrograms to 200 micrograms/ml increased the amplitudes of spontaneous contraction of the atria and electrically induced contraction of the ventricle, whereas the frequency of the spontaneous beating of the atria was reduced. The dose-dependent effects of matrine on the isolated preparations persisted as long as the compound was present. Tachyphylaxis was not observed with repeated applications of this compound to the isolated preparations. The positive inotropic effects on both atria and ventricle and the negative chronotropic effect on spontaneous beating of the atria by matrine were not blocked by diphenhydramine, atropine, phenoxybenzamine, propranolol, trifluoperazine, or methysergide. In contrast, verapamil significantly reduced the positive inotropic effect of matrine on the ventricle. In the isolated aortic strip preparation, matrine at a dose of 200 micrograms/ml led to a slight increase in muscle tone. The same dose of matrine induced a 35% increase of perfusion pressure in the hindleg perfusion model. These results suggest that the in vivo transient hypotensive effect of matrine is likely associated with a decrease in heart rate itself, since positive inotropic effects on both the atria and the ventricle, and vasoconstriction of some vascular beds could not be the cause of hypotension.(ABSTRACT TRUNCATED AT 250 WORDS)     

The hypothetical role of potassium conductance on the genesis of R-wave amplitude increase during ischemia in the isolated rat heart.

The effect of increased potassium conductance on the genesis of R-wave amplitude increase during acute myocardial ischemia has been studied in the isolated perfused rat heart by simultaneously recording the R-wave amplitude of epicardial electrograms (VEE), heart rate (HR), coronary flow rate (CFR), left ventricular diastolic pressure (LVDP), and left ventricular systolic pressure (LVSP). The experiments were performed during basal and partial or total ischemic conditions at spontaneous or fixed HR. In some experiments, potassium conductance was increased by means of high-calcium (8 mM) or acetylcholine chloride (10(-6) M) perfusion. In the control experiments, partial ischemic perfusion produced an increase in VEE and LVDP and a decrease in HR, CFR, and LVSP; total ischemic perfusion exaggerated these variations. High-calcium perfusion provoked an increase in VEE and LVDP and a decrease in HR, CFR, and LVSP during basal conditions (p less than 0.01 vs. control experiment); these modifications increased progressively during partial ischemic perfusion (p less than 0.01 vs. control experiment) and during total ischemic perfusion (p less than 0.01 vs. control experiment). Perfusion with acetylcholine chloride produced variations similar to those observed in high-calcium solution except that LVDP under basal conditions remained unchanged from control. When the HR was maintained at a constant value by means of atrial pacing the results were similar to those observed in the unpaced hearts. In conclusion, in the isolated perfused rat heart, increasing potassium conductance may influence the genesis of R-wave amplitude increasing during acute myocardial ischemia.     

Bradykinin-induced chemoreflexes from skeletal muscle: implications for the exercise reflex

We examined the cardiovascular response to bradykinin stimulation of skeletal muscle afferents and the effect of prostaglandins on this response. Intra-arterial injection of 1 microgram bradykinin into the gracilis muscle of cats reflexly increased mean arterial pressure by 16 +/- 2 mmHg, left ventricular end-diastolic pressure by 1.6 +/- 0.6 mmHg, maximal dP/dt by 785 +/- 136 mmHg/s, heart rate by 11 +/- 2 beats/min, and mean aortic flow by 22 +/- 3 ml/min. The hemodynamic responses were abolished following denervation of the gracilis muscle. The increases in mean arterial pressure and maximal dP/dt were reduced by 68 and 45%, respectively, following inhibition of prostaglandin synthesis with indomethacin (2-8 mg/kg iv). Treatment with prostaglandin E2 (PGE2, 15-25 micrograms ia) restored the initial increase in mean arterial pressure, but not dP/dt, caused by bradykinin stimulation. Injection of PGE2 (15-30 micrograms ia) into the gracilis, without prior treatment with indomethacin, augmented the bradykinin-induced increases in mean arterial pressure and dP/dt. We conclude that small doses of bradykinin injected into skeletal muscle are capable of reflexly activating the cardiovascular system and that prostaglandins are necessary for the full manifestation of the corresponding hemodynamic response. The pattern of hemodynamic adjustment following bradykinin injection into skeletal muscle is very similar to that induced by static exercise. Therefore, it is possible that intense exercise provides a stimulus for this bradykinin-induced reflex in vivo.     

Determination of cardiac contractility in awake unsedated mice with a fluid-filled catheter

Today, cardiac contractility in mice is exclusively measured under anesthesia or in sedated animals because the catheters available are too rigid to be used in awake mice. We therefore developed a new catheter (Pebax 03) to measure cardiac contractility in conscious mice. In this study, we evaluated the accuracy and utility of this new catheter for assessment of cardiac contractility in anesthetized and conscious mice. With the use of a balloon-pop test, the Pebax catheter with an inner diameter of 0.3 mm was found to exhibit a high natural frequency, a low damping coefficient, and a flat frequency of up to 50.5 +/- 0.6 Hz. Under anesthesia (0.5% or 1.0% halothane), no difference was found in heart rate (HR), left ventricular (LV) systolic pressure (LVSP), the maximum rates of LV pressure rise and fall (LV dP/dt(max) and LV dP/dt(min), respectively), ejection time (ET), and isovolumic relaxation time constant (tau) when measured with either the 1.4-Fr Millar or Pebax 03 catheter. However, when HR, LVSP, LV dP/dt(max), and LV dP/dt(min) were recorded with the Pebax catheter in awake mice, values were significantly higher, and ET and tau were lower, than under anesthesia, suggesting a major impact of anesthesia on these parameters. The Pebax catheter was also used in a normotensive one-renin gene mouse model of cardiac hypertrophy induced by DOCA and salt. In this model, DOCA-salt induced a severe decrease in cardiac contractility in the absence of changes in blood pressure. These data demonstrate that cardiac contractility can be measured very accurately in conscious mice. This new device can be of great help in the investigation of cardiac function in normal and genetically engineered mice.     

Interactions of nimodipine and cocaine on endogenous catecholamines in the squirrel monkey

The effects of nimodipine on the cocaine-induced alterations in blood pressure, heart rate, and plasma catecholamines were studied in the squirrel monkey. Cocaine in intravenously administered doses of 0.5, 1, and 2 mg/kg produced significant increases in blood pressure and significant decreases in heart rate. These cardiovascular changes were associated with transient episodes of arrhythmias and with significant increases in plasma concentrations of dopamine, epinephrine, and norepinephrine. Nimodipine, 1 micrograms/kg/min for 5 min administered intravenously 5 min after cocaine, corrects the cardiovascular and plasma catecholamine concentration changes induced by this alkaloid. The same dose of nimodipine administered 5 min before cocaine prevents elevations of blood pressure. Plasma catecholamine increments are also prevented except for the highest dose of cocaine. Cardiovascular changes induced by cocaine administration in the squirrel monkey are temporally associated with significant increments in plasma catecholamines. Administration of nimodipine prevents or minimizes these endocrine and physiologic changes.     

Effects of leukotriene D4 on mucociliary and respiratory function in allergic and nonallergic sheep

We determined the effect of aerosol challenge with leukotriene D4 (LTD4) on specific lung resistance (sRL) and tracheal mucous velocity (TMV) in conscious sheep with (allergic) and without (nonallergic) Ascaris suum hypersensitivity. In allergic sheep LTD4 in concentrations of 50, 100, and 150 micrograms/ml produced dose-dependent increases in mean sRL by 44 (P = NS), 154 (P less than 0.05), and 233% (P less than 0.05), respectively. The increase in sRL produced by 150 micrograms/ml LTD4 was prevented by FPL 55712, an antagonist of slow-reacting substance of anaphylaxis. In nonallergic sheep 150 micrograms/ml LTD4 failed to elicit a significant change in sRL. In contrast to the changes in airway mechanics, concentrations of LTD4 as low as 25 micrograms/ml produced significant decreases in TMV in allergic sheep. The maximum decrease in TMV at this dose occurred 2 h after challenge; with larger doses of LTD4 (100 and 150 micrograms/ml) the maximum effect was observed 3 h after challenge. Furthermore, 150 micrograms/ml LTD4 reduced TMV in nonallergic sheep (mean decrease 43%, P less than 0.05). FPL 55712 only had a minor effect on the LTD4-induced decreases in TMV. We conclude that allergic sheep exhibit greater airway responsiveness to inhaled LTD4 than nonallergic sheep but that this difference is not evident for the concomitant changes in mucociliary transport. This suggests that the allergic state is associated with an increased responsiveness to LTD4 in tissues controlling airway caliber but not in those contributing to mucociliary function.