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Biomedical subjects

J G Mill

Publications and source records attributed to J G Mill.

At least 55 records · Page 3Linked to original sources

Post-rest contractions of amphibian cardiac muscle.

Post-rest potentiated contractions have been reported to be more dependent on Ca2+ stored in intracellular sites than on transmembrane Ca2+ influx. The phenomenon was examined using toad ventricular strips contracting isometrically and superfused with Ringer solution. Toad ventricular strips did not present post-rest potentiation, a fact that may be explained by the reduced volume of the sarcoplasmic reticulum in the amphibian myocardium. Potentiated post-rest contractions were obtained after calcium influx blockade with 10 microM verapamil or 2 mM Mn2+ and the slow reduction of extracellular Ca2+ concentration obtained by slowly exchanging the bath fluid was accompanied by a progressive decrease of both steady-state and post-rest contractions. These data confirm the observations made on other species regarding the post-rest potentiation phenomenon and support the suggestion of the dependence of post-rest potentiation on activator calcium liberated from intracellular stores.

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Time course of changes in heart rate and sympathetic tone after coronary artery ligation in rats.

The purpose of this study was to investigate the changes of heart rate (HR) and sympathetic tone occurring after myocardial infarction. Male rats (200-250 g) were submitted to ligation of the anterior branches of the left coronary artery to produce infarction (INF, N = 26) or to sham surgery (SO, N = 24). Groups of animals (N = 6-8) were studied 1,3,7 and 15 days later. A group not submitted to surgical procedures was used as control (C,N = 6). Blood pressure and HR were measured in conscious unrestrained animals after cannulation of the femoral artery. Basal HR and mean arterial pressure (MAP) of the C group were 336 +/- 8 beats/min (bpm) and 110 +/- 3 mmHg, respectively. Similar values were observed in SO subgroups. One day after INF, HR increased to 417 +/- 9 bpm and MAP decreased to 97 +/- 2 mmHg. While MAP was unchanged for the remainder of the study, HR progressively decreased and normal HR values (360 +/- 18 bpm) were observed two weeks after INF. The sympathetic tone, which was evaluated from the reduction of HR after propranolol (2 mg/kg, iv), was increased during the tachycardic phase after INF. HR normalization paralleled the progressive reduction of sympathetic tone. The changes in HR after coronary artery ligation in rats seem to reflect the degree of sympathetic efferent activity during infarct healing.

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Heterometric regulation and calcium sensitivity of the infarcted rat heart.

1. The surviving hypertrophied muscle remaining after myocardial infarction in rats is less sensitive to extracellular Ca2+ than the normal myocardium. Since the inotropic effect of Ca2+ is modulated by sarcomere length, the present study was undertaken to determine if Ca2+ desensitization of infarcted left ventricles (LV) can be modulated by increasing the diastolic pressure (DP). 2. Rats submitted to left coronary artery ligation (N = 11) or sham-operation (N = 9) were killed 8-10 days later and their hearts perfused by the Langendorff technique. A balloon was introduced into the LV cavity to measure the isovolumic systolic pressure (ISP) produced by DP changes (0 to 25 mmHg) at three Ca2+ concentrations (0.8, 1.25 and 2.5 mM). 3. In control hearts submitted to a DP of 5 mmHg, the ISP increased from 36 +/- 3 to 63 +/- 4 and to 74 +/- 4 mmHg as external Ca2+ was changed from 0.8 to 1.25 and to 2.5 mM, respectively. In contrast, in infarcted hearts submitted to the same DP and Ca2+ concentrations, the ISP increased from 19 +/- 2 to 26 +/- 2 and to 27 +/- 3 mmHg. The depressed response to Ca2+ was not modified by increasing DP up to 25 mmHg, the greatest DP tested. At this DP, ISP increased from 75 +/- 4 to 103 +/- 5 and to 114 +/- 5 mmHg in control hearts and from 45 +/- 2 to 54 +/- 3 and to 55 +/- 4 mmHg in infarcted hearts.(ABSTRACT TRUNCATED AT 250 WORDS)

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[Effects of sympathetic block on post-infarction cardiac hypertrophy and their impact on myocardial contractility].

PURPOSE: To investigate the effects of chronic subcutaneous administration of reserpine (Res) or propranolol (Prop) on the postinfarction myocardial hypertrophy and the effects of Prop treatment on myocardial contractility in rats. METHODS: Male albino rats (3-month-old) were submitted to left coronary artery ligation to produce myocardial infarction. Rats submitted to a sham-operation were used as controls. Animals submitted to Res (0.5 mg/kg/day) were killed 8-10 days after surgery and those submitted to Prop (2.5 mg/kg twice a day) were killed 15 (G-15) or 30 (G-30) days later. Hypertrophy was evaluated according to cardiac chambers weight corrected to body weights. Isometric force (F) developed by isolated right ventricular (RV) strips was used as a contractile index. RESULTS: Atrial and RV hypertrophy were completely blocked by Res. Prop treatment did not significantly change infarct extension, evaluated by the fibrous scar area. Prop therapy also reduced atrial and RV hypertrophy. This effect was less intense compared to Res, however. In the G-30, for example, the relative right atrial and RV weights (mg/g) were 0.10 +/- 0.01 and 0.59 +/- 0.03 in sham-operated animals (n = 9), 0.12 +/- 0.01 and 0.079 +/- 0.07 in infarcted animals with Prop (n = 11) and 0.22 +/- 0.03 and 1.11 +/- 0.07 in those infarcted and treated with saline solution (n = 11). Basal F values were 25 to 30% lower in RV strips from infarcted than in sham-operated hearts. This reduction however was only 4% (G-15) and 8% (G-30) in infarcted hearts under Prop treatment. CONCLUSION: These data show that sympathetic blockade reduces the postinfarction myocardial hypertrophy and tends to preserve contractility of the surviving myocardium.

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[Comparison of negative chronotropic action of nitrendipine, nifedipine and verapamil on the isolated right atrium of normotensive and renovascular hypertensive rats].

PURPOSE: To study the negative chronotropic effects of nitrendipine, nifedipine and verapamil in isolated right atria from normotensive and renovascular hypertensive rats. MATERIAL AND METHODS: Hypertension (medium arterial pressure, MAP = 154 +/- 4 mmHg) was induced by applying a silver clip to the left renal artery and right nephrectomy. Control rats (MAP = 109 +/- 2 mmHg) were submitted to right nephrectomy only. The animals were studied 2 weeks after surgery. Different preparations were used to obtain cumulative dose-response curves (0.01 microM to 100 microM) with each drug. RESULTS: No difference in "in vitro" initial sinusal rate of control (243 +/- 7 bpm) and hypertensive (245 +/- 5 bpm) rats was observed. The negative chronotropic response produced by calcium channel blockers was similar in normotensive and hypertensive groups. 2 microM verapamil, 4 microM nitrendipine or 20 microM nifedipine was necessary to produce a 50% decrease of the initial sinusal rate. CONCLUSION: Sensitivity of the sinusal pacemaker to calcium antagonists does not change in this model of hypertension. Moreover, the negative chronotropic effect of nitrendipine is stronger than nifedipine and weaker than verapamil.

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Left ventricular length dependent activation in the isovolumetric rat heart.

STUDY OBJECTIVE: The aim of the study was to examine, in a whole heart preparation, the relationship between length changes in cardiac muscle and tension development and length dependent activation. DESIGN: Rat hearts were perfused by the Langendorff technique and isovolumetric pressure changes in the left ventricle, produced by increasing diastolic pressures (0, 5, 10, 15, 20, 25 mm Hg), were studied at different calcium concentrations (0.5, 1.25, 2.5, 3.75 mmol.litre-1). EXPERIMENTAL MATERIALS: 20 whole heart preparations were obtained from albino rats of either sex, weight 180-240 g (females) and 220-330 g (males). MEASUREMENTS AND MAIN RESULTS: In a comparison of ventricular diastolic upsilon systolic pressure curves, normalised with respect to maximum isovolumetric systolic pressure, there was a separation and an upward displacement of the curves with increments in calcium concentration in the perfusate. CONCLUSIONS: The results show, as in isolated preparations, that there is length dependent activation in the whole rat heart.

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Changes in performance of the surviving myocardium after left ventricular infarction in rats.

STUDY OBJECTIVE: The aim was to investigate left ventricular performance of infarcted hearts during scar formation and development of hypertrophy in the surviving myocardium. DESIGN: Hearts were perfused according to the Langendorff technique and left ventricular function curves were obtained by inserting a distensible balloon into the ventricular cavity. The isovolumetric systolic pressure was measured as diastolic pressure was changed from 0 to 25 mm Hg and during inotropic interventions produced by Ca and isoprenaline. EXPERIMENTAL MATERIALS: Hearts were obtained from albino rats of either sex, 180-250 g, killed 1, 3, 7 or 14 d after left coronary artery ligation (n = 24) or sham operation (n = 26). Normal rats (n = 6) were used as additional controls. MEASUREMENTS AND MAIN RESULTS: After infarction, there was a progressive and almost parallel displacement of the ventricular function curves toward higher diastolic pressures. The positive chronotropic response to isoprenaline was similar in infarcted and non-infarcted hearts. The inotropic response to Ca and isoprenaline, however, was significantly depressed in the infarcted hearts throughout the observation period. CONCLUSIONS: Hypertrophy in the surviving myocardium did not result in improvement of the left ventricular systolic function assessed under in vitro conditions during the first two weeks after infarction. The decreased inotropic response of the infarcted left ventricle to isoprenaline is likely to be dependent on the reduced Ca sensitivity of the surviving myocardium.

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Local activation of contraction in isolated rat ventricular myocytes.

The aim of this paper was to examine whether contraction (which is thought to result from Ca-induced release of Ca2+ from the sarcoplasmic reticulum) can propagate along a cardiac cell. The experiments were performed on isolated rat ventricular cardiac myocytes. Two techniques were used to initiate contraction in a localized region of the cell. 1) The cells were loaded with the "caged" Ca-containing compound nitr-5. A region of the cell was illuminated with ultraviolet light to increase intracellular Ca2+ concentration ([Ca2+]i) in that area. 2) The cells were superfused with a low (0.1 mM) Ca solution to abolish contraction. Ca was applied to a region of the cell by iontophoresis, and the cell was then electrically stimulated. In both cases a local contraction was produced that did not spread to the rest of the cell. Like the normal twitch, the local contraction was abolished by ryanodine, showing that it is produced by Ca release from the sarcoplasmic reticulum. In the final series of experiments, the cell was stimulated to contract in a control (1 mM Ca2+) solution. Cd2+ was then iontophoresed to a region of the cell. Only the region of the cell exposed to Cd stopped contracting. In conclusion, the above results show that the systolic rise of [Ca2+]i cannot propagate through a cell. This lack of propagation is suggested to be important in stopping a rise of [Ca2+]i in one cell spreading to the rest of the heart.

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Myocardial depression produced by unilateral nephrectomy in rats.

Previous experiments using 15 days renovascular hypertensive rats and their sham operated uninephrectomized controls suggested a decrease in contractile force developed by the papillary muscles from uninephrectomized rats. Because of the implications of such findings two sets of experiments were performed. The first set 15 days after operations, compared four groups of Wistar male rats: uninephrectomized, sham operated controls and renovascular hypertensive 1K1C and 2K1C. In the second set of experiments the time course effects of uninephrectomy was analysed. The first four groups of animals showed that mean blood pressure was normal in both controls and uninephrectomized rats, but the 1K1C and 2K1C groups were hypertensive. Contractile performance was analysed 24 hours after hemodynamic studies from isometric contracting left ventricle papillary muscles. Results showed similar force development in controls, 1K1C and in 2K1C muscles. However, the muscles from uninephrectomized rats showed a significant contractile depression when compared to the other groups, even under different inotropic interventions, like isoproterenol or post-rest potentiation. The study of the time course effects of uninephrectomy showed that the contractile activity is depressed 7, 15 and 30 days after unilateral nephrectomy. The results suggest that the mechanical depression, whatever its underlying mechanism, is located at the contractile machinery level.

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The relationship between extracellular calcium and isovolumic systolic pressure in the Langendorff-perfused rat heart.

The relationship between extracellular calcium concentration and isovolumic systolic pressure developed by left ventricles was studied in Langendorff-perfused rat hearts. At diastolic pressure lower than 15 mmHg the isovolumic systolic pressure increased when external calcium was changed from 0.5 to 1.25 mM. Pressure stabilized when external calcium was increased to 3.5 mM but then declined at 5 mM Ca2+. At higher diastolic pressures (20 and 25 mmHg) systolic pressure increased only up to 1.25 mM Ca2+, and declined with further increases in external calcium concentration. This behavior is probably related to "calcium overload" of the preparations at external calcium concentrations greater than 3.5 mM associated with a decreased perfusion pressure gradient at higher diastolic pressures.

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Effect of urea on the mechanical and electrical activity of the perfused rat heart.

The mechanical and electrical activities of Langendorff perfused isolated hearts from albino female rats were studied before and after the addition of 17 mM urea to the medium. The effect of urea on the osmolarity of the perfusing solution was evaluated by also carrying out the measurement in 17 mM saccharose. The rate of the spontaneously beating hearts did not change after urea or saccharose treatment. However, urea promoted a decrease in the left ventricle isovolumic systolic pressure and a reduction of the total QRS amplitude. Saccharose did not alter mechanical or electrical characteristics. Although the concentration of urea which reduced systolic isovolumic pressure development and altered the ECG is well below that required to modify protein conformation in vitro, our results suggest that its action could be at the sarcolemmal level.

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Effects of nifedipine on blood pressure and heart rate in conscious neurogenic hypertensive rats.

The effects of nifedipine (15 micrograms/kg, i.v.) on mean blood pressure (MBP) and heart rate were studied in neurogenic hypertensive rats (NHR), compared with renovascular hypertensive (RHR), and control (CR) rats. The maximal MBP reduction reached 32, 37 and 9%, respectively. The baseline MBP was recovered after 120, 150, and 5 min, respectively. The hypotension was not accompanied by changes in the baseline high heart rate of NHR and by tachycardia in CR and RHR groups. The data show the antihypertensive efficacy of nifedipine in both models of hypertension and indicate that under conditions of increased sympathetic tone the cardiac pacemaker cannot be easily inhibited by nifedipine.

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Right ventricular contractility depression in chronically infarcted rats.

We studied the in vitro mechanical performance of right ventricular strips obtained from male albino rats submitted to left coronary ligation for 30 days. The infarcted rats developed significant right ventricle hypertrophy together with a reduction of the isometric tension when compared to controls. The reduction was maintained even under positive inotropic intervention, i.e. the cumulative dose-response curves to calcium and adrenaline were displaced downward in parallel in the hypertrophied muscles. We conclude that after 30 days of left ventricle infarction the hypertrophied right ventricular myocardium presents a significant reduction of contractility.

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Mechanical behavior of rest contractions in cardiac muscle.

The effects of increasing rest periods on rest contractions and rest potentiation were analysed on isometric contractions of guinea pig papillary muscles at room temperature. Rest contraction amplitude is dependent on pause duration and potentiated for short pauses, which decreases as the rest period increases. their inotropic state is also dependent on the inotropic state of steady state control contractions. This statement is validated by the interdependence between control contractions and rest contractions amplitude and also because positive (5.0 mM CaCl2) and negative (0.5 mM NiCl2)inotropic interventions do not change the time course of dF/dt pause duration curves. They also show a slow activation characterized by a prolonged TTP that depends on pause duration being observed even in contractions occurring after short pauses. Rest contractions can be elicited under depolarized conditions produced by TKBa (Tyrode with high potassium and barium) and TKAdr (Tyrode with high potassium and adrenaline), showing that they are dependent on calcium influx occurring during the slow response of the cardiac action potential. The present study, carried out under depolarized conditions and in low extracellular Na+, shows that Na+ entry during the Na-dependent fast component of the action potential is necessary for the occurrence of rest potentiation. These findings suggest that the intracellular Na+, that can be exchanged by external calcium with the Na/Ca exchange mechanism, is necessary for the occurrence of the rest potentiation and to avoid the accelerated depression of the rest contractions with increasing pause duration.

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Enhanced inotropic response to isoproterenol in acute sinoaortic denervated rat heart.

The effects of acute sinoaortic baroreceptor denervation were studied in left ventricle papillary muscles obtained from rats after 3 days of sinoaortic denervation (SAD) and compared to sham-operated controls (SO). SAD and SO muscles developed similar force (F) and rate of force development (dF/dt). To test changes in beta-adrenoceptor sensitivity, isoproterenol (IPA) was used in four doses (0.1, 0.2, 0.4 and 0.8 micrograms/ml). F increased as expected, the increments tended to be larger in the SAD muscles although they were not statistically significant. dF/dt behaved in a similar way, but the increments produced by IPA were significantly larger for SAD muscles. The inotropic effects produced by pauses of increasing duration (5, 15 and 30 s) were also studied but in this case both the changes of F and dF/dt were similar. These results clearly show that there is a selective increase in beta-adrenoceptor sensitivity resulting from acute sinoaortic baroreceptor denervation.

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The effect of verapamil on potentiated rest contractions in the rat ventricular myocardium.

The effects of verapamil (0.3 to 30 microM) on potentiated rest contractions (PRC) were studied in isometric contractions of left ventricular papillary muscles of the rat. The post-rest potentiation was studied after rest periods of 5, 10, 15, 30, 60 and 120 s. Verapamil reduced the steady-state force and PRC in a dose-dependent manner. However, PRC were less depressed and the magnitude of this depression decreased as the rest period increased. The time constant of the recovery of steady state force after rest potentiation was shortened. These results indicate that the first PRC are less dependent on calcium entering the cell through the slow channels and apparently more dependent on an intracellular calcium store.

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Depression of myocardial force development after urea treatment.

Left ventricle papillary muscles from Wistar male rats were studied before, during and after urea treatment. Urea was used at a concentration (17 mM) equivalent to a plasma level of 100 mg/dl. To verify whether these effects were produced by an increase in osmolarity, the study was repeated using 17 mM saccharose. The results showed that isometric force development decreased after washing out urea from the bath but inotropic responses to isoproterenol (IPA) and increased extracellular calcium attained values similar to those obtained before urea treatment. Thus, the percentual increments due to IPA and calcium were enhanced after urea treatment. The increased osmolarity due to saccharose did not produce any change in contraction or in the responses to inotropic interventions. It is suggested that urea modifies the excitation-contraction coupling mechanism in heart muscle, reducing the force developed at the steady state control level without reducing the responses to the inotropic interventions.

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