Aprotinin has been reported to reduce plasma levels of inflammatory cytokines associated with cardiopulmonary bypass (CPB). Because CPB is also associated with elevated levels of bacterial lipopolysaccharide (LPS) and LPS stimulates release of inflammatory cytokines from the heart we tested the hypothesis that aprotinin would inhibit cardiac release of tumor necrosis factor-α (TNF) provoked by LPS. Isolated rat hearts were perfused Langendorf style. After 30 minutes of equilibration LPS (100 ng/mL) was infused for 60 minutes. Timed samples of coronary effluent were collected at 0, 30, 60, 90, 120, and 150 minutes after the initiation of LPS for the measurement of coronary flow and the determination of TNF and cyclic AMP. Other hearts were perfused with buffer containing aprotinin [137 kallikrein-inhibiting units (KIU)/mL or 250 KIU/mL] and then infused with LPS. An additional group received forskolin (10 μM) and LPS. In hearts perfused as controls with buffer alone no TNF was detected in the coronary effluent. In hearts perfused with LPS TNF was reliably detected in the coronary effluent at 60 minutes (606 ± 450 pg/min) and increased with time to a level of 1792 ± 650 pg/min at 150 minutes. The addition of aprotinin had no significant effect on LPS-stimulated TNF release. For instance in hearts perfused with 137 KIU/mL aprotinin LPS-stimulated release at 150 minutes was 2141 ± 732 pg/min and in hearts perfused with 250 KIU/mL LPS-stimulated TNF release was 2049 ± 789 pg/min. Forskolin administration was associated with release of cyclic AMP from the heart and completely inhibited LPS-stimulated TNF release. We conclude that LPS stimulated release of TNF from the heart. Adding aprotinin to the perfusion buffer in either high or low concentrations did not attenuate LPS-stimulated cytokine release. Elevating myocardial cyclic AMP with forskolin completely attenuated LPS-stimulated TNF release.
We have previously shown that volume overload heart failure is associated with a depressed inotropic response to isoprenaline, noradrenaline, glucagon, and calcium. In these present experiments, the inotropic response of the failing heart to ouabain was examined because ouabain has a mechanism of action that is different from these other agents. The studies were conducted in dogs with heart failure resulting from an aortocaval fistula. The principal finding was that during heart failure the inotropic response to isoprenaline was markedly depressed while the inotropic response to ouabain was unaltered. These findings, coupled with our previous observations, suggest that heart failure is not associated with some common defect in the excitation-contraction coupling mechanism that reduces the response to inotropic agents. Additionally, we made the first measurements of plasma noradrenaline levels in this model of heart failure and found them to be elevated four-fold.
The effects of afferent vagal stimulation, cerebroventricular vasopressin, and intravenous nitroprusside on cerebrospinal fluid (CSF) kinin levels, mean arterial pressure (MAP), and heart rate (HR) were determined in anesthetized dogs in which a ventriculocisternal perfusion system (VP) was established. Following bilateral vagotomy, stimulation of the central ends of both vagi for 60 min significantly increased MAP and CSF perfusate levels of kinin and norepinephrine (NE). MAP was increased a maximum of 32 +/- 4 mmHg, and the rates of kinin and NE appearance into the CSF perfusate increased from 4.2 +/- 1.4 to 22.1 +/- 6.9 and from 28 +/- 5 to 256 +/- 39 pg/min, respectively. A significant correlation was found between CSF kinin and NE levels in these experiments. In other experiments the addition of arginine vasopressin to the VP system caused a significant increase in CSF perfusate kinin without affecting MAP or HR. Intravenous infusion of nitroprusside lowered MAP without affecting kinin levels in the CSF. However, on cessation of nitroprusside infusion, CSF kinin increased significantly in association with the return in MAP to predrug level. Collectively the data are consistent with the hypothesis that central nervous system kinins have some role in cardiovascular regulation, and furthermore that this role may involve an interaction between brain kinin and central noradrenergic neuronal pathways.
Summary: Alterations in T wave morphology have been quantitated in seven open chest anesthetized dogs by simultaneous recording of electrograms from 10 epicardial sites across the anterior left ventricular wall under basal conditions, following left sympathetic stimulation (LSS) at 2, 4, 8, 12, and 16 Hz and during noradrenalin infusions (NAI) of 0.125, 0.25, 0.50, and 1.0 μg/kg/min. Overdrive atrial pacing at 175 beats/min was employed and rate of rise of left ventricular pressure (dP/dt) monitored. Linear log dose-response relationships were found between both peak T amplitude and left ventricular dP/dt for NAI between 0.125 and 0.50 μg/kg/min (peak T wave amplitude 4.0 ± 0.9 to 1.4 ± 0.7 mV). Following LSS, T wave amplitude responses were highly variable both between animals and between electrode sites in individual studies. A linear log dose-response relationship was found at stimulation frequencies between 8 and 16 Hz (T amplitude 3.9 ± 1.4 to 1.8 ± 1.2 mV). Changes in QT interval were minor and inconsistent. It is concluded that changes in peak T wave amplitude may provide a useful index of regional myocardial sympathetic responsiveness following NAI. but are more variable following LSS.
Administration of propranolol directly into the anterior descending branch of the left coronary artery (LAD) resulted in a localized increase in myocardial contractile force in the area of the left ventricle perfused by the LAD. The onset of the positive inotropic response occurred within 30 seconds after drug administration with a duration of action of approximately 8 minutes and was associated with a significant increase in the coronary sinus/arterial ratio of norepinephrine. Contractile force in an area of the left ventricle perfused by the circumflex artery decreased concomitantly with the characteristic negative chronotropic action of propranolol. Pretreatment with reserpine abolished the positive inotropic effect of propranolol while ganglionic blockade with hexamethonium failed to alter the character of the response. Imipramine pretreatment not only blocked the positive inotropic effect of propranolol but resulted in an exaggerated negative inotropic effect in both areas of the left ventricle along with a significant fall in systemic arterial blood pressure. The data demonstrate that propranolol can evoke the release of norepinephrine from cardiac adrenergic nerve endings and raise the possibility that propranolol may be taken up by the amine uptake system.
Three patients with brainstem tumors had orthostatic hypotension as the major presenting manifestation. Two patients had primary tumors that involved the dorsal medulla, pons, and rostra1 spinal cord; one was a malignant astrocytoma and the other a hemangioblastoma. The third patient had an oat cell carcinoma of the lung with subependymal spread to the medulla, pons, hypothalamus, and thalamus. Evaluation of baroreceptor function in the patient with the malignant astrocytoma showed a defect in the efferent sympathetic limb of the baroreceptor reflex arc.
