Depression, medical illness, and interleukin-1beta in older cardiac patients.

OBJECTIVE: A model has been proposed in which atherosclerosis contributes to depression in later life by the effects of cytokines on central monoamine systems. We collected pilot data to test the hypothesis that interleukin-1beta (IL-1beta) is associated with depression in a cardiac patient group. METHOD: Thirty-seven subjects completed research evaluations that included depression diagnosis (Structured Clinical Interview for DSM-III-R), depressive symptom severity (Hamilton Rating Scale for Depression), medical illness burden (Cumulative Illness Rating Scale), and serum IL-1beta level measured by enzyme linked immunosorbent assay. RESULTS: Serum IL-1beta level was not significantly associated with depressive symptom severity or depression diagnosis, whether or not controlled for medical illness burden, age, and gender. IL-1beta level was significantly correlated with medical illness burden. CONCLUSIONS: We did not confirm our study hypothesis. The correlation of IL-1beta level with medical illness burden likely reflects its release as part of the "sickness response" in a wide variety of disease states. Further research using a larger sample size and a non-cardiac comparison group is warranted.

Modulation of cytosolic free calcium concentration by alpha 1-adrenoceptors in rat atrial cells.

The effects of alpha 1-adrenoceptor stimulation by phenylephrine (PE) and beta-adrenoceptor stimulation by isoprenaline (ISO) on Ca2+ current (ICa) and free intracellular Ca2+ concentration ([Ca2+]i) were studied in isolated atrial myocytes from rat hearts. PE did not significantly affect the magnitude of ICa, whereas large increases of peak ICa were observed in response to ISO. In electrically driven cells, PE evoked a concentration-dependent, gradual increase in diastolic [Ca2+]i and, initially, an increase in the height of peak [Ca2+]i transients. When the diastolic [Ca2+]i was increased to a greater extent, the amplitude of [Ca2+]i transients was decreased. Simultaneous measurements of [Ca2+]i and membrane potential showed that the increase in diastolic [Ca2+]i was associated with a depolarization of the membrane, and the greater amplitude of [Ca2+]i transients with a prolongation of the action potential (AP). The PE-induced increase in diastolic [Ca2+]i was eliminated when the cells were voltage-clamped at the original resting membrane potential (RP); under these conditions, an increase in [Ca2+]i transients was observed in response to PE. ISO usually caused larger increases in the amplitude of [Ca2+]i transients with only minor changes in diastolic [Ca2+]i. These results suggest that PE and ISO increase the amplitude of [Ca2+]i transients in rat atrium in different ways. The increase in [Ca2+]i transients in response to beta-adrenoceptor stimulation is commonly thought to be mediated by a greater conductance of voltage-dependent Ca2+ channels causing a greater Ca2+ influx and a release of more Ca2+ from the sarcoplasmic reticulum during the AP. The increase in diastolic [Ca2+]i in response to PE is probably a consequence of the depolarization of the membrane, possibly involving the voltage-dependent Na(+)-Ca2+ exchange mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)

Ca2+ current and Ca2+ transients under action potential clamp in guinea pig ventricular myocytes.

Precise characterization of the magnitude and kinetics of transsarcolemmal Ca2+ influx during an action potential (AP) is essential for a complete understanding of excitation-contraction coupling in heart. Using a voltage-clamp protocol that simulated a physiological AP (AP clamp), we characterized the properties of the Ca2+ current (ICa) in guinea pig ventricular myocytes. The AP-generated ICa showed a complex time course that was different from ICa generated by a square pulse. ICa activated rapidly during the upstroke of the AP and then partially inactivated during the plateau. The fast component of ICa reached a peak value of -7.6 +/- 1.0 pA/pF at 2.40 +/- 0.30 ms after depolarization, followed by a slow component with a peak value of -2.9 +/- 0.4 pA/pF during the plateau. ICa generated by an AP was composed of both L- and T-type Ca2+ channels. T-type Ca2+ current contributed to the fast component of ICa and L-type Ca2+ current contributed to both fast and slow components of ICa. Activation of beta-adrenoceptors enhanced ICa with a maximal effect lasting throughout the entire plateau of the AP. Measurements of cytosolic Ca2+ transients using fura-2 indicated that the ICa was responsible for triggering Ca2+ release from the sarcoplasmic reticulum. The AP clamp provides a new approach for investigation of the relationship between ICa and Ca2+ transients under more physiological conditions.

Antipsychotic pimozide is a potent Ca2+ channel blocker in heart.

The diphenylbutylpiperidine (DPBP) antipsychotic pimozide was identified as a potent new Ca2+ channel antagonist in heart. In whole-cell patch-clamp experiments, pimozide blocked Ca2+ current through L type channels of rat ventricular myocytes, in a voltage-dependent manner. At holding potentials positive to -40 mV, approximately 90% of current was blocked by 200 nM pimozide. Nearly half of this block, 48 +/- 5% (mean +/- SE, n = 5), was relieved by 5-min hyperpolarization to -100 mV. In quin2-loaded myocytes, pimozide blocked 50 mM KCl-induced increases in intracellular Ca2+ concentration [( Ca2+]i) half maximally at a concentration of 75 +/- 15 nM (n = 5). Two other DPBPs, penfluridol and fluspirilene, also blocked the KCl-induced response at similar concentrations. The contractile force of cardiac tissue was also depressed by pimozide. One micromolar pimozide reduced twitch tension in rat papillary muscles by an average of 36 +/- 8% (n = 3). These results demonstrate that the DPBPs comprise a potent new class of Ca2+ antagonists in heart, which will be useful in studying cardiac Ca2+ channels. They also suggest that these agents may have therapeutic value outside the field of psychiatry.

Spatial heterogeneity of intracellular Ca2+ concentration in nonbeating guinea pig ventricular myocytes.

The spatial distribution of intracellular Ca2+ concentration was determined by fluorescent digital imaging microscopy in fura-2-loaded quiescent cardiac myocytes isolated from guinea pig ventricle. Fluorescent ratio images revealed discrete as well as clustered bright fluorescent spots ("hot spots"), which occupied approximately 20-50% of an individual cell's area. The fluorescent intensity and the area of the hot spots were increased by agents that deplete Ca2+ in the sarcoplasmic reticulum, namely, ryanodine (20-40 nM) and caffeine (5-15 mM). However, when cells were exposed to agents that deplete mitochondrial Ca2+, such as the protonophore, carbonyl cyanide m-chlorophenyl-hydrazone (CCCP, 100-300 nM), or the inhibitor of electron transport, antimycin A (4-40 nM), the fluorescent intensity and the area of the hot spots were reduced. These results indicate that the spatial distribution of intracellular Ca2+ concentration in the ventricular myocytes of guinea pig is quite heterogeneous. The ability of CCCP and antimycin A, but not of caffeine and ryanodine, to reduce the fluorescent intensity in the hot spots implies that Ca2+ compartmentation in the mitochondria is largely responsible for the intracellular Ca2+ heterogeneity seen in the present study.

Central gamma-aminobutyric acid involvement in blood pressure control.

The role of gamma-aminobutyric acid (GABA) in central nervous system (CNS) control of arterial blood pressure has been studied by testing the effects of drugs that either counteract or enhance CNS GABAergic mechanisms while monitoring the arterial pressure of normotensive and hypertensive animals. Drugs that antagonize the effects of GABA (either directly by blocking GABA-mediated responses or indirectly by inhibiting GABA synthesis) cause an increase in arterial pressure. This effect occurs in the forebrain and leads to an increase in sympathetic outflow to the vasculature, including the coronary vessels. GABA and drugs that stimulate GABA receptors (either directly or indirectly by inhibiting GABA metabolism, competing with an endogenous inhibitor of GABA, or activating a GABA chloride ionophore) cause a decrease in arterial pressure. This effect is, in some cases, associated with respiratory depression, and it occurs in the hindbrain, especially at the intermediate area on the ventral surface of the medulla. Hypertensive animals appear to be more sensitive to the hypotensive action of these agents. These results suggest that CNS GABA may have an important role in controlling blood pressure.

Influence of vagotomy on changes in feline plasma catecholamine levels induced by occlusion of either the left or right coronary vessel.

The purpose of this study was two-fold: (1) to determine the effect of occlusion of the left anterior descending branch (LAD) of the left coronary artery or the right coronary (RC) artery on plasma catecholamine levels, and (2) to determine whether bilateral vagotomy has an effect on changes in plasma catecholamine levels evoked by coronary occlusion. Chloralose anaesthetised cats subjected to LAD occlusion exhibited increases in plasma noradrenaline and adrenaline at 3 min post-occlusion. The increases in noradrenaline and adrenaline were unrelated to the hypotension that occurred at this time. Bilateral vagotomy did not appear to alter the effect of LAD occlusion on catecholamine release into the circulation but did unmask a significant correlation between the degree of hypotension and the magnitude of increase in plasma catecholamines. Right coronary occlusion in animals with intact and sectioned vagus nerves evoked noradrenaline and adrenaline release that was significantly correlated with a fall in arterial pressure. Bilateral vagotomy per se caused an increase in baseline plasma catecholamine levels. Pretreatment with atropine mimicked the increase in baseline catecholamine levels seen with vagotomy. These results indicate that occlusion of the LAD and RC arteries increase the release of catecholamines into the circulation. The role of the vagus nerves in this response was observed only with LAD occlusion and consisted of altering the relationship between the degree of hypotension and the magnitude of increase in plasma catecholamines. That is, after vagotomy, the decrease in blood pressure following LAD occlusion was effective in causing release of catecholamines, presumably because of the hypotension causing a decrease in baroreceptor stimulation. Finally, it appeared that vagotomy increases the release of noradrenaline into the circulation by removing efferent vagal tone that inhibits noradrenaline release. This inhibitory action is mediated by activation of muscarinic receptors.

Central cardiovascular effects produced by the GABA receptor agonist drug, THIP.

In chloralose-anesthetized cats, injection of THIP (30-1000 microgram) into the fourth ventricle produced dose-dependent decreases in blood pressure and heart rate. Administration of similar doses into either the lateral and third ventricle or administration of the largest dose intravenously did not produce these effects. Microinjection of THIP (1.95 microgram) into nucleus ambiguus reversed bradycardia evoked by microinjection of bicuculline methiodide (160 ng) into this nucleus. These results confirm previous findings indicating that activation of GABA receptors in the hindbrain produces hypotension and bradycardia as well as reversal of bicuculline-induced activation of cardiac parasympathetic nerves.

Hindbrain GABA receptors influence parasympathetic outflow to the stomach.

Blockade of gamma-aminobutyric acid receptor function by direct microinjection of bicuculline into the nucleus ambiguous in cats produced a marked increase in gastric motility which was mediated by the vagus nerve. This effect was reversed by muscimol. These data indicate that the nucleus ambiguous may be an important brain site influencing gastric function and that the neurotransmitter controlling parasympathetic overflow from this nucleus to the stomach is gamma-aminobutyric acid.