Effects of cardiac preload reduction and dobutamine on hepatosplanchnic blood flow regulation in porcine endotoxemia

Insufficient cardiac preload and impaired contractility are frequent in early sepsis. We explored the effects of acute cardiac preload reduction and dobutamine on hepatic arterial (Qha) and portal venous (Qpv) blood flows during endotoxin infusion. We hypothesized that the hepatic arterial buffer response (HABR) is absent during preload reduction and reduced by dobutamine. In anesthetized pigs, endotoxin or vehicle (n = 12, each) was randomly infused for 18 h. HABR was tested sequentially by constricting superior mesenteric artery (SMA) or inferior vena cava (IVC). Afterward, dobutamine at 2.5, 5.0, and 10.0 μg/kg per minute or another vehicle (n = 6, each) was randomly administered in endotoxemic and control animals, and SMA was constricted during each dose. Systemic (cardiac output, thermodilution) and carotid, splanchnic, and renal blood flows (ultrasound Doppler) and blood pressures were measured before and during administration of each dobutamine dose. HABR was expressed as hepatic arterial pressure/flow ratio. Compared with controls, 18 h of endotoxin infusion was associated with decreased mean arterial blood pressure [49 ± 11 mmHg vs. 58 ± 8 mmHg (mean ± SD); P = 0.034], decreased renal blood flow, metabolic acidosis, and impaired HABR during SMA constriction [0.32 (0.18-1.32) mmHg/ml vs. 0.22 (0.08-0.60) mmHg/ml; P = 0.043]. IVC constriction resulted in decreased Qpv in both groups; whereas Qha remained unchanged in controls, it decreased after 18 h of endotoxemia (P = 0.031; constriction-time-group interaction). One control and four endotoxemic animals died during the subsequent 6 h. The maximal increase of cardiac output during dobutamine infusion was 47% (22-134%) in controls vs. 53% (37-85%) in endotoxemic animals. The maximal Qpv increase was significant only in controls [24% (12-47%) of baseline (P = 0.043) vs. 17% (-7-32%) in endotoxemia (P = 0.109)]. Dobutamine influenced neither Qha nor HABR. Our data suggest that acute cardiac preload reduction is associated with preferential hepatic arterial perfusion initially but not after established endotoxemia. Dobutamine had no effect on the HABR.

Synaptic regulation of spike firing in interneurons of the striatum in vivo

The striatum, the major input nucleus of the basal ganglia, is numerically dominated by a single class of principal neurons, the GABAergic spiny projection neuron (SPN) that has been extensively studied both in vitro and in vivo. Much less is known about the sparsely distributed interneurons, principally the cholinergic interneuron (CIN) and the GABAergic fast-spiking interneuron (FSI). Here, we summarize results from two recent studies on these interneurons where we used in vivo intracellular recording techniques in urethane-anaesthetized rats (Schulz et al., J Neurosci 31[31], 2011; J Physiol, in press). Interneurons were identified by their characteristic responses to intracellular current steps and spike waveforms. Spontaneous spiking contained a high proportion (~45%) of short inter-spike intervals (ISI) of <30 ms in FSIs, but virtually none in CINs. Spiking patterns in CINs covered a broad spectrum ranging from regular tonic spiking to phasic activity despite very similar unimodal membrane potential distributions across neurons. In general, phasic spiking activity occurred in phase with the slow ECoG waves, whereas CINs exhibiting tonic regular spiking were little affected by afferent network activity. In contrast, FSIs exhibited transitions between Down and Up states very similar to SPNs. Compared to SPNs, the FSI Up state membrane potential was noisier and power spectra exhibited significantly larger power at frequencies in the gamma range (55-95 Hz). Cortical-evoked inputs had faster dynamics in FSIs than SPNs and the membrane potential preceding spontaneous spike discharge exhibited short and steep trajectories, suggesting that fast input components controlled spike output in FSIs. Intrinsic resonance mechanisms may have further enhanced the sensitivity of FSIs to fast oscillatory inputs. Induction of an activated ECoG state by local ejection of bicuculline into the superior colliculus, resulted in increased spike frequency in both interneuron classes without changing the overall distribution of ISIs. This manipulation also made CINs responsive to a light flashed into the contralateral eye. Typically, the response consisted of an excitation at short latency followed by a pause in spike firing, via an underlying depolarization-hyperpolarization membrane sequence. These results highlight the differential sensitivity of striatal interneurons to afferent synaptic signals and support a model where CINs modulate the striatal network in response to salient sensory bottom-up signals, while FSIs serve gating of top-down signals from the cortex during action selection and reward-related learning.

Inhibitory regulation of dendritic activity in vivo

The spatiotemporal control of neuronal excitability is fundamental to the inhibitory process. We now have a wealth of information about the active dendritic properties of cortical neurons including axonally generated sodium action potentials as well as local sodium spikelets generated in the dendrites, calcium plateau spikes, and NMDA spikes. All of these events have been shown to be highly modified by the spatiotemporal pattern of nearby inhibitory input which can drastically change the output firing mode of the neuron. This means that particular populations of interneurons embedded in the neocortical microcircuitry can more precisely control pyramidal cell output than has previously been thought. Furthermore, the output of any given neuron tends to feed back onto inhibitory circuits making the resultant network activity further dependent on inhibition. Network activity is therefore ultimately governed by the subcellular microcircuitry of the cortex and it is impossible to ignore the subcompartmentalization of inhibitory influence at the neuronal level in order to understand its effects at the network level. In this article, we summarize the inhibitory circuits that have been shown so far to act on specific dendritic compartments in vivo.