Regulatory processes interacting to maintain hepatic blood flow constancy: Vascular compliance, hepatic arterial buffer response, hepatorenal reflex, liver regeneration, escape from vasoconstriction

In 19 decerebrate and artificially ventilated cats, we analyzed, with a power spectral methodology, the variability simultaneously present in R-R interval and in thoracic preganglionic sympathetic outflow. R-R interval was characterized, as already described in humans and other experimental preparations, by two rhythmic components occurring at a frequency of about 0.1 Hz (low-frequency, LF) and at one corresponding to respiratory rate (high-frequency, HF) which, in these experiments, was set at 0.32 Hz. Two similar rhythmic components were also present in the sympathetic discharge. Arterial pressure changes were produced by aorta or vena cava flow obstruction in order to produce reflex responses in sympathetic activity. Reflex sympathetic excitations induced an increase in the LF component of both R-R interval and sympathetic discharge variabilities, while the HF components were simultaneously reduced. In contrast, reflex sympathetic inhibitions were accompanied by a decrease in LF components of both variability signals, while the HF components were simultaneously increased. A significant and positive correlation was found between changes in impulse activity and the amplitude of LF component of either R-R interval or sympathetic discharge variabilities. These data support the hypothesis that the low-frequency component of R-R variability can be used as a marker of sympathetic modulation.

Spectral analysis of sympathetic discharge, R-R interval and systolic arterial pressure in decerebrate cats.

The Hepatic circulation is unique among vascular beds. The most obvious unique features include the dual vascular supply; the mechanism of intrinsic regulation of the hepatic artery (the hepatic arterial buffer response); the fact that portal blood flow, supplying two thirds of liver blood flow, is not controlled directly by the liver; the fact that 20% of the cardiac output rushes through the most vascularized organ in the body, driven by a pressure gradient of only a few millimeters of mercury; the extremely distensible capacitance and venous resistance sites; the unidirectional acinar blood flow that regulates parenchymal cell metabolic specialization; and the high concentration of macrophagic (Kupffer) cells filtering the blood. The liver is the only organ reported to have regional blood flow monitored by the autonomic nervous system. This mechanism, when dysfunctional, accounts for the hepatorenal syndrome and offers a mechanistic therapeutic target to treat this syndrome. The trigger for liver regeneration is dependent on hepatic hemodynamics so that chronic liver blood flow regulates liver cell mass. In severe liver disease, the whole body circulation is reorganized, by forming portacaval shunts, to accommodate the increased intrahepatic venous resistance. These shunts protect the venous drainage of the splanchnic organs but lead to loss of major regulatory roles of the liver. The development of knowledge of the hepatic vasculature is presented from a historical perspective with modern concepts summarized based on the perspective of the author’s four decades of devotion to this most marvelous of organs.

Hepatic Circulation: Physiology and Pathophysiology

Administration of adenosine results in profound hypotension without the expected activation of reflex sympathetic and renin mechanisms in most animal models. This action can be explained by the vasodilatory and neuroinhibitory effects of adenosine. It is generally considered an inhibitory neuromodulator because it inhibits the release of virtually all neurotransmitters studied and produces hyperpolarization of neurons. In contrast, adenosine produces vasoconstriction of some vascular beds, including the renal and pulmonary circulations. Renal vasoconstriction is caused by activation of A1 receptors and involves an interaction with angiotensin II. In other vascular beds adenosine releases eicosanoids, including thromboxane, also resulting in vasoconstriction. Adenosine-induced vasoconstriction is transient and species dependent. Neither the receptor type, the molecular mechanisms of these actions, nor their significance to pathophysiological processes have been defined. Adenosine also has an apparent excitatory effect in the nucleus tractus solitarii. Microinjections of adenosine into this brain stem nucleus lead to decreased sympathetic tone and hypotension similar to those produced by the excitatory amino acid glutamate. The mechanism that explains this action has recently been explored and involves the release of glutamate by adenosine. Adenosine also stimulates afferent fibers mediating sympathetic activity, including renal and myocardial afferent nerves, and carotid and aortic chemoreceptors. Afferent nerve activation seems to be more pronounced in humans and may explain most of the cardiovascular and respiratory actions of adenosine in this species. Finally, animal studies suggest that endogenous adenosine plays a role in the regulation of the baroreceptor reflex and restrains the full expression of renin-dependent hypertension.

Contrasting excitatory and inhibitory effects of adenosine in blood pressure regulation.

Persistent excessive sympathetic activation greatly contributes to the pathogenesis of chronic heart failure (CHF) and hypertension. Cardiac sympathetic afferent reflex (CSAR) is a sympathoexcitatory reflex with positive feedback characteristics. Humoral factors such as bradykinin, adenosine and reactive oxygen species produced in myocardium due to myocardial ischaemia stimulate cardiac sympathetic afferents and thereby reflexly increase sympathetic activity and blood pressure. The CSAR is enhanced in myocardial ischaemia, CHF and hypertension. The enhanced CSAR at least partially contributes to the sympathetic activation and pathogenesis of these diseases. Nucleus of the solitary tract (NTS), hypothalamic paraventricular nucleus (PVN) and rostral ventrolateral medulla are the most important central sites involved in the modulation and integration of the CSAR. Angiotensin II, AT1 receptors and NAD(P)H oxidase-derived superoxide anions pathway in the PVN are mainly responsible for the enhanced CSAR in CHF and hypertension. Central angiotensin-(1-7), nitric oxide, endothelin, intermedin, hydrogen peroxide and several other signal molecules are involved in regulating CSAR. Blockade of the CSAR shows beneficial effects in CHF and hypertension. This review focuses on the anatomical and physiological basis of the CSAR, the interaction of CSAR with baroreflex and chemoreflex, and the role of enhanced CSAR in the pathogenesis of CHF and hypertension.

Cardiac sympathetic afferent reflex and its implications for sympathetic activation in chronic heart failure and hypertension

Recent clinical observations suggest that adenosine may produce cardiac pain; even though the mechanisms involved still need defining, one of the most convincing hypotheses seems to be a direct adenosine stimulation of the sympathetic nerve endings present in the myocardium. In 10 decerebrate and artificially ventilated cats, single sympathetic afferent fibres innervating the left ventricle were isolated from the third white thoracic ramus communicans of the left sympathetic chain. After locations of the fibre receptor field on the cardiac surface, we evaluated the effects of the local epicardial application of adenosine (0.1, 1 and 10 mg/ml) on the nervous discharge activity. These results were compared with those obtained by application of bradykinin, a potent natural algogenic substance which activates sympathetic afferents, and by a mechanical stimulus such as a slight increase of systolic arterial pressure (46 +/- 6% from 113 +/- 18 mmHg) induced by partial occlusion of the thoracic aorta. In particular, adenosine (1 mg/ml) elicited a significant increase in impulse activity (from 0.11 +/- 0.02 to 0.36 +/- 0.06 imp/0.1 s) with a latency of 16 +/- 2 s. Bradykinin application (20 micrograms/ml), in the same way, produced a significant increase in impulse activity (from 0.11 +/- 0.01 to 0.86 +/- 0.16 imp/0.1 s) with a latency of 8 +/- 1 s. Neither situation showed significant hemodynamic changes. An increased neural discharge (from 0.11 +/- 0.02 to 0.26 +/- 0.04 imp/0.1 s) was also observed during aortic occlusion. After purinergic receptor blockade by aminophylline (5 mg/kg, iv), the response to adenosine was no longer observed, while responses to bradykinin and aortic occlusion were unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

The excitatory effect of adenosine on the discharge activity of the afferent cardiac sympathetic fibers

We recorded discharge activity of 45 single neurons located in the rostral ventrolateral medulla (n = 21), lateral tegmental field (n = 10) and caudal raphe (n = 14) nuclei in baroreceptor-denervated decerebrate cats (n = 27). Autoregressive spectral analysis was performed on neuronal activity and systolic arterial pressure (SAP). The discharges of the recorded neurons were correlated to 2- to 6 Hz oscillations or 10 Hz rhythm present in sympathetic neural discharge. A low frequency (LF) oscillation (0.12 +/- 0.02 Hz) was observed in 25 (55%) units. The same rhythmicity was found in SAP variability in 25 of 45 (55%) recordings. In 21 of these cases the LF in SAP variability was highly correlated to LF in neural activity. Moreover, 32 out of 45 (71%) neurons showed a higher rhythm (HF; 0.34 +/- 0.06 Hz) related to the ventilation rate. These data demonstrate the presence of an LF oscillation in the discharge of single medullary neurons, involved in the regulation of cardiovascular system. This LF component was similar to that detectable in the spectral analysis of SAP variability, thus supporting the hypothesis of a central origin of this rhythm, largely independent of baroreceptor input.

[Role of low-frequency neuronal activity in the medulla in the regulation of the cardiovascular system].

A signal processing technique is proposed for the extraction of short-term variability rhythms from the discharge of cardiac sympathetic fibers In decerebrated and artificially ventilated cats the impulse activity of cardiac preganglionic fibers was recorded in a closed chest preparation together with ECG, arterial pressure, and respiration The neural signal was fed into an analog spike counter, obtaining a stepwise count signal Beat-by-beat variability series were extracted; the spike-count signal is sampled once per cardiac cycle convolving with a FIR low-pass filter The presence of low-frequency and high-frequency rhythms was demonstrated by parametric spectral and cross-spectral analyses >

F Lombardi

Papers

The excitatory effect of adenosine on the discharge activity of the afferent cardiac sympathetic fibers

[Role of low-frequency neuronal activity in the medulla in the regulation of the cardiovascular system].

Signal analysis of rhythmical discharge in cardiac preganglionic fibers and of heart rate variability

sympathovagal balance during graded orthostatic tilt Power spectrum analysis of heart rate variability to assess the changes in