Vital centers for the control of heart rate

Central integration

The medulla oblongata, specifically the medullary cardiovascular center (Fig. 8.1, inset), is the primary site of cardiovascular and baroreflex integration. In this region, the nucleus of the solitary tract (NTS) serves as the primary site for the first synapse of the baroreceptor afferents and is the key integrating site for all baroreceptor input including the cardiopulmonary baroreceptors. The NTS is a bilateral structure that receives monosynaptic inputs from afferents using glutamate as the primary neurotransmitter. The NTS integrates and relays baroreceptor afferent information via a polysynaptic pathway to other important medullary centers to control parasympathetic and sympathetic pathways to the heart and blood vessels.

The baroreflex-mediated parasympathetic pathways to the heart are regulated by a simple autonomic reflex arc. Excitatory pathways from the NTS project onto the cardioinhibitory area containing the nucleus ambiguus and dorsal motor nucleus of the vagus. The cardiac component of the baroreflex is largely mediated in these regions where activation of vagal preganglionic efferent fibers results in vagal stimulation to the heart and associated bradycardia (Fig. 8.1, inset).

The sympathetic pathways are more complex, with important control points in the NTS, caudal ventrolateral medulla (CVLM), and rostral ventrolateral medulla (RVLM). The NTS sends projections to inhibitory interneurons in the CVLM and also directly to the RVLM. Activation of GABAergic fibers in the CVLM results in inhibition of sympathoexcitatory neurons in the RVLM resulting in a reduction in MAP and sympathetic tone. The RVLM contains presympathetic neurons that project to the thoracic spinal cord and control sympathetic preganglionic fibers. Neurons in the rostral RVLM display spontaneous firing with each cardiac cycle and exhibit a variable firing frequency with each pulse of arterial pressure (Granata, 2003). Several reviews cover this material in more detail (Guyenet et al., 1990, 2010; Madden and Sved, 2003).

Much of the work on central integration has come from animal studies; however, a recent study has addressed this issue in humans. Macefield and Henderson showed that these same brain regions in resting humans are activated coincident to pulsatile changes in blood pressure and to spontaneous sympathetic nerve activity (Macefield and Henderson, 2010). Key medullary brain regions (including NTS, CVLM, and RVLM) were studied using functional magnetic resonance imaging (fMRI) during resting conditions with a simultaneous recording of MSNA. MSNA fluctuates in a phasic pattern linked to beat-to-beat blood pressure changes. As would be predicted from studies on animals, spontaneous increases in MSNA were associated with increases in neuronal activity in the presympathetic RVLM and decreases in activity in both the NTS and CVLM regions.

There is substantial central integration of inputs to the medullary cardiovascular centers including input from the arterial baroreceptors, cardiopulmonary baroreceptors, the arterial and central chemoreceptors, the cerebral cortex, the hypothalamus, and possibly others. The integration of these components determines efferent outflow of both the sympathetic and parasympathetic systems which serve to modulate MAP as part of the baroreflex circuitry.

Central Nervous System Integration

SNS and PNS outflow is coordinated in the cardiovascular centers of the medulla. The dorsolateral medulla initiates responses that raise blood pressure, and the ventromedial medulla initiates responses that lower blood pressure. Medullary cardiovascular centers receive descending input from cerebral cortex, thalamus, hypothalamus, and diencephalon (Fig. 8-12).

A variety of afferent inputs impact cardiovascular control. Arterial baroreceptors regulate both sympathetic and parasympathetic activity. Cardiopulmonary volume receptors selectively control renal sympathetic nerves and also antidiuretic hormone release. Peripheral chemoreceptors of the aortic body and carotid body mediate effects of blood gas changes on the SNS. Central chemoreceptors respond to high CO2 with general sympathetic activation, as seen in the central nervous system (CNS) ischemic response and in Cushing's reflex. The hypothalamus has some direct effects, notably body temperature—sensitive control of cutaneous circulation. Output from the cerebrum normally is pressor but occasionally is depressor, e.g., blushing and fainting. Pain fibers can elicit diverse cardiovascular responses: skin pain often is pressor and visceral pain often is depressor.

3. Reported Pharmacological Effects

TBE produces a generalized CNS depression, including both the respiratory and cardiovascular centers. In cats, the anesthetic dose by rectal administration is 300 mg/kg, but the margin of safety between anesthetic and lethal dose is narrow. Depression of respiration and circulation, together with its general unpredictability, eventually discouraged clinical use. In dogs, sedation occurs within 10–15 minutes after rectal administration and lasts for more than 1 hour, whereas in cats the depressant effects can last as long as 24 hours (Soma, 1971). In addition to rectal use in cats and dogs, TBE has been administered orally to mammals, reptiles, and birds (Mosby and Canter, 1956).

The duration of TBE anesthesia in mice varies considerably with strain and sex. Recommended TBE doses (IP) in mice range from 125 to 500 mg/kg with 1.25–2.5%) solution, with most authors recommending approximately 250 mg/kg (Buetow et al., 1999; Hogan et al., 1986; Papaioannou and Fox, 1993; Wixson and Smiler, 1997). At 250 mg/kg, surgical anesthesia lasting 16–20 minutes is produced, with good skeletal muscle relaxation, moderate respiratory depression, and full recovery reported within 40–90 minutes. In contrast, others have indicated a highly variable response to TBE, even at relatively high dosages. Koizumi et al. (2002) evaluated TBE sleep-time variation in outbred Jcl:ICR and MCH(ICR) mice; TBE was diluted to 2.5% and administered at 400 mg/kg IP. Sleep time ranged from 0 to 120 minutes, with a mean of 21.5 ± 2.2 minutes (SEM). Susceptibility of Jcl:ICR mice to TBE anesthesia was equivalent between experimental groups, but differed widely between male and female mice, with females showing more susceptibility (greater sleep time) than males. Sex differences were not observed in the inbred strains IAI, IQI, or MCH(ICR). Gardner et al. (1995) administered 400 mg/kg of 2.5% TBE IP to male Hsd:ICR mice. They reported a 3 minute onset of loss of righting reflex (range: 1–14.4 minutes), and a mean time of adequate anesthesia (based on loss of withdrawal reflex to toe pinch) of 6.9 minutes (range: 3.9–15.2 minutes), with 5 of 12 mice not reaching a surgical plane of anesthesia (retention of withdrawal response to interdigital toe pinch). They concluded that TBE produced a high degree of variability in induction times with a relatively short period of adequate anesthesia. Avila et al. (2001) administered TBE (300 mg/kg IP) to black Swiss outbred mice of mixed sex and noted that, in contrast to ketamine (250 mg/kg IP), the duration of anesthesia with TBE was sometimes too brief to conduct experiments measuring intraocular pressure lasting 30 minutes or less. Goelz (1994) concluded that TBE can produce an anesthetic state in CD-1 mice, but that it was inconsistent and often variable.

Generally speaking, cardiac performance is better in mice during TBE anesthesia than with ketamine combinations, but cardiac performance with TBE is not as repeatable over time as with the inhaled anesthetic isoflurane (Hart et al., 2001; Roth et al., 2002). Hart et al. (2001), using a combination of transthoracic echocardiography and closed chest cardiac catheterization, examined cardiac performance in male Swiss Webster mice administered xylazine/ketamine anesthesia (4.1 mg/kg xylazine, 65 mg/kg ketamine) or TBE (375 mg/kg). TBE produced less bradycardia, and less effect on cardiac loading and ventricular function than xylazine/ketamine. In male C57BL/6N mice, Roth et al. (2002) reported that 300 mg/kg TBE produced heart rates and echocardiographic fractional shortening values 15–20 minutes following IP administration similar to the inhaled anesthetic isoflurane. Midazolam/ketamine produced trends similar to, but absolute values lower than those of TBE, while xylazine/ketamine produced significant cardiac depression as evidenced by low heart rate and percent fractional shortening. Roth et al. concluded that isoflurane was the most consistent anesthetic in repeat studies at 12 days and that the anesthetic agent, the timing of echocardiographic measurements, and the genetic background were all critical variables during murine echocardiography.

A single dose of TBE before pregnancy results in impaired fertility (Kaufman, 1977), and administration following ovulation results in postimplantation parthenogenic development in (C57BL × A2G) F1 hybrid mice (Kaufman, 1975). In female Crl:CD-1(ICR)BR, Icolbm:OF-1, and Hanlbm:NMRI mice, xylazine (16 mg/kg) and ketamine (120 mg/kg), administered IP at a volume of 10 ml/kg, produces embryo transfer success rate similar to that observed with TBE (82% surviving offspring with X/K compared with 85% with TBE) (Zeller et al., 1998). In comparison, Papaioannou and Fox (1993) reported an embryo transfer success rate of 60% with TBE.

Thompson et al. (2002) investigated the effects of anesthetic agents, including TBE, on hepatic and splenic injury in ICR mice. Injury to lymphocytes and to hepatic Kupffer and endothelial cells occur within 3 hours, as indicated by marked increases in apoptosis in splenic follicles and hepatic Kupffer and endothelial cells; three to fourfold increases in serum aspartate transaminase were noted, as well. In adult male HsdBrhWH Wistar rats, TBE, but not chloral hydrate or pentobarbital, reduced TNFα´ mRNA levels in spleen (Bette et al., 2004).

Coordinating motor survival (autonomic) centres

The medulla contains the nuclei that control vital (survival) functions: the respiratory and cardiovascular centres, swallowing, blood pressure and vomiting (Box 6.3). A key nucleus involved in these functions is the nucleus of the solitary tract (NTS). It is involved in the coordination of swallowing and breathing so that one does not swallow air or inhale food or vomit. The NTS also receives afferents from stretch receptors in the lungs and from CSF chemoreceptors on the surface of the medulla. These fibres project onto neurones situated in the respiratory centres located in the medullary RF. NTS also receives information from aortic baroreceptors located in the carotid body in the carotid artery (via cranial nerve IX) and relays this information to the cardiovascular control centres (in the medullary RF) to regulate blood pressure (see Box 6.4).

Reticular formation

The reticular formation forms a polysynaptic network in the tegmentum of the brain stem. It contains the so-called vital centres (respiratory and cardiovascular) and mediates the airway-protective brain stem reflexes (e.g. cough, sneeze, gag). It also coordinates several stereotyped actions concerned with feeding, via connections with the cranial nerve nuclei. These include salivating, chewing, swallowing and vomiting. Other activities include control of: (i) bladder emptying (the micturition reflex); (ii) conjugate gaze (via the vertical and horizontal gaze centres of the midbrain and pons); and (iii) posture, muscle tone and gait.

The ascending reticular activating system (ARAS) is a diffuse projection that arises from the rostral brain stem. It receives afferents from each of the sensory systems and influences cortical excitability by release of excitatory neurotransmitters including acetylcholine and noradrenaline (Fig. 1.23). Activity in this system is influenced by general and special sensory afferents and is vital for maintaining wakefulness. For this reason, brain stem damage may result in coma (Clinical Box 1.1).

Phencyclidine

Phencyclidine (also known as PCP, angel, amoeba, butt naked) is clinically a very effective anesthetic because it does not cause depression of the respiratory and cardiovascular centers, but it may have an effect which mimics psychotic episodes. Drug users employ it for its hallucinogenic and euphoric effects. It is also a stimulant, depressant, analgesic, and anesthetic. It is smoked or snorted, taken orally in pill form, or mixed with liquid and injected. Actions involve stimulating glutamate receptors, an excitatory neurotransmitter. It is fat soluble and its intermittent release affects the hallucinogenic and euphoric properties.

In multiple drug use, PCP may commonly be dusted on tobacco or marijuana and smoked, a combination referred to as “angel dust.” A combination of PCP, heroin, and alcohol could cause intense psychoactive effects and fatality.

VII. Summary

In summary, arterial blood pressure is the main short-term regulated variable in the cardiovascular system. Sensory afferents located in the aorta and carotid arteries provide information to the brainstem cardiovascular centers related to arterial blood pressure, and sensory afferents in the heart, great vessels, and thoracic cavity provide these centers with information about “central blood volume.” This information is integrated, and under normal circumstances appropriate adjustments in cardiac output (most notably heart rate) and vascular resistance are made so that perfusion pressure remains in an acceptable range during changes in posture and with activities of daily living. In this context, orthostatic stress is one of the most profound but also routine challenges to the blood pressure–regulating system, and although this challenge is met under most circumstances, under some circumstances regulation and compensation fail and syncope occurs. The most common form of syncope is so-called vasovagal or neurocardiogenic syncope, which is marked by profound bradycardia and peripheral sympathetic withdrawal. Although the syndrome has been well described for many years, the precise initiating events are still subject to debate, but inadequate cerebral blood flow either just before or during a syncopal episode would appear to be a “final common pathway” associated with a faint, no matter the initiating series of events. Common vasovagal fainting can frequently be diagnosed with some certainty via a comprehensive history, and the simplest, safest, and generally most effective therapies appear to be education and practice of physiologically based long- and short-term counter-maneuvers. Understanding the physiology of blood pressure regulation and the pathophysiology of fainting are keys to appreciating, diagnosing, and treating common fainting in humans [4–6,8,9,24–26].

Cardiovascular effects

The major side effects of α2-adrenoceptor agonists are on the cardiovascular system. With all the agents and in all species there is marked bradycardia, due to suppression of the central cardiovascular centre and mediated through the vagus nerve. There may be a reflex component in response to the early hypertensive phase, but this is not the major cause – the bradycardia lasts long after the hypertensive phase has waned, and also occurs when peripheral antagonism has prevented the early phase rise in blood pressure (Bryant et al., 1998; Enouri et al., 2008; Honkavaara et al., 2008).

The administration of an anticholinergic drug to prevent the bradycardia induced by α2-agonists has been suggested. However, when anticholinergic agents are used in animals sedated with α2-agonists, although the fall in heart rate is prevented, there is tachycardia, and the hypertensive phase of the α2-agonist's action is enhanced (Alibhai et al., 1996). In cats sedated with xylazine, administration of glycopyrrolate further decreased cardiac output (Dunkle et al., 1986). Heart rates of normal sleeping dogs (Hall et al., 1991) and horses (Hall, unpublished data) drop to values similar to those seen in animals sedated by α2-adrenoceptor agonists. The bradycardia in the sedated animal can be over-ridden by toxaemia or by the administration of some anaesthetics. Thus, although anticholinergics may be used in emergency, it is generally accepted that their routine use is not advisable.

The effects of α2-agonists on arterial blood pressure depend on the relative effects of the central and peripheral stimulation. There is often an initial hypertensive phase, the extent and duration of which depend on the particular drug, its dose, route of administration, and the species of animal concerned. The hypertensive phase is followed by a more prolonged period of lower blood pressure, again dependent on the drug, route of administration and the species of animal. Cardiac output falls as a result of the bradycardia. The circulation appears to be slowed; the veins take time to fill and IV anaesthetic agents take longer than expected to exert their effects. The exact state of the peripheral circulation is more complicated and dose dependent. During the early phase of arterial hypertension with bradycardia, peripheral resistance is increased, presumably through vasoconstriction. How long this poor peripheral perfusion lasts is difficult to ascertain, as blood pressure may fall below pre-dosing values as a result of the bradycardia. In the later hypotensive phase, peripheral resistance is reduced.

Vasconstriction may result in changes in organ blood flow which may in turn have other effects. Cerebral vasoconstriction induced by α2-agonists may lead to a decrease in intracranial pressure (McCormick et al., 1993). Administration of α2-agonists decreases intraocular pressure (Trim et al., 1985; Virkkila et al., 1994).

The question of the possible direct effects of α2-agonists on the myocardium is an open one. There have been anecdotal reports of animals which were in a very excited state at the time of xylazine or detomidine administration suffering sudden cardiac arrest and the suggestion has been made that this drug might sensitize the heart to epinephrine-induced arrhythmias. Muir & Piper (1977) showed this to be the case in halothane anaesthetized dogs, but other studies have failed to show the same effect in horses, or with the other α2-agonist agents (Pettifer et al., 1996). α2-Adrenoceptors are present in the coronary vessels but, despite the potential for reduced myocardial blood flow, in humans, the use of α2-agonist agents during cardiac surgery reduces the overall morbidity and mortality from the procedures (Wijeysundera et al., 2009).

Arterial Baroreceptor Reflex

Arterial blood pressure is maintained within narrow limits by a negative feedback system called the arterial baroreceptor reflex.35,36 Its major components of this system are (Figure 21-15, A): (1) an afferent limb composed of baroreceptors in the carotid artery and aortic arch and their respective afferent nerves, the glossopharyngeal and vagus nerves; (2) cardiovascular centers in the medulla that receive and integrate sensory information; and (3) an efferent limb composed of sympathetic nerves to the heart and blood vessels and the parasympathetic (vagus) nerve to the heart. Figure 21-15, B, presents the neural relationships of the arterial baroreceptor reflex.37 Baroreceptors are stimulated by stretch of the vessel wall by increased transluminal pressure. Impulses originating in the baroreceptors tonically inhibit discharge of sympathetic nerves to the heart and blood vessels, and tonically facilitate discharge of the vagus nerve to the heart. A rise in arterial pressure reduces baroreceptor afferent activity, resulting in further inhibition of the sympathetic and facilitation of parasympathetic output. This produces vasodilation, venodilation, and reductions in stroke volume, heart rate, and cardiac output, which combine to normalize arterial pressure. A decrease in arterial pressure has opposite effects. The cardiovascular centers in the medulla are also under the influence of neural influences arising from the arterial chemoreceptors, hypothalamus, and cerebral cortex, and of local changes in PCO2 and PO2.