Heart rate, control parasympathetic

Gehrmann J, Meister M, et al. 2002. Impaired parasympathetic heart rate control in mice with a reduction of functional G protein beta-gamma-subunits. Am J Physiol Heart Circ Physiol 282 H445-H456. 

Although blood pressure control follows Ohm s law and seems to be simple, it underlies a complex circuit of interrelated systems. Hence, numerous physiologic systems that have pleiotropic effects and interact in complex fashion have been found to modulate blood pressure. Because of their number and complexity it is beyond the scope of the current account to cover all mechanisms and feedback circuits involved in blood pressure control. Rather, an overview of the clinically most relevant ones is presented. These systems include the heart, the blood vessels, the extracellular volume, the kidneys, the nervous system, a variety of humoral factors, and molecular events at the cellular level. They are intertwined to maintain adequate tissue perfusion and nutrition. Normal blood pressure control can be related to cardiac output and the total peripheral resistance. The stroke volume and the heart rate determine cardiac output. Each cycle of cardiac contraction propels a bolus of about 70 ml blood into the systemic arterial system. As one example of the interaction of these multiple systems, the stroke volume is dependent in part on intravascular volume regulated by the kidneys as well as on myocardial contractility. The latter is, in turn, a complex function involving sympathetic and parasympathetic control of heart rate intrinsic activity of the cardiac conduction system complex membrane transport and cellular events requiring influx of calcium, which lead to myocardial fibre shortening and relaxation and affects the humoral substances (e.g., catecholamines) in stimulation heart rate and myocardial fibre tension. 

The autonomic nervous system exerts the primary control on heart rate. Because the sympathetic and parasympathetic systems have antagonistic effects on the heart, heart rate at any given moment results from the balance or sum of their inputs. The SA node, which is the pacemaker of the heart that determines the rate of spontaneous depolarization, and the AV node are innervated by the sympathetic and parasympathetic systems. The specialized ventricular conduction pathway and ventricular muscle are innervated by the sympathetic system only. 

The resting heart rate of 60-80 bpm results from dominant vagal tone. The intrinsic rate generated by the sinoatrial (SA) node is 110 bpm. Control of heart rate is, therefore, through the balance of parasympathetic and sympathetic activity via the vagus and cardioaccelerator (T1-T5) fibres, respectively. 

Perhaps the most prominent and well-studied class of synthetic poisons are so-called cholinesterase inhibitors. Cholinesterases are important enzymes that act on compounds involved in nerve impulse transmission - the neurotransmitters (see the later section on neurotoxicity for more details). A compound called acetylcholine is one such neurotransmitter, and its concentration at certain junctions in the nervous system, and between the nervous system and the muscles, is controlled by the enzyme acetylcholinesterase the enzyme causes its conversion, by hydrolysis, to inactive products. Any chemical that can interact with acetylcholinesterase and inhibit its enzymatic activity can cause the level of acetylcholine at these critical junctions to increase, and lead to excessive neurological stimulation at these cholinergic junctions. Typical early symptoms of cholinergic poisoning are bradycardia (slowing of heart rate), diarrhea, excessive urination, lacrimation, and salivation (all symptoms of an effect on the parasympathetic nervous system). When overstimulation occurs at the so-called neuromuscular junctions the results are tremors and, at sufficiently high doses, paralysis and death. 

The autonomic nervous system is divided into the sympathetic and parasympathetic components, which typically exert opposing effects. The sympathetic system is involved in the fight or flight reaction (increased blood pressure and heart rate, and accommodation for increased vision, for example) that prepares the organism for stressful situations. The parasympathetic system conversely establishes a more relaxed situation, for instance, the rest period after a meal. The autonomic nervous system that is responsible for the independent control of the mechanical and secretory functions of the gastrointestinal tract is sometimes called the enteric system. 

Autonomic and hormonal control of cardiovascular function. Note that two feedback loops are present the autonomic nervous system loop and the hormonal loop. The sympathetic nervous system directly influences four major variables peripheral vascular resistance, heart rate, force, and venous tone. It also directly modulates renin production (not shown). The parasympathetic nervous system directly influences heart rate. In addition to its role in stimulating aldosterone secretion, angiotensin II directly increases peripheral vascular resistance and facilitates sympathetic effects (not shown). The net feedback effect of each loop is to compensate for changes in arterial blood pressure. Thus, decreased blood pressure due to blood loss would evoke increased sympathetic outflow and renin release. Conversely, elevated pressure due to the administration of a vasoconstrictor drug would cause reduced sympathetic outflow, reduced renin release, and increased parasympathetic (vagal) outflow. 

Recall that scopolamine, an ingredient in henbane, blocks muscarinic acetylcholine receptors. This blockade essentially removes the influence of the parasympathetic nervous system on the body. In the absence of this influence, the balance of forces is upset and the sympathetic nervous system gains the upper hand thus, your heart rate increases, your pupils dilate, salivation stops, your ability to urinate is impaired, and you become constipated overall, things get very uncomfortable. But none of this is directly lethal (unless the constipation makes one commit suicide). If you do die from an overdose of henbane, it is believed to result from either a complex series of events in your brain that lead to the loss of control of your diaphragm, causing death from asphyxiation, or from cardiac arrest. This is why the deadly nightshade is so deadly and how Shakespeare chose to kill King Hamlet with henbane. 

MR are present in, e.g. the central nervous system (CNS, for respiratory and cardiovascular activity, cognition and stress processing), peripheral nervous system (PNS, for smooth muscle contraction, control of heart rate, vasodilatation), as well as the sympathetic and parasympathetic ganglion cells [1], Five metabotropic cholinergic MR subtypes (M1-M5) were identified [1], but selectivity of TA is merely apparent [9] except for tiotropium and ipratropium [31]. 

In the peripheral nervous system, norepinephrine is an important neurotransmitter in the sympathetic branch of the autonomic system. Sympathetic nerve transmission operates below the level of consciousness in controlling physiological function of many organs and tissues of the body. The sympathetic system plays a particularly important role in regulating cardiovascular function in response to postural, exertional, thermal, and mental stress. With sympathetic activation, the heart rate is increased, peripheral arterioles are constricted, skeletal arterioles are dilated, and the blood pressure is elevated. In addition, sympathetic nerve stimulation dilates pupils inhibits smooth muscles of the intestines, bronchi, and bladder and closes the sphincters. Sympathetic signals work in balance with the parasympathetic portion of the autonomic nervous system to maintain a stable internal environment. 

Neural components that participate in the regulation of coronary blood flow include the sympathetic nervous system, the parasympathetic nervous system, coronary reflexes, and possibly, central control of coronary blood flow. Within the sympathetic system, stimulation of the stellate ganglion elicits coronary vasodilation, which is associated with tachycardia and enhanced contractility. This indirect coronary vasodilation is secondary to increased MVO2 related to increased heart rate, contractihty, and aortic pressure and occurs following stellate stimulation. The direct effect of the sympathetic system is a 1-mediated vasoconstriction at rest and during exercise. Other receptor types, 2 and have little influence on tone, whereas /32-stimulation produces a modest vasodUatory effect. Although coronary atherosclerosis may decrease blood flow secondary to obstruction, severe coronary atherosclerosis and obstruction also may increase the sensitivity of coronary arteries to the effects of aj-stimulation and vasoconstriction. 

The ANS is the major involuntary portion of the nervous system and is responsible for automatic, unconscious bodily functions, such as control of heart rate and blood pressure and both gastrointestinal and genitourinary functions. The ANS is divided into two major subcategories the parasympathetic autonomic nervous system (PANS) and the sympathetic autonomic nervous system (SANS). 

Baroreceptors monitor the pressure in the carotid sinuses, the aortic arch, and other large systemic arteries and increase their firing rate when the pressure increases. Their response is nonlinear and depends on whether they are exposed to mean pressure only, pulsatile pressure only, or a combination of both. Katona et al. [1967] developed a model of baroreceptor feedback that has become the basis for many CV neural control models. The output of the baroreceptor model is often passed through a low pass filter representing the CNS and then mapped back to changes in heart rate, contractility, vascular resistances, and vascular unstressed volumes through the sympathetic and parasympathetic nervous systems (Figure 10.8), for example, see Yu et al. [1990]. 

The injection of a vasoconstrictor, which causes an increase in mean arterial blood pressure, results in activation of the baroreceptors and increased neural input to the cardiovascular centers in the medulla oblongata. The reflex compensation for the drug-induced hypertension includes an increase in parasympathetic nerve activity and a decrease in sympathetic nerve activity. This combined alteration in neural firing reduces cardiac rate and force and the tone of vascular smooth muscle. As a consequence of the altered neural control of both the heart and the blood vessels, the rise in blood pressure induced by the drug is opposed and blunted. 

How did scopolamine and atropine, both components of henbane, kill King Hamlet To answer this, let s return to the autonomic nervous system. Recall the functions of the ANS that I mentioned previously. For example, it controls heart and breathing rate, intestinal motility, pupil dilation, salivation, and perspiration The two major components of the ANS, the parasympathetic and sympathetic nervous systems (see Fig. 2—4), essentially function in competition with each other to maintain... 

The heart is innervated by both sympathetic and parasympathetic nerve fibers of the autonomic nervous system. Although the heart can generate its own heartbeat independently of nervous control, stress, exercise, and physical trauma make it advantageous to adjust cardiac contraction to meet the needs at the time. Thus, the cardiovascular control system (Figure 6.20.5), which is located in the brain, controls the contractility of the myocardium (the muscle of the heart), and produces both inotrophic (force of contraction) and chronotrophic (rate of contraction) effects. 

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