Blood Pressure, Hypertension and the Nervous System
Cardiovascular activities within the human body are generally facilitated by the regulation of the sympathetic and parasympathetic afferent and efferent nerve fibers. Blood pressure is the relationship between the vascular resistance and the amount of blood that the heart pumps per minute (i.e. cardiac output). Cardiac output is affected by the following factors: end-diastolic volume, cardiac muscle contraction, and heart rate. While the sympathetic nervous system controls the blood volume and the tone of venous smooth muscle (determinants of end-diastolic volume) alone, the myocardial contraction and heart rate is controlled by both sympathetic and parasympathetic regions of the autonomic nervous system (Guyenet, 2006).
Blood pressure changes according to behavior. However, the twenty four-hour mean blood pressure is closely modulated. In cases of hypertension, there is a predominant elevation in the twenty four-hour blood pressure. Hypertension could even be considered as neurogenic if there is an observed abnormality within the autonomic nervous system as opposed to the typical vascular or renal disorders. Such abnormality could come from different afferent systems such as the baroreceptors, chemoreceptors, renal afferents or in the central nervous system (Guyenet, 2006; Kanagy, 2005).
A high degree of sympathetic nerve activity is a sign of most form of hypertension in humans. This relationship between hypertension and sympathetic nerve activity has been illustrated in several studies involving the efficacy of sympathologic drugs such as α1- or β-adrenergic receptor antagonists. These adrenergic receptors bind to norepinephrine or epinephrine to regulate blood pressure via facilitation of symphathetic regulation of blood pressure. Cathecolamines are synthesized in the sympathetic neurons and chromaffin cells in the medulla. While adrenaline is primarily produced in the chromaffin cells, noradrenaline is produced within the sympathetic neurons that lack phenylethanolamine-N-methyl transferase (PNMT) (Kanagy, 2005).
Alpha 2A Adrenergic Receptors
The α2-AR family functions to inhibit the release of neurotransmitters, regulate sympathetic efferent activities, and promote vasodilation and vasoconstriction of the smooth muscles. The α2-AR family has three different subtypes that could be found in the brain, kidneys and blood vessels: α2A-, α2B-, and α2C adrenoceptors. Each subtype affects the blood pressure and sympathetic transmission differently when activated. While α2B adrenoreceptors operates to retain sodium within the blood and promote vasoconstriction, the activation of α2C adrenoreceptors results in to cold-induced vasoconstriction thereby contributing also to the regulation of the tone of the carotid artery. The activation of α2A adrenoreceptors on the other hand leads to a decrease in blood pressure and plasma noradrenaline (norepinephrine) (Kanagy, 2005). The α2A are exclusively found in large arteries while α2B are found in small arteries.
The α2A adrenoreceptor could be found in both pre- and postsynaptic nervous system particularly in the cortex and in the central coeruleus. Some studies demonstrated that the α2 agonists are facilitated by α2A receptors in mice. Similarly these agonists are also facilitated by the same receptor subtype that is found in rhesus monkeys. Using antagonists such clonidine and guanficine to induce a hypotensive response in rhesus monkeys, Franowicz and Arnsten (2002) demonstrated the potential of MK-912 and idazoxan to improve cognitive function and hypotension. Their study suggests that the α2A receptors facilitate both cognitive enhancement and hypotension. In another study, a daily dose of 3-6 mg of guanfacine has been found to lower blood pressure and reduce saliva production. Norepinephrine and plasma content in the urine were significantly lowered during 8-10 weeks of guanfacine treatment (Reid, Zambouli and Hamilton, 1980).
RVLM as the Primary Site for Hypotensive Action
The central nervous system controls and regulates vasomotor tone and blood pressure via a feedback mechanism that functions in both short-term and long-term responses. The three main control centre of blood pressure are the rostral ventrolateral medulla (RVLM), nucleus of solitary tract (NTS), and hypothalamus. The RVML is the site where almost seventy percent of adrenaline is synthesized. It is also the site in which barosensitive sympathetic efferents are regulated. Barosensitive efferents assumes many roles such as the activation of lung afferents and carotic and aortic receptor inhibitor. The discharge of barosensitive afferents also indicates that an individual is subject to mental and physical stress (Guyenet, 2006).
Most RVLM vasomotors are part of the C1 adrenergic group. This group contains tyrosine hydroxylase and phenylethanolamine N-methyltransferase that catalyzes cathecolaminergic bundles. Nerve impulses going to the RVLM neurons may be excitatory or inhibitory, and gama aminobutyric acid (GABA) receptors facilitate these impulses that could either increase or decrease arterial pressure. There is an elevation of the arterial pressure if the response to the signal is blocked by α and β adrenoreceptors, spinal cord traffic, or degradation of sympathetic nerves via 6-hydroxydopamine (6-OHDA) (Guynet, 2006).
The hypotensive response and other sympatho-inhibitory response to adrenergic agonists of α2A adrenergic receptor is due to the inhibition of is attributed to the inhibition of sympathoexcitatory reticulospinal neurons located in the RVLM (Pinterova, Kunes, and Zicha, 2011). Milner and colleagues (1999) demonstrated the relationship between α2A adrenergic receptor immunoreactivity and the C1 group neuronal activity. Their findings show that α2A adrenergic receptor immunoreactivity is localized in the perikarya. The large dendrites of the neurons constitute about seventy percent of the enzyme tyrosine hydroxylase. However, α2A adrenergic receptor found in the endosomes and Golgi complex lacks tyrosine hydroxylase immunoreactivity. The study indicates that α2A adrenergic receptor located in the C1 region of the RVLM acts as heteroreceptors on the presynaptic axons and the terminals of catecholaminergic cells. Some α2A adrenergic receptor also supplies inhibitory nerve impulses to C1 neurons or other cathecolaminergic neurons through volume transmissions.
Post-synaptic α2 Receptors on Smooth Muscle Cells
Several studies have been documented regarding the coupling mechanism of α2 adrenergic receptors vis-a-vis the signalling pathways that facilitate the contraction of vascular smooth muscles cells. In a study of Aburto and colleagues (1993), they successfully demonstrated the mechanisms of signal transduction during the contraction of smooth muscle cells using tissues of post-synaptic α2 receptors. That is; there is a dual mechanism involved in the α2 adrenoreceptor-facilitated contraction of the smooth muscle. The first mechanism in their findings suggest that in a 2.5 mM Ca2+ bathing medium, the increase in vascular tone via α2-andrenergic receptor stimulation is caused by an increase in Ca2+ and MLC phosphorylation. The second mechanism shows that such sensitivity in the increase of Ca2+ concentration is independent of myosin phosphorylation. Another study using rats to illustrate the post-synaptic mechanism of α2 receptors shows that there are three distinct post-synaptic subtypes noted for the affinity of the receptors to yohimbine. There is more than one type of α2 adrenergic receptors that could be found in the bladder of the rat. α2 receptors are also found in the aorta while α1 adrenergic receptors are found in the portal veins. These differences in post-synaptic alpha adrenergic receptors suggest that there is a lack of neuroeffector junction alpha in the andrenergic receptor of rat aorta (Ruffolo et al., 1981).
References
Aburto, T. K., Lajoie, C. & Morgan, K. G. (1993). Mechanisms of signal transduction during alpha 2-adrenergic receptor-mediated contraction of vascular smooth muscle. Circulation, 72: 778-785.
Guyenet, P. G. (2006). The sympathetic control of blood pressure. Nature Reviews. Neuroscience, 7: 335-346.
Kanagy, N. L. (2005). α2-Adrenergic receptor signalling in hypertension. Review. Clinical Science, 109: 431–437.
Milner, T. A., Rosin, D. L., Lee, A. & Aicher, S. A. (1999). Alpha2A-adrenergic receptors are primarily presynaptic heteroreceptors in the C1 area of the rat rostral ventrolateral medulla. Brain Research, 821(1): 200-211.
Pinterova, M., Kunes, J. & Zicha, J. (2011). Altered neural and vascular mechanisms in hypertension. Review. Physiological Research, 60: 381-402.
Reid, J. L., Zamboulis, C. & Hamilton, C. (1980). Guanfacine: Effects of long-term treatment and withdrawal. British Journal of Clinical Pharmacology, 10: 183S-188S.
Ruffolo, R. R. Jr., Waddell, J. E. & Yaden, E. L. (1981). Postsynaptic alpha adrenergic receptor subtypes differentiated by yohimbine in tissues from the rat. Existence of alpha-2 adrenergic receptors in rat aorta. Journal of Pharmacology and Experimental Therapeutics, 217(2): 235-240.
