Neuronal and Non-Neuronal Modulation of Sympathetic Neurovascular Transmission (2024)

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Acta Physiol (Oxf). Author manuscript; available in PMC 2012 Sep 1.

Published in final edited form as:

Acta Physiol (Oxf). 2011 Sep; 203(1): 37–45.

Published online 2011 Mar 1. doi:10.1111/j.1748-1716.2010.02242.x

PMCID: PMC3139802

NIHMSID: NIHMS260854

PMID: 21362154

Heather Macarthur, Gerald H. Wilken, Thomas C. Westfall, and Lacy L. Kolo

Abstract

Norepinephrine, neuropeptide Y and adenosine triphosphate are co-stored in, and co-released from, sympathetic nerves. Each transmitter modulates its own release as well as the release of one another; thus, anything affecting the release of one of these transmitters has consequences for all. Neurotransmission at the sympathetic neurovascular junction is also modulated by non-sympathetic mediators such as angiotensin II, serotonin, histamine, endothelin and prostaglandins through activation of specific pre-junctional receptors. In addition, nitric oxide (NO) has been identified as a modulator of sympathetic neuronal activity, both as a physiological antagonist against the vasoconstrictor actions of the sympathetic neurotransmitters, and also by directly affecting transmitter release. Here we review the modulation of sympathetic neurovascular transmission by neuronal and non-neuronal mediators with an emphasis on the actions of NO. The consequences for co-transmission are also discussed, particularly in light of hypertensive states where NO availability is diminished.

Keywords: norepinephrine, NPY, ATP, nitric oxide, endothelium, hypertension

Introduction

Sympathetic neurovascular transmission was once thought to involve the single neurotransmitter norepinephrine. As evidence grew for the involvement of other neurotransmitters in this process, investigators, in conjunction with “Dale’s principle”, initially assigned a separate nerve to the transmitter in question (Burnstock, 1976, Stjarne, 1999). Hence, adrenergic, purinergic, peptidergic, and nitrergic nerves became accepted terms in describing the neural anatomy of the vascular system. However, we now understand that the simultaneous presence of different neurotransmitters at the vascular neuroeffector junction is elegantly explained by the concept of co-transmission of different neurotransmitters from the same nerves (Burnstock, 1976). As the concept of co-transmission became established, research revealed the regulation of co-transmission to be extremely fine-tuned and exerted by a wide variety of neuronal and non-neuronal mediators. Here we review the modulation of sympathetic neurovascular transmission by neuronal and non-neuronal mediators in a variety of in vitro and in vivo preparations. We also discuss the concept of differential modulation of sympathetic co-transmission. Finally, we focus on the cross-talk that exists between the endothelial lining of the blood vessel and the sympathetic nervous system via modulation of sympathetic neurovascular transmission by endothelial mediators and specifically nitric oxide (NO). Dysfunction of NO dependent modulation of sympathetic neurovascular transmission in the development of hypertension is also discussed.

Co-transmission at the Sympathetic Neurovascular Junction

It is well established that norepinephrine, neuropeptide Y (NPY), and adenosine triphosphate (ATP) are co-localized in, and co-released from sympathetic neurons (Ekblad et al., 1984, , , De Deyn P.P., 1989).

The most well studied sympathetic neurotransmitter is norepinephrine. Upon release from the sympathetic nerve terminal, norepinephrine diffuses to the smooth muscle target cell where it activates α₁ receptors causing contraction of the smooth muscle cell and overall blood vessel constriction. Norepinephrine also activates α₂ receptors located on the sympathetic nerve terminal inhibiting its own release, as well as the release of the co-transmitters (Morris and Gibbins, 1992).

NPY is co-localized with norepinephrine in large dense core storage vesicles in the sympathetic nerve terminal (Lundberg et al., 1982, Ekblad et al., 1984, DiMaggio et al., 1985, Uddman et al., 1985, De Potter et al., 1997, Westfall, 2004). Upon sympathetic nerve stimulation both NPY and norepinephrine are released from a variety of tissues including pig spleen, pig renal artery, guinea pig heart, rat mesenteric artery, rat portal vein and rat caudal artery (Lundberg et al., 1986, Lundberg et al., 1987, , Haass et al., 1989b, Haass et al., 1989a, Westfall, 2004). NPY activates post-junctional Y₁ receptors to directly contract vascular smooth muscle as well as potentiate the contractile effects of both norepinephrine and ATP in a variety of in vitro preparations including the rat mesenteric bed, rat portal vein, rat and rabbit cerebral vessels, rat, dog and guinea pig coronary vessels and also in vivo in the pithed rat (Westfall et al., 1987b, Westfall et al., 1988, Westfall et al., 1990b, , , Zukowska-Grojec, 1995, Westfall, 2004). The development and use of specific NPY antagonists (Abounader et al., 1995, Myers et al., 1995, Leban et al., 1995, Hegde et al., 1995, Kirby et al., 1995, Malmstrom et al., 2002, Westfall, 2004) has shown that NPY is an endogenous neurotransmitter at the sympathetic neurovascular junction. NPY plays a physiological role in the regulation of vascular tone in the guinea pig vena cava and the rat mesenteric bed, and in vivo in whole pigs and the pithed rat (, , Kennedy et al., 1997, Han et al., 1998b), as well as a pathophysiological role during stress and hypertension in both rats and humans (Erlinge et al., 1992, , Zukowska-Grojec et al., 1996, Han et al., 1998a). NPY also acts pre-junctionally through Y₂ receptors inhibiting the release of all three neurotransmitters both in vitro and in vivo (Westfall et al., 1987b, Westfall et al., 1988, Westfall et al., 1990b, , , Zukowska-Grojec, 1995).

The third sympathetic co-transmitter, ATP, is co-stored with norepinephrine in small synaptic vesicles and when released, activates P_2X receptors on the vascular smooth muscle to cause vasoconstriction in the guinea pig vas deferens, rabbit portal vein, rabbit aorta and rat caudal artery (, , , Westfall et al., 1987a, Sedaa et al., 1990). Responses to sympathetic nerve stimulation that are resistant to adrenergic antagonists, have been shown to be attenuated by purinergic receptor antagonists in many in vitro preparations including guinea pig and rat vas deferens, rabbit and guinea pig mesenteric arteries and rat tail artery (Fedan et al., 1981, , , , Ishikawa, 1985, , Allcorn et al., 1986, , Hoyle, 1992, Kennedy et al., 1996). In addition to contracting vascular smooth muscle, ATP also acts pre-junctionally via P_2Y receptors to inhibit the release of norepinephrine from many preparations including rat and rabbit portal vein, rabbit pulmonary artery, dog saphenous vein, and NPY from rat pheochromocytoma cells (, Westfall et al., 1990a, Chen et al., 1997). Lower frequencies of nerve stimulation are required for the release of vesicles containing ATP and norepinephrine than for vesicles containing norepinephrine and NPY (, ). In addition, studies carried out both in vitro and in vivo demonstrate that transmission from sympathetic vasoconstrictor neurons to vascular smooth muscle involves at least three phases with distinct temporal and pharmacological properties. The mediator of the first or fast phase is ATP, the second or slow phase is norepinephrine and the very slow phase is NPY (). Each phase of sympathetic neurotransmission can be blocked with P_2x, α₁ and Y₁ antagonists respectively (Ekblad et al., 1984, , , De Deyn P.P., 1989, , ).

It should be noted that other subtypes of P₂ receptors have been found both post and pre-junctionally in different tissues (Ralevic, 2009, ), and α₂ adrenoceptors reported post-junctionally (, Francis, 1988, ), however for the sake of simplicity this review will not focus on the involvement of these receptors in sympathetic neurotransmission.

Schema 1 is a representation of co-transmission at the sympathetic neurovascular junction.

Differential Modulation of Sympathetic Neurotransmission

Differential modulation of sympathetic co-transmitter release is concluded to have occurred when a particular modulating factor (e.g. an α₂ receptor agonist) has more of an effect upon the release of one co-transmitter over another, despite the evidence that shows they are co-released together and therefore ought to be equally affected. There is good evidence for differential modulation of sympathetic co-transmitters. In several preparations, including the mouse vas deferens, rabbit ileocolic artery, the guinea pig vas deferens and guinea pig ileum, activation of pre-junctional α₂-receptors depresses the release of norepinephrine more than the release of ATP (Hammond et al., 1988, Starke et al., 1989, Driessen et al., 1993, von Kugelgen et al., 1994). Additionally, when pre-junctional α₂ receptors are blocked by yohimbine, there is a greater increase in the overflow of norepinephrine than ATP or NPY, suggesting that endogenously released norepinephrine has a greater influence on its own release than that of its co-transmitters (Todorov et al., 1996, Kolo et al., 2004a).

ATP not only inhibits sympathetic neurotransmission through activation of pre-junctional P_2y receptors, it can also facilitate transmission via P_2x receptor activation (Boehm, 1999, Boehm, 2003). Furthermore, adenosine, the final product of ATP metabolism, modulates sympathetic neurotransmission through pre-junctional inhibitory A₁ and facilitatory A₂ receptors (Cunha, 2001). The fact that nucleotidases that metabolize ATP to ADP, AMP and finally adenosine, are released from sympathetic neurons along with ATP, make the presence of A₁ and A₂ receptors particularly significant to the modulation of sympathetic neurotransmission (Westfall et al., 2000a, Westfall et al., 2000b). The difference in types and actions of receptors, as well as the activity of nucleotidases could explain some of the differential modulation that exists at the sympathetic neurovascular junction.

Blockade of pre-junctional NPY Y₂ receptors enhances α₁ receptor mediated contractile responses in the canine splenic artery indicating that endogenous NPY inhibits norepinephrine release in this tissue. In contrast α-receptor sensitive contractions evoked by transmural stimulation in the guinea pig femoral artery are not modified in the presence of the Y₂ agonist, suggesting that control of sympathetic neurotransmission differs between tissue types.

Non-Sympathetic Modulation of Neurotransmission

Sympathetic neurotransmission is also modulated by a vast array of non-sympathetic mediators as evidenced by the pre-junctional location of inhibitory muscarinic (M₂ and M₄), serotonin, prostaglandin, histamine, enkephalin, endothelin, and dopamine receptors, as well as facilitatory adrenergic (β₂), angiotensin II (Ang II) and nicotinic receptors (, Wiklund et al., 1990). Like the modulation exerted by sympathetic neurotransmitters on their own release, activation of these non-sympathetic receptors also often exhibit differential properties. For example endothelin inhibits NPY but not norepinephrine overflow from the rat mesenteric bed whereas PGI₂ and PGE₂ decrease both transmitters equally (Hoang et al., 2002, Hoang et al., 2003). On the other hand endothelin inhibits ATP, but not catecholamine or NPY, release from the PC12 cell model of sympathetic neurons (Gardner et al., 2005) and yet does inhibit norepinephrine release from the isolated rat stomach (Nakamura et al., 2003). In addition although Ang II strongly increases norepinephrine overflow from sympathetic nerves via activation of pre-junctional AT₁ receptors, NPY overflow is only weakly enhanced (Nap et al., 2003, Byku et al., 2008). Interestingly the development of hypertension augments this AT₁ response on NPY overflow illustrating the fluidity of pre-junctional modulation and its contribution to pathophysiological conditions (Byku et al., 2008).

NO and Sympathetic Neurotransmission

The ability of the vascular endothelium to directly regulate vascular smooth muscle in an autocrine/paracrine fashion through the release of vasoactive substances is well established but, as discussed above, endothelial mediators, such as endothelin and prostaglandins, can also indirectly regulate vascular function by modulating sympathetic neurotransmission. The endothelial mediator Nitric Oxide (NO) has also been shown to possess such modulating effects. Studies have shown that upon sympathetic nerve stimulation, inhibition of NO synthesis with N^ω-nitro-L-arginine results in an increase in vasoconstriction in the rat tail artery (Vo et al., 1991), in the large coronary artery of anesthetized dogs () and in the vessels of the isolated adrenal medulla of the dog (Breslow et al., 1992). It has been proposed that the inhibitory effect of NO on the action of norepinephrine is due to post-junctional physiological antagonism (Cederqvist et al., 1991, ). While the enhancement of vasoconstriction may be partly due to the removal of the relaxation normally caused by NO, there is also evidence that in the absence of NO there is an increase in the amount of norepinephrine released from sympathetic nerves. Endogenous NO has been shown to have an inhibitory effect on the stimulated release of catecholamines from sympathetic nerves and the adrenal medulla since blocking NO synthase (NOS) with either N^G-monomethyl-L-arginine or N^ω-nitro-L-arginine facilitates the release of catecholamines into the plasma (Vo et al., 1991, Navarro et al., 1994, Ward et al., 1996). In addition NOS inhibition facilitates the release of norepinephrine from adrenergic nerves in canine and guinea pig pulmonary blood vessels (Greenberg et al., 1989, Cederqvist et al., 1991), and increases adrenal catecholamine release in pithed rats (McLean et al., 1999). In contrast NO has also been shown to increase norepinephrine overflow from renal sympathetic nerves (Tanioka et al., 2002, Stegbauer et al., 2008).

One explanation for the effect of NO on catecholamine release involves a pre-junctional activation of the cGMP second messenger pathway by NO within the nerve terminal, leading to either an inhibition (Greenberg et al., 1989) or potentiation (Yamamoto et al., 1993, Yamamoto et al., 1994) of norepinephrine release. An alternative explanation is that NO directly reacts with catecholamines resulting in a decrease in biologically active neurotransmitter (Macarthur et al., 1995). Indeed it has been shown that the biological activity of catecholamines decreases after incubation with either authentic NO, or the NO donors sodium nitroprusside or diethylamine NONOate, whereas NPY and ATP remain unaltered (Macarthur et al., 1995, Kolo et al., 2004b). Other investigators have demonstrated that in a test tube incubation, authentic NO almost completely converted dopamine, epinephrine and norepinephrine to their 6-nitro-derivatives (De la Breteche M., 1994, Daveu et al., 1997). These findings suggest that NO can modulate sympathetic neurotransmission by deactivating norepinephrine after it has been released from the sympathetic neuron.

Endogenous NO diminishes norepinephrine activity at the Sympathetic Neurovascular Junction

Inhibiting endogenous NOS with L-NAME in the perfused mesenteric bed of the rat increases nerve stimulated perfusion pressure responses and norepinephrine overflow (Kolo et al., 2004b). This finding is not mimicked by inhibiting soluble guanylate cyclase with ODQ (1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one) suggesting a direct interaction of NO with the norepinephrine portion of sympathetic neurotransmission, rather than a pre-junctional inhibition of release per se (Kolo et al., 2004b). Furthermore the increase in norepinephrine overflow in the presence of a NOS inhibitor is accompanied by an α₂-receptor dependent decrease in NPY (Kolo et al., 2004b). Therefore, it appears that NO is a physiological modulator of sympathetic neurotransmission, by deactivating norepinephrine in the neurovascular junction, and placing a "brake" on both the post- and pre-junctional activity of the transmitter.

Loss of NO modulation of Sympathetic Neurotransmission in Hypertension

The enhanced overflow of norepinephrine, as well as increased perfusion pressure responses, in mesenteric preparations taken from spontaneously hypertensive rats are, at least in part, due to the loss of NO modulation of norepinephrine (Kolo et al., 2004a). The events that lead to the development of hypertension are still unclear, but increased activity of the SNS and endothelial dysfunction have both been implicated (Goldstein, 1983, Westfall et al., 1987c, Anderson et al., 1989, Esler et al., 1990, Esler et al., 1991, Grisk et al., 2002), although the precise causal mechanisms leading to increased sympathetic activityare still poorly understood.

Increased oxidative stress, evident in hypertension (Griendling et al., 1994, Zalba et al., 2000, Berry et al., 2001, ), could well be a factor in the hyperactivity of the SNS since it will lead to loss of the bioavailability of NO as a result of a reaction with superoxide anion (O₂⁻) (Nava et al., 1998, Vaziri et al., 1998, Maffei et al., 2002). This loss of NO would lead to an increase in the amount of norepinephrine within the neurovascular junction and may explain the observations of compromised NO modulation of sympathetic neurotransmission in mesenteric preparations taken from hypertensive rats (Kolo et al., 2004a). Indeed, perfusing mesenteric preparations taken from hypertensive rats with the antioxidant N-acetylcysteine reduces the overflow of norepinephrine in a NOS-dependent manner signifying a restoration of NO activity (Macarthur et al., 2008). These observations appear to confirm that the hyperactivity of the sympathetic nervous system in hypertension may be driven, in part, by oxidative stress reducing the bioavailability of NO.

Schema 2 summarizes the NO modulation of sympathetic neurovascular transmission under normotensive and hypertensive conditions.

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Schema 2

A) Schema depicts the modulation exerted by nitric oxide (NO) on the norepinephrine (NE) portion of sympathetic neurotransmission under normal conditions. NO, produced in the endothelial cell from L-Arginine, diffuses to the vascular smooth muscle where it activates soluble guanylate cyclase (sGC) leading to an increase in cGMP and vasorelaxation. NO further diffuses into the neurovascular junction where it reacts with, and deactivates, NE, thus placing a “brake” on the post and pre-junctional activity of NE. As a consequence neuropeptide Y (NPY) release is enhanced. The effect on adenosine triphosphate (ATP) is unknown. B) Schema depicts how NO-induced modulation of NE alters during developing hypertension. Increased superoxide (O₂⁻) production within the vascular smooth muscle limits the activity of NO and thus limits the amount of NO that diffuses to the sympathetic neurovascular junction. The presence of less NO effectively removes the “brake” on the activity of NE resulting in enhanced NE-induced post-junctional vasoconstriction and pre-junctional inhibition of NPY release. The effect on ATP is unknown.

The role of NO in Differential Modulation of Sympathetic Neurotransmission

The modulation by NO of sympathetic neurotransmission is a possible explanation for some of the observed differential modulation discussed earlier. Some mediators that have apparent opposite effects on co-transmitter release may in fact be indirectly affecting neurotransmission through actions on NO and other endothelial mediators. For example Ang II greatly enhances norepinephrine overflow while only moderately affecting NPY in mesenteric preparations from normotensive rats (Byku et al., 2008). This may be due to the fact that, in addition to directly enhancing norepinephrine and NPY release through AT₁ receptors on nerve terminals, Ang II also stimulates O₂⁻ production in vascular smooth muscle. This increase in O₂⁻ will decrease NO availability and further augment norepinephrine levels in the neurovascular junction that will then blunt NPY release via negative feedback mechanisms. A further example is the observation that, in addition to direct pre-junctional inhibitory effects on norepinephrine and NPY overflow, the angiotensin metabolite, Ang 1–7 decreases norepinephrine overflow from the mesenteric bed in a NOS dependent manner (Byku et al., 2010).

Conclusion

The results reviewed here demonstrate that sympathetic neurotransmission at the neurovascular junction is modulated by a variety of neuronal and non-neuronal mediators. Moreover, the modulation by endothelial mediators underlines the existence of extensive cross-talk between two major centers of vascular control, namely the endothelium of the blood vessel and the sympathetic nervous system. It may be that this cross-talk is of more significance in some organ systems than others especially when considering the effects on overall control of arterial pressure. For example, renal sympathetic nerves are of major importance given that activation of these nerves stimulates the Renin-Angiotensin-Aldosterone system (Karagiannis et al., 1994, Taddei et al., 1994, Esler et al., 2010). Endothelial mediators are also known to be of vital importance to kidney function both for salt and water handling and also in the role played by the kidney in controlling arterial pressure (). Therefore it is fair to speculate that the modulation of sympathetic neurovascular transmission in the kidney by endothelial mediators including NO may have major consequences for overall control of arterial pressure, and that dysfunction in this system may ultimately play an important role in the development of hypertension. Finally, it is of special interest to note that many direct modulators of sympathetic neurotransmission can also release NO and prostaglandins from the endothelium. This adds another dimension to the interpretation of overall modulation of sympathetic neurovascular transmission.

Acknowledgements

The authors would like to acknowledge support from the United States National Institutes of Health Grants HL61836 (HM), HL60260 (TCW), and NIGMS-GM083036 (TCW), as well as from The American Heart Association (LLK).

Footnotes

Conflict of Interest

The authors declare no conflict of interest in the content of this manuscript.

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