Effects of clonidine on the reflex cardiovascular responses and release of substance P during muscle contraction.

Abstract

The effects of microdialyzing clonidine into the L-7 dorsal horn on the cardiovascular responses, renal sympathetic nerve activity (RSNA), and release of substance P (SP) evoked by static contraction of the triceps surae muscle were studied using anesthetized cats. A microdialysis probe was inserted into the spinal cord ipsilateral to the muscle being contracted or stretched. Contraction, evoked by stimulation of the distal ends of the cut L-7 and S-1 ventral roots for 1 minute, increased mean arterial pressure (MAP), heart rate (HR), and RSNA by 48+6 mm Hg, 18+2 beats per minute, and 66±5%, respectively. Passive stretch of the same muscle for 1 minute also increased MAP, HR, and RSNA by 51±6 mm Hg, 17+2 beats per minute, and 50+3%, respectively. . These results demonstrate that stimulation of a2-adrenergic receptors in the L-7 dorsal horn attenuates the cardiovascular responses and RSNA changes to static contraction and passive stretch. This attenuation by clonidine appears not to be mediated through presynaptic inhibition of SP release. (Circ Res. 1994;75:567-575.) Key Words * exercise pressor reflex * passive stretchsympathetic nerve activity * a2-adrenergic receptor .yohimbine Static muscle contraction evokes increases in arterial pressure (AP), heart rate (HR), cardiac contractility, and renal sympathetic nerve activity (RSNA) in anesthetized cats.1-6 These changes are a reflex arising from the contracting muscle, which is commonly known as the "exercise pressor reflex."4 The reflex cardiovascular and sympathetic nerve activity responses are initiated by a contraction-induced activation of thinly myelinated (group III) and unmyelinated (group IV) muscle afferents. The majority of the group III afferents display mechanosensitivity; ie, their endings respond to mechanical stimuli, whereas the majority of the group IV afferents respond to metabolic changes.7,8 The dorsal horn of the spinal cord is the site of the first synapse of the majority of group III and group IV muscle afferents.9'10 Thus, this region may play an important role in the reflex cardiovascular changes observed during muscle contraction. A variety of neurotransmitters and/or neuromodulators of group III and group IV afferents have been identified in the dorsal

Cardiovascular responses to static exercise in conscious cats: effects of intracerebroventricular injection of clonidine.

“…This result suggests that a2-adrenoceptors in the brain do not have a tonic influence on the neurons mediating the cardiovascular responses to static exercise in this preparation. This effect correlates with previous studies in which there was no tonic effect of a2-adrenoceptors in the brain (Williams et al 1987), or in the spinal cord (Ally et al 1994) regulating the cardiovascular responses to static muscle contraction. In addition, the dose of yohimbine was sufficient to inhibit the decrease in HR and blood pressure evoked by subsequent administration of 5 jug of clonidine.…”

“…Therefore, activation of the a2 -adrenergic system in the brain may reduce sympathetic nerve activity and, in turn, attenuate the reflex cardiovascular responses to static exercise. Previous reports have demonstrated that clonidine attenuates the reflex pressor response during static contraction either when injected intravenously, intracisternally, intrathecally or into the cerebral aqueduct, or when microdialysed into the L7 dorsal horn of the spinal cord of chloraloseanaesthetized cats (Williams, 1986;Williams, Blevins & Paul, 1987;Hill & Kaufman, 1991;Ally, Meintjes, Mitchell & Wilson, 1994). A recent report suggested that intravenously administered clonidine reduces baseline values of arterial pressure, HR and renal sympathetic nerve activity, and also attenuates the centrally induced increases in arterial blood pressure and renal sympathetic nerve activity, but not the HR responses to isometric exercise by conscious cats (Matsukawa, Wilson, Wall & Mitchell, 1995).…”

Glutamatergic receptor dysfunction in spinal cord contributes to the exaggerated exercise pressor reflex in heart failure

“…Several excitatory and inhibitory neurotransmitters or neuromodulators have been identified to be involved in the modulation of the EPR at the level of the dorsal horn, including glutamate, substance P, serotonin, ACh, ␣ 2 -adrenergic receptors, opiates, vasopressin, and oxytocin (2,12,17,19,27). Of these neurotransmitters or neuromodulators, the excitatory amino acid glutamate has been identified as a primary mediator of the EPR at the spinal cord level (8 -11, 38).…”