Endogenous calcitonin gene-related peptide mediates nonadrenergic noncholinergic depressor response to spinal cord stimulation in the pithed rat.

Abstract

The role of endogenous calcitonin gene-related peptide (CGRP) in the nonadrenergic noncholinergic depressor response to spinal cord stimulation was studied in the pithed rat in vivo. Pithed rats were given hexamethonium (2 mg/kg per minute i.v.) to block autonomic outflow, and mean blood pressure was artificially maintained at approximately 100 mm Hg with methoxamine (10-15 micrograms/kg per minute i.v.). Electrical stimulation of the spinal cord at the level of the lower thoracic vertebra (T9-12) caused a fall in blood pressure in a frequency-dependent (0.5-10 Hz), voltage-dependent (2.5-50 V), and pulse duration-dependent (0.25-8 msec) manner. The heart rate did not change during the depressor response. The depressor response was long lasting, and the maximum response was elicited by stimulation at 4-6 Hz. The neurotoxin tetrodotoxin (100 micrograms/kg i.v.) abolished the depressor response to spinal cord stimulation, whereas treatment with propranolol (0.5 mg/kg per minute i.v.), atropine (0.05 mg/kg per minute i.v.), or a combination of pyrilamine (0.5 mg/kg per minute i.v.) and cimetidine (0.5 mg/kg per minute i.v.) did not affect the response. In pithed rats treated with capsaicin (total dose of 500 mg/kg s.c.), spinal cord stimulation caused a slight depressor response. Exogenous CGRP, but not acetylcholine, isoproterenol, histamine, or substance P, caused a sustained fall in blood pressure that mimicked the spinal cord stimulation-induced depressor response. Continuous infusion of CGRP[8-37] (60 nmol/kg per minute i.v.), a CGRP receptor antagonist, markedly inhibited the depressor responses not only to spinal cord stimulation but also to exogenous CGRP.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic Hyperinsulinemia Enhances Adrenergic Vasoconstriction and Decreases Calcitonin Gene-Related Peptide-Containing Nerve-Mediated Vasodilation in Pithed Rats

“…Furthermore, the augmented pressor response was more pronounced for SCS than for exogenously applied NA. In pithed rats, pressor responses to SCS have been shown to be mediated by activation of sympathetic adrenergic nerves, since an adrenergic neuron blocker (guanethidine) and autonomic ganglionic blocker (hexamethonium) abolished the response (13,16). Therefore, it is very likely that sympathetic nerve activity is augmented in the chronic hyperinsulinemic state.…”

“…After the trachea was cannulated, the animals were pithed by inserting a stainless-steel rod (1.4 mm in diameter) through the right orbit and the foramen magnum and down into the spinal cord to the level of the sacral end, and then the tip of the rod was raised to the thoracolumbar vertebrae (Th 9-12) according to the method described previously (16,17). Artificial respiration (4.5 ml/breaths/kg, 70 breaths/min) with room air was immediately started using an artificial respirator (model 683; Harvard Apparatus, South Natic, USA).…”

Pharmacology and Physiology of Perivascular Nerves Regulating Vascular Function

“…It, therefore, raises the question how the sensory nerve is able to participate in the regulation of resistance vessel tone similar to the adrenergic efferent nerve. This question was resolved by the in vivo study of Taguchi et al (19) with the pithed rat in which blood pressure was artificially elevated by methoxamine in the presence of hexamethonium, an autonomic ganglion blocker. The findings of that study showed that electrical stimulation of lower thoracic spinal cord (Th9 -12) but not upper thoracic cord (Th1 -4) caused a frequency-dependent fall in blood pressure without changing heart rate.…”

Volatile Anesthetics Inhibit Calcitonin Gene-Related Peptide Receptor-Mediated Responses in Pithed Rats and Human Neuroblastoma Cells

“…In pithed animals, there is no intrinsic sympathetic nerve activity or centrally mediated compensatory reflex (Gray et al, 1990). The depressor response during spinal cord stimulation in the pithed rat is attributed to endogenous CGRP released from CGRPcontaining nerves (Taguchi et al, 1992). Volatile anesthetics inhibit NANC depressor responses through inhibition of the CGRP depressor effect, not through inhibition of CGRP release after NANC nerve stimulation in the pithed rat model (Yoshikawa et al, 2003), suggesting that volatile anesthetics inhibit vascular responses to CGRP.…”