Chemosensitive cardiopulmonary afferents and the haemodynamic response to simulated haemorrhage in conscious rabbits

Abstract

41 We set out to test whether the signal from the heart that initiates the decompensatory phase of acute central hypovolaemia in conscious rabbits is conveyed by chemosensitive afferents. 2 Haemorrhage was simulated by inflating an inferior vena caval cuff so that cardiac output fell at a constant rate of 8% of its baseline level per min. After sham or vehicle treatments the haemodynamic response had two phases. In the first, sympathoexcitatory, phase systemic vascular conductance fell in proportion to cardiac output so that mean arterial pressure fell by only 13 mmHg. When cardiac output had fallen by -50% a second, sympathoinhibitory, phase supervened. There was an abrupt rise of systemic vascular conductance and an abrupt fall of mean arterial pressure, to -40 mmHg. 3 The sympathoinhibitory phase was prevented by injection of the 6-opioid antagonist ICI 174864 (100-300nmol) or the ,u-opioid agonist H-Tyr-D-Ala-Gly-MePhe-NH(CH2)20H (DAMGO) (100-300pmol) into the fourth cerebral ventricle. 4 5-HT3 receptors on myocardial or pulmonary afferents were excited by injection of ascending doses of phenylbiguanide (6.25-400pg) into the left or right atrium respectively. Neuronal-type nicotinic cholinoceptors in the epicardium were excited by injecting ascending doses of nicotine bitartrate (6.25-400,g) into the pericardial sac. Each of these treatment regimens caused a reproducible, dose-dependent, fall in mean arterial pressure. Intravenous injection of the 5-HT3 antagonist MDL 72222 (1.0 mg kg-1) markedly attenuated the responses to phenylbiguanide. Intrapericardial injection of the neuronal-type nicotinic cholinoceptor antagonist mecamylamine HCl (0.1 mgkg-') abolished the effects of intrapericardial nicotine. Neither of these treatments affected the haemodynamic response to simulated haemorrhage. 5Injection into the fourth ventricle of ICI 174864 (100-300nmol) or DAMGO (100-300pmol) had no effects on the dose-response relationships for phenylbiguanide or nicotine. 6 We conclude that the cardiac afferents responsible for initiating the sympathoinhibitory phase of simulated haemorrhage in conscious rabbits do not correspond to the populations of phenylbiguanidesensitive cardiopulmonary afferents, nor to the population of nicotine-sensitive epicardial afferents. We also conclude that the reflex haemodynamic responses to atrial phenylbiguanide and intrapericardial nicotine do not depend on an endogenous 5-opioid receptor mechanism in the brainstem, and are not affected by exposure of the brainstem to exogeneous DAMGO.

The Effects of Primary Thoracic Blast Injury and Morphine on the Response to Haemorrhage in the Anaesthetised Rat

“…Morphine modified the cardiovascular response to haemorrhage after blast, resulting in an initial maintenance of arterial pressure and a tachycardia, with abolition of the bradycardia normally associated with haemorrhage. It has previously been shown that morphine and other m opioid receptor agonists attenuate the depressor reflex associated with severe haemorrhage (Evans et al 1989;Evans & Ludbrook, 1990, 1991Ohnishi et al 1997). Therefore, the most likely explanation is that the response to blast augmented the depressor reflex associated with severe haemorrhage, which overrode the baroreflex, leading to an early fall in blood pressure and bradycardia.…”

“…However, it is unlikely that morphine is acting within the spinal cord to block the depressor response to severe haemorrhage since it is blockade, rather than activation, of m receptors at this site that attenuates the depressor response to blood loss (Ang et al 1999). Potential sites of action for morphine include the nucleus tractus solitarius, an afferent nucleus for a number of cardiovascular reflexes, the rostral ventrolateral medulla and the nucleus ambiguus (Evans et al 1989;Evans & Ludbrook, 1990, 1991. Since morphine attenuated both the bradycardia and hypotension during severe haemorrhage it is possible that it is acting early in the reflex pathway, before the sympathetic and vagal limbs diverge.…”

“…Data are mean ± S.E.M. depressor response to haemorrhage (Evans et al 1989;Evans & Ludbrook, 1990, 1991Ohnishi et al 1997). However, it is unlikely that morphine is acting within the spinal cord to block the depressor response to severe haemorrhage since it is blockade, rather than activation, of m receptors at this site that attenuates the depressor response to blood loss (Ang et al 1999).…”

“…As haemorrhage progresses, and blood loss exceeds 20-30 % of total blood volume, a depressor phase becomes apparent. This involves a vagally mediated bradycardia (inhibited by atropine, Little et al 1989), a reduction in peripheral vascular resistance (Barcroft et al 1944;Evans & Ludbrook, 1991) and a marked fall in arterial blood pressure. This second phase is not due to a failure of the baroreflex, since the latter's sensitivity is increased at this stage (Little et al 1984), nor is it a preterminal event (Hoffman, 1972;Sander-Jensen et al 1986), but rather it is due to the activation of additional reflex(es).…”

Somatic and visceral afferents to the ‘vasodepressor region’ of the caudal midline medulla in the rat

“…However, it has been suggested also that nociceptive signals originating from ischaemic tissues may play an important role, i.e. if blood loss continues the combination of increased sympathetic (vasoconstrictor) drive to maintain arterial pressure (compensatory/phase I response) and falling cardiac output will produce severe ischaemia in many visceral and skeletal muscle beds (Evans & Ludbrook, 1991; Schadt & Ludbrook, 1991; Fitzpatrick et al ., 1993; Ludbrook, 1993; Evans et al ., 1994). With respect to the CMM and the role of nociceptive afferents triggering the decompensatory response, Johansson observed 40 years ago (Johansson, 1962) that electrolytic lesions of the midline medulla (including the CMM ‘vasodepressor’ region) blocked hypotension and bradycardia evoked by electrical stimulation of ‘nociceptive’ muscle afferents (i.e.…”