The unifying hypothesis is that general anesthetics cause cardiovascular dysfunction in part by compromising brainstem baroreflex control of heart rate via actions in the nucleus tractus solitarius (NTS) and nucleus ambiguus (NA). Experiments both in vivo and in isolated brain slices will be carried out. Preliminary studies suggest that no CNS sites above the brainstem are necessary for general anesthetic actions on the cardiovasular system. In these studies isoflurane and propofol depressed the bradycardia that follows MAP increase induced by iv phenyephrine in both intact and decerebrate rats.
Specific Aim 1 extends these studies by proposing that NTS is the critical region for anesthetic action on baroreflex control of heart rate. Baroreflex gain will be measured in two ways, as slope of a linear fit for heart rate changes induced by ramp changes of blood pressure in response to infusion of phenylephrine or sodium nitroprusside on a beat-to-beat basis, or closer to steady state, as a fit of heart rate to peak MAP changes induced by graded bolus injections of the vasoactive agents. In the latter, sympathetic and vagal contributions to changes in baroreflex will be assessed by injections of peripherally acting beta-adrenoceptor and muscarinic antagonists. Microinjection of general anesthetics into NTS will be used to determine whether this application mimics systemic delivery. Specific glutamate and GABA receptor agonists will be injected to test for the responsible receptors. Stimulation of the aortic depressor nerve will be used to determine whether systemic administration of general anesthetics alters response to amino acid neurotransmitters injected into NTS.
Specific Aim 2 asks whether general anesthetic action in NTS affects control of both sympathetic and parasympathetic outflow. In vivo studies will be carried out with pharmacologic blockers of either muscarinic or beta-adrenergic receptors. Recordings will be made from efferent nerves in both systems to assign changes to outflow versus direct cardiovascular actions on heart and vascular smooth muscle.
Specific aims 3 - 5 move to brain slices with a series of experiments in NTS to assign general anesthetic actions to various neurotransmitters and voltage-dependent ion channels by comparing the sensitivity of these effects with concentrations which alter heart rate and blood pressure. Four different general anesthetics will be examined, namely isoflurane, halothane, propofol, and ketamine, chosen for their contrasting effects on heart rate and mean arterial pressure.
