Differential contributions of cardiac, coronary and pulmonary artery vagal mechanoreceptors to reflex control of the circulation

Distinct populations of stretch‐sensitive mechanoreceptors attached to myelinated vagal afferents are found in the heart and adjoining coronary and pulmonary circulations. Receptors at atrio‐venous junctions appear to be involved in control of intravascular volume. These atrial receptors influence sympathetic control of the heart and kidney, but contribute little to reflex control of systemic vascular resistance. Baroreceptors at the origins of the coronary circulation elicit reflex vasodilatation, like feedback control from systemic arterial baroreceptors, as well as having characteristics that could contribute to regulation of mean pressure. In contrast, feedback from baroreceptors in the pulmonary artery and bifurcation is excitatory and elicits a pressor response. Elevation of pulmonary arterial pressure resets the vasomotor limb of the systemic arterial baroreflex, which could be relevant for control of sympathetic vasoconstrictor outflow during exercise and other states associated with elevated pulmonary arterial pressure. Ventricular receptors, situated mainly in the inferior posterior wall of the left ventricle, and attached to unmyelinated vagal afferents, are relatively inactive under basal conditions. However, a change to the biochemical environment of cardiac tissue surrounding these receptors elicits a depressor response. Some ventricular receptors respond, modestly, to mechanical distortion. Probably, ventricular receptors contribute little to tonic feedback control; however, reflex bradycardia and hypotension in response to chemical activation may decrease the work of the heart during myocardial ischaemia. Overall, greater awareness of heterogeneous reflex effects originating from cardiac, coronary and pulmonary artery mechanoreceptors is required for a better understanding of integrated neural control of circulatory function and arterial blood pressure. [Image: see text

Physiologic regulation of heart rate and blood pressure involves connexin 36-containing gap junctions

Chronically elevated sympathetic nervous activity underlies many cardiovascular diseases. Elucidating the mechanisms contributing to sympathetic nervous system output may reveal new avenues of treatment. The contribution of the gap junctional protein connexin 36 (Cx36) to the regulation of sympathetic activity and thus blood pressure and heart rate was determined, using a mouse with specific genetic deletion of Cx36. Ablation of the Cx36 protein was confirmed in sympathetic preganglionic neurons of Cx36 knockout (KO) mice. Telemetric analysis from conscious Cx36 KO mice revealed higher variance in heart rate and blood pressure during rest and activity compared to wildtype (WT) mice, and smaller responses to chemoreceptor activation when anesthetized. In the working heart brainstem preparation of the Cx36 KO mouse, respiratory-coupled sympathetic nerve discharge was attenuated and responses to chemoreceptor stimulation and noxious stimulation were blunted compared to WT mice. Using whole cell patch recordings, sympathetic preganglionic neurons in spinal cord slices of Cx36 KO mice displayed lower levels of spikelet activity compared to WT mice, indicating reduced gap junction coupling between neurons. Cx36 deletion therefore disrupts normal regulation of sympathetic outflow with effects on cardiovascular parameters

Alternating hemiplegia of childhood-related neural and behavioural phenotypes in Na+,K+-ATPase α3 missense mutant mice

Missense mutations in ATP1A3 encoding Na(+),K(+)-ATPase α3 have been identified as the primary cause of alternating hemiplegia of childhood (AHC), a motor disorder with onset typically before the age of 6 months. Affected children tend to be of short stature and can also have epilepsy, ataxia and learning disability. The Na(+),K(+)-ATPase has a well-known role in maintaining electrochemical gradients across cell membranes, but our understanding of how the mutations cause AHC is limited. Myshkin mutant mice carry an amino acid change (I810N) that affects the same position in Na(+),K(+)-ATPase α3 as I810S found in AHC. Using molecular modelling, we show that the Myshkin and AHC mutations display similarly severe structural impacts on Na(+),K(+)-ATPase α3, including upon the K(+) pore and predicted K(+) binding sites. Behavioural analysis of Myshkin mice revealed phenotypic abnormalities similar to symptoms of AHC, including motor dysfunction and cognitive impairment. 2-DG imaging of Myshkin mice identified compromised thalamocortical functioning that includes a deficit in frontal cortex functioning (hypofrontality), directly mirroring that reported in AHC, along with reduced thalamocortical functional connectivity. Our results thus provide validation for missense mutations in Na(+),K(+)-ATPase α3 as a cause of AHC, and highlight Myshkin mice as a starting point for the exploration of disease mechanisms and novel treatments in AHC

Alternating Hemiplegia of Childhood-Related Neural and Behavioural Phenotypes in Na+,K+-ATPase α3 Missense Mutant Mice

Missense mutations in ATP1A3 encoding Na(+),K(+)-ATPase α3 have been identified as the primary cause of alternating hemiplegia of childhood (AHC), a motor disorder with onset typically before the age of 6 months. Affected children tend to be of short stature and can also have epilepsy, ataxia and learning disability. The Na(+),K(+)-ATPase has a well-known role in maintaining electrochemical gradients across cell membranes, but our understanding of how the mutations cause AHC is limited. Myshkin mutant mice carry an amino acid change (I810N) that affects the same position in Na(+),K(+)-ATPase α3 as I810S found in AHC. Using molecular modelling, we show that the Myshkin and AHC mutations display similarly severe structural impacts on Na(+),K(+)-ATPase α3, including upon the K(+) pore and predicted K(+) binding sites. Behavioural analysis of Myshkin mice revealed phenotypic abnormalities similar to symptoms of AHC, including motor dysfunction and cognitive impairment. 2-DG imaging of Myshkin mice identified compromised thalamocortical functioning that includes a deficit in frontal cortex functioning (hypofrontality), directly mirroring that reported in AHC, along with reduced thalamocortical functional connectivity. Our results thus provide validation for missense mutations in Na(+),K(+)-ATPase α3 as a cause of AHC, and highlight Myshkin mice as a starting point for the exploration of disease mechanisms and novel treatments in AHC

Phasic negative intrathoracic pressures enhance the vascular responses to stimulation of pulmonary arterial baroreceptors in closed chest anaesthetized dogs

We investigated whether the reflex responses to stimulation of pulmonary arterial baroreceptors were altered by intrathoracic pressure changes similar to those encountered during normal breathing. Dogs were anaesthetized with -chloralose, a cardiopulmonary bypass was established, and the pulmonary trunk and its main branches as far as the first lobar arteries were vascularly isolated and perfused with venous blood. The chest was closed following connection to the perfusion circuit and pressures distending the aortic arch, carotid sinus and coronary artery baroreceptors were controlled. Changes in the descending aortic (systemic) perfusion pressure (SPP; flow constant) were used to assess changes in systemic vascular resistance. Values of SPP were plotted against mean pulmonary arterial pressure (PAP) and sigmoid functions applied. From these curves we derived the threshold pressures (corresponding to 5% of the overall response of SPP), the maximum slopes (equivalent to peak gain) and the corresponding PAP (equivalent to ‘set point’). Stimulus–response curves were compared between data obtained with intrathoracic pressure at atmospheric and with a phasic intrathoracic pressure ranging from atmospheric to around -10 mmHg (18 cycles min-1). Results were obtained from seven dogs and are given as means ±S.E.M. Compared to the values obtained when intrathoracic pressure was at atmospheric, the phasic intrathoracic pressure decreased the pulmonary arterial threshold pressure in five dogs; average change from 28.4 ± 5.9 to 19.3 ± 5.9 mmHg (P > 0.05). The inflexion pressure was significantly reduced from 37.8 ± 4.8 to 27.4 ± 4.0 mmHg (P < 0.03), but the slopes of the curves were not consistently changed. These results have shown that a phasic intrathoracic pressure, which simulates respiratory oscillations, displaces the stimulus–response curve of the pulmonary arterial baroreceptors to lower pressures so that it lies within a physiological range of pressures

Central nucleus of amygdala projections to rostral ventrolateral medulla neurones activated by decreased blood pressure

The central nucleus of amygdala (CeA) participates in cardiovascular regulation during emotional behaviour but it has not been established whether any of these effects are mediated through its direct connections to blood pressure-regulating neurones in the rostral ventrolateral medulla (RVLM). The RVLM contains barosensitive neurones that maintain resting blood pressure via their projections to sympathetic preganglionic neurones in the thoracic spinal cord. In this study on rats, we used combined anterograde neuronal tracing of CeA projections with confocal and electron microscopic immunohistochemical detection of phenylethanolamine-N-methyltransferase, the adrenaline-synthesizing enzyme present in C1 catecholamine neurones of the RVLM, and Fos, the protein product of the c-fos proto-oncogene. Fos expression in barosensitive neurones was stimulated by an intravenous infusion of the hypotensive agent sodium nitroprusside. Injection of the tracer biotin dextran amine (10-kDa form) into the CeA resulted in anterograde labelling of axons and varicosities throughout the RVLM without retrograde labelling of somata in any brain area. With confocal microscopy, presumptive CeA terminals were found in close apposition to adrenergic (phenylethanolamine-N-methyltransferase-immunoreactive) and non-adrenergic neurones that displayed Fos-immunoreactive nuclei in response to decreased blood pressure. Electron microscopic analysis confirmed that some labelled terminals of CeA axons made synaptic contact with c-fos-activated adrenergic neurones. The results provide evidence that cardiovascular influences elicited from the CeA during stressful events may be mediated, at least in part, via monosynaptic neural projections to barosensitive sympathetic blood pressure-regulating neurones in the RVLM

Absence of early resetting of coronary baroreceptors in anaesthetized dogs

Both carotid and aortic arch baroreceptors have been shown to reset after as little as 20 min exposure to a different conditioning pressure; the mid-point of the stimulus-response curve is displaced towards the conditioning pressure.Coronary baroreceptors operate over much lower pressures and induce slower reflex vasoconstriction than the other baroreceptors and this investigation was designed to determine whether their resetting characteristics are also different.In chloralose anaesthetized dogs, a perfusion circuit allowed independent control of pressures distending carotid, aortic and coronary baroreceptors. Stimulus-response curves were obtained for carotid and coronary baroreceptors after maintaining the distending pressure at 60 or 180 mmHg for 20 min.Neither the magnitude of the responses nor the baroreceptor pressure corresponding to 50 % of the response (BP50) of the coronary curves was changed by the conditioning regime. In contrast, conditioning carotid baroreceptors with the same regime produced significant shifts in the BP50 towards the conditioning pressure.No changes were obtained after conditioning the coronary baroreceptors at 60 or 120 mmHg for 40 min.These results confirm early resetting of carotid baroreceptors but show that coronary baroreceptors do not reset over a period of at least 40 min