John W. Manning

A Mathematical Model to Assess Changes in the Baroreceptor Reflex

A mathematical model relating carotid sinus pressure (CSP) to systemic arterial pressure (SAP) explains the relationship between CSP and SAP with an accuracy of 96 %. The 4 parameters of the model are

Effect of naloxone on baroreflex, sympathetic tone and blood pressure in the cat

Studies were designed to determine the effect of naloxone on sympathetic nerve activity and blood pressure and, also to investigate the central effect of naloxone in relation to the baroreflex system in alpha-chloralose-anesthetized cats. Following intravenous injection of naloxone (2 mg/kg), preganglionic splanchnic nerve (PSN) activity significantly increased in parallel to the increase in blood pressure. Set gain (mmHg-1) of carotid sinus baroreflex together with the operational range (mmHg) was increased after naloxone. Intraventricular (4th) injection of naloxone (0.2 mg/kg) produced identical responses in blood pressure and PSN activity as well as an altered set gain and range of the baroreflex. Additionally, the pressor response to carotid hypotension and medullary pressor area stimulation were augmented during naloxone activation but not the pressor response to posterior hypothalamus stimulation. The depressor responses to stimulation of both carotid sinus nerve and medullary depressor region were facilitated by naloxone. These data suggest that naloxone has an effect on the central autonomic blood pressure regulatory circuits which participate in the carotid sinus baroreflex system.

Suprapontlne Contributions to the Carotld Sinus Reflex in the Cat

Carotid sinus reflex response was measured before and after decerebration in 27 cats with and without the vagus nerves intact. Body temperature, central venous pressure, arterial oxygen saturation, PCO2 and pH were kept within normal limits. The anesthetized animals were uniformiy subjected to a wide range of controlied sirius pressure changes in each condition. A mathematical analog with four parameters was empioyed to relate carotid sinus pressure to systemic arterial pressure. The expression takes the form of a logistic curve, describes the reflex response with an accuracy of 98%, and provides a design in which errors are normally distributed for statistical testing of differences in parameters occurring with experimental intervention. The major effect on the sinus reflex of brainstem transection at the collicular level was a decrease in the effective range over which arterial pressure could be varied by changes in sinus pressure. Although a given change in sinus pressure in the median range of 70 to 100 mm Hg produced a proportional change in arterial pressure, transection markedly decreased reflex responses to lower sinus pressures. It was concluded that a transection at the coflicular level may not significantly change mean systemic pressure, but it does decrease the animals ability to adjust to variations in arterial pressure. The data lend credence to the hypothesis that supramedullary areas can and do function in directing autonomic activity during the carotid sinus reflex.

Muscle Cholinergic Dilators in the Sinus Baroreceptor Response in Cats

Experiments were done to evaluate the effect of the cholinergic vasodilator system on the flow-pressure relation in the isolated, perfused gastrocnemius and soleus muscles of the cat. Reflex changes in the muscle vascular resistance were produced by maintaining the isolated, perfused carotid sinus at different pressure levels. Flow-pressure curves were obtained from the isolated muscles at high, medium, and low carotid sinus pressures before and after administration of adrenergic or cholinergic blocking drugs or denervation, or both. Following cholinergic receptor blockade, flow-pressure relations at high sinus pressure showed a loss of a dilator component, hut curves at low and medium sinus pressures were the same as controls. Following adrenergic receptor blockade, flow-pressure curves at low and medium sinus pressures were superimposed; however high sinus pressure still produced a decrease in vascular resistance. The remaining vasodilation could be abated by either denervation or anticholinergic agents. The difference between the untreated and the cholinergically blocked flow-pressure responses represented 15−30% of the range of change in vascular resistance evoked by the sinus baroreceptor reflex. Thus, effective withdrawal of sympathetic vasoconstrictor tone did not account for total vasodilation. The data indicate that the sympathetic cholinergic vasodilator system participated in the vascular responses of skeletal muscle during baroreceptor stimulation.

The median preoptic area in cardiovascular reflex activity

Two examples are used to illustrate the flexibility within the central servocontrol system that regulates blood volume and blood pressure. The variations are seen in the modification of components directed both towards short-term and long-term control. The preferential circuit used in the servocontrol system can and does change. The interaction of baromechanisms with cerebellar-fastigial activation selectively engages sympathetic output to the kidney resulting in an enhanced release of renin that is disproportional to the rise in renal vascular resistance. The cerebellar component adds a feature to the reduction in vascular conductance that when fully developed increases vascular volume. The permissive role of sites in the anteroventral hypothalamus suggests a neural loop that, when absent, not only allows the sympathetic activity to run unabated but fails to prevent a tachycardia state or to develop a bradycardia in response to a rise in arterial pressure. The latter may be a transient feature not persisting for more than a day. However, when compared to the normal responses of the paired sham controls, such a change is taken as an example of dynamic shift in preferential pathways.

Visceral afferents and the fastigial nucleus in vascular and plasma renin adjustments to head-up tilting

A two min orthostatic stress of 30 degrees head-up tilting in alpha-chloralose anesthetized and paralyzed cats results in compensatory changes in cardiovascular parameters (systemic blood pressure, renal perfusion pressure) and renin release. The dynamics of the response leads to shifts in systemic arterial pressure characterized by 3 phases. The initial phase, a fall in systemic pressure, is followed by a rapid compensatory phase with a period that does not exceed 50 s. The near steady-state adjustment in blood pressure and renal vascular resistance represents the third phase, has a longer time constant and is adequately accounted for by both arterial and cardiopulmonary baroreflex mechanisms. Indeed, fixing carotid sinus pressure in the vagotomized cat at high or low levels alters only the magnitude of the steady-state pressure obtained with tilt and not the early rapid compensation of the second phase. By contrast, bilateral lesions of the fastigial nucleus of the cerebellum abates the rapid phase of systemic compensation to tilting. Renin secretion significantly increased (greater than 2 1/2) with tilt and this increase was abolished by vagotomy. By fixing carotid sinus pressure at high or low levels in the vagotomized cat, tilt resulted in only a modest rise in renin secretion. Following fastigial lesions such as upwards trend was abated. Three neural components (cerebellar fastigial pressor, arterial baroreflex and cardiopulmonary baroreflex) appear necessary for the integrated response in cardiovascular adjustment to head-up tilt. The adjustments to orthostatic stress comprise both rapid neural as well as long-term humoral responses.

Central Nervous System Control of Cardiac Rhythm

Stimulation of sites in the midbrain reticular formation and in the posterior hypothalamus of the cat resulted in a large to modest rise of arterial pressure and the induction of cardiac dysrhythmias. Most frequently, these arrhythmias developed upon cessation of brain stem stimulation but also occurred during the stimulus period in 5 of 23 cats studied. The arrhythmias disappeared upon cooling and reappeared upon rewarming the vagus nerves. The ventricular dysrhythmias also were abolished by methylscopolamine, by bilateral vagatomy, or by extirpation of the stellate ganglia. Simultaneous stimulation of both distal end of the cut right vagus nerve and the decentralized right stellate ganglion caused arrhythmias similar to those observed after diencephalic stimulation. These data are interpreted to indicate that the cardiac arrhythmias evoked by brain stem stimulation result from the interplay of both sympathetic and parasympathetic influences on the heart. The response patterns of a population of medullary neurons activated by carotid sinus nerve stimulation were modified by condition stimuli to posterior hypothalamic sites. From studies on unit activity of brain stem areas known to participate in cardiovascular adjustment, a schema is proposed of hypothalamic-medulla interaction as a central mechanism that may account for the development of ventricular arrhythmias.

Cardiovascular responses and central catecholamines in streptozocin-diabetic rats

Brain catecholamine levels, spinal cord levels of the norepinephrine metabolite methoxy-hydroxy-phenylglycol (MHPG), and heart rate were measured in nondiabetic and streptozocin-diabetic rats after sham surgery or bilateral carotid ligation. Although carotid ligation increased heart rate in both diabetic and nondiabetic rats, in diabetic animals the response did not differ from the response to sham surgery. Carotid ligation increased epinephrine concentrations in the medulla/pons of diabetic animals but was not associated with alterations in other central catecholamines. In all diabetic rats spinal ratios of MHPG/norepinephrine (an index of noradrenergic activity) were higher than in nondiabetics, and the change in heart rate (post-surgical-pre-surgical rate) correlated inversely with hypothalamic dopamine (R = -0.60). In sham-operated diabetic rats there were high inverse correlations of the change in heart rate with medullary epinephrine and of pre- and post-surgical heart rate with spinal MHPG/NE (R = -0.87 to -0.95). Central catecholamines and heart rate were not correlated in nondiabetic animals and correlated only weakly when nondiabetic and diabetic animals were pooled. Correlations in diabetic animals were usually abolished or reduced by carotid ligation. These findings suggest a link between central catecholamines and heart rate in diabetic rats subjected to surgical stress. Whether catecholaminergic neurons contribute to abnormal chronotropic responses in diabetic rats or respond to stimuli that affect both heart rate and neural function remains to be determined.

Pyrimido-pyrimidine derivative, RA642, a central pressor agent in cat endotoxin shock

The effects of a pyrimido-pyrimidine derivative, RA642, in endotoxin shock were studied. Blood pressure and preganglionic splanchnic nerve (PSN) activity were measured in alpha-chloralosed cats. Within 30 min of intravenous administration of E. coli endotoxin (1 mg/kg), blood pressure and PSN activity were 68 +/- 8% and 47 +/- 10% of control and by 60 min were depressed by 54 +/- 8% and 42 +/- 8%. RA642 (0.25 mg/kg) injected i.v. 30 min after endotoxin, caused blood pressure to recover significantly to 83 +/- 6% of control within 5 min and be maintained at that level. PSN activity was similarly increased to and maintained at 62 +/- 9% of control. The efficacy of RA642 in reversing the lethal consequences of endotoxin shock were dramatic; all treated animals survived whereas the mortality rate of non-treated animals was 83%. This strongly suggests that the central pressor agent, RA642, may have important therapeutic applications in the management of endotoxin shock.

Time dependence of mechanisms in the renin response to renal nerve stimulation.

The renin release responses to 1 and 5 min of renal nerve stimulation were determined. The left kidneys of alpha-chlorolose-anesthetized cats were pump perfused with blood while stimulating the decentralized renal nerves at different frequencies (0.5 ms, 10 V). With renal blood flow (RBF) held constant, 1 min of renal nerve stimulation increased renin secretion rate (RSR) at 1.0 (128%), 4.0 (168%) and 12.0 (160%) Hz. After 5 min of stimulation the responses were not different. Propranolol pretreatment prevented the increase in RSR at 1.0 Hz, and resulted in decreased RSR at 4.0 and 12.0 Hz. This response pattern occurred after 1 and 5 min of renal nerve stimulation. When renal perfusion pressure (RPP) was held constant, RSR at 1 min into the stimulation period was similar to that found in the constant RBF group. However, after 5 min the 4.0 Hz and 12.0 Hz responses were significantly greater than the 1 min responses (242% and 508%). Propranolol pretreatment resulted in renin responses after 1 min of stimulation which were similar to the beta-blocked constant RBF group. After 5 min of stimulation at 4.0 and 12.0 Hz RSR was greater than control levels. The results illustrate that renal nerve evoked renin release is time-dependent under constant RPP conditions. The data indicate the presence of 3 mechanisms in these responses. A beta-adrenergic receptor operates at all frequencies to increase renin release. When renal vasoconstriction occurs additional mechanisms are involved. One is inhibitory, independent of renal hemodynamic conditions and rapidly activated. The second is excitatory, occurs only under constant RPP conditions, and is activated slowly.