Vasodilator and vasoconstrictor neurones of the ventrolateral medulla in the cat.

Microinjections of D,L-homocysteic acid into the ventrolateral medulla, in the region of nucleus paragigantocellularis lateralis (PGL) which lies caudal to the facial nucleus and adjacent to the rostral third of the inferior olive, evoke a rise in arterial blood pressure and vasoconstriction in hindlimb muscle. Activation of a group of neurones located in a more rostral strip of tissue ventral to the facial nucleus produces vasodilatation in the hindlimb but no significant change in blood pressure. It appears that the ventrolateral medulla contains several subpopulations of neurones which can alter resistance to blood flow and hence distribution of flow and level of blood pressure by selective control of individual vascular beds.

Determinants of the delegation of healthcare aboard ships with women assigned.

The purpose of this study was to identify the potential determinants and distribution of shipboard patient delegation decisions. During a 1-month period, physicians aboard five U.S. Navy ships with women assigned estimated the minimum numbers of healthcare providers needed to diagnose and treat each patient (N = 2,725). Results indicated the following distribution of potential patient assignment: consultation 1.4%, medical officer 18.6%, physician assistant/nurse practitioner 8.7%, corpsman with additional OB/GYN training 2.2%, and corpsman 69.2%. Diagnosis was the best predictor of the indicated level of healthcare required. The patient's sex and pay grade were unrelated to the potential levels of care provided.

Evidence for phosphate as a mediator of functional hyperaemia in skeletal muscles.

Maximal twitch contractions of fast muscles of the cat caused an increase in phosphate concentration in the venous plasma from them: this efflux was greater as the contraction frequency was increased. At any given frequency of contraction, the phosphate efflux from contracting gastrocnemius was less than that from tibialis anterior and extersor digitorum longus, which have a higher proportion of fast fibres and exhibit greater functional hyperaemia. Soleus muscles, when contracting, released hardly any additional phosphate, except in the one experiment in which the muscle exhibited a functional hyperaemia. There was thus a consistent relationship between the extent of functional hyperaemia and phosphate efflux in different muscles and within any one group of muscles. Inorganic phosphate, given close arterially as NaH2PO4, was shown to be vasodilator.NaH2PO4 was much more potent than Na2HPO4, though this did not seem due simply to the associated change of pH. The functional hyperaemia of fast muscles could be matched, qualitatively and quantitatively, by injections or infusions of NaH2PO4. The possibility is discussed that the contraction hyperaemia of fast muscles is functionally related to phosphate release into the interstitial fluid during contractions.

The defence-arousal system and its relevance for circulatory and respiratory control.

It was proposed some fifty years ago that the visceral and hormonal changes accompanying fear and rage reactions can best be understood as adaptations which prepare an organism to cope with an emergency and specifically to perform the extreme muscular exertion of flight or attack. This is well exemplified by the pattern of cardiovascular response which is characteristic of the alerting stage of these reactions and consists of an increase in cardiac output directed mainly to the skeletal muscles. This group of behavioural responses has been collectively termed the defence reaction. The regions of the hypothalamus and brainstem which organize it have been mapped. They function as a reflex centre for the visceral components of the altering response as well as initiating the behavioural response. So far as the cardiovascular system is concerned, this is a preparatory reflex and not compatible with short-term homeostasis. Indeed, the baroreceptor reflex, which is homeostatic, is strongly inhibited. By contrast, the chemoreceptor reflex is facilitated. The input from peripheral chemoreceptors is itself an alerting stimulus. The visceral alerting response has been studied in most detail in the cat, but there is evidence for the same cardiovascular pattern and an accompanying group of respiratory changes in other mammalian species (rat, rabbit, dog, monkey and man). On the efferent pathway for the cardiovascular response pattern, there is a group of relay neurones near the ventral surface of the caudal medulla, which seem important for the maintenance of arterial blood pressure. The visceral alerting system may therefore be continually engaged to some extent in the awake state, as well as being acutely activated in response to novel, and especially to noxious, stimuli.

Dorsal root vasodilatation in cat skeletal muscle.

1. A study has been made, in the cat anaesthetized with chloralose, of the effects of antidromic stimulation of dorsal roots L6-S1 on the blood flow through the gastrocnemius muscle. 2. Stimulation of the peripheral ends of the ligated dorsal roots with current pulses of 0.3-0.5 msec duration and at intensities most effective in activating the smaller afferent fibres, for periods of 15-20 sec, produced a 50-60% increase in muscle vascular conductance which was slow in onset and long outlasted the stimulus. 3. This muscle vasodilatation could be evoked in the paralysed animal and was unaffected by guanethidine or atropine. It was, however, greatly reduced or even abolished by the prostaglandin synthetase inhibitors, indomethacin or acetylsalicylic acid, in doses which had no effect on the dilatation produced by a local injection of acetylcholine or the functional hyperaemia induced by muscle contraction. 4. It is concluded that activity in the smaller myelinated or unmyelinated afferent fibres of skeletal muscle produces an increase in muscle blood flow which is mediated, at least in part, by prostaglandins locally synthesized within the muscle.

A search for brain stem cell groups integrating the defence reaction in the rat.

The defence areas of the rat brain stem have been extensively explored using electrical and chemical stimulation in an attempt to locate the regions containing the perikarya of neurones which may initiate or integrate the visceral and behavioural components of the defence reaction. In rats anaesthetized with alphaxalone-alphadolone, a cannula electrode was used to compare the responses to electrical stimuli with those evoked by microinjection of the excitatory amino acid D,L-homocysteic acid (DLH), at the same site. A total of 128 sites throughout the brain stem was studied in 75 rats. The pattern of visceral and somatic changes characteristic of the defence reaction, viz. increases in arterial blood pressure and heart rate, vasodilatation in hind-limb muscles and vasoconstriction in the kidney, hyperpnoea and tachypnoea, exophthalmos, mydriasis, twitching of the vibrissae and retroflexion of the tail, was evoked by electrical stimulation within well-defined regions of the brain stem, from the anterior hypothalamus to the pons. Microinjection of DLH into the same regions could evoke the full defence reaction, as defined above, but only from the dorsomedial periaqueductal grey matter. Three other regions were defined from which almost all the autonomic components of the defence reaction were evoked, except that blood pressure fell. These were located: immediately dorsal to the optic chiasma, in the medial tuberal region of the hypothalamus and in the lateral pontine tegmentum. In conscious rats with implanted guide cannulae, darting and flight responses were evoked by microinjections of DLH into the periaqueductal grey matter but not from the hypothalamus or tegmentum. Brisk locomotion followed injections of DLH into the region overlying the optic chiasma. It is concluded that the brain stem neurones involved in integrating the somatic and visceral components of the defence reaction are concentrated within the four regions defined above. Whereas neurones in the periaqueductal grey matter can initiate the fully integrated defence reaction, those concentrated in the three other areas cannot be shown to do so. Of these three cell groups, the suprachiasmatic neurones seem to be closer in function to the periaqueductal group than are the neurones in the tuberal hypothalamus and pontine tegmentum.

Participation of the anterior hypothalamus in the baroreceptor reflex.

1. On the basis of discrete electrical stimulation in the pre-optic region and anterior hypothalamus of anaesthetized cats, a depressor area has been defined, stimulation of which elicits a fall of arterial blood pressure of 30-50 mm Hg and a bradycardia of some 25%, caused by inhibition of sympathetic vasomotor tone and by vagal activation respectively. These are accompanied by a reduction in rate and depth of respiration.2. The depressor area, from which this pattern of response is elicited, lies ventral and caudal to the anterior commissure, and extends caudally in the dorsal hypothalamus, dorsal to the fornix.3. The pattern of response elicited from identified points in the depressor area was shown to be indistinguishable from that to baroreceptor afferent stimulation.4. A lesion destroying the hypothalamic depressor area bilaterally reduced the response to baroreceptor afferent stimulation. Lesions in the medullary depressor area which spared a large part of the nucleus of the tractus solitarius also reduced, but did not abolish, the baroreceptor reflex response. The two lesions combined abolished the reflex.5. It is concluded that the whole brain-stem depressor area, from the hypothalamus through the mid-brain to the medulla, constitutes a functional unit which integrates the response to baroreceptor afferent stimulation.

The role of plasma kinin in functional vasodilatation in the pancreas.

1. Freshly collected pancreatic juice of the cat contained active kinin-forming enzyme (kallikrein) and, in addition, an active kininase.2. In response to successive doses of secretin, the kinin-forming activity of pancreatic juice fell off considerably. It was restored by pancreozymin.3. Stimulation of the dorsal vagus nerve caused an increase in venous outflow from the pancreas which was greater and more consistently seen when the splanchnic nerves had been sectioned.4. Intravenous injection of highly purified secretin usually had no effect on the outflow, whereas pancreozymin increased it up to 5 times.5. When the pancreas was perfused with oxygenated Locke solution, the effluent contained some kinin-forming enzyme when the gland was at rest. The enzyme activity did not increase when secretin was added to the perfusing fluid, but when acetylcholine or pancreozymin was added, the activity rose about fourfold.6. These results are discussed in relation to the theory that plasma kinins play a prominent role in the functional vasodilatation of glandular tissues.

Selective hypersensitivity to bradykinin in salivary glands with ligated ducts.

1. In submandibular salivary glands of cats in which the ducts have been tied for at least 3 days, the kallikrein activity of ;chorda' saliva is much reduced; but it is never absent, even after prolonged sympathetic stimulation.2. The relationship between the extent of the vasodilatation accompanying secretory activity and frequency of chorda stimulation is similar in normal glands and those with ducts ligated for 3 days, though, in the latter group, the variability is much greater.3. In glands of which the ducts have been tied for 3 days, the responses to close arterial injections of bradykinin are greatly increased, the dose-response curve being steeper and shifted to the left. This appears to be a selective increase in sensitivity, as the responses to the close arterial injections of ACh are, if anything, less than those in normal glands.4. In glands with ligated ducts, prolonged sympathetic stimulation reduces the vasodilatation following chorda stimulation.5. These results strengthen the conclusion that kinins participate in the vasodilatation accompanying glandular activity.

The pattern of cardiovascular response to carotid chemoreceptor stimulation in the cat.

1. The pattern of cardiovascular response evoked by carotid chemoreceptor stimulation has been investigated in cats anesthetized by continuous infusion of Althesin (Glaxo). 2. A variety of chemoreceptor stimulants, injected retrogradely into the lingual artery with the external carotid artery ligated, evoked hyperventilation with variable changes in arterial pressure and heart-rate, but a consistent vasodilatation in limb muscles and vasoconstriction in renal, mesenteric and cutaneous vasculature. 3. The muscle vasodilatation was still obtained after vagotomy and when the animal was paralysed and artificially ventilated; thus, it was not secondary to the hyperventilation. 4. In the majority of experiments the muscle vasodilatation was much reduced or abolished by atropine indicating it was mediated by sympathetic cholinergic fibres, which is characteristic of the alerting stage of the defence reaction in the cat. The cardiovascular pattern was accompanied by the other autonomic features of the alerting response, viz. pupillary dilatation, retraction of the nictitating membranes and pilo-erection. 5. In one and the same animal the pattern of response evoked by carotid chemoreceptor stimulation was the same as that evoked by noxious cutaneous stimulation, and by electrical stimulation in the brain stem defence areas. 6. It is concluded that peripheral chemoreceptor stimulation acts as an excitatory input to the hypothalamic and brain stem defence areas and that it can readily evoke the autonomic components of the alerting stage of the defence reaction. It is suggested that this has been missed in previous studies on anaesthetized animals because of the depressant action of chloralose and barbiturates on transmission in the hypothalamus and mid-brain.

The hypothalamic and brainstem areas from which the cardiovascular and behavioural components of the defence reaction are elicited in the rat.

Electrical stimulation has been employed to map areas of the rat's brain from which the cardiovascular and behavioural components of the defence reaction are elicited and hence to identify the defence areas in this species. In the anaesthetized rat, the cardiovascular pattern of response includes increases in arterial blood pressure and heart-rate, an atropine-resistant vasodilatation in the hind-limb skeletal muscle, with renal and splanchnic vasoconstriction. This was elicited from comparatively well localized areas, not confined to any particular nuclei. Responses were evoked from the rostro-caudal extent of the hypothalamus but most consistently from a region ventral to the fornix. In the midbrain, responsive sites were localized to the dorsal half of the central grey matter, the tegmentum ventro-lateral to it and a ventro-medial region which continued into the pons. Stimulation using implanted electrodes in conscious rats, within the hypothalamic and midbrain areas described above, elicited typical 'flight' and 'escape' behaviour: thus, the localized regions from which the visceral alerting response is elicited contain neurones or nerve fibres integrating the whole defence-alerting response in the rat, as in other species.

Vasodilatation in hind-limb skeletal muscle evoked as part of the defence reaction in the rat.

Electrical stimulation of the hypothalamic and mid-brain defence area of the rat's brain elicits a consistent cardiovascular pattern of response of which vasodilatation in the skeletal muscle is an integral component: the mechanisms mediating this vasodilatation were investigated. It is not sensitive to atropine in this species, but it was substantially affected, particularly its later stage (the prolonged tail-end of the response), by either beta-adrenoreceptor antagonists (propranolol, sotalol) or bilateral adrenalectomy. A major part of the hind-limb vasodilatation can therefore be attributed to the action of catecholamines released from the adrenal glands. The initial part of the vasodilatation, which still remained after beta-adrenoreceptor blockade and adrenalectomy, was abolished by intravenous injection of guanethidine and phentolamine and seems therefore due simply to withdrawal of vasoconstrictor tone. In confirmation, stimulation of the sympathetic outflow to the hind-quarters after phentolamine and guanethidine had been used to block vasoconstriction did not reveal a sympathetic vasodilator nerve supply to the hind-limb vasculature.

Ventral medullary neurones excited from the hypothalamic and mid-brain defence areas.

In cats anaesthetised with chloralose, the ventral medulla was explored in and around the strip previously identified as the location of the efferent pathway from the hypothalamic and mid-brain defence areas to the spinal cord, in a search for neurones excited by electrical stimulation of the defence areas. Such units were found mostly in the caudal part of this strip, at a depth of not more than 500 microns from the surface. Nearly all were located in the ventral part of nucleus paragigantocellularis lateralis (PGL) at the level of the rostral pole of the inferior olive. There was evidence of temporal and spatial facilitation, indicating a convergent excitatory input from the defence areas onto neurones in PGL. This is consistent with earlier evidence of a synaptic relay in the efferent pathway at this site. When the pathway is blocked at this site, arterial blood pressure falls profoundly, so activity in these neurones may be essential for the normal level of sympathetic nerve activity.

Possible mediators of functional hyperaemia in skeletal muscle.

1. (a) In experiments on gastrocnemius muscles of the cat performing external work, the work was graded, either by altering the intensity of motor nerve stimulation or by changing the load. Only under the former conditions was the steady-state increase in blood flow conductance at all consistently related to the work performed. (b) In such experiments, efflux of inorganic phosphate and of potassium were closely correlated with the increase in vascular conductance, in the form of a typical dose-response curve. There was no significant relationship between changes in plasma osmolarity and conductance. 2. (a) Whereas most soleus muscles in the cat exhibit virtually no functional vasodilation, those with a relatively low resting flow tend to do so. (b) There was a relationship between the vasodilation, if any, and release of phosphate in fifteen out of seventeen experiments on soleus muscles. No relationship was found between any release of potassium or change of plasma osmolarity, and absence or extent of functional vasodilation. 3. (a) Terminal arterioles and collecting venules in the rat's spinotrapezius muscle were observed in vivo under low power magnification while the muscle was bathed in various test solutions, so that the vasodilator properties of hyperosmolar solutions, potassium and phosphate could be studied. (b) The dilator effect of hyperosmolar solutions was much the weakest: solutions of 340 m-osmole/kg elicited the largest responses, but these seldom exceeded 50% mM-K+ and 3.2--6.4 mM-Pi (as NaH2PO4) elicited 25--50% of maximum dilation, while 9--10 mM-K+ and 16--20 mM-Pi dilated arterial vessels fully. The latency to onset of dilation was shortest (5 sec) with Pi and longest (15 sec) with K+. 4. These findings, together with those already in the literature, lead to the conclusions that (a) hypersomolarity is unlikely to be in an important factor initiating or maintaining functional hyperaemia in skeletal muscle, (b) while K+ release may contribute in fast muscle it can hardly be the factor initiating the response, and (c) inorganic phosphate is the only substance tested so far whose efflux is consistently related to the vascular response in all muscles under a variety of experimental conditions, and whose efficacy as a vasodilator seems adequate.

The ponto-medullary area integrating the defence reaction in the cat and its influence on muscle blood flow.

1. In anaesthetized cats the effects were investigated of electrical stimulation of regions in the caudal mesencephalon, pons and medulla on muscle blood flow, skin blood flow and arterial blood pressure.2. It was found that within the dorsal part of the well known pressor area there is a narrow strip, 2.5 mm lateral from the mid line, starting ventral to the inferior colliculus and ending in the medulla close to the floor of the IV ventricle, from which vasodilatation in skeletal muscles is selectively obtained. This strip is quite separate from the more ventral, efferent pathway for active vasodilatation running from the hypothalamic and rostral mesencephalic ;defence centre'.3. As in the case of the hypothalamic and rostral mesencephalic ;defence centre', the muscle vasodilatation obtained from the caudal strip is accompanied not only by a rise of arterial blood pressure, but also by tachycardia, vasoconstriction in the skin, pupillary dilatation and piloerection.4. Stimulation, restricted to the caudal strip, via implanted electrodes in unanaesthetized animals, produced a behavioural response resembling the defence reaction. The strip, therefore, is probably a caudal extension of the ;defence centre'.5. Unlike the vasodilatation elicited from the more rostral part of the ;defence centre' in the hypothalamus and mesencephalon, the muscle vasodilatation obtained on stimulation of the caudal strip was resistant to atropine, but was blocked by guanethidine.6. It is suggested that during naturally occurring defence reactions in the normal animal the ponto-medullary area is activated together with the hypothalamo-mesencephalic area, inhibition of vasoconstrictor tone then accompanying activation of the vasodilator nerve fibres in skeletal muscle.

Functional specializations of the vascular bed of soleus.

1. The venous outflow from the slow soleus muscle, at rest and during exercise, was compared with that of fast muscles. The blood flow through the soleus at rest was found to be, on average, 52 ml./100 g.min, which is about 4 times that of fast muscles.2. On stimulation of soleus through its motor nerve at low frequencies, up to 8/sec, hardly any increase in flow was observed, whereas fast muscles stimulated at the same rates showed a marked increase, the maximal functional hyperaemia being reached at 8/sec. Even when the soleus muscle was stimulated at frequencies of 40/sec the post-contraction hyperaemia was very small and sometimes absent.3. The relative absence of functional hyperaemia in the soleus does not appear to be due to low vascular tone, for small amounts of acetylcholine, injected close arterially, produced a considerable increase in blood flow. Further, in experiments in which the vascular tone was increased by lumbar sympathetic stimulation, no functional hyperaemia was seen. It is concluded that a contracting soleus does not release in adequate amounts the substance causing functional vasodilatation in fast muscles.4. No vasodilator effect of adrenaline could be demonstrated in soleus, and the vasodilator effect of isoprenaline was much smaller than that seen in fast muscles.5. The vasoconstrictor effect of lumbar sympathetic stimulation on the resistance vessels of soleus was much smaller than the effect seen in fast muscles. However, the responses of the resistance vessels in soleus to close arterial injections of noradrenaline were not very different from those of fast muscles, and it is suggested that the density of the terminal sympathetic innervation of the vessels of soleus differs from that of fast muscles.