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The effect of physiological changes in systemic blood pressure on the force output of working abductor pollicis (AP) muscle was studied in six normal subjects. Supramaximal tetanic stimulation at the ulnar nerve produced repeated isometric contractions at 1-s intervals. Force output declined gradually with time. During the train of contractions, subjects voluntarily contracted the knee extensors for 1 min; this raised systemic blood pressure by 29%. Force output from AP rose in parallel with blood pressure so that 18% of the contraction force lost through fatigue was recovered for each 10% increase in blood pressure. When blood pressure in the hand was kept constant despite the increased systemic pressure, force output did not rise. The results show that muscle performance is strongly affected by physiological changes in central blood pressure and suggest that sensory input concerning the adequacy of muscle performance exerts a feedback control over the increase in systemic blood pressure during muscular activity.

The effects of changes in arterial perfusion across the physiological range on the fatigue of a working human hand muscle were studied in seven normal subjects. With the hand above heart level, subjects made repeated isometric contractions of the adductor pollicis muscle at 50% of maximal voluntary contraction in a 6-s on, 4-s off cycle. To assess fatigue, a maximal isometric twitch was elicited in each "off" period by electrical stimulation of the ulnar nerve. The experiment was repeated at least 2 days later with the hand at heart level. Five subjects showed faster fatigue with the arm elevated, and two subjects showed little difference in fatigue for the two conditions. Central blood pressure rose in proportion to fatigue for the subjects overall and returned quickly to its initial level afterwards. We conclude that human muscle fatigue can be increased by physiological reductions in perfusion pressure. Central blood pressure increases as the muscle fatigues, a response that may partially offset declining muscle performance.

1. The effects of hydrostatic changes in perfusion pressure on performance of working fatigue-resistant muscle fibres in the hand were studied in six normal subjects. 2. Supramaximal stimuli were delivered in trains of 200 ms duration, at 1 train S-1, to the ulnar nerve proximal to the wrist to produce isometric contractions of adductor pollicis. The force of contraction was measured and, after a level contraction force was achieved, the arm was passively raised or lowered. 3. Lifting the hand 45 cm above the heart produced a decline in force output from the muscle within several seconds which, after 4 min, fell by 22% below the steady-state level. Lowering the hand 45 cm below heart level produced an 8% increase in force output. Greater changes in force output occur at higher workloads. 4. It is concluded that in human subjects, muscle performance is sensitive to changes in perfusion pressure that occur across the physiological range. At moderate work levels, force output of the working muscles in the hand can vary by up to 30% over the physiological range of blood pressure. This dependence of muscular force on blood perfusion is of potential importance to motor control during normal activities.

Galanin (GAL), 29 amino acid peptide, has previously been shown to inhibit cardiac vagal action, and to cause a fall in systemic blood pressure in anaesthetised cats, at a dose of 6.2 nmol/kg. Here, the biological activity of exogenous GAL fragments was assessed in anaesthetised cats. GAL 1-16 at a dose equimolar with the full GAL 1-29 peptide (6.2 nmol/kg) and at a dose five times the molar dose of GAL 1-29 (31 nmol/kg), was found to be biologically active although the effects were less than that of the full peptide. GAL 1-15 at doses up to 10-times the molar dose of GAL 1-29, however, was not active, suggesting that amino acid 16, isoleucine, is critical for activity. In addition, GAL 15-29 and 21-29 showed no biological activity at doses up to 10-times the molar dose of GAL 1-29. These results suggest that the N-terminal rather than the C-terminal end of the GAL molecule is the one responsible for most of GAL's biological activity in this preparation.

Effects of neuropeptide Y (NPY 2.35-4.7 nmol) and the fragment NPY 18-36 (3.6-36 nmol) were studied in anaesthetized rats before and after vagotomy for actions on blood pressure (a postjunctional action) and on the change in pulse interval evoked by stimulation of the cut, peripheral vagus nerve (a prejunctional action). In intact rats NPY increased blood pressure. Low doses of NPY 18-36 (2.3-4.7 nmol) also increased blood pressure slightly but higher doses only transiently increased blood pressure and this was followed by a prolonged decrease in blood pressure. In vagotomised rats NPY increased blood pressure and attenuated cardiac vagal action. In higher doses the presynaptic effect of NPY 18-36 was more marked than its pressor action. NPY 18-36 (3.6-36 nmol) also increased blood pressure and attenuated cardiac vagal action. Thus, we conclude that the hypotensive action of NPY 18-36 depends on the intact vagus nerves: in the vagotomised rat NPY 18-36 has similar biological activity to NPY, but with reduced potency. To examine further the mechanism of hypotensive action of NPY 18-36 arterial rings from the central artery of the rabbit ear were also tested for direct actions of the peptides. This preparation is also suitable for testing any potentiation of contraction evoked by injection of noradrenaline. Neither NPY nor NPY 18-36 caused direct constrictor action in concentrations up to 10 microM. NPY 18-36 had no relaxing effect on constricted arterial rings.(ABSTRACT TRUNCATED AT 250 WORDS)

Galanin (GAL) is distributed in sympathetic nerves in the cat, and exogenous GAL inhibits cardiac vagal action and lowers blood pressure in this species. This study on anaesthetised cats compares the effects on cardiac vagal action and blood pressure of human, rat and porcine GAL. Human GAL has only recently been sequenced. It is of particular interest as it is not C-terminally amidated, unlike porcine and rat GAL. Many regulatory peptides require a C-terminal amide group for their action. However, human GAL showed similar biological activity to the other (amidated) GALs here. Omission of a single amino acid (Ser6) from rat GAL significantly attenuated both cardiovascular actions studied here.

1. The cardiovascular responses to voluntary isometric contractions performed by human subjects are determined by the proportion of maximal tension achieved by the muscles contracting, and not by the mass of the contracting muscles, nor by the absolute tension achieved (Lind & McNicol, 1967; confirmed here). When two or more muscle groups contract simultaneously at different relative tensions, the increments in heart rate and blood pressure are the same as when the muscle group at the higher relative tension contracts alone at that tension (Lind & McNicol, 1967). It is known that there are both central and reflex stimuli to the cardiovascular system in exercise, and the present study examines whether the muscular reflex stimuli are related to the proportion of maximal tension achieved or to the mass of contracting muscle. 2. Isometric hind-limb contractions were induced in anaesthetized dogs and cats by stimulation of spinal ventral roots. Pressor responses to contraction of both hind limbs were greater than responses to contractions of either hind limb alone. No differences were observed between heart rate responses to single or combined hind-limb contractions. 3. When human subjects perform isometric contractions, a pressor response can be maintained beyond the conclusion of the exercise by occluding muscle blood flow. This response is generally attributed to a reflex set up in the muscle by the action of chemical factors on afferent nerves. When comparable pressor responses were evoked by comparable proportional efforts with either the whole hand or the little finger, it was found here that the pressor responses remaining during the period of post-exercise occlusion were greater when the greater mass of muscle had been exercised. 4. It is concluded that the muscular reflex drive in isometric exercise is related to the bulk of contracting muscle.

The strength of action of the parasympathetic innervation of the heart was tested, in anaesthetized dogs, by regular delivery of bursts of supramaximal electrical pulses at low frequency to the cut, cardiac end of the vagus nerve. Periods of 'conditioning' stimulation of the same nerve at relatively high frequencies (15-30 Hz, for 15-300 s) were found to cause a slowly developing potentiation (up to 280% increase in the vagally induced prolongation of pulse interval) of the cardiac action of the low-frequency stimulation. This potentiation lasted for periods of up to 30 min after the conditioning period. Similar potentiation could be elicited for the action of one vagus nerve by conditioning the vagus on the other side. Potentiation of vagal action was not associated with an enhancement of the response of the heart to injected methacholine. Several neuropeptides, reported to be present in cardiac autonomic nerves, were tested for ability to mimic this effect when administered by intravenous injection. Vasoactive intestinal polypeptide, neurotensin, somatostatin and substance P all failed to do so at the doses tested. Vasopressin did induce an enhancement of cardiac vagal efficacy, but effective pharmacological blockade of its action did not block the potentiation caused by conditioning stimulation. In the absence of any evidence of neuromodulation of vagal action by these neuropeptides, it was presumed that the effect could be attributed to a classical homosynaptic post-tetanic potentiation mechanism involving intracellular accumulation of calcium ions in prejunctional nerve terminals.

Neuropeptide Y (NPY), a putative co-transmitter in noradrenergic sympathetic nerves of the cardiovascular system, inhibits the negative chronotropic action of the cardiac vagus. In the present study, peptides related to NPY were tested for potency in producing this effect. In bilaterally vagotomized, anaesthetised dogs, the increase in pulse interval caused by electrical stimulation of the peripheral stump of the right vagus was measured before and after intravenous administration of peptide. The effects of doses of NPY were compared with those of equimolar doses of peptide YY (PYY), and of avian and human pancreatic polypeptides (APP and HPP). PYY inhibited the vagal action more effectively than did NPY. APP and HPP, however, caused no change in strength of vagal action at the doses used. The response to a second injection of NPY, given soon after the injection of APP or HPP, was not significantly different from the original. Thus no evidence was obtained for a competitive inhibition of the action of NPY by either pancreatic polypeptide. A C-terminal hexapeptide fragment of human pancreatic polypeptide was also tested. Like APP and HPP, it neither inhibited the cardiac vagus nor blocked the action of NPY. The order of potency obtained here (PYY greater than NPY much greater than APP, HPP, CFPP) can be expected to be of use in efforts to distinguish the active site(s) of the NPY molecule, and to characterise the receptors involved in these modulatory effects.

In anesthetized cats reducing local arterial pressure from 125 to 75 Torr decreased blood flow (53 +/- 5%) and force production (57 +/- 7%) in soleus and medial gastrocnemius. Force was produced in these muscles by aerobic, slowly fatiguing fibers. Similar reductions in arterial pressure did not affect force production in caudofemoralis, which contains mainly fast-fatiguing fibers. In human subjects the electromyogram produced by the ankle extensors during rhythmic constant-force contractions increased as the contracting muscles were raised above the heart during legs-up tilt. This suggests that force production of active muscle fibers at a given level of activation fell with muscle perfusion pressure, thus requiring augmentation of muscle activity to sustain the standard contractions. Because aerobic fibers contributed to these contractions, it appears that force production of human muscle fibers is sensitive to small changes in perfusion pressure and, presumably, blood flow. The critical dependence of developed muscular force on blood pressure is of importance to motor control and may also play a significant role in cardiovascular control during exercise.

1. The effects of neuropeptide Y (NPY) on the pressor responses to intravenous injections of phenylephrine and to reflex activation of the sympathetic nervous system by stimulation of the sciatic nerve were examined in anaesthetized rats. 2. NPY (10-20 micrograms/kg) always potentiated the pressor response to exogenous phenylephrine (by a mean of 28.1 +/- 5.0%). The effect of the same dose of NPY on the pressor response to sciatic nerve stimulation was variable (sometimes inhibition, sometimes potentiation). 3. NPY appears to act by potentiating post-synaptic alpha-adrenoceptor-mediated vasoconstrictor effects. It may also inhibit noradrenaline release by a presynaptic action. Thus the net effect of NPY on sympathetic activation in vivo may depend on the balance between these two opposing actions.

1. In anaesthetized and decerebrate cats isometric exercise of the hind limb muscles was elicited by stimulating the spinal ventral roots L7-S1. This caused a rise in arterial blood pressure, with small increases in heart rate and pulmonary ventilation. These changes were abolished by cutting the dorsal roots receiving afferents from the exercising muscle.2. When the triceps surae muscle was made to exercise by ventral root stimulation, occlusion of the femoral artery and vein through and beyond the period of exercise caused the blood pressure to remain raised until the occlusion was removed. The ventilatory and heart rate responses were not markedly altered or prolonged by such circulatory occlusion.3. Injection of small volumes of 5% NaCl or isotonic KCl into the arterial blood supplying hind limb muscles gave cardiovascular and respiratory responses similar to those evoked by exercise. Like the responses to exercise, these responses were abolished by dorsal root section.4. Direct current anodal block of the dorsal roots receiving afferents from the exercising muscle was used to block preferentially large myelinated fibres: this form of block did not abolish the evoked cardiovascular and respiratory responses. Local anaesthetic block of the dorsal roots was used to block preferentially unmyelinated and small myelinated fibres: this form of block abolished the cardiovascular and respiratory responses. It is concluded that the reflex responses are mediated by fibres within groups III and IV (small myelinated fibres and unmyelinated fibres).

1. Experiments were designed to show whether elements of the command descending from higher centres to exercising muscles provide an input for cardiovascular and respiratory control. Vibration, known to be a powerful stimulus to the primary afferents from muscle spindles, was applied to the biceps tendon of human subjects performing sustained isometric contractions with the biceps or the triceps muscle. When the biceps was contracting this activation of muscle spindle primary afferents in it provided an element of reflex excitation, so that less central command was required to achieve a given tension. When triceps was contracting, the activation of muscle spindle primary afferents in its antagonist, biceps, contributed an element of reflex inhibition, so that more central command than normally was required to achieve a given tension. The cardiovascular and respiratory responses to an isometric effort could thus be investigated at any tension when the central command was normal, decreased, or increased.2. Blood pressure, heart rate, and pulmonary ventilation all increase in an isometric effort. The increase in each is less when the central command is reduced. The increase in each is greater when the central command is increased.3. It is concluded that there is irradiation of cardiovascular and respiratory control centres by the descending central command during voluntary muscular contractions in man.