Post-exercise depression of baroreflex slowing of the heart in humans.

In normal human subjects, we tested whether a 20- to 30-min period of rhythmic exercise, intended to provoke strong activation of the sympathetic nerves, would lead to prolonged inhibition of vagally mediated bradycardia evoked reflexly by stimulation of the baroreceptors by neck suction. Negative pressure within the neck cuff (-40 to -80 mmHg) reflexly evoked a reproducible increase in pulse interval. Following exercise, this increase in pulse interval was reduced from 444 +/- 104 ms to 76 +/- 57 ms (mean +/- SEM). Recovery time was 42 +/- 9 min. These findings demonstrate a prolonged attenuation of cardiac vagal action following rhythmic exercise in normal human subjects. It is known that neuropeptide Y (NPY) is released from cardiovascular sympathetic nerves, that it attenuates cardiac vagal action and that plasma levels of NPY are elevated for a prolonged period after exercise. Therefore, it is proposed that NPY, released from sympathetic nerves during exercise, attenuates reflexly evoked cardiac vagal action for a prolonged period after exercise ends.

Effects of pituitary adenylate cyclase-activating polypeptide on cardiovascular and respiratory responses in anaesthetised dogs.

This study examines some of the cardiovascular and respiratory effects of pituitary adenylate cyclase-activating polypeptide (PACAP) in anaesthetised dogs. Intravenous injection of PACAP 27 caused an increase in arterial blood pressure and an increase in heart rate. The blood pressure response was significantly reduced by adrenoceptor blockade suggesting a mechanism of action mediated in part via catecholamines. The heart rate increase was unaltered by adrenoceptor blockade suggesting a direct effect of PACAP 27. PACAP 27 also caused potentiation of cardiac slowing caused by stimulation of the vagus nerve. In addition, PACAP 27 powerfully stimulated breathing. This was probably evoked by stimulation of arterial chemoreceptors, because bilateral section of the carotid sinus nerves abolished this effect. PACAP 27 had no effect on the ability of the cardiac sympathetic nerve to increase heart rate, nor on the interaction between the sympathetic and parasympathetic systems in the heart.

Inhibition of vagally induced gastric contractions by sympathetic stimulation, neuropeptide Y and galanin.

The effects on vagally-induced gastric contractions of local electrical stimulation of the gastric sympathetic nerves were investigated in anaesthetised cats. Sympathetic stimulation caused an inhibition of vagally mediated gastric contractions which survived beta-adrenoceptor blockade and could not be mimicked by the alpha-adrenoceptor agonist phenylephrine. We therefore concluded that the inhibition was not predominantly dependent upon activation of alpha or beta adrenoceptors, although some effect attributable to noradrenaline could not be entirely excluded. In an attempt to determine the mechanism of this phenomenon, we administered exogenous neuropeptide Y (NPY) and galanin (GAL), both of which are known to occur as cotransmitters in some sympathetic nerves in the cat. Both NPY and GAL were able to mimic the effect of sympathetic stimulation on vagally-induced gastric contractions but their effects were variable.

Sympathetic and parasympathetic interaction in vascular control of the nasal mucosa in anaesthetized cats.

1. In cats anaesthetized with pentobarbitone sodium (45 mg kg-1), electrical stimulation of the parasympathetic nerve fibres to the nasal mucosa evoked frequency-dependent increases in nasal arterial blood flow whereas stimulation of the superior cervical sympathetic nerve induced marked vasoconstriction. 2. Sympathetic nerve stimulation for 3 min at 10 Hz evoked significant (P < 0.05) and prolonged (> 30 min) attenuation of the vasodilatory response to subsequent parasympathetic stimulation. 3. Combined pretreatment with adrenergic and cholinergic blockers reduced the vasoconstrictory effect of sympathetic stimulation by 28 +/- 4% (mean +/- S.E.M.) and the parasympathetically evoked vasodilatation by 20 +/- 5%. 4. The vasodilatory effects of exogenous vasoactive intestinal polypeptide, peptide histidine isoleucine and galanin, and the vasoconstrictory effects of exogenous neuropeptide Y (NPY) and alpha,beta-methylene adenosine 5'-triphosphate were not altered by adrenoceptor antagonists and atropine whereas the effects of exogenous noradrenaline and acetylcholine were virtually abolished. 5. The atropine-resistant parasympathetic vasodilatation remained significantly attenuated for more than 30 min after the non-adrenergic sympathetically evoked vasoconstriction. 6. Exogenous NPY (25 x 10(-9) mol) mimicked the effect of sympathetic stimulation in attenuating subsequent parasympathetically evoked vasodilatation.

Modulation by neuropeptide Y of parasympathetic nerve-evoked nasal vasodilatation via Y2 prejunctional receptor.

1. In pentobarbitone anaesthetized dogs, preganglionic stimulation of the superior cervical sympathetic nerve (15V, 1 ms, 10 Hz) induced marked reduction of nasal arterial blood flow, whereas parasympathetic nerve stimulation (5 V, 1 ms, 10-30 Hz) evoked frequency-dependent vasodilatation. 2. Sympathetic nerve stimulation for 3 min at 10 Hz evoked significant (P < 0.05) and prolonged attenuation of the vasodilator response to subsequent parasympathetic stimulation. Pretreatment with phentolamine (0.5 mg kg-1 h-1), propranolol (1 mg kg-1) and atropine (0.5 mg kg-1) reduced the vasoconstrictor effect of sympathetic stimulation by 35 +/- 4% whereas the parasympathetic nerve-evoked vasodilatation was not significantly modified. Atropine-resistant parasympathetic vasodilatation remained significantly attenuated for more than 30 min after non-adrenergic sympathetic nerve-evoked vasoconstriction. 3. Vasodilator effects of exogenous vasoactive intestinal polypeptide and peptide histidine isoleucine and vasoconstrictor effects of exogenous neuropeptide Y (NPY) and the NPY analogue [Leu31, Pro34] NPY (Y1-receptor agonist, 8 nmol kg-1), were not altered by adrenoceptor antagonists and atropine f1p4eas the effects of exogenous noradrenaline and acetylcholine were virtually abolished. Attenuation of parasympathetic-evoked vasodilatation could be mimicked by exogenous NPY (8 nmol kg-1) and the NPY analogue, N-acetyl [Leu28, Leu31] NPY 24-36 (Y2-receptor agonist, 20 nmol kg-1) but not by exogenous Y1-receptor agonist. The Y2-receptor agonist did not show significant vasoconstrictor action. 4. It is concluded that sympathetic nerve stimulation attenuates parasympathetic vasodilatation via NPY release acting on prejunctional Y2 receptors.

The role of ATP in non-adrenergic sympathetic vascular control of the nasal mucosa in anaesthetized cats and dogs.

1. In anaesthetized cats and dogs, local intra-arterial injection of noradrenaline and alpha, beta-methylene adenosine 5'-triphosphate (mATP) reduced both nasal arterial blood flow and nasal mucosal volume (a measure of capacitance vessel function). The responses to mATP were not modified by pretreatment with the adrenoceptor antagonists phentolamine and propranolol or the purinoceptor antagonist suramin. The vascular effects of noradrenaline were not altered by suramin, but were virtually abolished by adrenoceptor antagonists. 2. After adrenoceptor blockade, frequency-dependent reductions in nasal arterial blood flow with sympathetic nerve stimulation were reduced by 25 and 39% in cats and dogs, respectively; whereas the volume response was reduced by 56% in cats and 54% in dogs. The remaining non-adrenergic sympathetic nerve-evoked vascular responses were not influenced by suramin. 3. During desensitization to mATP induced by local intra-arterial infusion for 5 min, the remaining non-adrenergic nasal blood flow and volume responses to sympathetic nerve stimulation were reduced in the dog but not in the cat. 4. It is suggested that both adrenergic and non-adrenergic mechanisms are involved in the sympathetic control of the nasal mucosa vascular bed of both species. Since desensitization to mATP markedly reduces the remaining non-adrenergic nasal vasoconstriction evoked by sympathetic nerve stimulation in the dog, ATP is a possible sympathetic mediator in the nasal vascular bed in this species.

Functional effects of a family of galanin antagonists on the cardiovascular system in anaesthetised cats.

Previous studies have shown that injection of galanin (GAL: 6.2 nmol/kg) causes prolonged inhibition of cardiac vagal action in anaesthetised cats. Stimulation of the cardiac sympathetic nerve (16 Hz for 5 min) also produces inhibition of cardiac vagal action, an effect which has been proposed to be due to the release of endogenous GAL from sympathetic nerves. In a previous study we tested galantide (M15) and in this study we compared galantide with two other GAL antagonists for their GAL antagonist activity in our experimental model. Each of these incorporate the N-terminal fragment GAL 1-13 and a C-terminal portion of another bioactive peptide and all are C-terminally amidated. GAL 1-13 Substance P 5-11 amide (galantide: M15: 62 nmol/kg and 156 nmol/kg), GAL 1-13 Spantide amide (C7: 156 nmol/kg) and GAL 1-13 NPY 24-36 amide (M32a: 62 nmol/kg) all significantly reduced the cardiac vagal inhibitory effect of exogenous GAL and also reduced the effect of sympathetic stimulation on subsequent cardiac vagal slowing, giving strong support to our hypothesis that GAL is involved in this phenomenon. No antagonist reduced the depressor effect of GAL. This study demonstrates the GAL antagonist properties of these agents on autonomic neuroeffector functions making them useful tools in elucidating further functions of endogenous GAL.

Galanin antagonist effects on cardiac vagal inhibitory actions of sympathetic stimulation in anaesthetized cats and dogs.

1. Galantide, a putative galanin antagonist composed of twenty amino acids, caused a significant reduction in the vagal attenuating action of galanin injection (20 micrograms/kg; 6.2 nmol/kg) in anaesthetized cats at both ten times (137 micrograms/kg; 62 nmol/kg) and twenty-five times (343 micrograms/kg: 156 nmol/kg) the molar dose of galanin. Galantide did not block the depressor action of galanin in these animals. 2. Galantide, at both doses, also significantly reduced the vagal attenuating action of a 5 min period of cardiac sympathetic stimulation at 16 Hz in anaesthetized cats. 3. In anaesthetized dogs, galantide, at the same dose used in cats (137 micrograms/kg; 62 nmol/kg) had no significant effect on the vagal attenuation evoked by cardiac sympathetic stimulation or injection of neuropeptide Y (35 micrograms/kg; 8.2 nmol/kg). 4. This study therefore demonstrates antagonist properties of galantide on the vagal inhibitory action of galanin. It supports the hypothesis that the vagal inhibitory factor released by cardiac sympathetic nerve stimulation in the cat, but not the dog, is galanin, although it does not exclude the possibility of other factors playing a more minor role. Because galantide was not shown to block the depressor action of galanin, this study also suggests that there may be more than one galanin receptor subtype.

The effects of galanin and galanin fragments on cardiac-vagal action and blood pressure in the anaesthetised cat.

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 sympathetic activity and galanin on cardiac vagal action in anaesthetized cats.

1. Stimulation of the right cardiac sympathetic nerve for 3 or 5 min at 16 Hz in the presence of effective beta-adrenoceptor blockade evoked prolonged attenuation of subsequent cardiac vagal action in anaesthetized cats. Concurrent sympathetic and vagal stimulation, both at 16 Hz for the same period of time as sympathetic stimulation alone, reduced or abolished the inhibition of vagal action which followed when sympathetic stimulation was given alone. 2. A series of three successive intravenous injections of galanin all caused attenuation of vagally induced slowing of the heart, but the effect of each injection was less than that of the previous one. A fourth injection of galanin given after a 45 or 60 min rest period showed return of sensitivity. 3. Sympathetic stimulation at 16 Hz for 5 min was less efficient in causing attenuation of vagal slowing when applied following the administration of exogenous galanin. This is consistent with galanin being the mediator of vagal attenuation following sympathetic stimulation.

Effects of human, rat and porcine galanins on cardiac vagal action and blood pressure in the anaesthetised cat.

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.