Analysis of the α‐adrenoceptor‐mediated, and other, components in the sympathetic vasopressor responses of the pithed rat

1 The possible involvement of neuropeptide Y (NPY) in relation to noradrenaline (NA) and adenosine triphosphate (ATP) mechanisms in the sympathetic nervous control of the vascular tone and capsule contraction in the blood perfused pig spleen was investigated in vivo. 2 Local injections or infusions of NA, NPY and a-, f-methylene ATP (mATP) caused vasonconstriction (perfusion pressure increase) and capsule contraction (increased venous blood flow). ATP only evoked vasodilatation. NPY was about 50 fold more potent than NA as a vasoconstrictor, and the NPY response was more long-lasting. Reserpine treatment did not change the effects of NPY. 3 Electrical stimulation of the splenic nerves in control animals caused a frequency-dependent, guanethidine-sensitive output of both NPY-like immunoreactivity (-LI) and NA, suggesting corelease. The output of NPY-LI relative to NA was enhanced at high frequency stimulation. Furthermore, a-adrenoceptor blockade by phentolamine enhanced both the output of NPY-LI and NA while inhibition of the neuronal uptake of NA with desipramine reduced the low frequency stimulation-evoked overflow of NPY-LI. Preganglionic denervation did not change the output of NPY-LI or NA. 4 Reserpine treatment reduced both the splenic content of NA and NPY-LI. Preganglionic denervation inhibited the reserpine-induced depletion of the NPY content but not of NA in terminal areas. The stimulation-evoked NPY overflow was markedly enhanced, especially at low-frequency stimulation after resperpine, and the plasma levels of NPY-LI in the venous effluent were then in the nmolar range (i.e. where exogenous NPY induced vasoconstriction). The perfusion-pressure increase upon stimulation in reserpine-treated, preganglionically-denervated animals was highly correlated (r = 0.91) to the NPY overflow. The functional 0.5 Hz responses were reduced after reserpine, while at higher frequencies the functional effects were of similar magnitude to controls but longer-lasting.5 Tyramine induced a release of NA but not of NPY-LI. Furthermore, the increase in perfusion pressure induced by tyramine was absent after reserpine.6 After tachyphylaxis to the vasoconstrictor effects of mATP, the nerve stimulation-evoked, functional response as well as the NA and NPY-LI overflow were unchanged. After reserpine treatment, both the perfusion-pressure increase and NPY-LI overflow to nerve stimulation were reduced after mATP tachyphylaxis. 7 In conclusion, release of NPY rather than ATP may explain the long-lasting, non-adrenergic, splenic functional responses in reserpinized animals upon sympathetic stimulation. However, NA is most likely the main splenic transmitter when low-frequency stimulation is used under control conditions. Neuropeptide Y (NPY), a peptide with 36 amino porcine brain (Tatemoto, 1982), co-exists with noracid residues which was originally isolated from adrenaline (NA) in postganglionic, sympathetic nerves in a variety of peripheral organs (Lundberg et

Section: Discussionsupporting

confidence: 83%

Evidence for co‐transmitter role of neuropeptide Y in the pig spleen

Lundberg

Rudehill

Sollevi

et al. 1989

“…It is possible that in the absence of an active sympathetic nervous system, this may be sufficient to induce adrenal catecholamine release. The catecholamine involved is most probably adrenaline, as this is the major catecholamine secreted in the pithed rat (Yamaguchi & Kopin, 1979), and the vascular effects of adrenal gland stimulation in the pithed rat are similar to those evoked by exogenous adrenaline (Flavahan et al, 1985).…”

Section: Discussionmentioning

confidence: 99%

Effect of artificial respiratory volume on the cardiovascular responses to an α₁‐ and an α₂‐adrenoceptor agonist in the air‐ventilated pithed rat

MacLean¹

1988

1 The effect of varying artificial respiratory volume (at a fixed rate of 54 min-) on cardiac output, its distribution and tissue blood flows were determined with tracer microspheres in control pithed rats or during pressor responses to either the a1-adrenoceptor agonist phenylephrine or the a2-agonist xylazine. Phenylephrine was investigated in the presence of propranolol (3 mg kg 1). The rats were pithed under halothane anaesthesia. 2 A respiratory volume of 15 ml kg-produced modest hypercapnia (Paco2 = 47 mmHg), hypoxia (Pao2 = 60 mmHg) and acidosis (pH = 7.35) relative to control animals respired at 20 ml kg1 (Paco2 = 32 mmHg; Pao2 = 77 mmHg; pH = 7.47). In rats respired at 15 ml kg 1, total peripheral resistance was lower, and cardiac output greater (due to increased stroke volume), than in the controls. Lowering respiratory volume reduced distribution of cardiac output to the kidneys, increased it to the large intestine and also increased blood flow through the gastrointestinal tract, skin and spleen. A respiratory volume of 30 ml kg-1 gave mild hypocapnia (Paco2 = 19 mmHg), hyperoxia (Pao2 = 101 mmHg) and alkalosis (pH = 7.59) compared to 20 ml kg'-but had no effect on cardiac output distribution or organ blood flow although heart rate was 29% greater at 30 ml kg-'. 3 Xylazine (500 pg bolus followed by lOOI gmin1 infusion) at all three respiratory volumes gave well-sustained mean pressor responses of 62-64 mmHg by increasing both total peripheral resistance and cardiac output (resulting from increased stroke volume). It increased the proportion of cardiac output passing to the liver, reduced that going to the spleen and gastrointestinal tract and increased cardiac, renal and hepatosplanchnic blood flows. 4 The secondary, relatively sustained, pressor effect of phenylephrine (5 pg bolus followed by 0.4 pg min1 infusion, i.v.) varied at the 3 respiratory volumes with mean values from 32 to 53 mmHg. This response was due to both increased total peripheral resistance and cardiac output (resulting from greater stroke volumes and/or heart rates). Phenylephrine increased the proportion of cardiac output passing to the gastrointestinal tract, heart, kidneys and hepatosplanchnic bed and increased cardiac, hepatosplanchnic, renal and gastrointestinal blood flows. 5 Respiratory volume had no effect on the cardiovascular effects of xylazine. However, respiratory volume modified the effects of phenylephrine on heart rate and changed the relative contributions of stroke volume and heart rate to the increased cardiac output. It also influenced the effects of phenylephrine on cardiac output distribution to the liver, epididimides and hepatosplanchnic bed and on blood flow through skeletal muscle and the large intestine. 6 Changes in respiratory volume of air ventilated pithed rats thus influence cardiac output, its distribution and regional blood flows. Such changes can also differently influence the responses of various vascular beds to phenylephrine whilst having no effect on their responses to xylazine.

“…Thirdly, only partial antagonism of the a-blocker-resistant pressor response was observed after ' Author for correspondence. cumulative addition of mATP (0.005-0.1 mgkg-1) (Flavahan et al, 1985). More recently, it was found that a novel administration regime of mATP in the pithed rat avoided the cardiotoxic effects of the drug.…”

Section: Introductionmentioning

confidence: 99%

“…The pressor response of the pithed rat to electrical stimulation of the preganglionic sympathetic nerves is biphasic, the first phase being due to direct vasoconstriction and the second phase due to the action of released adrenomedullary catecholamines on the vasculature (Gillespie et al, 1970;Flavahan et al, 1985). The initial 'neuronal' phase of this response has been shown to be resistant to a combination of c1-and a2-adrenoceptor blockade, whilst the secondary 'adrenal' phase was abolished by this treatment (Flavahan et al, 1985).…”

Section: Introductionmentioning

confidence: 99%

“…The initial 'neuronal' phase of this response has been shown to be resistant to a combination of c1-and a2-adrenoceptor blockade, whilst the secondary 'adrenal' phase was abolished by this treatment (Flavahan et al, 1985). These findings are of particular interest in the light of in vitro investigations which suggest the involvement of a nonadrenergic neurotransmitter, possibly ATP, acting as a cotransmitter with NA, in vascular sympathetic nerves (Sneddon & Burnstock, 1984;Muramatsu et al, 1984;Muramatsu, 1986;1987;Burnstock & Warland, 1987;Nagao & Suzuki, 1988;Machaly et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Investigation of the selectivity of α, β‐methylene ATP in inhibiting vascular responses of the rat in vivo and in vitro

Dalziel

Gray

Drummond

et al. 1990

1 The proposal that a,fi-methylene adenosine 5'-triphosphate (mATP) inhibits pressor responses in the pithed rat by selective desensitization of P2.-purinoceptors was examined by comparing the selectivity of its inhibitory effect on vascular responses in vitro and in vivo.2 In isolated ring preparations of rat femoral and tail artery, which had been denuded of endothelium, mATP markedly reduced the contractile response to exogenous ATP but had no effect on the response of the arteries to exogenous noradrenaline (NA). 3 In the pithed rat a substantial proportion of the pressor response to sympathetic nerve stimulation was resistant to a-adrenoceptor blockade, suggesting a non-adrenergic component to the sympathetic vasoconstriction. 4 In the pithed rat, repeated administration of desensitizing doses of mATP attenuated the pressor response to sympathetic nerve stimulation by approximately 80%, suggesting that a component of the sympathetic vasoconstriction is mediated by ATP acting on vascular P21-purinoceptors. However, the same mATP treatment also attenuated, to a similar degree, the pressor responses to intravenous NA, angiotensin II and vasopressin, indicating that the desensitization procedure was non-selective.5 These results demonstrate that while mATP can be used to desensitize selectively P2.-purinoceptors in vitro, its attenuation of the sympathetic nerve-mediated pressor response in vivo is non-selective.