Effects of nifedipine on electrical and mechanical responses of rat and guinea pig vas deferens

Blakeley, A. G. H.; Brown, D. A.; Cunnane, T.C.; French, A M; McGrath, J.C.; Scott, N C

doi:10.1038/294759a0

Cited by 112 publications

(53 citation statements)

References 9 publications

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“…This may seem an esoteric exercise but has advantages when attempting to correlate effects against contractile responses with other guides to neurotransmission.For example, in the vas deferens there is no solid evidence to connect e.j.ps, and the action potentials which they initiate, with the adrenergic contraction. However, these electrical events are implicated in the non-adrenergic contraction (Blakeley et al, 1981). In contrast, sympathetic transmitter output, measured as the nerve-induced overflow of noradrenaline (tritiated or endogenous), is more likely to correlate with an 'cx-adrenergic' contraction.…”

Section: Differential Effects Of Nifedipinementioning

confidence: 98%

See 1 more Smart Citation

Separation of adrenergic and non‐adrenergic contractions to field stimulation in the rat vas deferens

Brown

Docherty

French

et al. 1983

British J Pharmacology

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126

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Section: Differential Effects Of Nifedipinementioning

confidence: 98%

“…These observations could be reconciled if the 'nonadrenergic' response can be initiated by only a small proportion of the nerves in the organ, which is possible since it involves the spread of the action potential (Blakeley et aL, 1981).…”

Section: Differential Effects Of Nifedipinementioning

confidence: 99%

Separation of adrenergic and non‐adrenergic contractions to field stimulation in the rat vas deferens

Brown

Docherty

French

et al. 1983

British J Pharmacology

Self Cite

126

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“…The first phase of the response seems to result from the summation of ej.ps (Blakeley et al, 1981). There is considerable doubt as to whether the ej.ps and the initial contractile response are mediated by noradrenaline (NA).…”

Section: Introductionmentioning

confidence: 99%

Actions of α, β‐methylene ATP and 6‐hydroxydopamine on sympathetic neurotransmission in the vas deferens of the guinea‐pig, rat and mouse: support for co‐transmission

Allcorn

Cunnane

Kirkpatrick

1986

British J Pharmacology

114

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α‐Adrenoceptor antagonists (prazosin or phentolamine) reduced the contractile response to field stimulation of the isolated vasa deferentia of guinea‐pig, rat and mouse. α, β‐Methylene ATP (α, β‐MeATP) reduced that portion of the contraction which was resistant to α‐adrenoceptor blockade. α, β‐MeATP (1–800 μM) did not affect action potential conduction in the guinea‐pig vas deferens nerves, and (up to 10 μM) did not reduce the stimulation‐evoked overflow of [3H]‐noradrenaline from this tissue. Spontaneous excitatory junction potentials (s.e. j.ps) in the majority of cells of guinea‐pig, rat, and mouse vasa were abolished by α, β‐MeATP (0.1–10 μM). In a small number of cells s.e.j.ps were resistant to the actions of α, β‐MeATP (10 μM). Excitatory junction potentials (e.j.ps) in the majority of cells in vasa of all species studied were abolished by α, β‐MeATP (1–10 μM). E.j.ps elicited in some ‘resistant’ cells demonstrated marked facilitation characteristics. It is concluded that α, β‐MeATP inhibits s.e.j.ps and e.j.ps by a postjunctional action. In all species pretreatment of animals with 6‐hydroxydopamine produced a marked reduction in noradrenaline (NA) content (as determined by fluorescence histochemistry) and abolished e.j.ps, findings which suggest that e.j.ps originated from sympathetic nerves. The results support the hypothesis that NA and ATP are co‐transmitters in the sympathetic nerves of rodent vasa.

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“…Its potency (IC 50 ) in inhibiting ATP-elicited membrane currents was 24±5 μM at P2X 2 receptors and ~220 μM at P2X 4 receptors. At Group I (P2X 1 and P2X 3 ) receptors the potency was not determined, however the closely related DHP nifedipine was inactive at rat smooth muscle P2X 1 -like receptors (Blakeley et al, 1981) and at inhibitory P2Y receptors in pig ileum (Soto et al, 1999). Nicardipine was inactive at 100 μM as an antagonist of the effects of 2-MeSATP at turkey erythrocyte P2Y 1 receptors (J. Boyer, T.K.…”

Section: Resultsmentioning

confidence: 99%

“…Previously, the 1,4-DHP nifedipine was found to be inactive in blocking the effects of ATP at P2X 1 -like receptors in the rat vas deferens (Blakeley et al, 1981). Thus far, the new generation of P2X receptor antagonists tends to show good activity at the P2X 1 and P2X 3 subunits (see Section 1) but reduced activity at the P2X 2 and P2X 4 subunits.…”

Section: Discussionmentioning

confidence: 99%

In search of selective P2 receptor ligands: interaction of dihydropyridine derivatives at recombinant rat P2X2 receptors

Kim

King

2000

Journal of the Autonomic Nervous System

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Abstract1,4-Dihydropyridines are regarded as privileged structures for drug design, i.e. they tend to bind to a wide variety of receptor sites. We have shown that upon appropriate manipulation of the substituent groups on a 1,4-dihydropyridine template, high affinity and selectivity for the A 3 subtype of adenosine receptors ('P1 receptors') may be attained. In the present study we have begun to extend this approach to P2 receptors which are activated by ATP and other nucleotides. Nicardipine, a representative dihydropyridine, used otherwise as an L-type calcium channel blocker, was shown to be an antagonist at recombinant rat P2X 2 (IC 50 = 25 μM) and P2X 4 (IC 50 2 20 μM) receptors expressed in Xenopus oocytes. Thus, this class of compounds represents a suitable lead for enhancement of affinity through chemical synthesis. In an attempt to modify the 1,4-dihydropyridine structure with a predicted P2 receptor recognition moiety, we have replaced one of the ester groups with a negatively charged phosphonate group. Several 4-phenyl-5-phosphonato-1,4-dihydropyridine derivatives, MRS 2154 (2,6-dimethyl), MRS 2155 (6-methyl-2-phenyl), and MRS 2156 (2-methyl-6-phenyl), were synthesized through three component condensation reactions. These derivatives were not pure antagonists of the effects of ATP at P2X 2 receptors, rather were either inactive (MRS 2156) or potentiated the effects of ATP in a concentration-dependent manner (MRS 2154 in the 0.3-10 μM range and MRS 2155 at >1 μM). Antagonism of the effects of ATP at P2X 2 receptor superimposed on the potentiation was also observed at >10 μM (MRS 2154) or 0.3-1 μM (MRS 2155). Thus, while a conventional dihydropyridine, nicardipine, was found to antagonize rat P2X 2 receptors ninefold more potently than P2X 4 receptors, the effects of novel, anionic 5-phosphonate analogues at the receptor were more complex.

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Effects of nifedipine on electrical and mechanical responses of rat and guinea pig vas deferens

Cited by 112 publications

References 9 publications

Separation of adrenergic and non‐adrenergic contractions to field stimulation in the rat vas deferens

Separation of adrenergic and non‐adrenergic contractions to field stimulation in the rat vas deferens

Actions of α, β‐methylene ATP and 6‐hydroxydopamine on sympathetic neurotransmission in the vas deferens of the guinea‐pig, rat and mouse: support for co‐transmission

In search of selective P2 receptor ligands: interaction of dihydropyridine derivatives at recombinant rat P2X2 receptors

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