Pyrazine derivatives affect membrane fluidity of vascular smooth muscle microsomes in relation to their biological activity.
We have previously demonstrated that several structurally similar pyrazine derivatives, tetramethylpyrazine (TMP), triethylpyrazine (3EP) and tetraethylpyrazine (TEP) consistently inhibited a wide spectrum of plasmalemma-associated biological activities of vascular smooth muscles in contractility and radioligand binding studies in the following order of increasing potency, TMP < 3EP < TEP. We speculated that these pyrazine derivatives elicit multiple effects in the above order of potency by affecting, at least in part, the bulk physical properties of the lipid bilayers in the cell membrane. This hypothesis was tested in the current study using plasmalemma-enriched microsomes isolated from dog aortic smooth muscle using two different biophysical techniques: fluorescence polarization and electron spin resonance. The calculated membrane fluidity values obtained as a function of temperature by both methods are consistent with the above order of potency. The amount of incorporation of these pyrazine derivatives into the vascular smooth muscle membranes also increased with the increasing hydrophobicity of these drugs, i.e., TMP < 3EP < TEP. Our results are consistent with the contention that these pyrazine derivatives not only interact with receptor protein molecules in the biological membranes, but also modulate these receptor properties via their interaction with the lipid bilayer altering the membrane microviscosity.
Department of Biomedical Sciences, McMaster University Health Sciences Centre, Hamilton, Ontario, Canada.
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D000818:Animals; D001665:Binding Sites; D004285:Dogs; D004578:Electron Spin Resonance Spectroscopy; D005260:Female; D005454:Fluorescence Polarization; D066298:In Vitro Techniques; D008051:Lipid Bilayers / Q000378:metabolism; D008297:Male; D008560:Membrane Fluidity / Q000187:drug effects*; D008861:Microsomes / Q000187:drug effects* / Q000502:physiology; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D011719:Pyrazines / Q000378:metabolism / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology
D008051:Lipid Bilayers; D011719:Pyrazines; D014665:Vasodilator Agents; C072829:tetraethylpyrazine; C017953:tetramethylpyrazine