Influence of nonpeptide angiotensin II receptor antagonist, losartan, on neurogenic vasoconstriction.
The influence of the nonpeptide angiotensin antagonist losartan on andrenergic/purinergic cotransmission in pithed rat preparation before and after treatment with prazosin (alpha 1-antagonist), rauwolscine (alpha 2-antagonist), and/or the P2x desensitizing agent alpha, beta-methylene ATP (mATP) was examined. Stimulation of the spinal sympathetic outflow (T6-T8) through the pithing rod (1.0-cm electrode) at supramaximal voltage, 0.05-ms pulses, at different frequencies (1-40 Hz) evoked biphasic responses. Changes in diastolic blood pressure (DBP) were assessed at the early peak after the 1.0-train. The vasopressor responses to sympathetic nerve stimulation were partially blocked by prazosin, rauwolscine, mATP, and losartan. Administration of prazosin or mATP but not rauwolscine as compared with losartan alone could further reduce vasopressor responses to sympathetic nerve stimulation. In rats treated with losartan and either prazosin or rauwolscine, administration of mATP further reduced vasoconstrictor responses to sympathetic nerve stimulation. In contrast, rauwolscine did not further reduce vasoconstriction due to sympathetic nerve stimulation in rats that had received losartan and prazosin combined. Furthermore, the inhibitory actions of mATP were significantly greater in rats that had received losartan and prazosin as compared with rats that received losartan and rauwolscine. The results indicate that losartan in vivo is most effective in inhibiting nerve-mediated alpha 2-adrenoceptor responses as opposed to either alpha 1-adrenoceptor or P2x-purinoceptor responses.
Tabrizchi
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Department of Pharmacology & Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, Canada.
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000704:Analysis of Variance; D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D003655:Decerebrate State; D004558:Electric Stimulation; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D019808:Losartan; D008297:Male; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013564:Sympathetic Nervous System / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*; D015016:Yohimbine / Q000494:pharmacology
D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; D000804:Angiotensin II; D015016:Yohimbine; D000255:Adenosine Triphosphate; D019808:Losartan; C002630:alpha,beta-methyleneadenosine 5'-triphosphate; D011224:Prazosin