Effects of 2,3-butanedione monoxime on blood pressure, myocardial Ca2+ currents, and action potentials of rats.
2,3-Butanedione monoxime (BDM) has a negative inotropic effect on smooth muscles as well as the myocardium. Therefore, in the present study we compared the sensitivity to BDM of the cardiovascular system of the spontaneously hypertensive (SHR) and the normotensive Wistar-Kyoto (WKY) rat. While BDM significantly decreased the blood pressure (BP) for both strains, the SHR was significantly more responsive. Specifically, 5, 30, 100, and 200 mg/kg BDM (intravenously) reduced BP of the SHR by 9 +/- 3, 20 +/- 3, 49 +/- 5, and 63 +/- 7 mm Hg, respectively. The same doses of BDM reduced BP of the WKY by 0, 2 +/- 0.4, 18 +/- 3, and 26 +/- 3 mm Hg. The duration of the hypotensive effect of BDM was also greater for the SHR. In vitro, BDM had a greater suppressant effect on the L-type Ca2+ current (ICa(L)) of SHR ventricular myocytes; the IC50 for the suppression of ICa(L) was 17 and 29 mM for SHR and WKY ventricular myocytes, respectively. The beta-adrenergic receptor agonist isoproterenol antagonized the suppressant effect of BDM on ICa(L). Furthermore, BDM significantly reduced the duration of both spontaneous and electrically stimulated action potentials of cultured neonatal rat cardiomyocytes. Intracellular dialysis with the catalytic unit of protein kinase A antagonized BDM's effect on the action potential. These data suggest that suppression of myocardial activity contributes to the hypotensive effect of BDM. In addition, the elevated response to BDM of SHR cardiac myocytes may indicate that the conformation and/or modulation of the L-type Ca2+ channel differ for the SHR and WKY lines of rat.
Xiao
Y F
YF
Department of Pharmacology and Toxicology, New Jersey Medical (UMDNJ), Newark, NJ 07103-2714, USA.
McArdle
J J
JJ
D000200:Action Potentials / Q000187:drug effects; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003931:Diacetyl / Q000031:analogs & derivatives* / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY
D000318:Adrenergic beta-Agonists; D000959:Antihypertensive Agents; D015220:Calcium Channels; C004717:diacetylmonoxime; D017868:Cyclic AMP-Dependent Protein Kinases; D003931:Diacetyl; D007545:Isoproterenol