Peripheral vascular smooth muscle responsiveness to tumour-promoting phorbol esters in pacing-induced heart failure.
Contractions of the dorsal pedal artery and saphenous vein to phorbol 12,13-dibutyrate (PDBu), 12-O-tetradecanoylphorbol 13-acetate (TPA), and 4 alpha-phorbol 12,13-didecanoate (4 alpha-phorbol) were measured from dogs with and without pacing-induced heart failure. The effects of polymyxin B (a relatively selective protein kinase C inhibitor), nifedipine (calcium channel blocker), and prazosin (alpha 1-adrenoceptor antagonist) were examined on the contractions developed to PDBu before heart failure, after 1 week of pacing, and at end-stage heart failure. PDBu and TPA, but not 4 alpha-phorbol, produced concentration-dependent increases in contractile force in both the artery and the vein. In the dorsal pedal artery, efficacy of and sensitivity to PDBu and TPA were enhanced after 1 week of pacing, but returned to control level at end-stage heart failure. In the saphenous vein, the concentration-effect curve to PDBu was displaced to the left after 1 week of pacing; EC50 values for PDBu were 3.2 x 10(-9) and 3.2 x 10(-8) M for 1 week paced and control, respectively. Polymyxin B significantly decreased the efficacy of PDBu in the dorsal pedal artery at all time points, but was less effective with advancing heart failure. In contrast, in the vein, there was a significant increase in inhibitory potential at end-stage heart failure. In all cases, nifedipine inhibited PDBu in a concentration-dependent manner. With the progression of heart failure, the contractions of the saphenous vein, developed to PDBu, became more sensitive to inhibition by nifedipine. Prazosin failed to inhibit vascular effects of PDBu. These results are discussed in terms of protein kinase C involvement in vascular contractions and its role in the pathogenesis of heart failure.
Forster
C
C
Department of Medicine, University of Toronto, ON, Canada.
D000818:Animals; D001808:Blood Vessels / Q000187:drug effects*; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006333:Heart Failure / Q000503:physiopathology*; D008297:Male; D009119:Muscle Contraction; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology*; D010703:Phorbol Esters / Q000494:pharmacology*; D011493:Protein Kinase C / Q000494:pharmacology; D013997:Time Factors
D010703:Phorbol Esters; D015240:Phorbol 12,13-Dibutyrate; D011493:Protein Kinase C