Inhibition of the effects of adenosine on force of contraction and the slow calcium inward current by pertussis toxin is associated with myocardial lesions.
The effects of adenosine and the adenosine receptor agonist (-)-N(6)-phenyl-isopropyladenosine (PIA) in the presence of isoprenaline on isometric force of contraction and calcium dependent slow action potentials were studied in papillary muscles from guinea pigs pretreated with pertussis toxin and control guinea pigs. Hearts from guinea pigs treated in the same way with pertussis toxin or solvent alone underwent histological examination. For comparison, hearts from isoprenaline treated guinea pigs were also studied. Pertussis toxin specifically inactivates guanine nucleotide binding proteins (N proteins) involved in transmembrane signal transduction in many receptor systems (for example, adenosine receptors, m-cholinoceptors, and and alpha 2 adrenoceptors). In papillary muscles from control guinea pigs adenosine and PIA in the presence of isoprenaline produced a negative inotropic effect and inhibited the maximal rate of depolarisation of slow calcium dependent action potentials in potassium depolarised papillary muscles. After pretreatment with pertussis toxin the inhibitory effects both on force of contraction and on the maximal rate of depolarisation of adenosine and PIA were abolished. Treatment with pertussis toxin produced disseminated myocardial necrosis and a disseminated cellular calcium overload evidenced by glyoxal-2-bis-hydroxyanil (GBHA) staining. Similar lesions (for example, myocardial necrosis and cellular calcium overload) were also observed after treatment with isoprenaline. In controls neither myocardial necrosis nor cellular calcium overload was found. It is concluded that pertussis toxin sensitive N proteins are involved in the inhibitory effects of adenosine and PIA on force of contraction and on slow calcium inward current during beta adrenergic stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)
Böhm
M
M
Department of Pharmacology, Universitäts-Krankenhaus Eppendorf, University of Hamburg, Federal Republic of Germany.
Brückner
R
R
Schäfer
H
H
Schmitz
W
W
Scholz
H
H
D000200:Action Potentials / Q000187:drug effects; D000241:Adenosine / Q000037:antagonists & inhibitors*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D009202:Cardiomyopathies / Q000378:metabolism* / Q000473:pathology; D006168:Guinea Pigs; D007545:Isoproterenol / Q000037:antagonists & inhibitors; D009200:Myocardial Contraction / Q000187:drug effects*; D010210:Papillary Muscles / Q000187:drug effects / Q000473:pathology; D037342:Pertussis Toxin; D010660:Phenylisopropyladenosine / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*
D010566:Virulence Factors, Bordetella; D010660:Phenylisopropyladenosine; D037342:Pertussis Toxin; D000241:Adenosine; D007545:Isoproterenol; D002118:Calcium