Desensitization and resensitization of beta 1- and putative beta 4-adrenoceptor mediated responses occur in parallel in a rat model of cardiac failure.
1. Cardiostimulant effects of the non-conventional partial agonist, CGP 12177A, are mediated by a receptor distinct from the beta3-adrenoceptor and termed the putative beta4-adrenoceptor. Using a rat model of cardiac failure, induced by myocardial infarction (MI), we compared the desensitization and resensitization of responses to CGP 12177A with those to isoprenaline and RO 363 in left (LA) and right atria (RA). We also examined the ability of beta-adrenoceptor antagonists to block responses to CGP 12177A. 2. MI reduced the maximum inotropic response to isoprenaline by 48% (sham 4.1+/-0.6 mN, n=10; MI 2.1+/-0.4 mN, n=8, P<0.02), RO 363 by 61% (sham 4.2+/-0.5 mN, n=10; MI 1.8+/-0.3 mN, n=8, P<0.005) and CGP 12177A by 49% (sham 1.4+/-0.1 mN, n=5; MI 0.7+/-0.2 mN, n=7, P<0.05) in electrically stimulated LA. MI also reduced the sensitivity to isoprenaline (pEC50: sham 8.79+/-0.08, n=10; MI 8.30+/-0.10, n=8; P=0.001) and RO 363 (pEC50: sham 8.69+/-0.07, n=10; MI 8.33+/-0.10, n=8; P<0.01). The maximum chronotropic responses to isoprenaline, RO 363 and CGP 12177A in RA were unaffected. 3. Pertussis toxin treatment (10 microg kg-1, i.p.) restored the maximum inotropic response and sensitivity to isoprenaline (sham 3.5+/-0.5 mN, n=9; MI 3.2+/-0.6 mN, n=11, P=0.702) and CGP 12177A (sham 1.6+/-0.3 mN, n=6; MI 1.9+/-0.4 mN, n=7, P=0.537) in MI animals to levels similar to those in the sham group. 4. CGP 20712A (pKB: LA 6.7+/-0.2, n=6; RA 7. 1+/-0.1, n=4), ICI 118,551 (pKB: LA 6.4+/-0.1, n=5; RA 6.3+/-0.1, n=6), propranolol (pKB: LA 6.6+/-0.1, n=5; RA 6.8+/-0.1, n=6) and bupranolol (pKB: LA 7.2+/-0.1, n=6; RA 7.7+/-0.1, n=8), showed moderate affinity for the putative beta4-adrenoceptor. 5. Desensitization after MI and resensitization (after pertussis toxin treatment) to isoprenaline and CGP 12177A therefore occur in parallel, suggesting that the beta1- and putative beta4-adrenoceptor use the same signalling pathway. Antagonist affinity studies confirmed that drugs acting at beta1-adrenoceptors also interact with putative beta4-adrenoceptors with approximately 100 times lower affinity. We suggest that CGP 12177A produces its cardiac effects by interacting with a low affinity state of the beta1-adrenoceptor.
Kompa
A R
AR
Department of Pharmacology, Monash University, Wellington Road, Clayton, Victoria, 3168, Australia.
Summers
R J
RJ
D000818:Animals; D004195:Disease Models, Animal; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology*; D007700:Kinetics; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D009203:Myocardial Infarction / Q000378:metabolism / Q000503:physiopathology; D037342:Pertussis Toxin; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000378:metabolism / Q000502:physiology*; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism / Q000502:physiology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D011943:Receptors, Adrenergic, beta; D018342:Receptors, Adrenergic, beta-1; D010566:Virulence Factors, Bordetella; C120358:adrenergic beta-4 receptor; D037342:Pertussis Toxin