Repeated administration of selective adenosine A1 and A2 receptor agonists in the spontaneously hypertensive rat: tolerance develops to A1-mediated hemodynamic effects.
We investigated the effects of the selective A1 adenosine receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA), the selective A2 adenosine agonists 2-hexynyl-5'-N-ethyl-carboxamidoadenosine(2-hexynyl-NECA) and 2-[p-(2-carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamidoadenosi ne (CGS 21680), and the nonselective adenosine agonist 5'-N-ethylcarboxamidoadenosine (NECA) on systolic blood pressure (SBP), heart rate (HR) and receptor binding characteristics. The drugs were studied after acute and repeated i.p. administration in conscious, spontaneously hypertensive rats (SHRs). SBP and HR were recorded by the tail-cuff method. In acute studies the drugs induced a dose-dependent antihypertensive effect with the following order of potency: 2-hexynyl-NECA > NECA > CCPA = CGS 21680. As expected, the A1 agonist CCPA induced a dose-dependent bradycardia, whereas the A2 agonists had minimal influence on HR, and the nonselective agonist NECA induced bradycardia only at the two highest doses. In chronic experiments, the compounds were administered twice daily at equihypotensive doses. 2-Hexynyl-NECA, CGS 21680 and NECA maintained their antihypertensive effects throughout the experimental period. After 21 days, SBP levels were -32, -38 and -28% vs. baseline, respectively. HR was slightly affected. Conversely, tolerance developed to both hypotensive and bradycardic effects of CCPA: at day 21 SBP regained the pretreatment value (+2% vs. baseline), and HR also recovered (-14% vs. baseline). Binding studies were performed on cerebral tissues: no differences were observed between treated and control rats in number and affinity of either A1 and A2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Casati
C
C
Research Laboratories, Schering-Plough S.p.A., Milan, Italy.
Monopoli
A
A
Dionisotti
S
S
Zocchi
C
C
Bonizzoni
E
E
Ongini
E
E
D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000031:analogs & derivatives; D000818:Animals; D001921:Brain / Q000378:metabolism; D004361:Drug Tolerance; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D010627:Phenethylamines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D018047:Receptors, Purinergic P1 / Q000187:drug effects*
D010627:Phenethylamines; D018047:Receptors, Purinergic P1; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; C076864:2-hexynyladenosine-5'-N-ethylcarboxamide; D019830:Adenosine-5'-(N-ethylcarboxamide); C058394:2-chloro-N(6)cyclopentyladenosine; D000241:Adenosine