In vivo effects of a novel thromboxane A2/prostaglandin H2 (TXA2/PGH2) partial agonist, (+)5(Z)-7-[3-endo-phenylsulfonylamino[2.2.1]- bicyclohept-2-exo-yl]-heptenoic acid [(+)-S-145], on vascular, platelet and cardiac function.
A novel thromboxane A2/prostaglandin H2 (TXA2/PGH2) receptor ligand, (+)5(Z)-7-[3-endo-phenylsulfonylamino[2.2.1]-bicyclohept-2-e xo- yl]-heptenoic acid [(+)-S-145], was evaluated in guinea pigs to assess the in vivo pharmacodynamic profile of this compound at vascular, cardiac and platelet TXA2/PGH2 receptors. Comparison was made to the TXA2/PGH2 receptor antagonist SQ29548. Upon i.v. injection, (+)-S-145, but not SQ29548, elicited transient (approximately 1 min) increases in mean arterial blood pressure (ED50 +/- 95% confidence limit = 6.1 + 4.0, -2.2 micrograms/kg). The potency of i.v. (+)-S-145 (ID50 = 6.3 + 2.3, -2.3 micrograms/kg) against the pressor response to subsequent i.v. TXA2/PGH2 mimetic, U44069, was 9.5-fold greater than that of SQ29548 (ID50 = 59.1 + 52.9, - 52.9 micrograms/kg). Intravenous (+)-S-145 inhibited U44069-induced decreases in circulating platelet count (ID50 = 4.2 + 4.1, - 2.0 micrograms/kg). In thoracotomized guinea pigs, i.v. (+)-S-145 (31.6 micrograms/kg) and increasing i.v. doses of U44069 increased mean arterial blood pressure, total peripheral resistance, left ventricular end-diastolic pressure and left ventricular peak positive dP/dt (LV + dP/dt) and depressed cardiac output (P < .05). Pretreatment with i.v. (+)-S-145 (31.6 micrograms/kg) abolished these U44069-induced effects. In thoracotomized guinea pigs in which left ventricular end-diastolic pressure and HR were held constant, U44069 again increased LV + dP/dt (P < .05), but (+)-S-145 decreased LV + dP/dt (P < .05), which indicates the lack of an (+)-S-145 direct inotropic effect.(ABSTRACT TRUNCATED AT 250 WORDS)
Dubé
G P
GP
Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana.
Jakubowski
J A
JA
Brune
K A
KA
Bemis
K G
KG
Kurtz
W L
WL
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated; D006168:Guinea Pigs; D006439:Hemodynamics / Q000187:drug effects*; D006834:Hydrazines / Q000494:pharmacology; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011982:Receptors, Prostaglandin / Q000819:agonists / Q000037:antagonists & inhibitors*; D017482:Receptors, Thromboxane / Q000819:agonists* / Q000037:antagonists & inhibitors*; D044244:Receptors, Thromboxane A2, Prostaglandin H2
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005229:Fatty Acids, Monounsaturated; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D011450:Prostaglandin Endoperoxides, Synthetic; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D044244:Receptors, Thromboxane A2, Prostaglandin H2; C056566:S 145; C028429:U 44069; C045749:SQ 29548