The platelet thromboxane inhibitor, dazmegrel, does not reduce monocrotaline-induced pulmonary hypertension.
Monocrotaline injures rat pulmonary endothelium, and pulmonary vascular remodeling, pulmonary hypertension, and right ventricular hypertrophy then develop. Platelets contribute to development of the pulmonary hypertension because platelet depletion 1 wk after monocrotaline administration reduces the right ventricular hypertrophy. To determine whether the platelet action is through thromboxane A2 generation, we administered the long-acting thromboxane synthetase inhibitor dazmegrel (UK-38,485) to rats receiving monocrotaline. Both before and after monocrotaline treatment, dazmegrel effectively (p = 0.01) reduced thromboxane release during clotting, platelets being the main source. We then studied 4 groups of rats: 1 group of rats received only monocrotaline as a single subcutaneous injection at 0 h; a second group received, in addition, dazmegrel in drinking water starting at -48 h, then daily until Day 21; a third group received only dazmegrel; a control group received no treatment. Dazmegrel did not prevent monocrotaline-induced growth retardation. Despite adequate intake and coverage of the critical period at approximately 1 wk after monocrotaline treatment, dazmegrel did not significantly prevent the development by Day 21 of right ventricular hypertrophy. On Day 21, platelet counts and plasma thromboxane B2 levels were similar in all 4 groups, suggesting no major platelet involvement at that time. It seems that the platelet contribution to pulmonary hypertension after monocrotaline treatment is not mediated by thromboxane A2.
D000818:Animals; D001792:Blood Platelets; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy*; D007093:Imidazoles / Q000627:therapeutic use*; D008297:Male; D016686:Monocrotaline; D011763:Pyrrolizidine Alkaloids; D051381:Rats; D011919:Rats, Inbred Strains; D013931:Thromboxanes / Q000037:antagonists & inhibitors
D007093:Imidazoles; D011763:Pyrrolizidine Alkaloids; D013931:Thromboxanes; C039242:dazmegrel; D016686:Monocrotaline