TREATMENT WITH 5-HT POTENTIATES DEVELOPMENT OF PULMONARY-HYPERTENSIONIN CHRONICALLY HYPOXIC RATS

The aim of this study was to investigate the potential role of 5-hydro xytryptamine (5-HT) on development of pulmonary hypertension during ch ronic exposure to mild (15% O-2) and severe (10% O-2) hypoxia. In isol ated lungs from normoxic rats preconstricted with U-46619, 5-HT (10(-1 2)-10(-8) M) induced dose-dependent vasodilation (n = 6), which was su ppressed by the NO synthesis inhibitor nitro-L-arginine methyl ester ( L-NAME, 10(-4) M, n = 5) and reduced by the 5-HT3-receptor antagonist MDL-7222 (10(-5) M, n = 6). The vasoconstriction that was observed wit h higher concentrations of 5-HT (10(-7)-10(-4) M) was inhibited by ket anserin (10(-5) M) and methiothepin (10(-5) M, n = 6 each). The vasodi lator response to 5-HT was suppressed in lungs from rats exposed to 10 % O-2 but not 15% O-2(n = 6 each). In conscious rats, intravenous admi nistration of 5-HT potentiated the pulmonary presser response to acute hypoxia (10% O-2, n = 5), an effect that remained unchanged after pre treatment with a 5-HT1 and a 5-HT2 antagonist (n = 4) but was attenuat ed after treatment with the cyclooxygenase inhibitor meclofenamate (n = 4) Treatment with 5-HT (5 nmol/h iv by osmotic pumps) for 2 wk in ra ts simultaneously exposed to 10% O-2 increased pulmonary arterial pres sure, right ventricular hypertrophy, and muscularization of pulmonary vessels in comparison with their hypoxic controls (n = 12 each). No ch anges occurred in 15% O-2 hypoxic rats (n = 12 each). The present find ings show that 5-HT potentiates development of pulmonary hypertension in rats exposed to chronic hypoxia.