Mechanism of the antihypertensive action of DL-alpha-monofluoromethyldopa: implications for the role of the sympathetic nervous system in maintenance of elevated blood pressure in spontaneously hypertensive rats.
We investigated the mechanism of the antihypertensive action of DL-alpha-monofluoromethyldopa (MFMD), an irreversible inhibitor of L-aromatic amino acid decarboxylase, in spontaneously hypertensive rats (SHR). MFMD, 25 mg/kg i.p. daily for 3 days, reduced mean arterial blood pressure by 47 +/- 11 mm Hg (n = 6; p less than 0.001). The effect was associated with marked attenuation of the responses to stimulation of the whole sympathetic outflow in pithed preparations and with substantial reductions in the norepinephrine concentrations of hearts and portal veins. Similar functional and biochemical deficits were produced in age-matched, Wistar--Kyoto, normotensive rats, but blood pressure in these animals fell only by an average of 8 +/- 4 mm Hg (n = 5; NS). Blood pressure of SHR, lowered by MFMD, was restored to pretreatment levels by infusion with dopamine (0.1 mg/kg/min for 5 min), and there was a concomitant return towards normal of both the peripheral sympathetic transmitter stores and the response to stimulation of the nerves supplying the cardiovascular system. Neither the dopamine nor the norepinephrine concentrations of the brain, depleted by treatment with MFMD, were altered following infusion of dopamine. These results provide direct evidence that attenuation of sympathetic function arising from depletion of the peripheral transmitter store is the mechanism by which MFMD lowers blood pressure in SHR. They further lend strong support to the view that hyperactivity of the sympathetic nervous system plays a primary role in the maintenance of the elevated blood pressure in the genetically hypertensive rat.
D000818:Animals; D000959:Antihypertensive Agents; D004298:Dopamine / Q000494:pharmacology; D006973:Hypertension / Q000503:physiopathology*; D008297:Male; D008750:Methyldopa / Q000031:analogs & derivatives* / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013564:Sympathetic Nervous System / Q000503:physiopathology*; D013997:Time Factors
D000959:Antihypertensive Agents; D008750:Methyldopa; C019494:alpha-monofluoromethyldopa; D004298:Dopamine; D009638:Norepinephrine