The effect of hydrochlorothiazide on vascular reactivity to various drugs was studied in rabbit and dog. In rabbit, dose response in the mesenteric artery and vein was examined in vitro following a treatment with hydrochlorothiazide for 6 to 10 weeks. Norepinephrine produced significantly less contraction in the vein of treated than of control animals (P < 0.005), but the effect of aeetylcholine, barium chloride, angiotensin, papaverine, and adenosine triphosphate (ATP) was not altered. In the hindlimb of dogs treated with hydrochlorothiazide for 6 to 8 weeks, intra-arterial norepinephrine caused substantially less pressure increment in the resistance vessels, perfused at constant flow rate, of treated than of control animals. Stimulation of lumbar sympathetic nerves also augmented pressure in the femoral artery less in treated than in control dogs. No such difference in the effect of intra-arterial ATP or angiotensin was observed between the two groups of animals. Preliminary results both in the rabbit and in the dog failed to demonstrate a significant alteration in water, sodium, potassium, and calcium content of the iliap artery or vein after hydrochlorothiazide treatment. Diminished response to norepinephrine in the vessels after hydrochlorothiazide treatment may be responsible for the antihypertensive effect after the prolonged administration of this drug.

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