Evidence for the Site of Action of Glycerol Trinitrate and Diltiazem in Inhibiting Vasoconstrictor Responses to Norepinephrine in Isolated Renal Arteries

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Abstract
The inhibitory effects of glycerol trinitrate (GTN) and diltiazem (DZ) on contractions produced by submaximal concentrations (ED 75) of norepinephrine (NE) and potassium chloride (KC1) were studied in isolated canine renal artery rings. In addition, the site of action of these compounds in blocking NE-induced contractions was determined by using zero calcium (Ca++) buffer + 2 mM EGTA (calcium-free solution). GTN was more potent than DZ in relaxing KCl-induced contractions (potential-operated calcium channels) as well as NE-induced contractions (receptor-operated calcium channels). In a Ca++-free buffer, the response to NE was reduced to approximately 20–25% of the response in normal Ca++ (1.25 mM) buffer. GTN (1 × 10–9–1 × 10–4M) produced a marked inhibition of NE-induced contractions in Ca++-free buffer, whereas DZ had no inhibitory effect even at very high concentrations (1 × 10–4M). Thus, GTN and DZ appear to interfere with different components of Ca++ entry through slow channels and intracellular Ca++ release. DZ primarily blocks the influx of Ca++ from the extracellular space, whereas GTN appears to act by inhibiting Ca++ movements at an intracellular site.

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