Preferential renal vasodilator effects of CGP 22979A in conscious spontaneously hypertensive rats

CGP 18137A (2-hydrazino-5-n-butyl-pyridine) and its prodrug CGP 22979A [N-acetyl-L-glutamic acid-N-[N2-(5-n-butyl-2-pyridyl)hydrazide]] were evaluated for their blood pressure-lowering potency and regional hemodynamic actions in conscious spontaneously hypertensive rats. The effects were compared to those of hydralazine. Animals were instrumented with miniaturized pulsed Doppler flowprobes to allow continuous simultaneous measurement of renal, mesenteric and hindquarter blood flow. From changes in mean arterial pressure and the respective flows, changes in renal, mesenteric and hindquarter resistance were calculated. After i.v. administration, hydralazine and CGP 18137A were equally potent with regard to their blood pressure-lowering effect in a dose range of 0.1 to 1 mg/kg. Hydralazine was more effective than CGP 18137A in lowering renal and hindquarter resistance. Neither of the two drugs, however, caused preferential dilation in any of the three beds studied. CGP 22979A in doses of 1 to 30 mg/kg caused a much smaller acute blood pressure-lowering response. However, already at low doses (1-10 mg/kg) it caused a significant reduction of renal resistance, without affecting either hindquarter or mesenteric resistance. At the highest dose (30 mg/kg), selectivity was no longer retained, which is probably due to excessive leakage of the active vasodilator into the peripheral circulation. These findings suggest that CGP 22979A is a renal-selective prodrug for CGP 18137A and thereby is capable of preferentially dilating the renal vasculature in conscious unrestrained spontaneously hypertensive rats.