Pinacidil. Preclinical investigations.

Routine pharmacological screening of thiourea compounds led to the selection of pyridyl cyanoguanidines for their antihypertensive effects. From this cyanoguanidine class of compounds, P 1134 (pinacidil) was synthesised. Pinacidil has an asymmetrical carbon atom in the pinacolyl radical and the (-) enantiomer is more active than the (+) enantiomer both in vitro and in vivo. Pinacidil is rapidly absorbed following oral administration with the time to peak plasma concentration being 0.5 to 1 hour and, for the extended release formulation, 1 to 3 and 5 to 7 hours. The antihypertensive effect of pinacidil is proportional to the dose administered. Pyridine-N-oxide is the principal metabolite and accounts for approximately half of the dose excreted in the urine within 24 hours. In hypertensive rats and dogs, the blood pressure-lowering effect of pinacidil is dose-dependent and linearly related to the baseline blood pressure. The haemodynamic profile is characterised by an increased cardiac output as a consequence of increased stroke volume. An increase in heart rate follows the depressor response. The fall in blood pressure is preceded and superseded by a fall in the total peripheral resistance. Preclinical haemodynamic studies suggest that pinacidil is a directly acting precapillary vasodilator. The resting membrane potential of smooth muscle cells is approximately -60mV whereas the equilibrium potential for potassium is more negative, between -80 and -90mV. Pinacidil opens K+ channels and allows potassium to attain its equilibrium potential, resulting in hyperpolarisation of the cell at rest. A hyperpolarised cell is less prone to depolarisation, and without depolarisation there is no activation of the voltage-operated Ca2+ channels and, hence, no muscle contraction.