Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P50583 (asymmetrical)
 12,197 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 The fall in blood pressure is preceded and superseded by a fall in the total peripheral resistance.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.
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PMID:Pinacidil. Preclinical investigations. 307 34