N''-cyano-N-4-pyridyl-N'-1,2,2-trimethylpropylguanidine, monohydrate (P 1134) is a new agent which induces a marked and sustained hypotensive response in normotensive and renal, neurogenic, and spontaneously hypertensive rats, as well as in normotensive and renal hypertensive dogs. The overall potency of this compound is 2-3 times greater than that of hydralazine. The fall of blood pressure is accompanied by an increase in heart rate and cardiac output and a decrease in total peripheral resistance. The hypotensive effect appears to be due primarily to a direct relaxant effect on vascular smooth muscle.
The effects of timolol and bendroflumethiazide, either alone or combined in a fixed ratio of 4:1, on blood pressure, plasma renin activity, and plasma potassium concentration, have been investigated in normotensive and renal hypertensive dogs, and in normotensive and spontaneously hypertensive rats. In addition, the urinary kallikrein excretion has been measured in normotensive and hypertensive rats. When administered to hypertensive dogs and rats, the drug combination significantly reduced the blood pressure. Marginal reductions were observed in normotensive animals or after the administration of the single drugs. The thiazide–induced hypokalemia and hyperreninaemia were almost completely antagonised by the concomitant administration of timolol in both animal species. A highly significant elevation of urinary kallikrein excretion was also observed in rats treated with the drug combination. A less marked increase of kallikrein excretion was noted in the bendroflumethiazide treated rats. The possibility that renal haemodynamic changes, in addition to the inhibition of the increase in plasma renin, play a role in the observed antihypertensive effects is discussed.
Ring preparations of rabbit aorta were contracted by potassium (127 mM). Pinacidil (P 1134), a new vasodilator (2.3×10−5 M), the calcium antagonists verapamil (3.4×10−7 M), nifedipine (3.4×10−9 M) and hydralazine (1.9×104 M) relaxed the preparation by 50%. 50% relaxation of noradrenaline‐contracted tissues was obtained with pinacidil, 6.8×10−5 M, verapamil, 2.4×10−4 M and hydralazine, 1.9×10−3 M. At 2×10−7 M concentration nifedipine was almost inactive. In ring preparations of rabbit aorta exposed to calcium‐free medium and then depolarized with potassium (127 mM), pinacidil, 5×10−5 M and nifedipine, 10−8 M significantly inhibited the contractions by cumulative addition of calcium. Hydralazine, 10−3 M had no effect. Noradrenaline‐induced contractions in calcium‐free medium or in presence of increasing amounts of calcium were significantly inhibited by nifedipine, 10−8 M and hydralazine, 10−3 M. Pinacidil, 10−4 M had no effect. Pinacidil, 1.3×10−5 M and verapamil, 2.0×10−5 M inhibited by 50% the serotonin‐induced increase of perfusion pressure of isolated rabbit ear artery. The noradrenaline effect in this preparation were 50% inhibited by pinacidil, 2.4×10−4 M and by verapamil, 8.8×10−5 M. Hydralazine, 10−3 M exerted minor inhibitory effect. It is suggested that interference with calcium influx contributes to the vasodilator activity of pinacidil.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.