N″-cyano-N-4-pyridyl-N′-1,2,2-trimethylpropylguanidine, monohydrate (P 1134): A new, potent vasodilator

Arrigoni-Martelli, E; Nielsen, C. K.; Olsen, Uffe Bang; Petersen, H

doi:10.1007/bf01975139

Cited by 82 publications

(28 citation statements)

References 8 publications

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“…Only a few studies have described the vasodilator profiles of other potassium channel activators (Arrigoni-Martelli et al, 1980;Buckingham et al, 1986;Cook & Hof, 1988). Cook & Hof (1988) ments the increase in 02-demand caused by the increase in heart rate was fully compensated for by the decrease in arterial blood pressure.…”

Section: Discussionmentioning

confidence: 99%

Haemodynamic profile of the potassium channel activator EMD 52692 in anaesthetized pigs

Sassen

Duncker

Gho

et al. 1990

British J Pharmacology

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1 The systemic and regional haemodynamic effects of the potassium channel activator EMD 52692 or its solvent were investigated after intravenous and after intracoronary administration in anaesthetized pigs.2 Consecutive intravenous 10min infusions of EMD 52692 (0.15, 0.30, 0.60, 1.20pgkg Imin-'; n = 7) dose-dependently decreased mean arterial blood pressure by up to 50%. This was entirely due to peripheral vasodilatation, since cardiac output did not change. Heart rate increased by up to 50%, while left ventricular end diastolic pressure decreased dose-dependently from 6 + mmHg to 3 + mmHg (P <0.05), and stroke volume decreased from 30 + 2 ml to 21 + 2 ml (P < 0.05). Left ventricular dP/dt.. was not affected. 3 Although cardiac output did not change, EMD 52692 caused a redistribution of blood flow from the arteriovenous anastomoses to the capillary channels. Blood flow to the adrenals, small intestine, stomach, bladder, spleen and brain increased, while renal blood flow decreased and blood flow to several muscle groups and skin were not altered. Vascular conductance was increased dose-dependently in all organs, except for the kidneys, where after the initial increase, vascular conductance returned to baseline with the highest dose. Particularly striking were the effects on the vasculature of the brain. With the highest dose of EMD 52692 blood flow more than doubled, while vascular conductance increased four fold. 4 Transmural myocardial blood flow increased slightly, which was entirely due to an increase in subepicardial blood flow. Myocardial O2-consumption and segment length shortening were not significantly affected. 5 After consecutive 10min intracoronary infusions (0.0095, 0.019, 0.0375 and 0.075Sugkg-'min-1; n = 7) into the left anterior descending coronary artery (LADCA), mean arterial blood pressure was maintained with the lowest two doses, but decreased by up to 15% with the higher doses, whereas heart rate increased by up to 24%. Blood flow to the LADCA-perfused myocardium doubled with the highest dose, the subepicardium benefitting the most. Coronary venous O2-saturation increased dose-dependently from 23 + 2% to 60 + 4%, while myocardial 02-consumption of the LADCA-perfused myocardium was not affected by the drug. 6 It is concluded that EMD 52692 is a potent vasodilator, with particularly pronounced effects on vasculature of the brain. Its selectivity for vascular smooth muscle cells exceeds that for the myocytes, since with doses that are much higher than those of potential clinical interest no negative inotropic effects were observed. The compound primarily dilates arteries but some venodilatation may also occur.

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Section: Discussionmentioning

confidence: 99%

Haemodynamic profile of the potassium channel activator EMD 52692 in anaesthetized pigs

Sassen

Duncker

Gho

et al. 1990

British J Pharmacology

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“…The present experiments were designed for this purpose. Pinacidil (Arrigoni-Martelli et al, 1980) and cromakalim (Buckingham et al, 1986), both new antihypertensive agents, appear to be suitable reference agents for this purpose. Pinacidil has been shown to open 86Rb-permeable K-channels in rat vascular smooth muscle (Bray et al, 1987) and to increase membrane K-conductance in guinea-pig single ventricular cells (Iijima & Taira, 1987).…”

Section: Introductionmentioning

confidence: 99%

The negative inotropic effect of nicorandil is independent of cyclic GMP changes: a comparison with pinacidil and cromakalim in canine atrial muscle

Yanagisawa¹,

Hashimoto²,

Taira³

1988

British J Pharmacology

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The negative inotropic effects of nicorandil, a nitrate with K‐channel opening properties, have been compared with those of pinacidil, cromakalim and nifedipine, in canine right atrial muscle. Cromakalim, pinacidil and nicorandil all produced a negative inotropic effect. However, even at their maximally effective concentrations, the force of contraction remained at about 10% of control levels, whereas contraction was abolished by nifedipine. The pD2 values for the negative inotropic effects of cromakalim, pinacidil and nicorandil were 5.93, 5.37 and 4.35, respectively. The negative inotropic effects of cromakalim (3 × 10−5 m), pinacidil (3 × 10−5 m and 3 × 10−4 m) and nicorandil (3 × 10−5 m) were not accompanied by changes in cyclic AMP and cyclic GMP levels, whereas that of 3 × 10−4 m nicorandil was accompanied by an increase in cyclic GMP but not cyclic AMP concentrations. The negative inotropic effect produced by 3 × 10−4 m nicorandil was greatly reduced by 10−2 m tetraethylammonium, whereas the increase in cyclic GMP produced by this concentration of nicorandil was not significantly changed. Sodium nitroprusside (10−3 m) produced a large increase in cyclic GMP concentrations but had no significant negative inotropic effect. It is concluded that the negative inotropic effects of nicorandil like those of cromakalim and pinacidil do not result from an increase in cyclic GMP concentrations. Instead these effects may be due to their action as K‐channel openers.

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“…In animal studies pinacidil (N" -cyano-N-4-pyridyl-N'-1 ,2,2-trimethyl-propylguanidine, monohydrate) has a hypotensive action due primarily to direct relaxation of vascular smooth muscle, with a potency greater than that of hydralazine (Arrigoni-Martelli et al, 1980). In an uncontrolled study in untreated hypertensive patients a single oral dose of 25 mg pinacidil caused a substantial fall in blood pressure, accompanied by reduced total peripheral resistance, tachycardia and increased cardiac output (Carlsen et al, 1981).…”

Section: Introductionmentioning

confidence: 99%

Preliminary evaluation of pinacidil in hypertension.

Ramsay¹,

Freestone²

1983

Brit J Clinical Pharma

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In a balanced single‐blind placebo controlled study in six hypertensive patients treated with diuretic and beta‐adrenoceptor blocker, a single oral dose of 10 mg pinacidil lowered blood pressure significantly, by a maximum of 26/13 mm Hg lying and 15/12 mm Hg standing at 3 h. The duration of action was less than 6 h. Chronic treatment of four patients (mean dose 20 mg twice daily for 3–7 weeks) lowered blood pressure by only 15/7 mm Hg. All four patients experienced side‐effects of the type often observed during treatment with potent vasodilators. In the formulation studied pinacidil is unlikely to offer any advantage over the antihypertensive drugs currently available.

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N″-cyano-N-4-pyridyl-N′-1,2,2-trimethylpropylguanidine, monohydrate (P 1134): A new, potent vasodilator

Cited by 82 publications

References 8 publications

Haemodynamic profile of the potassium channel activator EMD 52692 in anaesthetized pigs

Haemodynamic profile of the potassium channel activator EMD 52692 in anaesthetized pigs

The negative inotropic effect of nicorandil is independent of cyclic GMP changes: a comparison with pinacidil and cromakalim in canine atrial muscle

Preliminary evaluation of pinacidil in hypertension.

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