Cardiovascular Effects of the Novel Potassium Channel Opener UR-8225

Tamargo, Juan; Pérez, Onésima; Delpón, Eva; García-Rafanell, Julián; Gómez, Luis Alberto; Cavalcanti, F. L.

doi:10.1097/00005344-199508000-00016

Cited by 12 publications

(14 citation statements)

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“…The decrease in MAP produced by SKP-818 and SKP-310 was accompanied by a dose-dependent increase in HR, which persisted during hypotension. As reported for other potassium channel activators [17,18], a ß-adrenoceptor blocker prevented the tachycardia induced by SKP-450 without affecting the hypotensive response of the drug, suggesting that the increase in HR evoked by SKP-450 was probably of reflex origin and represents a hemodynamic counterregulation of the decrease in MAP rather than a direct action of drug on the heart. Glybenclamide, a specific blocker of ATP-sensitive potassium channels, significantly antagonized the antihypertensive effects of SKP-450 in rats, which suggests that the hypotensive effects of SKP-450 could be mediated by activation of ATP-sensitive potassium channels.…”

Section: Discussionsupporting

confidence: 64%

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Cardiovascular Pharmacology of SKP-450, a New Potassium Channel Activator, and Its Major Metabolites SKP-818 and SKP-310

et al. 1998

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The cardiovascular effects of SKP-450, a newly synthesized potassium channel activator, and its two major metabolites SKP-818 and SKP-310 were evaluated on isolated rat aorta and in freely moving rats and anesthetized beagle dogs. The rank order of potency in relaxing rat aorta precontracted with norepinephrine was SKP-450>SKP-818>lemakalim>SKP-310 (EC₅₀: 0.12, 0.55, 0.71 and 5.89 µmol/l, respectively). In rats, SKP-450, SKP-818 and lemakalim (3–100 µg/kg, i.v.) induced a dose-dependent decrease in mean arterial pressure (MAP; ED₂₀: 9.8, 11.7 and 22.4 µg/kg, respectively) followed by reflex tachycardia. In dogs, SKP-818 and SKP-310 (0.3–1,000 µg/kg, i.v.) had quite similar hemodynamic profiles to SKP-450 but with a smaller potency. SKP-450, SKP-818 and SKP-310 dose-relatedly decreased MAP (ED₂₀: 2.6, 4.2 and 588.8 µg/kg, respectively). They slightly increased left ventricular positive dP/dt_max with a transient decrease at the highest dose, while inducing a dose-related decrease in rate-pressure product, tension time index and systolic time. SKP-450, SKP-818 and SKP-310 induced a marked dose-dependent increase in coronary blood flow (E_max: 172.8, 257.9 and 178.7%, respectively) with less effects on blood flow through other arteries. Glybenclamide antagonized all the hemodynamic effects of SKP-450 in rats and dogs, whereas propranolol antagonized its reflex tachycardia in rats. These results indicate that SKP-450 is a potent coronary and peripheral vasodilator in rats and dogs activating ATP-sensitive potassium channels and that SKP-818 and SKP-310 exert a similar hemodynamic profile to the parent compound with equi- and weaker potency, respectively.

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Section: Discussionsupporting

confidence: 64%

“…was also evaluated in conscious rats. Glybenclamide (20 mg/kg), at a dose comparable to that used by other investigators in rats [17], was intravenously injected 20 min prior to SKP-450 administration.…”

Section: Antihypertensive Effects In Conscious Ratsmentioning

confidence: 99%

Cardiovascular Pharmacology of SKP-450, a New Potassium Channel Activator, and Its Major Metabolites SKP-818 and SKP-310

et al. 1998

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“…In the DOCA salt-induced hypertensive rat, a low-renin model of volume dependent hypertension, UR-8225 (0.03-1 mg/kg) produced a dose-dependent decrease in MAP (ED,, = 0.02 f 0.008 mg/kg) and an increase in HR (18,43). As shown in Fig.…”

Section: Effects On Blood Pressure and Heart Rate In Conscious Ratsmentioning

confidence: 79%

“…The antihypertensive response produced by UR-8225 at 0.3 mg/kg was also accompanied by a significant increase in plasma renin activity and aldosterone plasma In conscious WKY rats UR-8225 or levcromakalim (0.1-1 mg/kg) produced a dosedependent reduction of MAP (ED,, = 0.17 ? 0.03 and 0.10 t 0.018 mglkg, respectively) and an increase in HR (43). Even when the maximal hypotensive effect was similar for both drugs, that produced by 0.3 mgikg UR-8225 decreased progressively so that predrug values were reached after 3.5 h, while that produced by 1 mg/kg of UR-8225 or by 0.3 and 1 mg/kg of levcromakalim persisted throughout the 6 h recording period.…”

Section: Effects On Blood Pressure and Heart Rate In Conscious Ratsmentioning

confidence: 93%

“…To ascertain whether UR-8225 might inhibit the L-type Ca2+ current (I,-,), its effects were studied on slow action potentials recorded in guinea pig ventricular muscles perfused with 27 mM KCI and driven at 0.12 Hz. Under these conditions, Na+ channels were voltage-inactivated by partial depolarization (to about -45 mV) and isoproterenol(1 FM) induced slowed rising action potentials by increasing the I,, (43). UR-8225 (0.1-10 pM) had no effect on the characteristics of slow action potentials, whereas at 30 pM it significantly decreased the V, , , of the upstroke (from 17.0 * 0.5 V/s to 15.5 + 0.9 V/s; P < 0.05) and shortened the APD,, (from 240.8 k 12.4 ms to 208.0 ?…”

Section: Electrophysiological Effects In Isolated Cardiac Preparationsmentioning

confidence: 98%

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