Effects of Isradipine on Plasma Renin Activity in Sodium-Loaded and -Depleted Conscious Rabbits

Rp, Hof; Umemura, Kazuo; Jp, Evenou; A, Hof; Pc, Ruegg

doi:10.1097/00005344-199204000-00005

Cited by 2 publications

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“…Potassium channel activators such as lemakalim, nicorandil and pinacidil are known to reduce blood pressure in several experimental animal models of hypertension by reducing peripheral vascular resistance [1][2][3][4]. The mechanism of vasodilator activity of these drugs is suggested to be due to the activation of ATP-sensitive potassium channels leading to a hyperpolarization of the smooth muscle membrane that causes vasorelaxation by preventing the opening of voltageactivated calcium channels [5][6][7][8][9]. Potassium channel activators are also known as potent coronary vasodilators [10][11][12], which may make them potentially useful in the treatment of angina and myocardial ischemia [13,14].…”

Section: Introductionmentioning

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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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: Introductionmentioning

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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Hemodynamic Profile of SKP-450, a New Potassium-Channel Activator

Lee

Yoo²,

Shin³

1998

Journal of Cardiovascular Pharmacology

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Hemodynamic profiles of SKP-450, a newly synthesized potassium-channel activator, were evaluated in conscious hypertensive rats of several types, and in anesthetized and conscious beagle dogs. In freely moving conscious rats, orally administered SKP-450 (0.03-0.3 mg/kg) dose-dependently decreased arterial pressure in spontaneously hypertensive rats (SHRs), renally hypertensive rats (RHRs), DOCA/salt-induced hypertensive rats (DHRs), and normotensive rats (NRs) with a greater potency than lemakalim except in DHRs (ED20 values: SKP-450, 0.021, 0.013, 0.024, and 0.034 mg/kg; lemakalim, 0.107, 0.018, 0.016, and 0.063 mg/kg, respectively). The blood pressure-reducing effects of SKP-450 reached their maximum within 30 min and lasted for approximately 4 h in all rats, and >6 h, particularly, in SHRs. In NRs, pretreatment with glibenclamide (20 mg/kg, i.v.) antagonized the hypotensive effect of SKP-450, whereas propranolol (2 mg/kg, i.v.) antagonized the tachycardiac response of SKP-450 (0.03 mg/kg, i.v.) without affecting its hypotensive response in NRs. In anesthetized beagle dogs, intraduodenally administered SKP-450 (0.003-0.03 mg/kg) dose-relatedly decreased arterial pressure (ED20 value, 0.007 mg/kg) for > or =3 h with its peak effects reached within 15 min and without significant changes in heart rate (HR). Antihypertensive effects of SKP-450 were accompanied by concurrent reduction in total peripheral resistance and dose-dependent increase in cardiac output. Indirect measures of myocardial oxygen demand such as rate-pressure product, tension-time index, and systolic time interval were dose-dependently decreased by SKP-450 without significant change in left ventricular dP/dt(max). SKP-450 significantly increased coronary blood flow and decreased coronary vascular resistance dose-dependently with a rapid onset of action and long duration of >4 h (maximal changes, 276 and 83.7% at 0.03 mg/kg, respectively). In conscious dogs, orally administered SKP-450 (0.03-0.3 mg/kg) produced a dose-related decrease in arterial pressure for > or =3 h, with its peak effects reached within 20 min (ED20 value, 0.030 mg/kg) accompanied by tachycardia. These results suggest that SKP-450 is a potent, orally active peripheral vasodilator activating ATP-sensitive potassium channels.

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Effects of Isradipine on Plasma Renin Activity in Sodium-Loaded and -Depleted Conscious Rabbits

Cited by 2 publications

References 0 publications

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

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

Hemodynamic Profile of SKP-450, a New Potassium-Channel Activator

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