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Hemodynamic profile of SKP-450, a new potassium-channel activator.

Abstract
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.
AuthorsB H Lee, S E Yoo, H S Shin
JournalJournal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 31 Issue 1 Pg. 85-94 (Jan 1998) ISSN: 0160-2446 [Print] United States
PMID9456282 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Benzopyrans
  • Potassium Channels
  • Pyrrolidinones
  • KR 30450
Topics
  • Anesthesia
  • Animals
  • Benzopyrans (pharmacology)
  • Blood Pressure (drug effects)
  • Coronary Circulation (drug effects)
  • Dogs
  • Dose-Response Relationship, Drug
  • Heart Rate (drug effects)
  • Hemodynamics (drug effects)
  • Hypertension (drug therapy)
  • Male
  • Potassium Channels (agonists)
  • Pyrrolidinones (pharmacology)
  • Rats
  • Rats, Inbred SHR
  • Rats, Sprague-Dawley

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