kr-30450 and Hypertension

The vasorelaxant actions of adenosine 5'-triphosphate (ATP)-dependent K+ channel openers and sodium nitroprusside in isolated thoracic aorta and pulmonary artery of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats (14-18 weeks old) were investigated. Cumulative addition of sodium nitroprusside and different ATP-dependent K+ channel openers (pinacidil, cromakalim, nicorandil, 2-(2"(1",3"-dioxolone)-2-methyl-4-(2'-oxo-1'-pyrrolidinyl)-6-nitro -2H-1-benzopyren (KR-30450) and aprikalim) to these preparations caused a concentration-dependent relaxation of noradrenaline-pre-contracted aorta and pulmonary artery from both strains. The relative order of relaxation potency, estimated by comparing the IC50, was sodium nitroprusside > KR-30450 > aprikalim > or = cromakalim > pinacidil > nicorandil in pulmonary artery and aorta from both strains. At high concentrations (> or =1 microM), cromakalim, aprikalim and KR-30450 produced a greater percentage relaxation in SHR aorta than in WKY aorta. However, there was no apparent difference between SHR and WKY in the relaxation response to all drugs tested on the pulmonary artery. The effects of cromakalim, aprikalim, pinacidil and KR-30450 observed in aorta and pulmonary artery were significantly attenuated by 3 microM glibenclamide. 6-Anilino-5,8-quinolinequinone (LY 83583, 1 microM), a soluble guanylate cyclase inhibitor, abolished the vasorelaxant effects of nicorandil and sodium nitroprusside. In conclusion, sodium nitroprusside and ATP-dependent K+ channel openers cause relaxation of noradrenaline-pre-contracted aorta and pulmonary artery from both strains. However, all the drugs tested failed to cause selective relaxation of the pulmonary artery relative to the thoracic aorta.

Topics: Adenosine Triphosphate; Aminoquinolines; Animals; Aorta, Thoracic; Apamin; Benzopyrans; Charybdotoxin; Cromakalim; Dose-Response Relationship, Drug; Glyburide; Hypertension; In Vitro Techniques; Male; Muscle Relaxation; Muscle, Smooth, Vascular; NG-Nitroarginine Methyl Ester; Nicorandil; Nitroprusside; Norepinephrine; Picolines; Pinacidil; Potassium; Potassium Channels; Pulmonary Artery; Pyrans; Pyrrolidinones; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Vasodilator Agents

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.

Topics: Anesthesia; Animals; Benzopyrans; Blood Pressure; Coronary Circulation; Dogs; Dose-Response Relationship, Drug; Heart Rate; Hemodynamics; Hypertension; Male; Potassium Channels; Pyrrolidinones; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley

Antihypertensive effects of SKP-450 (KR-30450, CAS 172489-10-0, (-)-(2R)-2"-(1",3"-dioxolan-2-yl)-2-2methyl-4-(2'-oxopyrr olidin-1-yl)-6- nitro-2H-1-benzopyran), a newly synthesized potassium channel activator, and its major metabolites SKP-818 ((-)-(2R)-2"-hydroxymethyl-2-methyl-4-(2'-oxopyrrolidin-1-yl)-6-ni tro- 2H-1-benzopyran) and SKP-310 ((-)-(2R)-2"-carboxy-2-methyl-4-(2'-oxopyrrolidin-1-yl)-6-nitro-2H -1- benzopyran) were evaluated in freely moving spontaneously hypertensive (SHR), renally hypertenisve (RHR), DOCA/salt-induced hypertensive (DHR) and normotensive rats (NR). The effects of long-term treatment with SKP-450 on blood pressure and arterial reactivity were also studied in SHR. SKP-450 (3-300 micrograms/kg, p.o.) and SKP-818 (3-100 micrograms/kg, i.v.) dose-dependently decreased mean arterial pressure (MAP) (potency order: SKP-450, RHR > SHR = DHR > NR; SKP-818, DHR = SHR = RHR > NR); however, SKP-310 did not influence MAP. Compared with lemakalim, SKP-450 was 2 to 5 fold more potent in SHR and NR, and equipotent in RHR and DHR. Repeatedly administration of SKP-450 to SHR over 21 days (10 and 30 micrograms/kg, p.o., once a day), had no significant effect on the degree and pattern of its antihypertensive effects and on the reactivity of isolated aorta to various vasoconstrictors and vasodilators. These results suggest that SKP-450 is a potent peripheral vasodilator acting without the development of tolerance and the alteration in vascular reactivity. SKP-818 and SKP-310 may play a role as an active metabolite and inactive intermediary, respectively.

Topics: Animals; Antihypertensive Agents; Benzopyrans; Blood Pressure; Cromakalim; Desoxycorticosterone; Heart Rate; Hypertension; Hypertension, Renal; Male; Potassium Channels; Pyrroles; Pyrrolidinones; Rats; Rats, Inbred SHR; Vasodilator Agents