Antihypertensive and haemodynamic properties of the potassium channel activating (-) enantiomer of cromakalim in animal models.
The present studies describe the blood pressure lowering, and some other haemodynamic effects, of the potassium channel activator, BRL 38227 ((-) enantiomer of cromakalim, CAS 94470-67-4) in various animal models. BRL 38227 was a potent antihypertensive agent following oral administration to conscious spontaneously hypertensive rats, SHR, (0.038, 0.075 and 0.15 mg/kg), renal hypertensive cats (0.035 and 0.05 mg/kg) and renal hypertensive dogs (0.05 and 0.1 mg/kg). The (+) enantiomer of cromakalim (BRL 38226) was without effect on blood pressure in the conscious rat and cat confirming the stereospecific mode of action of this potassium channel activator. Tachycardia accompanied the antihypertensive effect of BRL 38227 in these models and in the rat this effect could be abolished by pretreatment with atenolol (conscious SHR), diltiazem, verapamil, propranolol and alinidine (anaesthetised rats). In addition to reflex tachycardia, BRL 38227 also increased plasma renin activity and aldosterone levels in the conscious renal hypertensive cat. In both the anaesthetised normotensive cat (0.001 mg/kg/min i.v.) and dog (0.0025 to 0.02 mg/kg i.v.) BRL 38227 lowered blood pressure and total peripheral resistance while increasing cardiac output via increased heart rate and stroke volume in the cat and via increased heart rate alone in the dog. BRL 38227 reduced renal vascular resistance in both conscious (0.01, 0.015 and 0.02 mg/kg p.o.) and anaesthetised (0.001 mg/kg/min i.v.) cats and the effect was maintained despite marked reductions in blood pressure. In the anaesthetised dog, BRL 38227 was a potent coronary arterial dilator and this effect was also maintained in the face of marked blood pressure lowering activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Clapham
J C
JC
SmithKline Beecham Pharmaceuticals, Medicinal Research Centre, Harlow, Essex, U.K.
Hamilton
T C
TC
Longman
S D
SD
Buckingham
R E
RE
Campbell
C A
CA
Ilsley
G L
GL
Gout
B
B
D000758:Anesthesia; D000818:Animals; D000959:Antihypertensive Agents; D001578:Benzopyrans / Q000494:pharmacology*; D002415:Cats; D019806:Cromakalim; D004285:Dogs; D005260:Female; D005905:Glyburide / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006977:Hypertension, Renal / Q000503:physiopathology; D008297:Male; D015221:Potassium Channels / Q000187:drug effects*; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011919:Rats, Inbred Strains; D012079:Renal Circulation / Q000187:drug effects; D013237:Stereoisomerism
D000959:Antihypertensive Agents; D001578:Benzopyrans; D015221:Potassium Channels; D011758:Pyrroles; D019806:Cromakalim; D005905:Glyburide