Pharmacological studies of N-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(4-morpholinyl)-3-pyridazinamine hydrochloride (MDL-899), a new long-acting antihypertensive vasodilator.
N-(2,5-Dimethyl-1H-pyrrol-1-yl)-6-(4-morpholinyl)-3-pyridazinamine hydrochloride (MDL-899) is a new long-acting antihypertensive vasodilator which reduces the blood pressure of conscious hypertensive rats and dogs to normal levels. The oral doses that reduce blood pressure by 50 mmHg are: 4.4 mg/kg in conscious spontaneously hypertensive rats (SHR), 18 mg/kg in conscious Milan hypertensive strain (MHS) and 1.7 mg/kg in conscious renal hypertensive dog (RHD). The i.v. doses are 1.26, 3.2 and 0.9 mg/kg. The reduction in blood pressure is slow (peak effect at 3 h) and long-lasting (more than 7 h) after p.o. or i.v. administration. Tolerance to MDL-899 is seen to develop in hypertensive dogs, whereas in hypertensive rats this phenomenon never occurs. The compound antagonizes the development of hypertension when given to SHR between days 25 and 88. The haemodynamic study in conscious normotensive rats (labelled microspheres) demonstrated that the fall in blood pressure is accompanied by increases in heart rate and cardiac output and a decrease in total peripheral resistance. The lack of alpha-blocking activity, in the rat caudal artery "in vitro"; beta 2-stimulating activity, in SHR pretreated with propranolol, and prostaglandin (PG) release activity, in SHR pretreated with indomethacin, excludes the possibility that the hypotension is due to one of these mechanisms. MDL-899 given orally to rats has no important depressant effects on the CNS at hypotensive or higher doses and induces no adrenergic system stimulation symptoms (midriasis, exophthalmus). In comparison with hydralazine, it is slower in onset and longer lasting, devoid of adrenergic system stimulation, less toxic and nonmutagenic. They are equipotent after p.o. treatment.
Baldoli
E
E
Bianchi
G
G
Corsico
N
N
Di Francesco
G F
GF
D000284:Administration, Oral; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D004285:Dogs; D006439:Hemodynamics / Q000187:drug effects; D006591:Hexobarbital / Q000494:pharmacology; D006977:Hypertension, Renal / Q000503:physiopathology; D007213:Indomethacin / Q000494:pharmacology; D007275:Injections, Intravenous; D008297:Male; D010433:Pentylenetetrazole / Q000037:antagonists & inhibitors; D004856:Postural Balance / Q000187:drug effects; D011724:Pyridazines / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011919:Rats, Inbred Strains; D012890:Sleep / Q000187:drug effects; D013045:Species Specificity; D014665:Vasodilator Agents / Q000494:pharmacology*
D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D011724:Pyridazines; D014665:Vasodilator Agents; C038811:mopidralazine; D006591:Hexobarbital; D010433:Pentylenetetrazole; D007213:Indomethacin