Pharmacological studies with the alpha 2-adrenoceptor antagonist midaglizole. Part I: Respiratory and cardiovascular systems.
Respiratory and cardiovascular effects of midaglizole (DG-5128, CAS 66529-17-7) were investigated in comparison with yohimbine, idazoxan and tolbutamide. 1. Respiration: Midaglizole had little or no effect on respiration of anesthetized dogs. Yohimbine and idazoxan augmented respiration at low dose. Tolbutamide depressed respiratory rate and depth at high dose. 2. Blood pressure and heart rate: Midaglizole produced dose-related hypotension and bradycardia in anesthetized dogs which had laparotomy, whereas it had little or no effect on blood pressure and heart rate of dogs which had no laparotomy (unlaparotomized dogs). Tendency of slight hypertension was observed after high dose of tolbutamide in laparotomized dogs, and transient hypotension was induced in unlaparotomized dogs. Yohimbine and idazoxan increased blood pressure at low dose in unlaparotomized dogs. In laparotomized dogs, yohimbine produced hypertension and hypotension at low and high doses, respectively. In isolated guinea pig atria, midaglizole produced bradycardia which was not observed after yohimbine. Tolbutamide decreased the pulse rate at high concentration. 3. Cardiac contractility: Midaglizole produced increase in cardiac contractility of anesthetized dogs. Yohimbine and idazoxan, at low dose, showed similar inotropic activity. Prazosin also produced a positive inotropic effect, whereas tolbutamide lacked the activity. The inotropic effects of midaglizole and yohimbine were antagonized by pretreatment with propranolol or hexamethonium, whereas a similar effect of prazosin was not influenced by both blockers. In isolated guinea pig atria, midaglizole showed slight inotropic activity. Yohimbine was without any effect, whereas tolbutamide reduced the contractile force. 4. Femoral blood flow: Midaglizole produced a transient increase in femoral blood flow and a decrease in femoral arterial resistance of anesthetized dogs. Yohimbine and idazoxan, at low dose, showed similar vasodilator activity. Prazosin also produced a vasodilator effect, whereas tolbutamide lacked the activity. The vasodilator effects of midaglizole and yohimbine were not affected with propranolol, but inhibited after hexamethonium. 5. Mesenteric blood flow: Midaglizole significantly decreased mesenteric blood flow and increased the arterial resistance of anesthetized dogs in a dose dependent manner. Tolbutamide induced a decrease in blood flow and an increase in arterial resistance only at the highest dose used. Yohimbine increased mesenteric blood flow at low dose and decreased it at high dose. 6. Renal blood flow: Midaglizole dose-relatedly decreased renal blood flow of anesthetized dogs. Tolbutamide and yohimbine at high dose produced a long-lasting decrease of the blood flow. Midaglizole produced a slight transient reduction of renal arterial resistance which was followed by a slight increase. Tolbutamide increased the arterial resistance at high dose.(ABSTRACT TRUNCATED AT 400 WORDS)
Research Institute, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
M
M
Hirohashi
K
K
Takasuna
N
N
Yamashita
K
K
Tamura
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000758:Anesthesia; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004146:Dioxanes / Q000494:pharmacology; D004285:Dogs; D004562:Electrocardiography; D005260:Female; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D019329:Idazoxan; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D012039:Regional Blood Flow / Q000187:drug effects; D012079:Renal Circulation / Q000187:drug effects; D012119:Respiration / Q000187:drug effects*; D013152:Splanchnic Circulation / Q000187:drug effects; D014044:Tolbutamide / Q000494:pharmacology; D015016:Yohimbine / Q000494:pharmacology
D000317:Adrenergic alpha-Antagonists; D004146:Dioxanes; D007093:Imidazoles; D015016:Yohimbine; C032368:midaglizole; D014044:Tolbutamide; D019329:Idazoxan