Systemic and regional hemodynamic characterization of alpha-1 and alpha-2 adrenoceptor agonists in pithed rats.
In pithed rats, blood pressure dose-response curves to i.v. cirazoline, methoxamine and phenylephrine (full alpha-1 adrenoceptor agonists) exhibited higher maxima than those to B-HT 920, M-7, UK-14,304 (full alpha-2 adrenoceptor agonists) and indanidine (Sgd 101/75: partial alpha-1 adrenoceptor agonist). For an 80 mm Hg increase in blood pressure, full alpha-1 adrenoceptor agonists enhanced total peripheral, renal and mesenteric vascular resistances significantly more than alpha-2 adrenoceptor stimulants or indanidine. In contrast, all compounds produced a similar degree of hindquarter vasoconstriction, suggesting that both types of alpha adrenoceptors have the same functional importance in this skeletal muscle vascular bed. Application of a multivariate discriminant analysis to the drug-induced changes in the total peripheral and mesenteric vascular resistances associated with a pressor effect of 80 mm Hg allowed their assignment to two distinct groups corresponding to the full alpha-1 and the full alpha-2 adrenoceptor agonists plus indanidine. All investigated compounds in low doses increased cardiac output, which returned to base-line values after high doses of alpha-1 but plateaued after high doses of alpha-2 adrenoceptor agonists or indanidine. alpha-1 adrenoceptor agonists decreased whereas alpha-2 stimulants and indanidine successively increased and then decreased renal blood flow. Finally, all investigated compounds increased hindquarter blood flow at low doses but decreased it at high doses. The ratios of the doses of cirazoline required to produce a 100% rise in systemic and local vascular resistances in the presence or in the absence of prazosin were of similar magnitude. This was also true for M-7 when studied in the presence or in the absence of yohimbine. These findings suggest pharmacological identity within alpha-1 as well as within alpha-2 adrenoceptor populations in all investigated vascular beds. Finally, the calcium entry blocker diltiazem did not affect the increases in systemic and regional resistances evoked by cirazoline but depressed profoundly the effects of M-7 and indanidine. In conclusion, full alpha-1 and alpha-2 adrenoceptor agonists can be discriminated easily on the basis of their systemic and regional hemodynamics in the pithed rat. That the hemodynamic effects of the partial alpha-1 adrenoceptor agonist indanidine are similar to those of alpha-2 adrenoceptor agonists and susceptible to calcium channel blockade suggests that the alpha-1 adrenoceptors stimulated by this drug have the same coupling modality as alpha-2 adrenoceptors and share with the latter the same functional expression when stimulated.
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D003655:Decerebrate State; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D009928:Organ Specificity; D051381:Rats; D012039:Regional Blood Flow / Q000187:drug effects; D013329:Structure-Activity Relationship; D014655:Vascular Resistance / Q000187:drug effects
D000316:Adrenergic alpha-Agonists