REGULATION OF VASCULAR SMOOTH-MUSCLE GROWTH BY ALPHA(1)-ADRENOCEPTOR SUBTYPES IN-VITRO AND IN-SITU

Rat aorta smooth muscle cells which express all three alpha(1)-adrenor eceptors (alpha(1A), alpha(1B) and alpha(1D)) were used to determine t he effect of stimulation of alpha(1)-adrenergic receptor subtypes on c ell growth. ''Combined'' alpha(1)-adrenoreceptor subtype stimulation w ith norepinephrine alone caused a concentration-dependent, prazosin se nsitive increase in protein content and synthesis: 48 h of stimulation at 1 mu M increased cell protein to 216 +/- 40% of time-matched contr ols (p = 0.008) and RNA to 140 +/- 13% (p = 0.03); protein synthesis i ncreased to 167 +/- 13% (p < 0.01) after 24 h, Stimulation with norepi nephrine plus the selective alpha(1A)/alpha(1D) antagonist 5-methylura pidil produced greater increases in alpha-actin mRNA (270 +/- 40% at 8 h; p = 0.007), total cell protein (220 +/- 45% at 24 h; p = 0.004), a nd RNA (135 +/- 8% at 24 h; p = 0.01). These effects were prevented by pretreatment with the selective alpha(1B) antagonist chloroethylcloni dine. Comparable results were obtained for intact aortae. Stimulation with norepinephrine plus 5-methylurapidil increased (p < 0.05) tissue protein, RNA, dry weight, and alpha-actin mRNA; and as in cultured cel ls, combined stimulation with norepinephrine alone attenuated these re sponses. By comparison, adventitia (fibroblasts) was unaffected, Remov al of endothelial cells had no effect. alpha(1B) mRNA decreased by 42 +/- 12% (p = 0.01) in cultured cells during combined alpha(1)-adrenore ceptor stimulation and by 23 +/- 8% (p = 0.03) for intact aorta. alpha (1D) and beta-actin mRNA were unchanged in cultured cells, aorta media , and adventitia. These findings suggest that prolonged stimulation of chloroethylclonidine-sensitive, possibly alpha(1B)-adrenoreceptors in duces hypertrophy of arterial smooth muscle cells and that stimulation of 5-methylurapidil-sensitive, non-alpha(1B)-adrenoreceptors attenuat es this growth response.