Changes in adrenoceptors and G-protein-coupled receptor kinase 2 in L-NAME-induced hypertension compared to spontaneous hypertension in rats.

This work compares the expression of adrenoceptors (ARs) and G-protein-coupled receptor kinase (GRK) 2 (RT-PCR and immunoblotting) and functional responses in conductance (aorta) and resistance vessels (mesenteric resistance arteries; MRA) in two different models of rat hypertension: hypertension induced by chronic treatment with L-NAME (N(G)-nitro-L-arginine methyl-ester) (L-NAME-treated rats; LNHR), and genetically induced hypertension (spontaneously hypertensive rats; SHR). Changes found in the aorta, but not in the MRA, were: (1) a loss of contractile capacity, more evidently in α1-AR-mediated contraction, and an impairment of endothelium-dependent vasorelaxation, with both changes occurring independently of the hypertensive model; (2) a diminished sensitivity to α1-AR-induced vasoconstriction along with increased β2-AR-mediated vasodilation in LNHR, and (3) a lower expression of ARs and GRK2 in LNHR. The two latter changes are the opposite of those previously found in aortas of SHR.

Acute and chronic captopril, but not prazosin or nifedipine, normalize alterations in adrenergic intracellular Ca2+ handling observed in the mesenteric arterial tree of spontaneously hypertensive rats.

The effect of hypertension and acute (36-h) or chronic (from age 6 to 16 weeks) antihypertensive treatment with prazosin (2 mg kg(-1) per day), nifedipine (50 mg kg(-1) per day), or captopril (50 mg kg(-1) per day) on Ca2+ mobilization due to alpha1-adrenoceptor activation was analyzed in functional studies using arterial rings [four conductance/distributing vessels: aorta, main mesenteric, iliac, and tail arteries and two resistance vessels; first and second small mesenteric artery branches obtained from spontaneously hypertensive rats (SHR, 6 and 16 weeks old) and age-matched Wistar Kyoto rats (WKY)]. Maximal response to noradrenaline in the presence of extracellular Ca2+ is not affected by hypertension or by the antihypertensive treatment. The extracellular Ca2+-independent contractile responses increased with age in iliac, tail, and small mesenteric arteries (SMA) and were further increased in SHR in SMA from both young and adult animals and in the main mesenteric artery of adult SHR.

Simplified tetrandrine congeners as possible antihypertensive agents with a dual mechanism of action.

A series of O- and/or N-substituted derivatives of (+/-)-coclaurine (1a) were synthesized as simplified structural mimics of the antihypertensive alkaloid tetrandrine (2) and assayed for binding to brain cortical sites labeled with the alpha(1)-adrenergic radioligand [(3)H]prazosin or the calcium channel radioligand [(3)H]diltiazem. The introduction of O-benzyl groups on the coclaurine molecule, which exhibits only adrenergic antagonist activity, led to the appearance of calcium channel blocking activity comparable to that of tetrandrine while retaining adrenolytic activity in the same concentration range. Contraction of aortal rings with noradrenaline or KCl was relaxed more potently by some of these coclaurine derivatives than by tetrandrine, suggesting leads for the development of novel antihypertensive drugs with a dual mechanism of action.