Background and Purpose-Pretreatment with angiotensin II AT 1 receptor antagonists protects against cerebral ischemia.We studied whether modulation of cerebral blood flow (CBF) and morphometric changes in brain arteries participated in this protective mechanism. Methods-We pretreated adult spontaneously hypertensive rats with equally antihypertensive doses of candesartan (0.1 or 0.3 mg/kg per day), nicardipine (0.1 mg/kg per day), or captopril (3.0 mg/kg per day) for 3 or 28 days via subcutaneous osmotic minipumps followed by permanent left middle cerebral artery (MCA) occlusion distal to the origin of the lenticulostriate arteries. We measured CBF by autoradiography with 4-iodo-[N-methyl-14 C]antipyrine 3 hours after operation and the areas of infarct and tissue swelling 24 hours after operation. Morphometric changes in the MCA were studied after antihypertensive treatment. Results-Twenty-eight days of candesartan pretreatment decreased the infarct area by 31%; reduced the CBF decrease at the peripheral area of ischemia and the cortical volume of severe ischemic lesion, where CBF was Ͻ0.50 mL/g per minute; increased the MCA external diameter by 16%; and reduced the media thickness of the MCA by 23%. Captopril pretreatment for 28 days decreased the infarct area by 25%. Pretreatment with candesartan for 3 days or nicardipine for 28 days was ineffective. Conclusions-Angiotensin II system inhibition protects against neuronal injury more effectively than calcium channel blockade. Protection after AT 1 receptor blockade is not directly correlated with blood pressure reduction but with normalization of MCA media thickness, leading to increased arterial compliance and reduced CBF decrease during ischemia at the periphery of the lesion.

AT(2) receptors may act in opposition to and in balance with AT(1) receptors, their stimulation having beneficial effects. We found renal AT(2) receptor expression in female mice higher than in male mice. We asked the question of whether such expression might be estrogen dependent. In male, female, ovariectomized, and estrogen-treated ovariectomized mice, we studied renal AT(1) and AT(2) receptors by immunocytochemistry and autoradiography, AT(2) receptor mRNA by RT-PCR, and cAMP, cGMP, and PGE(2) by RIA. AT(1) receptors predominated. AT(2) receptors were present in glomeruli, medullary rays, and inner medulla, and in female kidney capsule. AT(1) and AT(2) receptors colocalized in glomeruli. Female mice expressed fewer glomerular AT(1) receptors. Ovariectomy decreased AT(1) receptors in medullary rays and capsular AT(2) receptors. Estrogen administration normalized AT(1) receptors in medullary rays and increased AT(2) receptors predominantly in capsule and inner medulla, and also in glomeruli, medullary rays, and inner stripe of outer medulla. In medullas of estrogen-treated ovariectomized mice there was higher AT(2) receptor mRNA, decreased cGMP, and increased PGE(2) content. We propose that the protective effects of estrogen may be partially mediated through enhancement of AT(2) receptor stimulation.

Angiotensin II (Ang II) AT₁ receptors are involved in the regulation of the stress response. In adult male rats, acute restraint increased AT_1A mRNA in paraventricular nucleus. Repeated restraint increased AT_1A mRNA and AT₁ binding in paraventricular nucleus and AT₁ binding in subfornical organ and median eminence. AT_1B and AT₂ receptors were not expressed in brain areas involved in the stress response. Acute restraint increased anterior pituitary AT_1A mRNA and AT₁ binding and decreased AT_1B mRNA. During repeated restraint, the increase in AT_1A mRNA in the anterior pituitary was maintained, but AT_1B mRNA and AT₁ binding returned to normal levels. In adrenal zona glomerulosa, AT_1B mRNA, AT₁ binding, AT₂ mRNA and AT₂ binding decreased during acute restraint. Receptor mRNA and binding returned to normal after repeated stress, with the exception of rebound increase in adrenal zona glomerulosa AT₂ mRNA. In adrenal medulla, AT_1A mRNA increased and AT₂ mRNA decreased during acute restraint. AT_1A mRNA remained increased during repeated restraint, while alterations in AT₂ mRNA were no longer present. Expression of AT_1A, AT_1B and AT₂ receptors in the hypothalamic-pituitary-adrenal axis is tissue specific and is different in acute and repeated stress. Increased brain, pituitary and adrenomedullary AT_1A receptor expression correlates with hypothalamic-pituitary-adrenal axis stimulation, supporting the hypothesis of Ang II, through selective AT_1A receptor stimulation, as an important determinant of the acute and repeated stress response. Decreased adrenal zona glomerulosa and anterior pituitary AT_1B receptors during acute stress can be interpreted as compensatory to increased stimulation by Ang II. There may be additional roles for adrenal AT₂ receptors during acute stress, possibly related to interaction or cross-talk with AT₁ receptors.

1 We investigated in the present study whether 5-HT is able to exert direct relaxant responses in canine basilar and middle cerebral arteries via the 5-HT 7 receptor. 2 In arterial rings deprived of endothelium and pre-contracted with prostaglandin F 2a (2 mM), 5-HT, 5-carboxamidotryptamine (5-CT), 5-methoxytryptamine, sumatriptan or a-methyl-5-HT produced further increase in tone and/or slight relaxation. Blockade of 5-HT 1B/1D and 5-HT 2A receptors with GR127935 (1 mM) and ketanserin (0.1 mM), respectively, antagonized the vasoconstrictor component of the response and unmasked a concentration-dependent relaxation to 5-HT, 5-CT and 5-methoxytryptamine; sumatriptan and a-methyl-5-HT remained inactive as relaxant agonists. The rank order of agonist potency in both arteries was 5-CT45-HT45-methoxytryptamine44sumatriptan5a-methyl-5-HT. 3 In dog basilar artery, pre-incubated with GR127935 (1 mM) and ketanserin (0.1 mM) and precontracted with prostaglandin F 2a (2 mM), the 5-HT 7 ligands, clozapine (1 mM), mesulergine (0.3 mM), methiothepin (3 nM), risperidone (3 nM), spiperone (1 mM) and LY215840 (10 ± 100 nM), produced signi®cant rightward shifts of the concentration-response curves for 5-HT and 5-CT. Only methiothepin and risperidone reduced signi®cantly the maximum relaxant response (E max ), whilst the other drugs behaved as competitive antagonists with a nity values (pK B ) that signi®cantly correlated with their binding a nity (pK i ) at recombinant 5-HT 7 receptors. 4 These data disclosing the involvement of the 5-HT 7 receptor in cerebrovascular relaxation may be strongly relevant in the light of : (1) the involvement of 5-HT in migraine; (2) the putative linkage between cephalovascular vasodilatation and migraine headache; and (3) the relatively high 5-HT 7 receptor a nity of migraine prophylactic 5-HT antagonists.