1 The effects of the nonpeptide angiotensin II receptor (AT) antagonists losartan and PD 123319 on actions of angiotensin II in the rat caudal artery and rat vas deferens preparations were investigated. 2 Angiotensin 11 (1.0 I1M) increased perfusion pressure in isolated segments of the rat caudal artery.This increase in perfusion pressure was prevented by the AT,-antagonist, losartan (0.1 JAM) but was not affected by the AT2-antagonist, PD 123319 (0.1 JAM). 3 Angiotensin II (0.1-3.01M) produced a concentration-dependent enhancement of the stimulationinduced (S-I) efflux of [3H]-noradrenaline from isolated segments of rat caudal artery in which the noradrenergic transmitter stores had been labelled with [3H]-noradrenaline. The maximum enhancement of S-I efflux was approximately 60% with 1.O01M angiotensin II. 4 Losartan (0.01 and 0.1 AM) reduced the enhancement of S-I efflux produced by 1.0 JAM angiotensin II in the caudal artery. 5 PD 123319 (0.01 JAM) did not affect the enhancement of S-I efflux produced by angiotensin II (1.0 JAM) in the caudal artery. However, in a higher concentration (0.1 JAM), PD 123319 reduced the enhancement of S-I efflux produced by 1.O0JM angiotensin II. 6 Angiotensin II produced concentration-dependent enhancement of the purinergic twitch responses (1 pulse/60 s) in the rat vas deferens, 7 Losartan (0.03 JAM) and PD 123319 (0.03 JM) each reduced the angiotensin II-induced enhancement of the twitch responses in the rat vas deferens. 8 These findings indicate that the enhancement of sympathetic neuroeffector transmission in both the caudal artery and vas deferens of the rat involves angiotensin receptor subtype(s) sensitive to both losartan and PD 123319. In contrast, the direct vasoconstrictor effect of angiotensin II in the rat caudal artery involves activation of a receptor subtype sensitive only to losartan. Keywords: Angiotensin II; losartan; PD 123319; vasoconstriction; sympathetic neuroeffector transmission IntroductionThe renin-angiotensin system plays a central role in cardiovascular homeostasis by influencing vascular tone, extracellular fluid and electrolyte balance, and the sympathetic nervous system (Sealey & Laragh, 1989). The interactions of the renin-angiotensin system with the cardiovascular system are predominantly mediated by the octapeptide, angiotensin II. Angiotensin II influences cardiovascular function by several mechanisms, including direct constriction of resistance and capacitance vessels and direct cardiac inotropic and chronotropic activity (Sealey & Laragh, 1989). In addition, angiotensin II has been shown to facilitate noradrenergic neuroeffector transmission by enhancing stimulation-induced release of noradrenaline from sympathetic nerves, although it has also been reported to increase the rate of synthesis of noradrenaline and to inhibit neuronal uptake of the transmitter (Story & Ziogas, 1987 that, in the rabbit vas deferens, angiotensin II produces the usual enhancement of noradrenergic transmission, but that the peptide inhibits the purinergic comp...
Onset of tumors in breast cancer is a multi-factorial event at different ages and ethnic populations. The conventional treatment strategy suggests use of anti-estrogen drugs and selective estrogen receptor modulators (SERMs). Although, this strategy has achieved significant success to prevent tumor growth and metastasis and is still developing under an active field of research, the emergence of immunotherapy is a potential modern approach for breast cancer. In addition to SERMs, the screening of selective agonists for toll-like receptor (TLR) signals confers a new area of breast cancer therapy. Recent investigations also indicate significance of TLR signals in the regulation of tumor suppressor p53 gene expression. The TLR agonists have an ability to facilitate activation of natural killer cells, CD8 T cells, B cells, and alpha and beta interferons and induce cellular cytotoxicity. The ongoing developments in cancer research also suggested an approach for intra-tumoral generation of cellular cytotoxicity to induce apoptosis. Both of these events promote destruction of tumor cells in a localized manner and thus, having impact on immunotherapy. Keeping a cautious eye on the context, we propose the prospect of TLR signals in the development of therapy for breast cancer.
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