Reduction of Cold-Induced Hypertension by Antisense Oligodeoxynucleotides to Angiotensinogen mRNA and AT ₁ -Receptor mRNA in Brain and Blood

Abstract

Abstract-Rats exposed chronically to mild cold (5°C/41°F) develop hypertension and cardiac hypertrophy. This provides a unique model of hypertension that is environmentally induced. The blood renin-angiotensin system (RAS) has been shown to play a role in both initiating and maintaining the high blood pressure (BP) in cold-induced hypertension. The mechanism also appears to involve both the tissue and brain RAS because there is increased mRNA for angiotensinogen (AGT) and angiotensin type 1 (AT 1 ) receptors in brain and peripheral tissues, an increased spontaneous drinking response, and an increased dipsogenic response to acute administration of angiotensin II (Ang II) in cold-treated rats. Key Words: hypertension, cold-induced Ⅲ angiotensinogen Ⅲ angiotensin II Ⅲ RNA Ⅲ receptors Ⅲ antisense elements R ats exposed to mild cold (5°C/41°F) develop hypertension. [1][2][3][4] This CIH is a nongenetic, nonsurgical model for studying hypertension in rats. Our previous studies have shown that the blood-borne RAS either prevents or attenuates CIH. 5,6 The mechanism also appears to involve both peripheral tissue and central RAS because there is increased mRNA for AGT and/or AT 1 -R in brain and peripheral tissues, 7 increased spontaneous drinking response, and increased dipsogenic response to acute administration of Ang II either centrally or subcutaneously. 8 The receptors for Ang II in the diencephalon of rats have been correlated directly with the drinking response to Ang II. 9,10 Furthermore, studies also suggest that there is a direct correlation between the state of receptors for Ang II in the diencephalon and development of hypertension, ie, upregulation of receptors for Ang II has been linked to the induction of both deoxycorticosterone acetate-salt and spontaneously induced hypertension. -13Tests of the dipsogenic responsiveness to Ang II, spontaneous drinking response to cold, and AT 1 -R mRNA in brain show much greater responses in cold-treated rats.8 This suggests that the receptors for Ang II are upregulated in rats exposed chronically to cold. Additional studies have shown an increased amount of mRNA for AGT, the substrate for the RAS, in the brains of cold-treated rats compared with rats kept at room temperature as controls. This raises the possibility that both increased production of Ang II and upregulation of Ang II receptors contribute to the elevation of BP during exposure to cold. An increased amount of mRNA of AGT and/or AT 1 -R in peripheral tissues (liver, adrenal glands, and aorta) of cold-treated rats suggests that an overactive peripheral tissue RAS is involved in CIH as well. AS-ODN, targeted to AGT mRNA or AT 1 -R mRNA, have been shown to reduce BP in SHR, which demonstrates that AS-ODN are specific and reduce an overactive RAS. 14 -18 Therefore, to assess more directly the role of the central RAS in CIH, AS-ODN to AGT mRNA and to AT 1 -R mRNA were

Selective Inhibition of the Renal Dopamine Subtype D 1A Receptor Induces Antinatriuresis in Conscious Rats

“…15,16 The utility of this strategy has been demonstrated successfully by in vivo administration of AS-ODNs against neural and inducible isoforms of nitric oxide synthase, the angiotensin subtype 1 receptor, the Na ϩ -P i cotransporter, intercellular adhesion molecule-1, and transforming growth factor-␤1 in the kidney. [25][26][27][28][29][30][31] In the present study, effective renal cellular uptake of AS-ODN was confirmed by distribution of Texas red-labeled ODN in renal tubular epithelium and vasculature 24 hours after renal interstitial injection.…”

Somatic gene therapy for hypertension

“…Most of the uptake is in the kidney and liver. A reduction in AT 1 -R after treatment with the AT 1 -AS-ODN reveals reductions in the protein in kidney, aorta and liver (8).…”

AAV delivery of mineralocorticoid receptor shRNA prevents progression of cold-induced hypertension and attenuates renal damage

“…Animals did not appear stressed during BP measurement. The tail-cuff method is a common method used by Sun et al, [27][28][29] Wang et al, 31,32 Peng et al 33 and Zhu et al 34 to delineate CIH. It has been confirmed by the intraarterial cannulation that the non-invasive tail-cuff method is effective and reliable in monitoring systolic BP in rats exposed to cold.…”