Effect of Chronic Treatment with Losartan Potassium (DuP 753) on the Elevation of Blood Pressure during Chronic Exposure of Rats to Cold

Abstract

Elevation of diastolic, systolic, and mean blood pressures and cardiac hypertrophy occur in rats exposed to cold (5°C) for 1-3 weeks. The renin-angiotensin-aldosterone system is believed to play a role in the development of cold-induced hypertension since plasma renin activity increases within the first 2 weeks, presumably initiating the hypertensive process, and then returns to control level. The present study was designed to assess the role of angiotension II (Ang II) in the hypertensive process by chronic administration of losartan potassium, an Ang II i receptor antagonist. Twenty-four rats were divided into four equal groups. After a 1-week control period, one group was kept at 25°C while the remaining three groups were exposed to cold (5°C). One of the cold-treated groups was untreated while the remaining two were given losartan in drinking water at a concentration calculated to provide 56 and 112 mg/kg/day. The untreated cold-exposed group had a significant elevation of systolic blood pressure within 1 week of exposure to cold. Losartan at both doses prevented the elevation of blood pressure and blocked both the dipsogenic and vascular responses to administration of Ang II. Exposure to cold increased food intake, urine output and water intake significantly above that of warm-adapted controls. Treatment with losartan tended to decrease each of these toward the level of controls. At the conclusion of the seventh week of exposure to cold, the rats were sacrificed and heart, kidneys, and brown fat removed and weighed. Chronic exposure to cold increased the weight of heart, kidneys, and brown fat above that of warm-adapted controls. Treatment with losartan failed to prevent the increases in these organ weights. Thus, although treatment with losartan prevented the elevation of systolic blood pressure induced by chronic exposure to cold, it did not prevent cardiac and renal hypertrophy and the increase in brown fat. It would appear that losartan does not affect these and that an elevation of blood pressure does not sustain them.

Angiotensinogen Gene Knockout Delays and Attenuates Cold-Induced Hypertension

“…The blood pressure (116Ϯ4 mm Hg) of the cold-exposed Agt-KO mice was at the level of the WT mice kept in warm (25°C, room temperature) at 5 weeks after exposure to cold. Consistently, our previous studies showed that the antihypertensive agents, such as propranolol, 18 captopril, 29 losartan potassium, 30 and L-arginine, 42 effectively reduced or prevented the coldinduced elevation of blood pressure but failed to prevent or attenuate cardiac hypertrophy. Thus, the occurrence of coldinduced cardiac hypertrophy is independent of either pressure overload or tachycardia.…”

Heart-specific inhibition of protooncogene c-myc attenuates cold-induced cardiac hypertrophy

“…Previous studies from our laboratory indicate that CICH is independent of pressure overload because prevention or attenuation of CIH does not attenuate CICH. [30][31][32]37,40,42 The present finding that the occurrence of CICH preceded that of CIH further reveals the disassociation of CICH and CIH. c-myc antisense on cold-induced cardiac hypertrophy M Bello Roufai et al…”

“…Numerous studies have shown that the sympathetic nervous system (SNS) or the rennin-angiotensin system (RAS) is not involved in CICH as evidenced by the fact that blockade of a-or b-adrenergic receptors or inhibition of the RAS at different levels does not attenuate CICH. 30,32,37,40,42,45 It was found that circulating levels of thyroid hormones (T 3 and T 4 ) were increased by cold exposure and may be involved in CICH. 46 A cell culture study indicated that thyroid hormone-induced myocyte hypertrophy requires p38 mitogen-activated protein kinase (p38MAPK).…”

“…[27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] However, prevention or attenuation of cold-induced hypertension (CIH) does not attenuate CICH, indicating that CICH is not caused by high blood pressure (BP). [30][31][32]37,40,42 Indeed, CIH is moderate hypertension (systolic BPE150 mm Hg). Thus, the development of CICH is independent of pressure overload, making it a unique animal model of CH to study.…”

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

“…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.…”