Double blockade of angiotensin II (AT(1) )-receptors and ACE does not improve weight gain and glucose homeostasis better than single-drug treatments in obese rats

Abstract

Background and purpose: Combination therapies are becoming increasingly important for the treatment of high blood pressure. Little is known about whether double blockade of angiotensin II (AT(1) ) receptors and angiotensin-converting enzyme (ACE) exert synergistic metabolic effects.

Experimental approach: Spontaneously hypertensive rats were allowed to choose between palatable chocolate bars and standard chow and were simultaneously treated with the AT(1) blocker telmisartan (8 mg·kg(bw) (-1) ·day(-1) ), the ACE inhibitor ramipril (4 mg·kg(bw) (-1) ·day(-1) ) or a combination of the two (8 + 4 mg·kg(bw) (-1) ·day(-1) ) for 12 weeks.

Key results: Although food-dependent energy intake was increased by telmisartan and telmisartan + ramipril compared with ramipril or controls, body weight gain, abundance of fat and plasma leptin levels were decreased. Increased insulin levels in response to an oral glucose tolerance test were comparably attenuated by telmisartan and telmisartan + ramipril, but not by ramipril. During an insulin tolerance test, glucose utilization was equally as effectively improved by telmisartan and telmisartan + ramipril. In response to a stress test, ACTH, corticosterone and glucose increased in controls. These stress reactions were attenuated by telmisartan and telmisartan + ramipril.

Conclusions and implications: The combination of telmisartan + ramipril was no more efficacious in regulating body weight and glucose homeostasis than telmisartan alone. However, telmisartan was more effective than ramipril in improving metabolic parameters and in reducing body weight. The association between the decrease in stress responses and the diminished glucose levels after stress supports our hypothesis that the ability of telmisartan, as an AT(1) receptor blocker, to alleviate stress reactions may contribute to its hypoglycaemic actions.

Figure 1

Influence of telmisartan (8 mg·kg_bw⁻¹·day⁻¹) (blue symbols), ramipril (4 mg·kg_bw⁻¹·day⁻¹) (red symbols) and telmisartan + ramipril (8 + 4 mg·kg_bw⁻¹·day⁻¹)(purple symbols) on body weight. Controls (open symbols) received water. (A) Development of body weight within the treatment period. (B) An overall correlation between plasma leptin and body weight may be assumed. However, correlation analysis for each group did not indicate any group-specific correlation. Means ± SEM, n= 12–14.

Figure 2

Distribution of the visceral and s.c. fat in CD-fed SHR after treatment with telmisartan (8 mg·kg_bw⁻¹·day⁻¹), ramipril (4 mg·kg_bw⁻¹·day⁻¹), telmisartan + ramipril (8 + 4 mg·kg_bw⁻¹·day⁻¹) or water.(A) Exemplary 3D images obtained by transverse T1-weighted turbo spin echo MRT. The abundance of visceral (B) and s.c. fat (C) depots was quantified by planimetry (see Methods). Visceral fat (Pearson r= 0.734; P= 0.016; D) and s.c. fat (Pearson r= 0.899; P < 0.0001; E) correlated with body weights only in controls (CON), but not in rats treated with TEL, RAM or TEL + RAM. Means ± SEM, n= 10–11; *P < 0.05 versus controls.

Figure 3

Plasma leptin and energy intake of CD-fed SHR that were treated with telmisartan (8 mg·kg_bw⁻¹·day⁻¹), ramipril (4 mg·kg_bw⁻¹·day⁻¹), telmisartan + ramipril (8 + 4 mg·kg_bw⁻¹·day⁻¹) or water (controls), respectively. (A) Alterations in plasma leptin within the treatment period. (B) Weekly energy intake related to body weight. (C) Correlation between plasma leptin at day 0, 46 and 60 and the corresponding energy intake (not related to body weight); CON: r= 0.766, P < 0.0001; TEL: r= 0.309, P= 0.0368; RAM: r= 0.795 P < 0.0001, TEL + RAM: r= 0.330, P= 0.029. (D) Cumulative energy intake related to body weight. The hatched bars represent the proportion fed with chow, and the open bars the proportion fed CD; means ± SEM, n= 12–14; *P < 0.05 versus control; (a) total energy intake (chow + CD) P < 0.05 versus control; (b) chow intake P < 0.05 versus control; (c) CD intake P < 0.05 versus control. For key to symbols used see legend of Figure 1.

Figure 4

(A) Circadian home cage activity of CD-fed SHR (con) after 11 weeks of feeding. (B) Influence of telmisartan (tel; 8 mg·kg_bw⁻¹·day⁻¹), ramipril (ram; 4 mg·kg_bw⁻¹·day⁻¹) and a combination of the two (tel + ram; 8 + 4 mg·kg_bw⁻¹·day⁻¹) on the integrative home cage activity within 48 h compared with controls. Means ± SEM, n= 12–14.

Figure 5

Plasma concentrations of glucose and insulin in response to an oral glucose tolerance test in CD-fed SHR, that were treated with water, telmisartan (8 mg·kg_bw⁻¹·day⁻¹), ramipril (4 mg·kg_bw⁻¹·day⁻¹) or telmisartan + ramipril (8 + 4 mg·kg_bw⁻¹·day⁻¹). AUCs were calculated for each individual animal on the basis of their Δ values. Means ± SEM, n= 12–14, *P < 0.05 versus controls.

Figure 6

Influence of telmisartan (8 mg·kg_bw⁻¹·day⁻¹), ramipril (4 mg·kg_bw⁻¹·day⁻¹) or telmisartan + ramipril (8 + 4 mg·kg_bw⁻¹·day⁻¹) on blood glucose in response to an insulin tolerance test (0.5 IU insulin i.p./kg body weight). Controls were treated with water. (A) Glucose development after insulin injection. (B) Minimum glucose values. (C) Half-life was determined by linear regression analysis of log values. Means ± SEM, n= 12–14 *P < 0.05 versus CON.

Figure 7

Plasma concentrations of ACTH, corticosterone and glucose in response to a stress test (forced swim test) in CD-fed SHR treated with water, TEL, RAM or TEL + RAM. Means ± SEM, n= 12–14 *P < 0.05 versus CON; †P < 0.05 versus before stress.