Bombesin-like receptor 3 regulates blood pressure and heart rate via a central sympathetic mechanism

Abstract

Bombesin-like receptor 3 (BRS-3) is an orphan G protein-coupled receptor that regulates energy expenditure, food intake, and body weight. We examined the effects of BRS-3 deletion and activation on blood pressure and heart rate. In free-living, telemetered Brs3 null mice the resting heart rate was 10% lower than wild-type controls, while the resting mean arterial pressure was unchanged. During physical activity, the heart rate and blood pressure increased more in Brs3 null mice, reaching a similar heart rate and higher mean arterial pressure than control mice. When sympathetic input was blocked with propranolol, the heart rate of Brs3 null mice was unchanged, while the heart rate in control mice was reduced to the level of the null mice. The intrinsic heart rate, measured after both sympathetic and parasympathetic blockade, was similar in Brs3 null and control mice. Intravenous infusion of the BRS-3 agonist MK-5046 increased mean arterial pressure and heart rate in wild-type but not in Brs3 null mice, and this increase was blocked by pretreatment with clonidine, a sympatholytic, centrally acting α2-adrenergic agonist. In anesthetized mice, hypothalamic infusion of MK-5046 also increased both mean arterial pressure and heart rate. Taken together, these data demonstrate that BRS-3 contributes to resting cardiac sympathetic tone, but is not required for activity-induced increases in heart rate and blood pressure. The data suggest that BRS-3 activation increases heart rate and blood pressure via a central sympathetic mechanism.

Keywords: blood pressure; bombesin-like receptor 3; energy metabolism; heart rate; sympathetic nervous system.

Fig. 1.

Conscious Brs3^−/y mice have a reduced resting heart rate and an activity-dependent increase in mean arterial pressure (MAP). A and B: light-phase MAP and heart rate from 13 to 24 wk of age in the same cohort of mice. Data at each age are from a weekday 2 h undisturbed interval early in the light phase. C and D: histograms of MAP and heart rate during 1-min intervals. For statistical analysis, the cumulative frequency percentiles for each mouse were compared (n = 5–6/group). MAPs in percentiles 57–80 were higher and all heart rate percentiles were lower (P < 0.05 by t-test without multiplicity correction). E and F: light-phase MAP and heart rate histograms for physically inactive and active intervals. In wild-type (WT) and Brs3^−/y (KO) mice, 26% and 34% of intervals were active, respectively. G and H: dark-phase MAP and heart rate histograms for inactive and active intervals. Active intervals were 66% for both genotypes. In C–H, data are the same 48 h in 13-wk old mice as in Table 1. Histogram bins are 2.5 mmHg for MAP and 10 beats/min for heart rate.

Fig. 2.

Conscious Brs3^−/y mice have a reduced response to propranolol and a normal intrinsic heart rate. Heart rate 31 to 45 min after treatment with vehicle (Veh, saline), propranolol (Pro, 5 mg/kg ip), atropine (Atro, 1 mg/kg ip), or propranolol plus atropine (Pro + Atro). WT, wild-type controls; KO, Brs3^−/y mice. Data are means ± SE; n = 4–6/group. *P < 0.05, Pro or Atro or Pro + Atro vs. vehicle within genotype; †P < 0.05, WT vs. KO within treatment. Experiment is a crossover design with mice age 19–23 wk.

Fig. 3.

MK-5046 increases MAP and heart rate. The MAP (A–C) and heart rate (D–F) response to MK-5046 (3 mg/kg ip) or vehicle (saline) was studied in conscious wild-type (WT) and Brs3^−/y (KO) mice at 16–17 wk of age. Data are change from the baseline, 120 to 1 min before treatment. C and F: mean change in MAP and heart rate at 61–120 min postinjection. Baseline MAPs were 98 ± 1 (WT/Veh), 97 ± 2 (WT/MK-5046), 102 ± 2 (KO/Veh), and 102 ± 2 (KO/MK-5046) mmHg. Baseline heart rates were 526 ± 16 (WT/Veh), 513 ± 16 (WT/MK-5046), 482 ± 15 (KO/Veh), and 490 ± 15 (KO/MK-5046) beats/min. Data are means ± SE; n = 5–6/group. *P < 0.05 vs. vehicle.

Fig. 4.

Clonidine attenuates the increase in MAP and heart rate caused by MK-5046. Effects of intravenous MK-5046 (1 mg/kg in 5% dimethylacetamide in saline) were studied in anesthetized wild-type (WT) and Brs3^−/y (KO) mice at 12–16 wk of age. A and D: baseline MAP and heart rate from 12 to 2 min before infusion. *P < 0.05 vs. WT. B and E: change in MAP and heart rate response to MK-5046 or vehicle (Veh) at 1 to 5 min after infusion. *P < 0.05 MK-5046 vs. vehicle; †P < 0.05, genotype effect within MK-5046 treatment. C and F: in wild-type mice, effect of pretreatment with clonidine (40 μg/kg ip) or saline given 1 h before MK-5046 on MAP and heart rate response to MK-5046 or vehicle (Veh) at 1 to 5 min after infusion. Data are means ± SE; n = 6–7/group. *P < 0.05 MK-5046 vs. vehicle; †P < 0.05, clonidine effect within MK-5046 treatment.

Fig. 5.

Central MK-5046 increases MAP and heart rate. Effect of intrahypothalamic MK-5046 (2 μg total) in anesthetized wild-type (WT) and Brs3^−/y (KO) mice. A and C: changes from baseline (12 to 2 min before infusion) in MAP and heart rate, respectively. B and D: mean change from baseline at 2–25 min after infusion. Baseline MAPs were 66 ± 4 (WT/Veh), 70 ± 3 (WT/MK), and 65 ± 3 (KO/MK) mmHg. Baseline heart rates were 337 ± 9 (WT/Veh) 313 ± 10 (WT/MK) and 339 ± 22 (KO/MK) beats/min. Data are means ± SE; n = 6–12/group. *P < 0.05, MK-5046 vs. vehicle within genotype; †P < 0.05, WT vs. KO within treatment.