Ambient air temperatures (T_a) of 29°C have been shown to induce large changes in arterial blood pressure and heart rate in homeotherms. The present study was designed to investigate whether small incremental changes in T_a, such as those found in typical laboratory settings, would have an impact on blood pressure and other cardiovascular parameters in mice and rats. We predicted that small decreases in T_a would impact the cardiovascular parameters of mice more than rats due to the increased thermogenic demands resulting from a greater surface area-to-volume ratio in mice relative to rats. Cardiovascular parameters were measured with radiotelemetry in mice and rats that were housed in temperature-controlled environments. The animals were exposed to different T_a every 72 h, beginning at 30°C and incrementally decreasing by 4°C at each time interval to 18°C and then incrementally increasing back up to 30°C. As T_a decreased, mean blood pressure, heart rate, and pulse pressure increased significantly for both mice (1.6 mmHg/°C, 14.4 beats·min⁻¹·°C⁻¹, and 0.8 mmHg/°C, respectively) and rats (1.2 mmHg/°C, 8.1 beats·min⁻¹·°C⁻¹, and 0.8 mmHg/°C, respectively). Thus small changes in T_a significantly impact the cardiovascular parameters of both rats and mice, with mice demonstrating a greater sensitivity to these T_a changes.

The laboratory mouse is a facultative daily heterotherm in that it experiences bouts of torpor under caloric restriction. Mice are the most frequently studied laboratory mammal, and often, genetically modified mice are used to investigate many physiological functions related to weight loss and caloric intake. As such, research documenting the cardiovascular changes during fasting-induced torpor in mice is warranted. In the current study, C57BL/6 mice were implanted either with EKG/temperature telemeters or blood pressure telemeters. Upon fasting and exposure to an ambient temperature (T_a) of 19°C, mice entered torpor bouts as assessed by core body temperature (T_b). Core T_bfell from 36.6 ± 0.2°C to a minimum of 25.9 ± 0.9°C during the fast, with a concomitant fall in heart rate from 607 ± 12 beats per minute (bpm) to a minimum of 158 ± 20 bpm. Below a core T_bof 31°C, heart rate fell exponentially with T_b, and the Q₁₀was 2.61 ± 0.18. Further, mice implanted with blood pressure telemeters exhibited similar heart rate and activity profiles as those implanted with EKG/temperature telemeters, and the fall in heart rate and core T_bduring entrance into torpor was paralleled by a fall in blood pressure. The minimum systolic, mean, and diastolic blood pressures of torpid mice were 62.3 ± 10.2, 51.9 ± 9.2, 41.0 ± 7.5 mmHg, respectively. Torpid mice had a significantly lower heart rate (25–35%) than when euthermic at mean arterial pressures from 75 to 100 mmHg, suggesting that total peripheral resistance is elevated during torpor. These data provide new and significant insight into the cardiovascular adjustments that occur in torpid mice.

Torpor, a state characterized by a well-orchestrated reduction of metabolic rate and body temperature (T_b), is employed for energetic savings by organisms throughout the animal kingdom. The nucleotide AMP has recently been purported to be a primary regulator of torpor in mice, as circulating AMP is elevated in the fasted state, and administration of AMP causes severe hypothermia. However, we have found that the characteristics and parameters of the hypothermia induced by AMP were dissimilar to those of fasting-induced torpor bouts in mice. Although administration of AMP induced hypothermia (minimum T_b= 25.2 ± 0.6°C) similar to the depth of fasting-induced torpor (24.9 ± 1.5°C), ADP and ATP were equally effective in lowering T_b(minimum T_b: 24.8 ± 0.9°C and 24.0 ± 0.5°C, respectively). The maximum rate of T_bfall into hypothermia was significantly faster with injection of adenine nucleotides (AMP: −0.24 ± 0.03; ADP: −0.24 ± 0.02; ATP: −0.25 ± 0.03°C/min) than during fasting-induced torpor (−0.13 ± 0.02°C/min). Heart rate decreased from 755 ± 15 to 268 ± 17 beats per minute (bpm) within 1 min of AMP administration, unlike that observed during torpor (from 646 ± 21 to 294 ± 19 bpm over 35 min). Finally, the hypothermic effect of AMP was blunted with preadministration of an adenosine receptor blocker, suggesting that AMP action on T_bis mediated via the adenosine receptor. These data suggest that injection of adenine nucleotides into mice induces a reversible hypothermic state that is unrelated to fasting-induced torpor.

Many small mammals have the ability to enter torpor, characterized by a controlled drop in body temperature (T_b). We hypothesized that ghrelin would modulate torpor bouts, because torpor is induced by fasting in mice coincident with elevated circulating ghrelin. Female National Institutes of Health (NIH) Swiss mice were implanted with a T_b telemeter and housed at an ambient temperature (T_a) of 18°C. On fasting, all mice entered a bout of torpor (minimum T_b: 23.8 ± 2.0°C). Peripheral ghrelin administration (100 μg) during fasting significantly deepened the bout of torpor (T_b minimum: 19.4 ± 0.5°C). When the arcuate nucleus (ARC) of the hypothalamus, a ghrelin receptor-rich region of the brain, was chemically ablated with monosodium glutamate (MSG), fasted mice failed to enter torpor (minimum T_b = 31.6 ± 0.6°C). Furthermore, ghrelin administration had no effect on the T_b minimum of ARC-ablated mice (31.8 ± 0.8°C). Two major pathways that regulate food intake reside in the ARC, the anorexigenic α-melanocyte stimulating hormone (α-MSH) pathway and the orexigenic neuropeptide Y (NPY) signaling pathway. Both A_y mice, which have the α-MSH pathway blocked, and Npy −/− mice exhibited shallow, aborted torpor bouts in response to fasting (T_b minimum: 29.1 ± 0.6°C and 29.9 ± 1.2°C, respectively). Ghrelin deepened torpor in A_y mice (T_b minimum: 22.8 ± 1.3°C), but had no effect in Npy −/− mice (T_b minimum: 29.5 ± 0.8°C). Collectively, these data suggest that ghrelin's actions on torpor are mediated via NPY neurons within the ARC.

Torpor, a controlled rapid drop in metabolic rate and body temperature (T_b), is a hypometabolic adaptation to stressful environmental conditions, which occurs in many small mammals, marsupials, and birds. To date, signaling pathways required for torpor have not been identified. We examined the role of the sympathetic nervous system (SNS) in mediating the torpor adaptation to fasting by telemetrically monitoring theT_bof dopamine β-hydroxylase knock-out (Dbh–/–) mice, which lack the ability to produce the SNS transmitters, norepinephrine (NE), and epinephrine. Control (Dbh+/–) mice readily reduced serum leptin levels and entered torpor after a fast in a cool environment. In contrast,Dbh–/– mice failed to reduce serum leptin and enter torpor under fasting conditions, whereas restoration of peripheral but not central NE lowered serum leptin levels and rescued the torpor response. Torpor was expressed in fastedDbh–/– mice immediately after administration of either the nonselective β-adrenergic receptor agonist isoproterenol or the β3-adrenergic receptor (AR)-specific agonist CL 316243 [disodium (RR)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino]propyl]-1,3-benzodioxazole-2,2-dicarboxylate], but not after administration of β1, β2, or α1 agonists. Importantly, the β3-specific antagonist SR 59230A [3-(2-ethylphenoxy)-1-[(1,S)-1,2,3,4-tetrahydronapth-1-ylamino]-2S-2-propanol oxalate] severely blunted fasting-induced torpor in control mice, whereas other AR antagonists were ineffective. These results define a critical role of peripheral SNS activity at β3-AR-containing tissues in the torpor adaptation to limited energy availability and cool ambient temperature.