Increased haemodynamic adrenergic load with isoflurane anaesthesia in type 2 diabetic and obese rats in vivo

Abstract

Background: Increasing numbers of type 2 diabetic and obese patients with enhanced rates of cardiovascular complications require surgical interventions, however they have a higher incidence of perioperative haemodynamic complications, which has been linked to adrenergic dysfunction. Therefore, we aimed to determine how α- and β-adrenoceptor (AR)-mediated haemodynamic responses are affected by isoflurane anaesthesia in experimental type 2 diabetes and obesity in vivo.

Methods: Sixteen-week old male Zucker type 2 Diabetic Fatty (ZDF) rats, Zucker Obese rats and their lean counterparts (n = 7-9 per group) were instrumented with radio telemeters to record blood pressure and heart rate and with vascular access ports for non-invasive intravenous drug delivery in vivo. Haemodynamic effects of α-AR (phenylephrine; 1-100 μg x kg(-1)) or β-AR (dobutamine; 2-120 μg x kg(-1)) stimulation were assessed under conscious and anaesthetised (isoflurane; 2%) conditions.

Results: Vascular α-AR sensitivity was increased in both diabetic (non-diabetic 80 ± 3 vs. diabetic 95 ± 4 ΔmmHg at 100 μg x kg(-1); p < 0.05) and obese (lean 65 ± 6 vs. obese 84 ± 6 ΔmmHg at 20 μg x kg(-1); p < 0.05) conscious rats. Interestingly, anaesthesia exacerbated and prolonged the increased α-AR function in both diabetic and obese animals (non-diabetic 51 ± 1 vs. diabetic 68 ± 4 ΔmmHg, lean 61 ± 5 vs. obese 84 ± 2 ΔmmHg at 20 μg x kg(-1); p < 0.05). Meanwhile, β-AR chronotropic sensitivity was reduced in conscious diabetic and obese rats (non-diabetic 58 ± 7 vs. diabetic 27 ± 8 Δbpm, lean 103 ± 12 vs. obese 61 ± 9 Δbpm at 15 μg x kg(-1); p < 0.05). Anaesthesia normalised chronotropic β-AR responses, via either a limited reduction in obese (lean 51 ± 3 vs. obese 66 ± 5 Δbpm; NS at 15 μg x kg(-1)) or increased responses in diabetic animals (non-diabetic 49 ± 8 vs. diabetic 63 ± 8 Δbpm, at 15 μg x kg(-1); NS at 15 μg x kg(-1)).

Conclusions: Long term metabolic stress, such as during type 2 diabetes and obesity, alters α- and β-AR function, its dynamics and the interaction with isoflurane anaesthesia. During anaesthesia, enhanced α-AR sensitivity and normalised β-AR function may impair cardiovascular function in experimental type 2 diabetes and obesity.

Figure 1

Experimental protocols. Overview of the study, indicating one week gentling and post-surgical recovery periods, and twice-weekly experimental sessions for randomised protocols (a). Protocols for the acute administration of incrementing doses of the α-adrenergic agonist phenylephrine at five minute intervals (b), and the β-adrenergic agonist dobutamine at ten minute intervals (c). Sodium nitroprusside (SNP) was injected at the initiation of each experiment to confirm vascular access port (VAP) patency. Sal represents saline injection to flush the VAP. All solutions were administered as a bolus.

Figure 2

α-adrenoceptor agonist responses in Zucker Diabetic Fatty rats. Peak change in mean arterial pressure (top) and heart rate (bottom) in response to 1–100 μg.kg⁻¹ phenylephrine under conscious conditions (a and c) and during isoflurane anaesthesia (b and d). *significantly different from non-diabetic littermate controls, ^†significantly different from conscious measure and # significant overall group difference, n = 8, p < 0.05, values are means ± SE.

Figure 3

β-adrenoceptor agonist responses in Zucker Diabetic Fatty rats. Peak change in heart rate (top) and mean arterial pressure (bottom) in response to 2-120 μg.kg⁻¹ dobutamine under conscious conditions (a and c) and during isoflurane anaesthesia (b and d). *significantly different from non-diabetic littermate controls and ^†significantly different from conscious measure, n = 7-8, p < 0.05, values are means ± SE.

Figure 4

α-adrenoceptor agonist responses in Zucker Obese rats. Peak change in mean arterial pressure (top) and heart rate (bottom) in response to 1–100 μg.kg⁻¹ phenylephrine under conscious conditions (a and c) and during isoflurane anaesthesia (b and d). *significantly different from lean littermate controls, ^†significantly different from conscious measure and # significant overall group difference, n = 8, p < 0.05, values are means ± SE.

Figure 5

β-adrenoceptor agonist responses in Zucker Obese rats. Peak change in heart rate (top) and mean arterial pressure (bottom) in response to 2-120 μg.kg⁻¹ dobutamine under conscious conditions (a and c) and during isoflurane anaesthesia (b and d). *significantly different from lean littermate controls, ^†significantly different from conscious measure and # significant overall group difference, n = 7-9, p < 0.05, values are means ± SE.

Figure 6

Time courses of α-adrenoceptor stimulation. Change in mean arterial pressure in response to 20 (a and d), 40 (b and e) and 100 (c and f) μg.kg⁻¹ phenylephrine in Zucker Diabetic Fatty (a, b and c) and Zucker Obese (d, e and f) rats. Statistical significance is indicated by the bars above each graph; con: conscious, ana: anaesthetised, ND: non-diabetic, D: diabetic, L: lean, Ob: obese. n = 7-9, p < 0.05, values are means ± SE.

Figure 7

Summary of α- and β-adrenoceptor function in conscious and anaesthetised Zucker Diabetic Fatty rats. Peak responses to mid-dose phenylephrine (a) or dobutamine (b). *significantly different from lean littermate controls, ^†significantly different from conscious measure, n = 7-9, p < 0.05, values are means ± SE.