Modulation of the baroreceptor reflex by alpha 2A-adrenoceptors: a study in alpha 2A knockout mice

Abstract

1. Our objective was to determine whether alpha(2A)-adrenoceptors modulate the baroreceptor reflex. The efficacy of the reflex was evaluated by measuring the spontaneous blood pressure and heart rate variability at rest and the heart rate responses to evoked changes in blood pressure. Experiments were carried out in conscious, unrestrained, and anaesthetized alpha(2A)-adrenoceptor-deficient (alpha(2A)-KO) mice and WT mice. 2. In conscious alpha(2A)-KO mice, the spontaneous blood pressure variability was greater, and the spontaneous heart rate variability was lower than in conscious WT mice. This was also observed in anaesthetized animals. 3. The reflex bradycardia after intravenous injection of phenylephrine was greatly attenuated in conscious alpha(2A)-KO compared to conscious WT mice; the baroreceptor reflex gain (ratio maximal change in heart rate/maximal change in mean arterial pressure) was decreased by 40%. 4. Similar results were obtained when reflex bradycardia was elicited by intra-arterial volume loading of conscious WT and alpha(2A)-KO mice. The baroreceptor reflex gain upon volume loading was also low in anaesthetized alpha(2A)-KO mice. 5. The reflex tachycardia evoked by intravenous sodium nitroprusside injection was also significantly less in alpha(2A)-KO mice as compared to WT, conscious as well as anaesthetized; the baroreceptor reflex gains were decreased by 50 and 65%, respectively. 6. Direct stimulation of cardiac beta-adrenoceptors by the agonist isoprenaline produced similar cardioacceleration in alpha(2A)-KO and WT animals. 7. Our results show that the baroreceptor reflex function is impaired in mice lacking alpha(2A)-adrenoceptors. We conclude that central alpha(2A)-adrenoceptors facilitate the reflex response to both loading and unloading of the arterial baroreceptors.

Figure 1

Typical 10 min recordings of mean arterial pressure and heart rate in a conscious WT and α_2A-KO mouse. After a 35–50 min stabilization period, the MAP and HR were measured every second during the next 10 min. Note that the recording conditions were the same in the two animals. The tracings are representative of 23 (WT) and 24 (α_2A-KO) animals.

Figure 2

Typical BP and HR responses to phenylephrine or sodium nitroprusside injection in conscious WT and α_2A-KO mice. PHE or SNP was injected i.v., as indicated by the arrows. The tracings are representative of six experiments each.

Figure 3

Reflex bradycardia evoked by injection of phenylephrine in conscious WT and α_2A-KO mice. After determination of baseline values (PRE), PHE 50 μg kg⁻¹ was injected i.v., as indicated by the arrow. The MAP and HR were then evaluated every 30 s during the next 5 min. The baroreceptor reflex gain is the ratio of the maximal HR change over the maximal MAP change. Means±s.e.m. of six experiments each. ^*P<0.05 versus WT.

Figure 4

Reflex bradycardia evoked by volume loading in conscious WT and α_2A-KO mice, and in anaesthetized α_2A-KO mice. After determination of baseline values (PRE), dextran solution (10 ml kg⁻¹ i.a.) was infused for 2 min, as indicated by the horizontal bar (from t=−2 to 0 min). The MAP and HR were then evaluated every 30 s from the beginning of infusion. The baroreceptor reflex gain is the ratio of the maximal HR change over the maximal MAP change. Means±s.e.m. of six (conscious WT and α_2A-KO) and four (anaesthetized α_2A-KO) experiments. ^*P<0.05 versus WT. +P< 0.05 versus conscious α_2A-KO.

Figure 5

Reflex tachycardia evoked by injection of SNP in conscious WT and α_2A-KO mice. After determination of baseline values (PRE), SNP 500 μg kg⁻¹ was injected i.v., as indicated by the arrow. The MAP and HR were then evaluated every 30 s during the next 5 min. The baroreceptor reflex gain is the ratio of the maximal HR change over the maximal MAP change. Means±s.e.m. of six experiments each. ^*P<0.05 versus WT.

Figure 6

Reflex tachycardia evoked by injection of SNP in anaesthetized WT and α_2A-KO mice. After determination of baseline values (PRE), SNP 500 μg kg⁻¹ was injected i.v., as indicated by the arrow. The MAP and HR were then evaluated every 30 s during the next 5 min. The baroreceptor reflex gain is the ratio of the maximal HR change over the maximal MAP change. Means±s.e.m. of six experiments each. ^* P<0.05 versus WT.

Figure 7

Maximal changes in MAP and HR evoked by isoprenaline in conscious WT and α_2A-KO mice. Isoprenaline 5 μg kg⁻¹ was injected i.v. Means±s.e.m. of five (WT) and six (α_2A-KO) experiments.