Prevention of cardiac events caused by surgical stress in aged rats: simultaneously activating β₂-adrenoceptor and inhibiting β₁-adrenoceptor

Figures & data

Figure 1. Fold increase of plasma epinephrine and norepinephrine induced by operation and hypoxia. The results were expressed as the fold increase of plasma epinephrine or norepinephrine level in operated rats relative to normal rats. Mean ± SD. n = 7 rats in each group. **p < 0.01 versus corresponding normal adult or aged rats; ##p < 0.01 versus operated adult.

Table 1. Operation and hypoxia elevated plasma epinephrine and norepinephrine.

	Epinephrine (pg/ml)	Norepinephrine (pg/ml)
Normal adult	92.7 ± 11.2	306.7 ± 15.2
Normal aged	105.7 ± 16.4	323.7 ± 18.2
Sham adult	1076.8 ± 18.7*	1287.9 ± 21.5*
Sham aged	1892.6 ± 23.8†	2487.7 ± 25.6†

Each value represents the mean ± SD; n = 7 hearts in each group.

*p < 0.01 versus normal adult; †p < 0.01 versus normal aged.

Figure 2. Combined use of selective β₁AR antagonist and β₂AR agonist increased the survival rate of myocytes. Each value represents the mean ± SD. n = 7 rats in each group. **p < 0.01 versus normal group; ##p < 0.05 versus surgery group; Δp < 0.05 and ΔΔp < 0.01 versus group.

Figure 3. Combined use of selective β₁AR blocker and β₂AR agonist smoothed the fluctuations of MAP and HR in the perioperative period. a: Changes in MAP in the perioperative period. b: Changes in HR in the perioperative period. Each value represents the mean ± SD. n = 10 rats in each group. *p < 0.05 versus normal group at corresponding time point; #p < 0.05 versus surgery group at corresponding time point; $p < 0.05 versus group at corresponding time point; Δp < 0.05 versus group at corresponding time point. Pre: day 3 after administration (pre-operation); Ope: intra-operation; Day 1: day 1 after surgery; Day 3: day 3 after surgery; Day 7: day 7 after surgery.

Figure 4. Combined use of selective β₁AR blocker and β₂AR agonist normalized RPP in the perioperative period. Each value represents the mean ± SD. n = 10 rats in each group. *p < 0.05 versus normal group at corresponding time point; #p < 0.05 versus surgery group at corresponding time point; $p < 0.05 versus group at corresponding time point; Δp < 0.05 versus group at corresponding time point. Pre: day 3 after administration (pre-operation); Ope: intra-operation; Day 1: day 1 after surgery; Day 3: day 3 after surgery; Day 7: day 7 after surgery.

Figure 5. Combined use of selective β₁AR blocker and β₂AR agonist decreased the release of LDH in the perioperative period. Each value represents the mean ± SD. n = 10 rats in each group. *p < 0.05 versus normal group at corresponding time point; #p < 0.05 versus surgery group at corresponding time point; Pre: day 3 after administration (pre-operation); Ope: intra-operation; Day 1: day 1 after surgery; Day 3: day 3 after surgery; Day 7: day 7 after surgery.

Figure 6. Combined use of selective β₁AR blocker and β₂AR agonist improved LVEDP and ±dP/dt_max in the perioperative period. a: Changes in LVEDP in each group. b: Changes in +dp/dt_max in each group. c: Changes in −dp/dt_max in each group. Each value represents the mean ± SD. n = 10 rats in each group.*p < 0.05 versus normal group at corresponding time point; #p < 0.05 versus surgery group at corresponding time point; $p < 0.05 versus at corresponding time point; Pre: day 3 after administration (pre-operation); Ope: intra-operation; Day 1: day 1 after surgery; Day 3: day 3 after surgery; Day 7: day 7 after surgery.

Figure 7. Selective β₁AR blocker or/and β₂AR agonist changed myocytes shortening amplitudes in the perioperative period. Each value represents the mean ± SD. n = 7 rats in each group. *p < 0.05 versus normal group at corresponding time point; #p < 0.05 versus surgery group at corresponding time point; $p < 0.05 versus group at corresponding time point; Pre: day 3 after administration (pre-operation); Day 1: day 1 after surgery; Day 3: day 3 after surgery; Day 7: day 7 after surgery.

Table 2. The time to peak contraction (TTP, ms) of cardiomyocytes.

	Pre	Day 1	Day 3	Day 7
Normal	112 ± 5	112 ± 5	112 ± 5	112 ± 5
Surgery	110 ± 4	144 ± 9*	129 ± 6	121 ± 6
	115 ± 5	125 ± 7	119 ± 9	116 ± 7
	101 ± 7	113 ± 6†	117 ± 7	107 ± 6
	100 ± 9	108 ± 8‡	115 ± 9	102 ± 8

Each value represents the mean ± SD; n = 7 hearts in each group. *p < 0.05 versus normal group; †p < 0.05 versus surgery group; Pre: day 3 after administration; Day 1: day 1 after surgery; Day 3: day 3 after surgery; Day 7: day 7 after surgery.

Table 3. The time to 90% relaxation (R90, ms) of cardiomyocytes.

	Pre	Day 1	Day 3	Day 7
Normal	369 ± 11	369 ± 11	369 ± 11	369 ± 11
Surgery	361 ± 7	346 ± 7*	362 ± 6	369 ± 6
	386 ± 9	366 ± 13	369 ± 9	375 ± 9
	402 ± 10*†	375 ± 5†	380 ± 6	380 ± 6
	405 ± 8*†	376 ± 11†	386 ± 7	389 ± 8

Each value represents the mean ± SD; n = 7 hearts in each group. *p < 0.05 versus normal; †p < 0.05 versus the surgery group. Pre: day 3 after administration; Day 1: day 1 after surgery; Day 3: day 3 after surgery; Day 7: day 7 after surgery.

Figure 8. ECG recorded from extremities in standard lead II. a: Normal ECG; b: Ventricular bigeminy occurred in surgery group; c: Ventricular trigenimy occurred in surgery group; d: Frequent premature ventricular contractions occurred in surgery group; e: Myocardial ischemia occurred in surgery group; f: Paroxysmal ventricular tachycardia occurred in group.

Table 4. The rate of cardiac complications.

Group	Arrhythmia	Myocardial ischemia	Mortality
Surgery	14 (28%)	4 (8%)	3 (6%)
	5 (10.0%)	2 (4%)	0
	8 (16%)	2 (4%)	1 (2%)
	2 (4%)*	0	0

*p < 0.05 versus surgery group, n = 50 rats in each group. Chi-square test with a Bonferroni-correction was conducted to test for differences of probability of occurring arrhythmia. Fisher’s exact test was used for comparing the differences of probability of occurring myocardial ischemia and mortality. Statistical significance was set at p < 0.05, except for when the Bonferroni correction was used for multiple comparisons, in which case statistical significance was set at p < 0.05/6 = 0.0083.