Thomas C J, Head G A, Woods R L
From the Baker Medical Research Institute, Prahran, Victoria, Australia.
Hypertension. 1998 Sep;32(3):548-55. doi: 10.1161/01.hyp.32.3.548.
In previous studies we demonstrated that in normotensive rats, but not in spontaneously hypertensive rats (SHR), atrial natriuretic peptide (ANP) enhances bradycardic reflexes through an action on cardiac vagal afferent pathways. The present study aimed to determine whether cardiac hypertrophy, hypertension, or a nonreversible genetic factor accounted for the insensitivity of SHR to ANP action on cardiac reflex pathways. SHR were treated with the angiotensin-converting enzyme (ACE) inhibitor perindopril (3 mg/kg per day) for 6 weeks from 4 to 9 weeks of age (SHR-S, n=10) or for 9 weeks from 4 to 12 weeks of age (SHR-L, n=10) or were untreated (SHR, n=10) to produce differential effects on blood pressure and left ventricle/body weight ratio (LV/BW). Untreated normotensive Wistar-Kyoto rats (WKY, n=10) were also studied. At 13 weeks of age, all rats were instrumented with aortic and jugular catheters, and at 14 weeks we measured heart rate reflexes to rapid intravenous infusions of methoxamine (100 microg/kg, cardiac baroreflex) and serotonin (5 to 60 microg/kg, von Bezold-Jarisch cardiac chemosensitive reflex), with either alpha-rat ANP (150 ng/kg per minute IV) or saline vehicle (270 microL/h IV) infusion. Perindopril treatment for 6-week (SHR-S) and 9-week (SHR-L) durations maintained blood pressure at normotensive levels in both groups. SHR-S exhibited a small degree of cardiac hypertrophy (LV/BW was 8% higher than in WKY but 11% less than in untreated SHR), but LV/BW was normalized in SHR-L (to within 1% of WKY LV/BW). In WKY, ANP significantly (P<0.05) enhanced bradycardic responses to both the cardiac baroreflex (by 42+/-10%) and von Bezold-Jarisch chemosensitive reflex (by 17+/-5%) activation but had no effect in SHR. The cardiac reflex action of ANP was restored in SHR-L (ANP enhanced reflex bradycardia by 28+/-12% and 36+/-8%, baroreflex and von Bezold-Jarisch reflex, respectively; P<0.05), but SHR-S, which developed some cardiac hypertrophy, remained unresponsive to ANP. Our results suggest that the inability of ANP to sensitize cardiac vagal (nonarterial) afferents in SHR was not due to an inherited irreversible component, or the hypertension per se, but was associated with the presence of cardiac hypertrophy. A functional consequence of hypertension-induced cardiac hypertrophy may be the inhibition of the cardioprotective action of ANP through cardiac vagal reflexes.
在先前的研究中，我们证实，在正常血压大鼠中，心房利钠肽（ANP）可通过作用于心脏迷走传入神经通路增强心动过缓反射，但在自发性高血压大鼠（SHR）中则不然。本研究旨在确定心脏肥大、高血压或不可逆遗传因素是否导致SHR对ANP作用于心脏反射通路不敏感。从4周龄至9周龄，对SHR给予血管紧张素转换酶（ACE）抑制剂培哚普利（每天3 mg/kg）治疗6周（SHR-S，n = 10）；或从4周龄至12周龄治疗9周（SHR-L，n = 10）；或不进行治疗（SHR，n = 10），以对血压和左心室/体重比（LV/BW）产生不同影响。还对未治疗的正常血压Wistar-Kyoto大鼠（WKY，n = 10）进行了研究。在13周龄时，所有大鼠均植入主动脉和颈静脉导管，在14周时，我们测量了快速静脉注射甲氧明（100 μg/kg，心脏压力反射）和5-羟色胺（5至60 μg/kg，贝佐尔德-雅里什心脏化学感受性反射）时的心率反射，同时静脉输注α-大鼠ANP（每分钟150 ng/kg）或生理盐水载体（每小时270 μL）。培哚普利治疗6周（SHR-S）和9周（SHR-L）均使两组血压维持在正常血压水平。SHR-S表现出轻度心脏肥大（LV/BW比WKY高8%，但比未治疗的SHR低11%），但SHR-L的LV/BW恢复正常（与WKY的LV/BW相差1%以内）。在WKY中，ANP显著（P<0.05）增强了对心脏压力反射（增加42±10%）和贝佐尔德-雅里什化学感受性反射（增加17±5%）激活的心动过缓反应，但对SHR无影响。ANP的心脏反射作用在SHR-L中恢复（ANP分别使压力反射和贝佐尔德-雅里什反射的反射性心动过缓增加28±12%和36±8%；P<0.05），但已出现一定程度心脏肥大的SHR-S对ANP仍无反应。我们的结果表明，SHR中ANP无法使心脏迷走（非动脉）传入神经敏感化，并非由于遗传不可逆因素或高血压本身，而是与心脏肥大的存在有关。高血压诱导的心脏肥大的一个功能后果可能是通过心脏迷走反射抑制ANP的心脏保护作用。
