Verwaerde P, Bordet R, Portolan G, Tran M A, Marques M A, Montastruc J L, Sénard J M
Laboratoire de pharmacologie médicale et clinique, INSERM U317, faculté de médecine de Toulouse.
Arch Mal Coeur Vaiss. 1996 Aug;89(8):1097-1101.
The synthetic somatostatin analogue, octreotide, has recently been proposed for the treatment of both postprandial and orthostatic hypotension (OH) in humans with autonomic failure related to multiple system atrophy (MSA) or diabetes mellitus. However, pharmacodynamic data are not still available in experimental models of orthostatic hypotension. We investigated in a model of neurogenic orthostatic hypotension, obtained by chronic sinoaortic denervation (SAD) in chloralose-anaesthetized dogs, the effects of octreotide (0.1 mg/kg, subcutaneous route) during a double-blind cross-over study vs placebo. Blood pressure (BP) and heart rate (HR) average values, SBP and HR short-term variabilities (using fast Fourier transformation) in both low (LF: 50-150 mHz) and high frequency range (respiratory rate +/- 50 mHz) and plasma noradrenaline (NA) levels (HPLC) were measured in supine position and during head-up tilt test (HUT: 80 degrees, 10 min) before and 45 min after drug administration. In controls, as expected, head-up tilt test induced a significant increase in DBP (+14 +/- 8 mmHg), HR (+36 +/- 21 beat/min), NA (296 +/- 118 vs 141 +/- 63 pg/ml), SBP-LF (25 +/- 5 vs 14 +/- 3%) whereas HR-HF significantly decreased. The changes during head-up tilt test were not modified after placebo or octreotide administration. In SAD dogs, head-up tilt test elicited a dramatic fall in SBP (-74 +/- 39 mmHg), DBP (-20 +/- 15 mmHg) without any significant change in HR (-5 +/- 12 beat/min), NA (708 +/- 213 vs 606 +/- 331 pg/ml), SBP-LF (16 +/- 3 vs 16 +/- 3%), HR-HF (8 +/- 2 vs 7 +/- 1%). Octreotide or placebo failed to significantly modify any of the measured parameters during head-up tilt test performed 45 min after drug administration. At the dose used, octreotide elicited a 80% decrease in insulin plasma levels after 45 min in both normal and SAD dogs. These results suggest that 1) this experimental model of orthostatic hypotension in SAD dogs is reproductible and can be used to investigate the pharmacological effects of antihypotensive drugs, 2) cardiovascular and biochemical characteristics of the SAD model are similar to those observed in MSA and 3) octreotide, in these experimental conditions, is not able to correct the BP fall during head-up tilt test.
合成生长抑素类似物奥曲肽最近被提议用于治疗与多系统萎缩（MSA）或糖尿病相关的自主神经功能衰竭患者的餐后低血压和直立性低血压（OH）。然而，在直立性低血压的实验模型中仍没有药效学数据。我们在氯醛糖麻醉的犬慢性去窦弓神经（SAD）建立的神经源性直立性低血压模型中，通过双盲交叉研究，对比安慰剂，研究了奥曲肽（0.1mg/kg，皮下给药）的作用。在仰卧位以及给药前和给药后45分钟的头高位倾斜试验（HUT：80度，10分钟）期间，测量血压（BP）和心率（HR）平均值、收缩压（SBP）和HR在低频（LF：50 - 150mHz）和高频范围（呼吸频率±50mHz）的短期变异性（使用快速傅里叶变换）以及血浆去甲肾上腺素（NA）水平（高效液相色谱法）。在对照组中，正如预期那样，头高位倾斜试验导致舒张压显著升高（+14±8mmHg）、心率升高（+36±21次/分钟）、NA升高（296±118对141±63pg/ml）、SBP-LF升高（25±5对14±3%），而HR-HF显著降低。安慰剂或奥曲肽给药后，头高位倾斜试验期间的变化未被改变。在SAD犬中，头高位倾斜试验引起收缩压急剧下降（-74±39mmHg）、舒张压下降（-20±15mmHg），心率（-5±12次/分钟）、NA（708±213对606±331pg/ml）、SBP-LF（16±3对16±3%）、HR-HF（8±2对7±1%）无任何显著变化。给药后45分钟进行的头高位倾斜试验期间，奥曲肽或安慰剂未能显著改变任何测量参数。在所使用的剂量下，奥曲肽在正常犬和SAD犬中45分钟后均使胰岛素血浆水平降低80%。这些结果表明：1）SAD犬的这种直立性低血压实验模型是可重复的，可用于研究抗低血压药物的药理作用；2）SAD模型的心血管和生化特征与MSA中观察到的相似；3）在这些实验条件下，奥曲肽不能纠正头高位倾斜试验期间的血压下降。
