Department of Pharmacology and Experimental Therapeutics (J.K.M., J.C.S., J.G., D.R.K.), Louisiana State University Health Sciences Center, 1901 Perdido St, New Orleans, LA.
Cardiovascular Center of Excellence (D.R.K.), Louisiana State University Health Sciences Center, 1901 Perdido St, New Orleans, LA.
Hypertension. 2022 Feb;79(2):379-390. doi: 10.1161/HYPERTENSIONAHA.121.18503. Epub 2021 Dec 2.
Nalfurafine is a G-protein-biased KOR (kappa opioid receptor) agonist that produces analgesia and lacks central nervous system adverse effects. Here, we examined the cardiovascular and renal responses to intravenous and oral nalfurafine alone and in combination with furosemide, hydrochlorothiazide, or amiloride. We hypothesized that nalfurafine, given its distinct mechanism of vasopressin inhibition, would increase urine output to these diuretics and limit electrolyte loss. Following catheterization, conscious Sprague-Dawley rats received an isotonic saline infusion and were then administered an intravenous bolus of nalfurafine, a diuretic, or a combination. Mean arterial pressure, heart rate, and urine output were recorded for 90 minutes. In another study, rats were placed in metabolic cages and administered drug in an oral volume load. Hourly urine samples were then collected for 5 hours. Intravenous and oral nalfurafine produced a marked diuresis, antinatriuresis, antikaliuresis, and a decrease in mean arterial pressure. Compared with diuretic treatment alone, intravenous coadministration with nalfurafine significantly increased urine output to furosemide and hydrochlorothiazide and decreased sodium and potassium excretion. Notably, mean arterial pressure was reduced with nalfurafine/diuretic combination therapy compared to diuretics alone. Similarly, oral coadministration of nalfurafine significantly increased urine output to hydrochlorothiazide and decreased sodium and potassium excretion, whereas combination with furosemide only limited the amount of sodium excreted. Further, both intravenous and oral coadministration of nalfurafine enhanced the diuresis to amiloride and decreased sodium excretion. Together, these findings demonstrate that nalfurafine enhances the diuresis to standard-of-care diuretics without causing an excessive loss of electrolytes, offering a new approach to treat several cardiovascular conditions.
纳呋拉啡是一种 G 蛋白偏向性的 κ 阿片受体（KOR）激动剂，具有镇痛作用且无中枢神经系统不良反应。在此，我们研究了纳呋拉啡单独及与呋塞米、氢氯噻嗪或阿米洛利联合应用时对心血管和肾脏的影响。我们假设，由于纳呋拉啡抑制血管加压素的独特机制，它会增加这些利尿剂的尿量并限制电解质丢失。在导管插入术后，清醒的 Sprague-Dawley 大鼠接受等渗盐水输注，然后静脉注射纳呋拉啡、利尿剂或两者的组合。记录 90 分钟内的平均动脉压、心率和尿量。在另一项研究中，大鼠被放置在代谢笼中，并口服给予药物。然后每小时收集 5 小时的尿液样本。静脉内和口服纳呋拉啡均产生明显的利尿、排钠减少、排钾减少和平均动脉压降低。与单独使用利尿剂相比，静脉内联合纳呋拉啡显著增加了呋塞米和氢氯噻嗪的尿量，并减少了钠和钾的排泄。值得注意的是，与单独使用利尿剂相比，纳呋拉啡/利尿剂联合治疗组的平均动脉压降低。同样，口服联合纳呋拉啡也显著增加了氢氯噻嗪的尿量，并减少了钠和钾的排泄，而与呋塞米联合仅限制了钠的排泄量。此外，静脉内和口服联合应用纳呋拉啡均可增强阿米洛利的利尿作用并减少钠的排泄。总之，这些发现表明，纳呋拉啡增强了标准治疗利尿剂的利尿作用，而不会导致电解质过度丢失，为治疗多种心血管疾病提供了一种新方法。
