Renal Denervation Prevents Atrial Arrhythmogenic Substrate Development in CKD.

BACKGROUND: In patients with chronic kidney disease (CKD), atrial fibrillation (AF) is highly prevalent and represents a major risk factor for stroke and death. CKD is associated with atrial proarrhythmic remodeling and activation of the sympathetic nervous system. Whether reduction of the sympathetic nerve activity by renal denervation (RDN) inhibits AF vulnerability in CKD is unknown. METHODS: Left atrial (LA) fibrosis was analyzed in samples from patients with AF and concomitant CKD (estimated glomerular filtration rate [eGFR], <60 mL/min per 1.73 m2) using picrosirius red and compared with AF patients without CKD and patients with sinus rhythm with and without CKD. In a translational approach, male Sprague Dawley rats were fed with 0.25% adenine (AD)-containing chow for 16 weeks to induce CKD. At week 5, AD-fed rats underwent RDN or sham operation (AD). Rats on normal chow served as control. After 16 weeks, cardiac function and AF susceptibility were assessed by echocardiography, radiotelemetry, electrophysiological mapping, and burst stimulation, respectively. LA tissue was histologically analyzed for sympathetic innervation using tyrosine hydroxylase staining, and LA fibrosis was determined using picrosirius red. RESULTS: Sirius red staining demonstrated significantly increased LA fibrosis in patients with AF+CKD compared with AF without CKD or sinus rhythm. In rats, AD demonstrated LA structural changes with enhanced sympathetic innervation compared with control. In AD, LA enlargement was associated with prolonged duration of induced AF episodes, impaired LA conduction latency, and increased absolute conduction inhomogeneity. RDN treatment improved LA remodeling and reduced LA diameter compared with sham-operated AD. Furthermore, RDN decreased AF susceptibility and ameliorated LA conduction latency and absolute conduction inhomogeneity, independent of blood pressure reduction and renal function. CONCLUSIONS: In an experimental rat model of CKD, RDN inhibited progression of atrial structural and electrophysiological remodeling. Therefore, RDN represents a potential therapeutic tool to reduce the risk of AF in CKD, independent of changes in renal function and blood pressure.

Efficacy of Antihypertensive Drugs of Different Classes After Renal Denervation in Spontaneously Hypertensive Rats.

BACKGROUND: Renal denervation (RDN) lowers blood pressure (BP) in patients with uncontrolled hypertension. Limited data exist on the effectiveness of different antihypertensive medications following RDN on BP and maladaptive cardiac phenotypes. METHODS: Eighty-nine male spontaneously hypertensive rats with continuous BP recording underwent RDN or sham operation. Ten days postsurgery, spontaneously hypertensive rats were randomized to receive no antihypertensive medication, amlodipine, olmesartan, hydrochlorothiazide, bisoprolol, doxazosin, or moxonidine for 28 days. Cardiac remodeling was determined histologically, and activation of the renin-angiotensin-aldosterone system was explored. RESULTS: Before initiation of antihypertensive drugs, RDN reduced mean arterial pressure (-12.6 mm Hg [95% CI, -14.4 to -10.8]; P<0.001). At study end, mean arterial pressure was lower in RDN compared with sham operation in drug-naïve controls (P=0.006), olmesartan (P=0.002), amlodipine (P=0.0004), hydrochlorothiazide (P=0.006), doxazosin (P=0.001), and bisoprolol (P=0.039) but not in animals receiving moxonidine (P=0.122). Compared with pooled BP change of all other drug classes, mean arterial pressure change was largest for olmesartan (-15.9 mm Hg [95% CI, -18.6 to -13.2]; P<0.001) and amlodipine (-12.0 mm Hg [95% CI, -14.7 to -9.3]; P<0.001). In drug-naïve controls, RDN reduced plasma renin activity (-5.6%¸ P=0.03) and aldosterone concentration (-53.0%; P=0.005). In the presence of antihypertensive medication, plasma renin activity and aldosterone remained unchanged after RDN. Cardiac remodeling was not affected by RDN alone. In animals receiving olmesartan after RDN, cardiac perivascular fibrosis was attenuated. Amlodipine and bisoprolol following RDN reduced cardiomyocyte diameter. CONCLUSIONS: Following RDN, treatment with amlodipine and olmesartan resulted in the largest BP reduction. Antihypertensive medications mediated heterogeneous effects on renin-angiotensin-aldosterone system activity and cardiac remodeling.

Non-classical effects of androgens on testes from neonatal rats.

The intratesticular testosterone concentration is high during the early postnatal period although the intracellular androgen receptor expression (iAR) is still absent in Sertoli cells (SCs). This study aimed to evaluate the non-classical effects of testosterone and epitestosterone on calcium uptake and the electrophysiological effects of testosterone (1µM) on SCs from rats on postnatal day (pnd) 3 and 4 with lack of expression of the iAR. In addition, crosstalk on the electrophysiological effects of testosterone and epitestosterone with follicle stimulating hormone (FSH) in SCs from 15-day-old rats was evaluated. The isotope (45)Ca(2+) was utilized to evaluate the effects of testosterone and epitestosterone in calcium uptake. The membrane potential of SCs was recorded using a standard single microelectrode technique. No immunoreaction concerning the iAR was observed in SCs on pnd 3 and 4. At this age, both testosterone and epitestosterone increased the (45)Ca(2+) uptake. Testosterone promoted membrane potential depolarization of SCs on pnd 4. FSH application followed by testosterone and epitestosterone reduced the depolarization of the two hormones. Application of epitestosterone 5 min after FSH resulted in a delay of epitestosterone-promoted depolarization. The cell resistance was also reduced. Thus, in SCs from neonatal Wistar rats, both testosterone and epitestosterone act through a non-classical mechanism stimulating calcium uptake in whole testes, and testosterone produces a depolarizing effect on SC membranes. Testosterone and epitestosterone stimulates non-classical actions via a membrane mechanism, which is independent of iAR. FSH and testosterone/epitestosterone affect each other's electrophysiological responses suggesting crosstalk between the intracellular signaling pathways.