Pharmacodynamic effects of the K ⁺ binder patiromer in a novel chronic hyperkalemia model in spontaneously hypertensive rats

Abstract

Currently described hyperkalemia (HK) animal models are typically acute and cause significant distress and mortality to the animals, warranting new approaches for studying chronic HK in a more appropriate clinical setting. Using the spontaneously hypertensive rat (SHR) model as a more relevant disease template, as well as surgical (unilateral nephrectomy), dietary (3% potassium [K+] supplementation), and pharmacological (amiloride) interventions, we were able to stably induce HK on a chronic basis for up to 12 weeks to serum K+ elevations between 8 and 9 mmol/L, with minimal clinical stress to the animals. Short‐term proof‐of‐concept and long‐term chronic studies in hyperkalemic SHRs showed concomitant increases in serum aldosterone, consistent with the previously reported relationship between serum K+ and aldosterone. Treatment with the K+ binder patiromer demonstrated that the disease model was responsive to pharmacological intervention, with significant abrogation in serum K+, as well as serum aldosterone to levels near baseline, and this was consistent in both short‐term and long‐term 12‐week chronic studies. Our results demonstrate the feasibility of establishing a chronic HK disease state, and this novel HK animal model may be suitable for further evaluating the effects of long‐term, K+‐lowering therapies on effects such as renal fibrosis and end‐organ damage.

Comparative Study of the Aftereffect of CO2 Inhalation or Tiletamine–Zolazepam–Xylazine Anesthesia on Laboratory Outbred Rats and Mice

“…Hyperkalemia in rats predisposes to both hyperexcitability of the heart (ventricular tachycardia, ventricular fibrillation) and depression (bradycardia, atrioventricular block, interventricular conduction delay, and asystole) [ 37 ]. However, it was reported [ 38 ] that prolonged induced hyperkalemia up to 10 mmol/L (with a normal potassium level of 5.3 mmol/L) in SHR rats does not lead to clinical distress.…”

The Role of Patiromer in Delaying the Onset of Renal Replacement Therapy in Patients with Advanced Renal Failure

“…In addition, patiromer use was also associated with decreased systolic and diastolic blood pressure, as well as albuminuria [32]. Pharmacodynamic effects of patiromer in an animal model with chronic hyperkalemia showed a significant reduction in serum K + that correlated with serum aldosterone [33]. e effect of patiromer on aldosterone may be related indirectly to reduction in serum K + level but remains unexplained.…”