The effects of chronic administration of a histamine-N-methyltransferase inhibitor on blood pressure and renal damage in the Dahl SS rats

Abstract

Background. Inflammation is one of the key mechanisms for the development of salt-sensitive hypertension (SS-HTN) and damage to the kidney. We have previously reported that the kidneys express components of the histaminergic system, and are capable of local production of histamine, a well-known inflammatory mediator. We showed that renal histamine level is increased in SS-HTN. Histamine content is tightly regulated by the enzyme histamine-N-methyltransferase, which has higher abundance in the kidney compared to other organs. We hypothesized that an increasing histamine level by limiting its breakdown will have beneficial effects on blood pressure (BP) and kidney damage in SS-HTN. Methods. Male Dahl SS rats at 9 weeks of age fed a NS diet (NS, 0.4% NaCl, Dyets) were implanted with telemeters and s.c. osmotic pumps filled with SKF91488 (N-methyltransferase inhibitor, prevents histamine breakdown, n=5) and vehicle (veh, n=5) with infusion rate 0.03875 mg/hr. Then, the animals were placed on a high salt (HS, 4% NaCl, Dyets AIN-75-based) diet for 21 days to induce SS-HTN. Telemetric measurements of BP were carried out. Metabolic cage studies were performed at the beginning and at the end of the protocol. At the endpoint, glomerular filtration rate (GFR) was measured; plasma and urinary electrolytes were analyzed. PSR and Masson Trichrome staining were employed for histological analysis. OriginPro ( t-test,1-way or 2-way ANOVA) were used for statistical analysis. Wire myography was performed for vascular relaxation analysis in renal or interlobular arteries from rats on NS and HS diets subjected to histamine (no SKF infusion). Results. At the end of the HS diet, MAP was lower in the SKF91488 infusion group compared to veh group (148.7±10.9 vs 162.9±10.8, 144.2±12.6 vs 166.1±11.1, 143.3±14.2 vs 171.1±10.5 mmHg on days 18-20 of HS diet, p<0.05). GFR was lower in the SKF91488 rats compared to veh group (0.44±0.05 vs 0.56±0.04 mL/min/100gBW, respectively, p=0.07). Electrolyte analysis showed trends towards higher urinary Na+ and Cl- excretion in the SKF91488 group ( p=0.089 and p=0.07, respectively). Urine flow, plasma electrolytes, kidney/body weight and water intake were similar. A significant amount of protein casts was found in the SKF91488 compared to vehicle group (8.31±0.76 vs 5.12±1.04%, p<0.05); pathology assessment revealed recruitment of immune cells into the kidney cortex in the SKF91488 group. Vascular relaxation dose responses to histamine were similar in HS rats vs NS rats (no SKF; p>0.05). Conclusion. We report that chronic administration of a histamine-N-methyltransferase inhibitor significantly reduced BP in the Dahl SS rats, whereas protein cast formation and recruitment of immune cells in the renal tissue was augmented. This study offers new insights into the role of the renal histaminergic system in the development of SS-HTN and renal damage and suggests potential differential effects of histamine in vasculature and renal epithelium. NIH R01HL148114 and AHA 23POST1020105 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.