Chronic Histamine-N-Methyltransferase Inhibition Attenuates Blood Pressure Development in Dahl SS Rats

Background: Inflammation is one of the primary mechanisms behind the onset and advancement of renal disease in salt-sensitive hypertension (SS-HTN). One of the key mediators of inflammation is histamine, and there is a gap in knowledge regarding renal effects of histamine. We have shown that Dahl SS rats (a model of SS-HTN) exhibit elevated renal histamine levels. Further, we have reported that kidneys express all components of the histaminergic system and are capable of local histamine production. Highly abundant in the kidney, enzyme histamine N-methyltransferase (HNMT) is essential for the regulation of histamine levels. We hypothesized that the inhibition of HNMT-induced degradation of histamine would improve blood pressure and reduce renal tissue damage in the Dahl SS rat. Methods: At 8 weeks of age, male Dahl SS rats fed an NS diet (NS, 0.4% NaCl, Dyets) were implanted with telemeters and s.c. osmotic pumps filled with SKF91488 (HNMT inhibitor, n=7) and vehicle (veh, n=8) with infusion rate 0.04 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, and 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, plasma and urinary electrolytes, biometric data were analyzed. Picrosirius red stain (PSR) and kidney injury molecule-1 (KIM-1) staining were employed for histological analysis to assess renal fibrosis and damage. OriginPro ( t-test,1-way or 2-way ANOVA ) was used for statistical analysis. Results: At the end of the HS diet, mean arterial pressure was lower in the SKF91488 group compared to vehicle (on day 21, the MAP was 132.6±11.8 vs 160.3±6.5 mmHg, respectively, p<0.05 ); heart rates were similar between the groups (367.5±15.1 vs 363.4±5.3 BPM respectively, day 21, p>0.05). We report a significant increase in the water consumption, urinary output, Na + and Cl - excretion in both vehicle and SKF91488 groups at end point compared to the start date (p<0.05). KIM-1 levels were lower after SKF91488 treatment (1.7±0.2 vs 0.8±0.1 a.u. in veh vs SKF groups, respectively, p<0.05). The analysis of PSR staining indicated similar protein cast formation in SKF91488 compared to the vehicle group (scoring 2.3±0.4 vs 1.9±0.5 a.u. out of 5). Conclusion: The chronic infusion of HNMT inhibitor results in a reduction of blood pressure and attenuation of renal damage compared to vehicle-infused animals. This study provides new perspectives on the role of the renal histaminergic system in mediating SS-HTN mechanisms. R01 HL148114, AHA 24TPA1283630, U54HL169191 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.