Unintended Consequences: Renal Denervation Attenuates Hypertension Development but Impairs Glucose Metabolism in Female Fawn‐Hooded Hypertensive Rats

Abstract

For both men and women, hypertension (HTN) is the highest risk factor for cardiovascular disease and stroke – the two leading causes of morbidity and mortality throughout the world. Though HTN etiology remains debated, altered sympathetic nervous activity, particularly to the kidney (RSNA), is regarded as a primary contributor to the development and maintenance of HTN. Ablation of renal sympathetic nerves (RDNx) reportedly prevents and/or reverses several forms of experimental hypertension. Several off‐target improvements are also reported, such as glucose metabolism. However, an overwhelming majority of these experimental models and mechanisms focus only on responses in male subjects. Moreover, the sex differences in sympathetic control of blood pressure in hypertension remain poorly defined. In this study, we assessed the role of RDNx to prevent hypertension development and metabolic dysfunction in the Fawn‐Hooded Hypertensive (FHH) rat model. We hypothesized that RDNx would attenuate the development of HTN, and improve glucose handling in female and male rats. FHH rats (10 weeks old) underwent sham or bilateral RDNx surgeries (n=5/group). For the following six weeks, 24‐hour mean arterial pressure (MAP) was monitored by radiotelemetry. Glucose handling was assessed biweekly by glucose tolerance test (GTT). Cardiovascular data was averaged weekly, and analyzed by two‐way ANOVA with a Bonferroni post‐hoc test (α=.05). Data presented as mean ± SEM. Six weeks post‐treatment, RDNx attenuated the HTN in the females (p<.05) vs. sham controls (107±5 vs. 118±3). Interestingly, no difference in MAP between RDNx and sham males was observed (129±2 vs. 125±1mmHg). Regarding glucose metabolism, baseline fasting blood glucose (FBG) and glucose tolerance (GT) were similar between males and females prior to RDNx. After six weeks, FBG in female sham FHH (100.9±2.3mg/dL) was higher (p<.05) than male shams (89.2±2.7mg/dL). Likewise, GT was impaired in female rats compared to male shams. In contrast to our hypothesis, RDNx worsened the FBG (110±2.6mg/dL) and GT in female vs. female shams. No effect of time or RDNx on glucose handling was observed males. In summary, RDNx attenuated HTN development in female FHH rats; however, glucose metabolism was impaired by RDNx in females but not in males. These results suggest that sex may need to be considered in the use of RDNx to treat HTN. These findings are clinically important in that RDNx responses may be partially dependent on sex, and may result in negative outcomes such as impaired glucose metabolism in females. Further examination of sex differences in the responses to RDNx is underway.Support or Funding InformationNIH 5R01HL116476; NIH 2T32HL7741