BACKGROUND Hypertensive individuals with higher heart rates and anxiety have greater cardiovascular morbidity and mortality. Despite the correlation between hypertension, heart rate, and anxiety, scant attention has been paid to the effect of hypertension drug therapy on behavioral outcomes in cardiovascular disease. Ivabradine, an inhibitor of hyperpolarization-activated, cyclic nucleotide-gated funny channels (HCNs), has been used clinically to reduce heart rates and has been shown to improve quality of life in patients with angina and heart failure. We postulated that in addition to lowering heart rate, ivabradine could reduce anxiety in mice exposed to a significant stress paradigm. METHODS Mice underwent a stress induction protocol, subsequently they received either vehicle or ivabradine (10 mg/kg) via osmotic minipumps. Blood pressure and heart rates were measured with tail cuff photoplethysmography. Anxiety was assessed quantitatively through the open field test (OFT) and the elevated plus maze (EPM). Cognition was assessed with an object recognition test (ORT). Pain tolerance was measured by the hot plate test or subcutaneous injection of formalin. HCN gene expression was measured with RT-PCR. RESULTS Ivabradine reduced resting heart rate in the stressed mice by 22%. Stressed mice treated with ivabradine displayed significantly greater exploratory behavior in the OFT, EPM, and ORT. The expression of central HCN channels was significantly reduced following stress. CONCLUSION It is suggested from our findings that ivabradine can reduce anxiety following significant psychological stress. Reductions in heart rate may directly improve quality of life by reducing anxiety in patients with hypertension and high heart rates.

Sympathomimetics are effective, centrally acting drugs that induce weight loss through their potent anorexic and locomotor properties. We reported that sympathomimetics antagonize catecholamine-dependent, alpha-2 adrenergic receptor-dependent signal transduction mediated by chloride/bicarbonate transport. We posit that other drugs that target cellular chloride/bicarbonate antiport would similarly demonstrate anorectic properties, induce locomotion, and diminish weight gain. Male and female inbred mice were housed in groups or stressed by prolonged social isolation. Mice consumed either normal chow or a high fat, high fructose corn syrup, (i.e. “Western”) diet. To inhibit chloride/bicarbonate transport, acetazolamide (ACT, 3 mM) was added to the drinking water. Rodents underwent evaluations of exploratory locomotion and learning with the object recognition test. Mice consuming a “Western” diet gain more weight compared to mice given a normal diet. When placed on a “Western” diet, stressed mice gained weight more rapidly than unstressed. The body weight of mice fed a normal diet with ACT was significantly reduced compared to control mice not given ACT (weight, g ± SEM), 23.7 ± 0.8 v. 21.0 ± 0.5, p = 0.02. ACT did not reduce weight gain in animals chronically maintained on a “Western” diet. Compared to unstressed mice, living in social isolation reduced spontaneous exploratory locomotion time, an indicator of anxiety, in male mice (sec +SEM) from 22.8 ± 3.5 to 12.2 ± 2.1 (p < 0.001), and in female mice, from 47 ± 5.7 to 19.6 ± 2.3 (p < 0.001). ACT had no effect on exploration time in unstressed mice, but ACT completely restored the diminished exploratory locomotion time found in stressed mice compared to unstressed mice. The ratio of time spent exploring new objects compared to familiar items (discrimination ratio [DR]) was reduced following social isolation in males from 2.6 ± 0.5 to 1.2 ± 0.2 (p < 0.05) and in females from 3.8 ± 0.6 to 1.5 ± 0.2 (p < 0.01). ACT normalized the DR ratio of the stressed mice. Decreased food consumption and greater locomotor activity induced by ACT may contribute to acute weight loss; this effect is diminished when rodents were maintained on an unhealthful Western diet. Inhibition of chloride/bicarbonate transport through agents such as acetazolamide could offer a safe, new approach to achieving weight loss.

We demonstrate that inhibition of catecholamine synthesis with alpha-methyltyrosine (αMT) improves cardiovascular and behavioral outcomes following TBI.

BackgroundAlpha‐2 adrenergic receptor (α2AR) agonists, such as clonidine or dexmedetomidine, can decrease the working memory acquisition of a traumatic event, and also, blocking the post‐synaptic action of the catecholamines with a β‐adrenergic receptor (β‐AR) antagonist, propranolol, can reduce the emotional response to memories of the traumatic event. α2ARs and β‐ARs divergently regulate neuronal intracellular cyclic adenosine monophosphate (cAMP) concentrations. It is suggested that other pharmacologic mechanisms that similarly lead to reductions in neuronal cAMP could also be salutary in the treatment of post‐traumatic stress (PTSD). In the central nervous system, hyperpolarization‐activated, cyclic nucleotide‐gated (HCN) “funny” channels are important for dendritic integration, synaptic transmission, setting membrane potential, and neuronal firing rate. These funny channels (HCN1 and HCN2) are expressed in the forebrain and pre‐frontal cortex where they are co‐located and cross talk with A2ARs that mediate intracellular cAMP concentrations and drive working memory and the emotional valence associated with memories. Also, targeted disruption of HCN gene expression, or inhibition of cyclic nucleotide binding to HCN channels in the brain, has been shown to result in antidepressant‐like behavior with improved coping in animal models of stress.HypothesisWe postulated that pharmacological inhibition of HCN channels would diminish the anxiolytic and cognitive decline that occurs in an animal model of PTSD.MethodsWe infused an HCN antagonist, ivabradine (10 mg/kg/day), subcutaneously or performed sham surgery in a mouse model of PTSD. After six days of random cued and contextual fear conditioning, mouse anxiety and cognition was assessed by their performance over five minutes on three standard behavioral challenges—Open Field Test (OFT), Elevated Plus Maze (EPM), and Object Recognition Test (ORT).ResultsDuring the OFT, ivabradine did not significantly affected the total exploratory distance traveled. However, ivabradine significantly increased the time the mice spent in the center of the field (all values expressed in sec ± SEM), from 19.0 ± 2.2 to 27.7 ± 3.2, p = 0.029. During EPM, ivabradine increased the time mice spent traversing the open arm from 66.8 ± 8.5 to 116 ± 11.5, p = 0.002, During the ORT, social isolation during PTSD reduced total exploratory time from 24.7 ± 4.9 to 13.1 ± 2.2, and the ivabradine group increased exploratory time to 30.0 ± 3.3 compared to the mice living in isolation with PTSD (p = 0.0004). Furthermore, when compared to the untreated PTSD mice living in social isolation, ivabradine significantly increased the exploratory times of both familiar (14.3 ± 1.9 vs. 5.6 ± 1.1, p=0.0008) and novel objects (15.8 ± 2.4 vs. 7.5 ± 1.6, p = 0.01).ConclusionIvabradine may offer salutary advantage to men and women who experience PTSD.Support or Funding InformationDepartment of DefenseThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.