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Cannabinoid Administration Does Not Affect Mean Arterial Pressure or Glomerular Filtration Rate in DOCA‐Salt Hypertensive Rats
Author(s) -
Gauthier Madeline,
Rafet Dennis Melissa,
Parvin Irin,
Schwartz Kyle,
Banek Christopher
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.04100
Subject(s) - medicine , renal function , cannabinoid , endocrinology , fatty acid amide hydrolase , inflammation , agonist , cannabinoid receptor type 2 , blood pressure , pharmacology , cannabinoid receptor , receptor
Hypertension remains the leading cause of cardiovascular disease – the leading cause of morbidity and mortality worldwide, and effective pharmacological options remain limited. Recent studies have shown HTN may result from increased renal inflammation and elevated renal sensory nerve activity, particularly in the deoxycorticosterone acetate (DOCA)‐salt rat model of salt‐sensitive hypertension. Cannabinoid administration is demonstrated to mitigate peripheral inflammation as well as sensory nerve activation in models of rheumatoid arthritis and cancer‐related pain through cannabinoid receptor type 2 (CB 2 ). Therefore, we hypothesized CB 2 activation through either endogenous cannabinoid accumulation with a fatty acid amide hydrolase inhibitor (URB‐597) or selective CB 2 agonist (JWH‐015) would attenuate DOCA‐salt HTN and improve renal function and inflammation. To test this hypothesis, uninephrectomized male Sprague Dawley rats (300‐400 g) received DOCA (100 mg, SC), 0.9% NaCl drinking water, and one of the following drug treatments administered by osmotic mini‐pump for 21 days: JWH‐015 (JWH; 1mg/kg/day; n=5), URB‐597 (URB; 1mg/kg/day; n=5), or vehicle (VEH; 10% DMSO, 10% Tween 80, 80% PBS; n=10). 24‐hour mean arterial pressure (MAP) was measured by implanted telemeters. Final glomerular filtration rate (GFR) and renal inflammation were assessed by transcutaneous FITC‐sinistrin clearance and histological analysis, respectively. Data presented as mean ±SEM. Following the 21‐day DOCA‐salt treatment, MAP increased in VEH animals (∆62.6 ± 4.2 mmHg), and no differences in URB (∆74.4 ± 7.5 mmHg) or JWH (∆51.1 ± 6.0 mmHg) were detected vs. VEH. Regarding renal function, no improvements in GFR were detected in URB (0.81 ± 0.09 mL/min/100mg bodyweight) nor JWH (0.78 ± 0.06 mL/min/100mg bodyweight) treatments vs. VEH (0.73 ± 0.07 mL/min/100 mg bodyweight). Finally, no differences in bodyweight, kidney, or heart weights were detected between any treatment groups. Renal inflammation analysis and final serum cannabinoid concentration measurements are currently underway. Collectively, these data did not support our initial hypothesis, as no mitigating effects of either URB or JWH on MAP or renal function were detected in this model of hypertension. Though similar doses reportedly mitigate inflammation and pain in other preclinical models disease including rheumatoid arthritis and cancer‐related pain, we conclude peripheral CB 2 activation through exogenous or endogenous cannabinoid therapies (JWH‐015 and URB‐597) do not prevent the renal or cardiovascular pathophysiology in this preclinical model of salt‐sensitive hypertension. Future dose‐response studies are required to evaluate any potential effect beneficial effect of cannabinoid treatment in this model.