Blood pressure lowering effects of the CFTR‐F508del mutation are associated with reduced arterial reactivity rather than circulating blood volume (700.1)

Abstract

CFTR‐F508del mutation is the most common cause of cystic fibrosis. F508del homozygous patients and female F508del carriers have decreased blood pressure (BP). We tested the hypothesis that heterozygote F508del mice have lower BP and reduced aortic contractility. By radiotelemetry, female F508del carriers had significantly lower systolic BP than wild‐type C57 controls (112±1 versus 119±2 mmHg). Although male carriers did not have lower baseline BP, they had significantly lower diastolic pressures after intraperitoneal co‐injection of isoproterenol + epinephrine (60±3 versus 78±8 mmHg). Aortas isolated from male and female F508del carriers had reduced constriction to noradrenaline (0.9±0.2 versus 2.9±0.7 mN). Inhibition of wild‐type CFTR or the inositol triphosphate receptor replicated the phenotype of F508del aortas. CFTR carrier status did not alter circulating blood volume. We conclude the CFTR‐F508del mutation decreases aortic contractility and arterial pressures. As a cAMP‐activated chloride channel that facilitates calcium mobilization, we speculate wild‐type CFTR co‐activation during beta‐adrenergic receptor stimulation buffers the vasodilatory response to catecholamines, and loss of this compensatory vasoconstrictor tone may contribute to the lower BP seen in heterozygote carriers of a CFTR‐F508del mutation.Grant Funding Source: Supported by NIH R01 HL102659