RESEARCH ARTICLE


CAR Selectively Enhances the Pulmonary Vasodilatory Effect of Fasudil in a Microsphere Model of Pulmonary Hypertension



Abraham Rothman1, 2, *, Humberto Restrepo1, 2, William N. Evans1, 2, Valeri Sarukhanov1, David Mann3
1 Children’s Heart Center, Nevada3131 La Canada, Suite 230, Las Vegas, NV 89169, USA
2 Department of Pediatrics, University of Nevada Las Vegas, School of Medicine, 2040 W Charleston Blvd Ste. 402, Las Vegas, NV 89109, USA
3 Vascular BioSciences, 72 Santa Felicia Dr, Goleta, CA 93117, USA


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Creative Commons License
© 2023 Rothman et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

* Address corresponding to this author at the Children’s Heart Center Nevada 3131 La Canada St. Suite 230, Las Vegas NV 89169 USA; Tel: (702) 732-1290; Fax: (702) 732-1385; E-mail: arothman@chcnv.org


Abstract

Background:

Despite the approval of several medications for pulmonary hypertension, morbidity and mortality are unacceptably high. Systemic hypotension may limit the use of pulmonary hypertension medications.

Objectives:

This study aimed to assess whether the homing peptide CAR (CARSKNKDC) improves the vasodilatory selectivity of fasudil in the pulmonary circulation or systemic circulation in a porcine pulmonary hypertension model.

Materials and Methods:

Pulmonary hypertension (to approximately 2/3-3/4 systemic pressure levels) was induced by chronic and acute administration of microspheres in 3 micro Yucatan pigs (mean weight 19.9 kg, mean age 4.3 months). Fasudil (0.3 mg/kg) was administered without and with CAR (1.5 mg/kg), and the effect on aortic (Ao) and right ventricular (RV) pressure was recorded with indwelling catheters.

Results:

Immediately after fasudil administration, there was a decrease in Ao pressure followed by prompt recovery to baseline. The RV pressure decrease was progressive and sustained. Fasudil alone resulted in a 12% decrease in RV pressure, whereas co-administration of CAR with fasudil resulted in a 22% decrease in RV pressure (p < 0.0001). Fasudil alone caused an average decrease of 34% in the RV/Ao pressure ratio, and fasudil + CAR caused an average decrease of 40% in the RV/Ao pressure ratio (p < 0.0001).

Conclusion:

The homing peptide CAR selectively enhanced the acute vasodilatory effects of fasudil on the pulmonary vascular bed in a porcine experimental model of pulmonary hypertension.

Keywords: Animal research, CAR, Homing peptide, Fasudil, Pulmonary hypertension, Swine.