Use of modified vasoactive intestinal peptides in the treatment of hypertension
The present invention is based on the discovery that a VIP having a binding preference for VPAC2 can provide long-acting blood pressure control synergistically with concomitant anti-hypertensive therapies. Accordingly, methods and compositions useful for the treatment and/or amelioration of hypertension are provided.
1. A method for treating hypertension in a patient, comprising administering to the patient: a vasoactive intestinal peptide (VIP) and at least one anti-hypertensive drug selected from a β1 receptor antagonist, an ACE inhibitor, and a calcium channel blocker, wherein the VIP comprises the amino acid sequence of SEQ ID NO: 13 with the N-terminal His at position 2, an N-terminal methionine, and an elastin-like peptide (ELP) at the C-terminus, wherein the ELP comprises at least 90 repeats of VPGXG (SEQ ID NO: 3), and wherein X is V, A, and G in a ratio of about V5, A2, and G3, and wherein the co-administration of the VIP and the anti-hypertensive drug produces reduced side effects compared to administering VIP alone.
2. The method of claim 1 , wherein said hypertension is selected from pulmonary hypertension, uncontrolled essential hypertension, pulmonary arterial hypertension, and resistant hypertension.
3. The method of claim 1 , wherein said vasoactive intestinal peptide induces vaso-relaxation.
4. The method of claim 1 , wherein said vasoactive intestinal peptide induces a decrease of at least one of systolic pressure, diastolic pressure, and mean arterial pressure.
5. The method of claim 1 , wherein said elastin-like peptide comprises 120 repeating units of VPGXG (SEQ ID NO: 3).
6. The method of claim 5 , wherein said vasoactive intestinal peptide has the amino acid sequence of SEQ ID NO: 14.
7. The method of claim 1 , wherein said vasoactive intestinal peptide and said anti-hypertensive drug are administered separately.
8. The method of claim 1 , wherein said vasoactive intestinal peptide is administered parenterally.
9. The method of claim 8 , wherein said vasoactive intestinal peptide is administered subcutaneously.
10. The method of claim 1 , wherein said vasoactive intestinal peptide is administered about once per day.
11. The method of claim 1 , wherein said vasoactive intestinal peptide is administered about once per week.
12. The method of claim 1 , wherein said vasoactive intestinal peptide has the amino acid sequence of SEQ ID NO: 14 and is administered at a dose of about 1 microgram to about 100 milligrams per kilogram of body weight.
13. The method of claim 12 , wherein said vasoactive intestinal peptide is administered at a dose of about 10 micrograms to about 10 milligrams per kilogram of body weight.
14. The method of claim 1 , wherein said patient is a human patient.
15. A pharmaceutical composition comprising a vasoactive intestinal peptide (VIP) and at least one anti-hypertensive drug selected from a β1 receptor antagonist, an ACE inhibitor, and a calcium channel blocker, wherein the VIP comprises the amino acid sequence of SEQ ID NO: 13 with the N-terminal His at position 2, an N-terminal methionine, and an elastin-like peptide (ELP) at the C-terminus, and wherein the ELP comprises at least 90 repeats of VPGXG (SEQ ID NO: 3), and wherein the co-administration of the VIP and the anti-hypertensive drug produces reduced side effects compared to administering VIP alone.
16. The pharmaceutical composition of claim 15 , wherein the composition is formulated for once per day dosing.
17. The pharmaceutical composition of claim 15 , wherein the composition is formulated for once per week dosing.
18. The method of claim 1 , wherein the VIP has a binding preference for the Vasoactive Intestinal Peptide Receptor 2 (VPAC2).
19. The pharmaceutical composition of claim 15 , wherein the VIP has a binding preference for the Vasoactive Intestinal Peptide Receptor 2 (VPAC2).