Method for electively achieving reversible hyperpolarized cardiac arrest

• US 5,428,039 A
• Filed: 02/20/1994
• Issued: 06/27/1995
• Est. Priority Date: 02/20/1994
• Status: Expired due to Fees

• Current Assignee: Virginia Commonwealth University
• Original Assignee: The Center For Innovative Technology
• Inventors: Cohen, Neri
• Primary Examiner(s): Hollinden, Gary E.
• Assistant Examiner(s): TILL, MARY C
• Application Number:
  US08/190,549
• Time in Patent Office: 492 Days
• Field of Search: 514/275, 514/336, 514/337, 514/353, 514/355, 514/414, 514/422
• US Class Current: 514/275
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/35 having six-membered rings with one oxygen as the only ring hetero atom
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/54 having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame

Abstract

While performing cardiopulmonary bypass, the aorta is cross-clamped and the beating heart is stopped by introducing of an ATP-dependent potassium channel opening agent. The infusion into the coronary circulation shortens the cardiac action potential thereby arresting the heart muscle at a hyperpolarized membrane potential. This maintains the heart in a state of minimal metabolic requirement, thereby preserving transmembrane ionic gradients, intercellular energy stores and cellular integrity. Cardiac arrest is reversed simply by flushing the heart by the coronary circulation upon removal of the aortic cross-clamp. This use is also germane to organ preservation during transport for transplantation. For example, the donor heart is arrested using an ATP-dependent potassium channel opening agent, it is then removed and transported to the recipient and transplanted. Cardiac arrest is reversed by reperfusing the orthotropic graft.

Claims

1. A method for electively achieving reversible cardiac arrest, comprising the steps of:

interrupting coronary blood circulation surgically in a patient in need of a cardiac or great vessel operation or other operation requiring elective cardiac arrest;

introducing into the heart of said patient a sufficient amount of an ATP-dependent potassium channel opening agent to cause hyperpolarization of heart cells and arrest the beating of the heart; and

re-establishing coronary blood circulation in said patient.

2. The method of claim 1 wherein said step of introducing is performed by local administration of said ATP-dependent potassium channel opening agent to the heart.

3. The method of claim 2 wherein said local administration is performed by intracoronary injection.

4. The method of claim 2 wherein said local administration is performed by infusion.

5. The method of claim 1 wherein said ATP-dependent potassium channel opening agent is selected from the group consisting of aprikalim, cromakalim, lemakalim, pinacidil, nicorandil, minoxidil, bimakalim, celikalim, RP 49356, EP-A-0376524, SR 44866, LP-805, Ro 31-6930, SO121, HOE-234, and other agents whose primary action is the opening of cardiac K_ATP channels.

6. The method of claim 1 wherein said ATP-dependent potassium channel opening agent is aprikalim.

7. The method of claim 1 wherein said ATP-dependent potassium channel opening agent is nicorandil.

8. The method of claim 1 wherein said ATP-dependent potassium channel opening agent is minoxidil.

9. The method of claim 1 wherein said sufficient amount of an ATP-dependent potassium channel opening agent establishes a concentration in the heart of said ATP-dependent potassium channel opening agent ranging between 75 μ

M and 150 μ

M.

10. The method of claim 9 wherein said concentration in the heart of said ATP-dependent potassium channel opening agent ranges between 90 μ

M and 110 μ

M.

11. The method of claim 1 wherein said step of introducing into the heart said sufficient amount of an ATP-dependent potassium channel opening agent is performed at approximately normal body temperature.

12. The method of claim 1 wherein said step of introducing into the heart said sufficient amount of an ATP-dependent potassium channel opening agent is performed at hypothermia.

13. The method of claim 1 further comprising the step of performing a cardiac surgical procedure after said step of introducing into the heart said sufficient amount of an ATP-dependent potassium channel opening agent and before said step of reestablishing coronary blood circulation.

14. The method of claim 13 wherein said step of performing said cardiac surgical procedure is performed at approximately normal body temperatures.

15. The method of claim 13 wherein said step of performing said cardiac surgical procedure is performed at hypothermia.