title: Beneficial clinical effects of perhexiline in patients with stable angina pectoris and acute coronary syndromes are associated with potentiation of platelet responsiveness to nitric oxide.
abstract: OBJECTIVE
  To examine whether the prophylactic antianginal agent perhexiline potentiates platelet responsiveness to nitric oxide (NO) in patients with stable angina pectoris (SAP) and acute coronary syndromes (ACS: unstable angina pectoris or non-Q-wave myocardial infarction).
  
  
  RESULTS
  Blood samples were obtained from patients before and after initiation of treatment with perhexiline. ADP-induced platelet aggregation and its inhibition by the NO donor sodium nitroprusside (SNP) were determined via impedance aggregometry in whole blood (WB) and platelet-rich plasma (PRP). Intraplatelet cGMP content was assayed by RIA, and superoxide (O(2)(-)) level by lucigenin-derived chemiluminescence. In patients with ACS not receiving perhexiline (n=12), platelet responsiveness to SNP did not vary significantly over the first 3 days post admission to hospital. Therapy with perhexiline for 3 days was associated with increases in SNP-induced inhibition of aggregation from 29+/-2% to 43+/-4% (n=50,P <0.001) in WB and from 20+/-5% to 42+/-7% (n=12, P<0.01) in PRP. Resolution of symptomatic ischaemia (n=39) was associated with significantly greater (P<0.01) increases than non-resolution (n=11). Similar increases in SNP responsiveness (P<0.001) occurred following institution of perhexiline therapy in patients with SAP (n=30), associated with a 85% decrease in anginal frequency. Treatment with perhexiline potentiated the cGMP-elevating effects of SNP in platelets (n=9,P =0.03). Although perhexiline did not alter whole blood O(2)(-) concentration ex vivo, it inhibited (P<0.01) O(2)(-) release from neutrophils in vitro.
  
  
  CONCLUSIONS
  Perhexiline potentiates platelet responsiveness to NO both in SAP and ACS patients; in the latter group this improvement was predictive of resolution of ischaemic symptoms. The predominant mechanism of perhexiline effect is an increase in platelet cGMP responsiveness. Perhexiline also may reduce the potential for NO clearance by neutrophil-derived O(2)(-).
authors.affiliation: Cardiology Unit, The Queen Elizabeth Hospital, Department of Medicine, The University of Adelaide, Adelaide, Australia.
authors.forename: S R
authors.initials: SR
authors.lastname: Willoughby
authors.forename: S
authors.initials: S
authors.lastname: Stewart
authors.forename: Y Y
authors.initials: YY
authors.lastname: Chirkov
authors.forename: J A
authors.initials: JA
authors.lastname: Kennedy
authors.forename: A S
authors.initials: AS
authors.lastname: Holmes
authors.forename: J D
authors.initials: JD
authors.lastname: Horowitz
mesh_terms: D000368:Aged; D000787:Angina Pectoris / Q000188:drug therapy; D001792:Blood Platelets / Q000378:metabolism; D002317:Cardiovascular Agents / Q000627:therapeutic use*; D003327:Coronary Disease / Q000188:drug therapy*; D006152:Cyclic GMP / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D009504:Neutrophils / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000627:therapeutic use; D009599:Nitroprusside / Q000627:therapeutic use; D010480:Perhexiline / Q000627:therapeutic use*; D010974:Platelet Aggregation / Q000187:drug effects*; D013481:Superoxides / Q000378:metabolism
chemical_list: D002317:Cardiovascular Agents; D020030:Nitric Oxide Donors; D013481:Superoxides; D009599:Nitroprusside; D009569:Nitric Oxide; D006152:Cyclic GMP; D010480:Perhexiline