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Role of thromboxane A2 in the cardiovascular response to intracoronary C5a
G L Stahl1, E A Amsterdam, J D Symons
1Department of Internal Medicine, University of California, Davis 95616.
Insights
Complement component C5a reduces coronary blood flow and cardiac function. Acetylsalicylic acid and SQ29548 partially mitigated these effects by inhibiting thromboxane A2 pathways.
Area of Science:
- Cardiovascular Physiology
- Immunology
- Pharmacology
Background:
- Complement component C5a (C5a) triggers cardiovascular responses, including reduced coronary blood flow and left ventricular function.
- These C5a effects are linked to granulocyte accumulation in the heart muscle.
Purpose of the Study:
- To investigate the role of cyclooxygenase (COX) and thromboxane A2 (TXA2) in C5a-induced cardiovascular effects.
- To evaluate the efficacy of acetylsalicylic acid (a COX inhibitor) and SQ29548 (a TXA2 receptor antagonist) in mitigating these responses.
Main Methods:
- Open-chest anesthetized pigs were used to measure hemodynamic parameters, coronary blood flow, and left ventricular segment shortening.
- Measurements included blood gases, lactate, leukocytes, and thromboxane B2 in arterial and coronary venous blood.
- Animals were treated with either acetylsalicylic acid or SQ29548 before C5a administration.
Main Results:
- Intracoronary C5a caused transient decreases in coronary blood flow and ventricular shortening, with no tachyphylaxis at 60-minute intervals.
- Acetylsalicylic acid attenuated C5a-induced reductions in coronary blood flow and ventricular shortening, and blocked TXB2 increase.
- SQ29548 also reduced C5a-induced coronary blood flow and shortening changes.
Conclusions:
- Cyclooxygenase inhibition and TXA2 receptor antagonism partially ameliorate C5a-induced cardiovascular dysfunction.
- These findings highlight the involvement of the TXA2 pathway in C5a-mediated cardiac responses.
- The granulocyte trapping mechanism was not affected by the interventions.
Abstract:
Intracoronary administration of complement component C5a induces transient decreases in coronary blood flow and regional left ventricular segment shortening, associated with intramyocardial granulocyte trapping. We evaluated the influence of a cyclooxygenase inhibitor (acetylsalicylic acid, n = 8) or a thromboxane A2/prostaglandin H2 receptor antagonist (SQ29548, n = 6) on these C5a-induced cardiovascular responses. Open-chest anesthetized pigs were instrumented to monitor heart rate, arterial blood pressure, left anterior descending coronary blood flow, regional left ventricular segment shortening, and dP/dt. Oxygen content, lactate concentration, leukocyte count, and thromboxane B2, the stable metabolite of thromboxane A2, were measured in arterial and regional coronary venous blood. Repetitive injections of intracoronary C5a (500 ng) given 60 minutes apart showed no tachyphylaxis of the hemodynamic response. However, tachyphylaxis was seen in coronary blood flow changes when injections were spaced 30 minutes apart. An increase in myocardial oxygen extraction and lactate production was observed after intracoronary C5a. Administration of acetylsalicylic acid (50 mg/kg i.v.) attenuated C5a-induced decreases in coronary blood flow (-8 +/- vs. -3 +/- 1 ml/min) and regional left ventricular segmental shortening (-10 +/- 3% vs. -2 +/- 1%) and blocked the maximal increase in coronary venous thromboxane B2 (2.0 +/- 0.1 vs. 0.2 +/- 0.1 pmol/ml plasma). Furthermore, SQ29548 (30 micrograms/kg/min) reduced C5a-induced changes in coronary blood flow (-13 +/- 2 vs. -4 +/- 2 ml/min) and segmental shortening (-14 +/- 2% vs. -3 +/- 1%). Neither cyclooxygenase inhibition nor thromboxane A2/prostaglandin H2 antagonism blocked the decrease in coronary venous granulocyte count.(ABSTRACT TRUNCATED AT 250 WORDS)