Endothelin is a recently discovered endothelium-derived peptide with potent coronary constrictor properties in vitro. To evaluate endothelin's cardiac actions in vivo, we measured coronary flow and regional myocardial shortening when intracoronary porcine endothelin was given to anesthetized open-chested pigs. Bolus adminstration into the left anterior descending (LAD) coronary artery of six pigs caused dose-related rapidly reversing depression of LAD flow and local shortening. Marked reductions in flow [-71 +/- 8 (SE) %] and shortening (-83 +/- 2%) after 30 pmol/kg demonstrated endothelin's potency in cardiac tissues. Systemic hemodynamic values were unaltered except for transient rises in left ventricular end-diastolic pressure. Endothelin-induced decrement in LAD flow was accompanied by electrocardiographic signs of myocardial ischemia and net release of local myocardial lactate. Intracoronary infusion of endothelin, 15 pmol.kg-1.min-1, caused progressive decline in LAD flow and local shortening followed by severe persistent hypotension and terminal ventricular fibrillation in four of five pigs. Unlike intracoronary delivery of other potent coronary constrictors, intracoronary administration of endothelin did not lead to rapid escape from the peptide's deleterious influence. Coronary exposure to endothelin under pathophysiological circumstances could result in uniquely persistent decrements in myocardial perfusion and contractile function.
Platelet-activating factor (PAF-acether) is a lipid mediator that can exhibit potent vasoconstrictor influence in the pulmonary vessels. Therefore, the release of PAF-acether during inflammatory conditions in newborns might cause deleterious increases in pulmonary vascular tone. Thirty-four anesthetized open-chest newborn piglets were given 0.01-1 nmol PAF-acether iv. In separate experiments, animals were untreated or treated with either indomethacin (a cyclooxygenase inhibitor), SQ 29548 (a thromboxane receptor blocker), or LY 171883 (a leukotriene receptor blocker). The primary hemodynamic change was a 67 to 1,537% increase in the pulmonary vascular resistance index (PVRI) (P less than 0.01): mean pulmonary artery pressure (PAP) rose significantly at all doses tested, whereas only the largest dose consistently decreased cardiac index. Treatment with indomethacin or SQ 29548 prevented the decrease in cardiac index and attenuated the PAF-acether-induced rises in PAP and PVRI. Vehicle and LY 171883 had no effect. The inhibitory influence of indomethacin and SQ 29548 suggests that an important component of PAF-acether's pulmonary vasoconstrictor action is mediated (at least in the newborn piglet) by cyclooxygenase products, most likely thromboxane.
Thyrotropin receptor (TSHR) mRNA expression has previously been detected in human heart, suggesting a possible role for the receptor in cardiac function and pathophysiology. In the present study we examined the regional distribution of TSHR mRNA in pig heart to map potential cardiac sites of TSH action. Polyadenylated mRNA extracted from thyroid, atria, ventricles, aorta, coronary arteries, epicardial fat, and purified preparations of atrial and ventricular cardiomyocytes was subjected to reverse-transcriptase polymerase chain reaction (RT-PCR) using primers designed to amplify a 311 base pair (bp) DNA segment of the human TSHR. After reverse transcription of 100 ng mRNA, cDNA was amplified by PCR using TSHR primers and compared by electrophoresis on 2% agarose gels. Relative levels of TSHR cDNA (normalized to glyceraldehyde 3-phosphate dehydrogenase [GAPDH]) were as follows: Coronary arteries, epicardial fat > right atrium > left atrium > right ventricle, aorta > left ventricle, ventricular cardiocytes. In contrast to ventricular cardiocytes, purified atrial cardiocytes expressed levels of TSHR mRNA readily detectable with RT-PCR. These findings demonstrate that TSHR mRNA expression in porcine heart varies regionally, and furthermore suggest that areas of highest expression (coronary arteries, adipose tissue, right atrium) are potential sites for a functional or pathologic role of the TSHR.
Endothelin, a recently described endothelial cell-derived peptide, produces pulmonary and coronary vasoconstriction in mature animals. We investigated the acute hemodynamic effects of porcine endothelin in 14 anesthetized open-chest new-born piglets during normoxia (Pao2 = 102 +/- 5 mmHg) and hypoxia (fractional inspired O2 concentration = 0.12 X 15 min, Pao2 = 31 +/- 1 mmHg). Six of these animals were pretreated with indomethacin, a cyclooxygenase inhibitor. Low-dose (100 pmol/kg) intravenous bolus injection of endothelin decreased pulmonary vascular resistance index (PVRI) (42 +/- 6 to 16 +/- 4 mmHg.l-1.min.kg, P less than 0.01) and increased coronary blood flow (CBF) (17 +/- 2%, P less than 0.01); cardiac index (CI) and coronary vascular resistance were unaffected. The pulmonary and coronary responses to endothelin were preserved during hypoxia: PVRI fell (160 +/- 22 to 83 +/- 13 mmHg.l-1.min.kg, P less than 0.05) and CBF rose (35 +/- 11%, P less than 0.05). Low-dose endothelin moderately increased mean arterial pressure (61 +/- 3 to 75 +/- 6 mmHg, P less than 0.05) and systemic vascular resistance index (SVRI) (375 +/- 23 to 491 +/- 41 mmHg.l-1.min.kg, P less than 0.01). High-dose (1,000 pmol/kg) endothelin mildly decreased PVRI (51 +/- 7 to 35 +/- 12, NS), moderately increased SVRI (375 +/- 45 to 594 +/- 95 mmHg.l-1.min.kg, P less than 0.05), and markedly diminished CBF (-54 +/- 6%, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
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