Action and localization of vasoactive intestinal peptide in the coronary circulation: evidence for nonadrenergic, noncholinergic coronary regulation.

Vasoactive intestinal polypeptide, a neurotransmitter peptide detected in animal and human hearts, has been found in nerves of coronary arteries. To determine the amount and distribution of vasoactive intestinal polypeptide in the large coronary vessels and its possible participation in coronary vasoregulation, two groups of animals were studied. In the first group, 11 anesthetized dogs were sacrificed to collect three (1 cm) segments along the circumflex and left anterior descending coronary arteries. These segments represented proximal (I), middle (II) and distal (III) portions of the two arteries. Concentrations (ng/g) of vasoactive intestinal polypeptide-like immunoreactive substance were determined by radioimmunoassay. Vasoactive intestinal polypeptide-like immunoreactivity was present in the left anterior descending (I = 7.28 +/- 1.65, II = 3.74 +/- 0.57, III = 2.29 +/- 0.53) and circumflex (I = 4.16 +/- 1.52, II = 4.58 +/- 1.13, III = 4.00 +/- 0.81) coronary arteries. The difference in vasoactive intestinal polypeptide-like immunoreactivity among epicardial segments of the anterior descending artery was significant, but there was no significant difference among segments of the circumflex coronary artery. In the second group (eight closed chest anesthetized dogs), the effects of vasoactive intestinal polypeptide intracoronary infusion on epicardial coronary constriction were examined at rest and with the artery constricted by serotonin. Left anterior descending (segments I, II and III) artery responses (% area change) to vasoactive intestinal polypeptide and vasoactive intestinal polypeptide plus serotonin were examined using quantitative coronary angiography. Vasoactive intestinal polypeptide infusion resulted in significant vasodilation in all the segments (I, II and III) of the left anterior descending artery.(ABSTRACT TRUNCATED AT 250 WORDS)

Substance P distribution and effects in the canine epicardial coronary arteries.

Substance P (SP), a vasoactive neuropeptide detected in animal and human hearts has been reported to increase coronary blood flow in animals. However, no data are available on SP effects on epicardial coronary arteries, the site of coronary disease. To determine the amount and distribution of SP and its action in the large coronary vessels, we studied two groups of dogs. One group was anesthetized for collecting three 1 cm segments of the circumflex coronary artery (CX) and left anterior descending artery (LAD) through a left thoracotomy. These segments represented proximal (I), middle (II), and distal (III) portions of the two arteries. Concentrations (ng/g) of SP-like immunoreactivity (SP-LI) were determined by radioimmunoassay. SP-LI was present in LAD (I: 1.17 +/- 0.20, II: 1.08 +/- 0.36, III: 1.14 +/- 0.25) and CX (I: 1.44 +/- 0.38, II: 1.51 +/- 0.47, III: 0.70 +/- 0.20). SP differences among segments of LAD and segments I and II of CX were not significant, but there was a significant difference between segment III of CX and the others. In the second group of closed chest anesthetized dogs, we examined the effects of intracoronary SP infusion before and during administration of serotonin (5HT). LAD and CX artery responses (% area change) to SP and to SP plus 5HT were examined using quantitative coronary angiography. Intracoronary 133Xe in saline provided coronary flow data. SP infusion produced significant vasodilation in segment II (15% area increase) and III (17%) during the highest dose (1 microgram/min). The three SP doses infused with 5HT (0.05 mg/min) did not produce vasodilation, although LAD segment III constriction from 5HT was abolished during the highest dose of SP infusion. The presence of SP, and its dilatory effect on the coronary arteries, suggests a role in maintaining vasodilator tone in the coronary arteries.

Effects of thromboxane analog U46619 on endothelial damaged canine coronary arteries in vivo.

We studied the effects of the thromboxane analog, U46619, infused into the left anterior descending (LAD) artery of intact dogs before and after producing endothelial denudation of the mid portion of the LAD. Proximal artery cross-sectional area (CSA) decreased by 47% with 0.1 microgram/min infusion of U46619 with intact and denuded endothelium, while resting CSA reduced spontaneously following denudation. Coronary resistance vessels demonstrated a marked constrictor response to U46619 with a rise in resistance and a fall in flow and myocardial O2 consumption. U46619 produces significant narrowing of proximal epicardial coronary arteries as well as resistance coronary vessels. This effect could cause ischemia in patients with moderate coronary atherosclerosis.

Increased vasoconstrictor activity of proximal coronary arteries with endothelial damage in intact dogs.

In this study we examined the hypothesis that endothelial damage increases proximal coronary arterial vasomotor tone and sensitivity to vasoconstrictor stimulation. The response of the left anterior descending coronary artery (LAD) (% area change) to serotonin and nitroglycerin were examined in eight anesthetized (Innovar + nitrous oxide), closed-chest dogs by means of quantitative coronary angiography. Dose-response curves of percent change in arterial cross-sectional area for three doses of intracoronary serotonin were examined before and after endothelial damage produced by a balloon catheter in the LAD. Endothelial damage was verified by postmortem scanning electron microscopic examination. Intracoronary injection of 133Xe provided coronary flow data. The damaged segment of LAD showed spontaneous vasoconstriction and further constriction in response to serotonin (33 +/- 5% before and 52 +/- 6% area reduction after damage; p less than .05). Nitroglycerin reversed serotonin-induced vasoconstriction in LAD segments without damage but not in the LAD segment with endothelial damage. No significant changes were observed in aortic pressure, and heart rate was kept constant by pacing. Blood flow in the LAD was not affected by endothelial damage itself (control, 2.44 +/- 0.09 ml/min/g; damage, 2.53 +/- 0.22 ml/min/g). Endothelial damage induced spontaneous proximal coronary constriction and diminished the relaxant response to nitroglycerin in the presence of serotonin. These results suggest that focal coronary narrowing that occurs in some patients after provocation with vasoconstrictor agents may be caused by local areas of damaged endothelium.

Effects of angiotensin and ergonovine on large and small coronary arteries in the intact dog.

Angiotensin (ATN) and ergonovine (ERG) are known to cause vasoconstriction of the coronary bed. However, ATN effects have been described mainly on the coronary resistance vessels, while ERG effects have been described on proximal conductance vessels. Recent studies have shown that proximal and distal coronary arteries are regulated independently. To examine both proximal and distal effects of ATN and ERG on the same heart, we studied 7 intact dogs, anesthetized with Innovar (Fentanyl 0.4 mg, Droperidol 20 mg, in 1 ml) and nitrous oxide, which were subjected to direct left anterior (LAD) coronary infusion of angiotensin (0.1, 0.5 and 5 micrograms/min) and ergonovine (0.5, 5, and 25 micrograms/min). Using a quantitative angiographic technique to measure artery dimensions and microspheres to measure flow, ERG infusion showed significant large artery constriction at all doses (maximum: 38.9 +/- 7.8% area reduction), and a significant decrease in LAD coronary artery flow, while endocardial/epicardial flow ratio remained unchanged. ATN produced a biphasic effect on the large coronary arteries. The lowest dose produced constriction (12.3 +/- 3.7% area reduction), which returned toward control value with the 0.5 micrograms/min dose (6.0 +/- 1.0% area reduction), and the 5 micrograms/min dose (1.5 +/- 9.5% area reduction), and no significant changes were observed in LAD flow with ATN infusion. Endocardial/epicardial ratio was unchanged, but aortic pressure was significantly increased during 0.5 and 5 micrograms/min ATN infusion. Coronary resistance (pressure/flow) increased with both ERG and ATN. ERG and ATN produce large and small coronary artery constriction. The coronary response to ERG in dogs is similar to the human coronary response, even though previous data indicated a minimal constrictor response to ERG in canine coronary arteries.