Response of Large and Small Coronary Arteries to Adenosine, Nitroglycerin, Cardiac Glycosides, and Calcium Antagonists

Abstract

Some electric membrane properties of isolated large (>1.0 mm) and small (< 500 μm) coronary arteries of the dog were studied with intracellular microelectrodes. The resting membrane potential was not significantly different in large and small arteries (average -56 mV and -53 mV, respectively). Spontaneous action potentials were not present in either sized vessels, and action potentials could not be induced upon electric stimulation. Addition of tetraethylammonium ion (TEA, 10 mM) permitted overshooting action potentials to be elicited by electric stimulation. The relationship between action potential amplitude and log[Ca++]0 was linear (between 0.5 to 5.0 mM) with a slope of 30 mV decade; the action potential amplitude was unaffected by removal of Na+. This suggests that the inward current during the action potential is primarily carried by Ca++. We tested two categories of vasoactive agents for their ability to affect the TEA-induced action potentials; relaxants of smooth muscle (adenosine, nitroglycerin, verapamil, and Mn++) and smooth muscle constrictors (the cardiac glycosides, ouabain and digoxin). Adenosine (10-5 M) blocked the Ca++-dependent action potentials in small coronary arteries, but had no effect on the action potential in large arteries. In contrast, nitroglycerin (10-5 M) blocked the action potential in large coronary arteries, but not in small ones. Verapamil (5 × 10-6 M) and Mn++ (1 mM) blocked the action potential irrespective of the size of the vessel. The cardiac glycosides (4 ×10-9 M to 1 × 10-7 M) increased the frequency, amplitude and maximal rate of rise of the TEA-induced action potentials in small (< 500 μm) coronary arteries in a dose-dependent manner. In the presence of a subthreshold concentration of TEA (5 mM) the cardiac glycosides induced spontaneous action potentials. The effects of cardiac glycosides occurred before any significant depolarization, and the effects were not mimicked by phenylephrine (α-agonist) nor reduced by phentolamine (α-antagonist). Verapamil (10-5 M) and Mn++ (2 mM) abolished all spike activity produced by the cardiac glycosides. The results suggest that several vasoactive agents have the ability to affect the inward slow Ca++ current in coronary artery smooth muscle cells. Such an action could help to explain [1] the differential relaxation of large and small coronary arteries produced by adenosine and nitroglycerin, [2] the general relaxing effect of Ca++-antagonists such as verapamil and Mn++, and [3] the coronary vasoconstriction produced by cardiac glycosides that may be a factor in digitalis toxicity and could be blocked by Ca++-antagonists. In view of the possible role of adenosine as a local regulator of coronary blood flow, the present results may suggest a mechanism whereby adenosine controls coronary vascular resistance.