Coronary artery aneurysm formation following directional coronary atherectomy.

Directional coronary atherectomy has recently become available to treat coronary stenosis by excision and removal of tissue. The optimal depth of resection by this method has not been determined and complications have occurred. This report describes the formation of a coronary aneurysm at an atherectomy site in an asymptomatic patient, a finding not reported previously.

Mechanism of antihypertensive action of dilevalol compared with that of "cardioselective" beta-blocking agents.

The hemodynamic effects of dilevalol, a nonselective beta-adrenergic blocking agent with vasodilating properties, were evaluated in 34 hypertensive patients and compared with those of the "cardioselective" beta blockers atenolol and metoprolol in 21 patients. Hemodynamic measurements were obtained at baseline, after acute treatment (first dose) with dilevalol (400 mg) and atenolol (50 mg) or metoprolol (100 mg), and again after subchronic treatment with these agents. After both acute and subchronic treatment (mean daily dose 1,042 mg), dilevalol significantly reduced mean arterial pressure (MAP, p less than 0.0001), by significantly reducing systemic vascular resistance index (SVRI, p less than 0.001), and by not significantly altering cardiac index (CI). In contrast, atenolol and metoprolol significantly reduced MAP (p less than 0.002) by significantly reducing CI (p less than 0.0001), with a concomitant increase in SVRI (p less than 0.007). Heart rate (HR) was reduced significantly less (p less than 0.006) with dilevalol than with the cardioselective agents. Correlation of the decrease in MAP with other hemodynamic parameters revealed that the effects on MAP of acute treatment with the cardioselective drugs are related to a decrease in HR (r = 0.63, p = 0.002), whereas those of subchronic treatment are correlated to a decrease in CI (r = 0.59, p = 0.01). The decrease in MAP after acute and subchronic dilevalol treatment is correlated primarily with SVRI (r = 0.46 to 0.49, p less than 0.01) and only secondarily with HR (r = 0.34, p less than 0.05). Therefore, the main mechanism of antihypertensive action for dilevalol is vasodilation, in contrast to the cardioselective agents, which is beta blockade.

Effects of dilevalol on rest and supine exercise hemodynamics in mild to moderate systemic hypertension.

Eight mildly to moderately hypertensive subjects free of any antihypertensive medications and on a normal salt diet performed maximal supine arm exercise. Before starting the exercise, a right-sided cardiac catheterization was performed to measure hemodynamic parameters before and during exercise. All patients had normal increases in cardiac output for the level of exercise performed and the peripheral vascular resistance diminished appropriately. An increase in the right atrial and pulmonary artery wedge pressures during exercise could be explained by increased venous return. After the baseline testing, rest and exercise hemodynamics were repeated 2 hours after the administration of 400 mg of dilevalol, a new beta blocker. For the next 2 weeks the patients received 400 mg of the study drug twice a day, with repeat studies obtained thereafter. As with other beta blockers, dilevalol decreases the heart rate and cardiac output on exercise, but, in addition, it induces a decrease in the resting systemic vascular resistance. This action is similar to its isomer, labetalol.

Incidence of renal artery stenosis in a population having cardiac catheterization.

Patients with renovascular hypertension comprise only a small percentage of those with hypertension. In our study 102 consecutive patients who had cardiac catheterization were screened at the time of the procedure for renal artery stenosis. Only 65 (64%) of the 102 patients were hypertensive, and 14 of the total population (13.7%) had renal artery stenosis. Of these 14 patients, only five had more than 50% narrowing of the arterial lumen. By renal vein renin determination, only four of the five patients with significant renal artery stenosis had lateralizing renins. The frequency of significant renovascular hypertension does not justify the routine search for this problem during catheterization procedures, though it may be worthwhile if the patients are hypertensive. This area deserves further evaluation.

Structure-activity relationships for N6-substituted adenosines at a brain A1-adenosine receptor with a comparison to an A2-adenosine receptor regulating coronary blood flow.

A series of 145 N6-substituted adenosines have been screened as inhibitors of the binding of [3H]cyclohexyladenosine to an A1-adenosine receptor in rat brain membranes and the results compared to the potencies of these analogs in increasing coronary blood flow via activation of an A2-adenosine receptor. The A1 receptor shows greater stereoselectivity in the N6 region of the receptor towards asymmetric aralkyl substituents, and shows greater bulk tolerance in the N6 region of the receptor such that it retains affinity for certain N6-tertiary alkyladenosines and N6-cycloalkyladenosines that are inactive at the coronary A2 receptor. At the A1 receptor, the most potent analogs have either aliphatic N6-substituents with four or more methylene residues or have an N6-halophenyl substituent. At the A2 receptor, the most potent analogs have an N6-phenethyl or similar heteroarylethyl substituent. Certain sets or series of analogs appear useful for identifying the subtypes of adenosine receptors involved in physiological functions.

Dog coronary artery adenosine receptor: structure of the N6-alkyl subregion.

The moderately potent and stereoselective coronary vasoactivity of N6-[1-phenyl-2(R)-propyl]adenosine (1) is the basis for the present study that maps the N6 region of the coronary artery adenosine receptor by means of the structure-coronary vasoactivity relationships of 81 analogues of 1 in the open-thorax dog. Stereoselectivity is a general property of N6-substituted adenosines that have a chiral center adjacent to N6. The activity ratio of 1 to its S diastereomer is 10, the result of the positive interaction with the receptor of the propyl C-3 group of the R diastereomer in combination with the steric hindrance exerted by this group of the S diastereomer. Replacing the benzyl moiety of 1 by an ethyl, phenyl, phenethyl, or naphthyl group lowers potency of the R diastereomer and, accordingly, the R/S ratio. Propyl C-1 of 1 interacts with a receptor region large enough to accommodate three methylene residues and the propyl C-3 residue with a separate region large enough to accommodate two. The receptor subregion that interacts with the propyl C-1 of 1 is more tolerant of bulk and of polar substituents than the subregion that interacts with propyl C-3. Evidence bearing on the possible contribution of N6 to activity, e.g. through hydrogen bonding, is ambiguous. These results support a provisional model of the N6-alkyl subregion.

Invasive exercise testing.

The normal hemodynamic response to dynamic supine exercise embodies the following features: progressive increase in heart rate relative to the work intensity; an increase in cardiac output of 600 ml or greater for every 100-ml increment in oxygen consumption; minimal increase in stroke volume; a progressive increase in oxygen extraction, attaining near-maximal levels during moderate exercise; and a minimal increase in left ventricular end-diastolic, pulmonary capillary wedge, pulmonary arterial, and right ventricular end-diastolic pressures. In heart disease, the major purpose of invasive exercise testing is to assess cardiac functional reserve capacity. An evaluation of the degree of encroachment on cardiac reserve by disease processes establishes hemodynamic correlates of clinical symptomatology and aids in selecting the proper therapeutic modality for each individual patient. In patients with ischemic heart disease, preliminary evidence indicates that invasive exercise testing in conjunction with angiographic findings may contribute additional substantial prognostic information.

Forskolin potentiates the coronary vasoactivity of adenosine in the open-chest dog.

Forskolin, a plant diterpene, directly stimulates adenylate cyclase and also potentiates receptor-mediated stimulation of this enzyme by many stimulatory--but not inhibitory--agonists. We exploited the potentiating effect of forskolin to test the hypothesis that adenosine initiates coronary relaxation through activation of adenylate cyclase. In six open-chest dogs, intracoronary forskolin infusions which produced plasma concentrations between 0.15 and 0.48 microM barely changed coronary flow and had no effect on cardiac performance or oxygen metabolism, and did not cause hypotension. Under these conditions, the EC50 of adenosine, 0.66 microM (range 1.3-2.4), P less than 0.05. In five of the six dogs, higher doses of forskolin, 0.6-6.3 microM, produced the previously described positive inotropic, chronotropic, and systemic hypotensive effects of this drug. These larger doses of the drug increased coronary flow and MVO2 but decreased oxygen extraction, reflecting a combination of direct and metabolic vasodilation. The potentiation of the vasoactivity of adenosine by forskolin supports the hypothesis that the coronary receptor is an adenylate cyclase stimulatory (Ra or A2) receptor.

Dependence of ventricular fibrillation propensity on coronary blood flow without myocardial ischemia.

Ventricular fibrillation threshold (VFT) changes have been linked to coronary blood flow (CBF) in the context of CBF reduction and subsequent myocardial hypoxia. To clarify the effect of CBF on VFT in the absence of myocardial hypoxia, 18 open-chest pentobarbital-anesthetized dogs with uniformly controlled heart rate, cardiac output, and mean systemic arterial pressure (SAP) were studied as follows: CBF, coronary sinus O2 content (CcsO2), and thereby myocardial O2 consumption were continuously monitored. Baseline VFT determined by the single stimulus scanning technique was 33.0 +/- 3.9 mA. Initial values of CBF index (I) and VFT (n = 18) were positively correlated (VFTmA = 0.8 +/- 0.245 . CBFI ml/min . 100g-1LV; r = 0.60, p less than 0.01). Stepwise CBFI increments up to five times in excess of initial 131.5 +/- 9.7 ml/min . 100g-1LV were then induced by changing in random order. SAP (n = 10), left coronary perfusion pressure (n = 7), and arterial O2 content (n = 10) with VFT determined at each step; CcsO2 remained above 5.5 vol% while CBFI and VFT changes were positively correlated, and mean weighted slope of VFTmA = 16.6 +/- 0.103 . CBFI ml/min . 100 g-1Lv (r = 0.82, p less than 0.05). Systemic or coronary perfusion pressure and arterial or coronary sinus O2 content did not appear to affect VFT independently. It is concluded that even in the absence of myocardial hypoxia, CBF itself is a major determinant of VFT and thereby of innate arrhythmogenic propensity.

Effect of arterial pressure on left ventricular O2 consumption, coronary blood flow, and reserve capacity following coronary occlusion.

The effect of mean systemic arterial pressure (SAP) on myocardial O2 consumption (MVO2) coronary blood flow (CBF) and the reduction of left ventricular (LV) reserve capacity resulting from coronary artery occlusion was studied in 25 open-chest pentobarbital anesthetized dogs with fixed cardiac output and controlled heart rate (HR) and SAP. In all animals, baseline MVO2 and CBF were obtained and LV reserve capacity was determined by identifying the HR and SAP level which raised mean left atrial pressure to 12 mm. Hg. After uniform placement of a pericoronary snare, the dogs were randomized to five equal groups, and SAP was set at 40, 70 (two groups), 100, and 130 mm. Hg. MVO2 and CBF were redetermined and the coronary artery was ligated in all except one group (70 mm. Hg) which served as sham control. thirty minutes after coronary occlusion, MVO2, CBF, and LV reserve capacity were determined again. Percent of nonperfused myocardium did not differ among groups (27.6 +/- 1%). MVO2 bore a linear relationship to SAP setting wheras CBF bore a curvilinear relationship. Coronary occlusion did not modify these relationships. Significant, but similar decreases in tolerated HR (23.1 +/- 4.7 min.-1) and SAP (41.9 +/- 6.2 mm. Hg) from control values were observed in all four groups regardless of SAP setting. We concluded that the impact of coronary ligation on MVO2, CBF, the loss of functional reserve capacity, and possibly the extent of ischemic injury of the left ventricle, is not modified by afterload changes. However, optimal O2 supply-to-demand ratio appears at SAP of about 100 mm. Hg.