Reversible and irreversible inhibition of rat brain muscarinic receptors is related to different substitutions on bisquaternary pyridinium oximes

The role of the functional substituents on the pyridinium ring of bisquaternary pyridinium compounds, mostly oximes, in exerting reversible and irreversible inhibition of binding of [³H]-N-methyl-4-piperidyl benzilate ([³H]-4NMPB) to rat brain stem muscarinic receptors was studied. The drugs tested, i.e. HGG-42, HGG-12, HGG-52, HI-6, obidoxim, SAD-128 and TMB-4, could reversibly inhibit binding of [³H]-4NMPB, with the highest potency (K_I=1.7–6 M) exhibited by analogs possessing hydrophobic substituents at position 3 or 4 of the pyridinium ring. Bisquaternary drugs possessing an oxime moiety at position 2, but not at position 4 of the pyridinium ring, could also induce about 30% reduction of maximal binding capacity (B_max) (loss of muscarinic receptors) in addition to their reversible effect. Thus the structural correlates of the reversible and the irreversible effects of these drugs are different.     

Cardioplegic arrest of the myocardium with calcium blocking agents.

This study was designed to compare the effects of the calcium slow channel blocking agents verapamil (0.15 mg/kg), diltiazem (0.15 mg/kg), and nifedipine (50 micrograms/kg) on the myocardium after global ischemia and reperfusion in the in situ canine model. Animals were subjected to 120-min normothermic global ischemia, followed by 45-min reperfusion. Cardioplegic arrest of the myocardium was achieved by administering one of the three calcium antagonists in a multidose fashion. Superior preservation (p less than 0.01) of left ventricular (LV) systolic function was achieved in group I (verapamil cardioplegia). dP/dt, at an intraventricular balloon volume of 25 cc, was 83% of control after reperfusion in group I. Group II (diltiazem) and group III (nifedipine) achieved only 55 and 63% of their preischemic dP/dt values. LV chamber stiffness was increased in hearts protected with nifedipine. The exponential constant m was increased from 0.04 +/- 0.01 to 0.08 +/- 0.01. Coronary blood flow after reperfusion increased from 120 to 184 cc/100 gr/min in group I (p less than 0.01). The hyperemic response in group III was negligible. The O2 consumption of the reperfused myocardium was not significantly altered in any of the treatment groups. Lactate metabolism during ischemia and after reperfusion was similar in all groups. ATP values were markedly reduced in all groups (p less than 0.05). Immediately after ischemia, ATP was 50, 28, and 44% of control in group I, II, and III, respectively. The excellent preservation of systolic function and a physiologic hyperemic response by verapamil could not be correlated with improved preservation of high-energy compounds or with significant changes in myocardial O2 consumption.(ABSTRACT TRUNCATED AT 250 WORDS)     

A Comparison of the Safety,Efficacy, and Distribution of Ceforanide and Cephalothin in Coronary Artery Bypass Graft Surgery

Antibiotic prophylaxis in open-heart operations is a widely accepted practice. Introduction of new antibiotics with differences in tissue distribution, spectrum of activity, and therapeutic index prompts their evaluation as possible effective prophylactic agents. We compared the distribution, clinical efficacy, and safety of ceforanide with cephalothin as a prophylactic agent in coronary artery bypass graft (CABG) procedures. The results indicated that the intravenous administration of ceforanide at the dose of 1 gm every 12 hours for 2.5 days was equivalent to cephalothin 1 gm every 6 hours for 2.5 days. Serum, muscle, and bone concentrations of ceforanide were significantly greater than those of cephalothin. These concentrations consistently exceeded the minimal inhibitory concentration for Staphylococcus aureus, the major pathogen implicated in wound infections. No toxicity was observed with either antibiotic. Ceforanide merits consideration as a prophylactic antibiotic in CABG operations.     

Autologous rectus sheath grafts. V. Growth in aortic grafts.

Experiments were designed to test autologous rectus sheath as a replacement for the thoracic aorta in the growing dog. Adequacy of graft function was determined by angiography at 4 month intervals; stress-strain measurements and microscopic examination were made at the time of autopsy. A 3 cm tubular graft of rectus sheath tissue was employed as an aortic graft in 13 mongrel puppies. Nine puppies (70%) were long-term survivors and were put to death between 6 and 22 months postoperatively. No deaths were due to graft failure. Angiographic studies demonstrated patency of the graft without development of pressure gradients. An increase in diameter of the aorta (21.25%) and the rectus sheath graft %22.87%) were demonstrated in all cases. During the time of observation, the compliance of the growing aorta (93,120 dynes/cm2) decreased to one fourth that of the control aortic tissue (24,800 dynes/cm2), whereas the compliance of the rectus sheath graft (547,1000 dynes/cm2) decreased to only one eighth that of the control rectus sheath (47,400 dynes/cm2). Tensile strength is maintained in both the growing aorta (4.5 x 10(7) dynes/cm2) and the rectus sheath graft (4.7 x 10(7) dynes/cm2; p less than 0.05). Microscopic examination showed no calcification, thinning, or weakness. Vascularization of the graft had occurred, with cellular proliferation and development of more than 30 lamellar-like units in the media and an adventitia-like surface.     

Acute aortic arch dissection: reevaluation of the indications for medical and surgical therapy.

Of 42 patients with dissection of the aorta, 4 had important arch involvement. Results were good in 2 patients treated medically. In two other patients wrapping the arch with a Dacron graft successfully prevented fatal hemorrhage. This technique avoids the need for arch replacement in selected cases. From this experience and a review of others a flow sheet was developed to guide decision-making in the surgical and medical management of patients with aortic dissection.     

Pharmacologic support of the myocardium following aortocoronary bypass surgery: a comparative study

To evaluate the hemodynamic effects of simultaneous nitroglycerin and epinephrine infusion following aortocoronary bypass surgery, 16 patients were monitored and studied in the early postoperative period. All patients were given intravenous nitroglycerin, epinephrine, epinephrine combined with nitroglycerin, and dobutamine in a randomized manner. The dose of pharmacologic agent was gradually increased to achieve the required circulatory response. The measured variables included heart rate (HR), central venous pressure (CVP), arterial blood pressure (BP), pulmonary artery pressure (PA), pulmonary artery wedge pressure (PAWP), cardiac output, and arterial and venous oxygen saturations. A nitroglycerin infusion at 1.1 +/- 2 micrograms/kg/min caused the PAWP to decrease by 37% (P less than or equal to .005). All other parameters were not significantly different from control. Epinephrine at a dose of 0.06 +/- 0.02 micrograms/kg/min increased the mean blood pressure by 21% (P less than or equal to .005). The rate-pressure product (RPP) and PAWP were elevated by 18% and 12%, respectively (P less than or equal to .005). Cardiac index, however, was not increased. When nitroglycerin was added to the epinephrine infusion, a PAWP increase was not seen. Also the right ventricular stroke work index was increased by 23% (P less than or equal to .01), and the left ventricular stroke work index increased by 21% (P less than or equal to .01). Dobutamine 4.8 +/- 1.0 micrograms/kg/min caused ventricular stroke work indexes to increase significantly (P less than or equal to .005). The CVP and PAWP were unchanged with this mode of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

The Cardiac Veins and Retrograde Coronary Venous Perfusion

Study of retrograde coronary venous perfusion has been greatly overshadowed in the past decade by the advent and success of direct coronary artery revascularization. Recently there has been renewed interest in retrograde venous perfusion as a possible means of restoring myocardial circulation in selected patients. This paper reviews the anatomy and physiology of the cardiac venous system and the history of retrograde venous perfusion, with emphasis on recent experimental work and clinical trials involving retrograde coronary vein perfusion (RCVP).