Bisoprolol improves perfusion of ischaemic myocardium in anaesthetized pigs.

1. The ability of the cardioselective beta-adrenoceptor antagonist bisoprolol ((+/-)-1-[4-(2-isopropoxyethoxymethyl)-phenoxy]-3-isopropyl-amino -2-propanol hemifumarate, EMD 33512) to suppress isoprenaline-induced increases in heart rate and maximal rate of rise in left ventricular pressure (LVdP/dtmax) was studied in 6 anaesthetized pigs given 4 cumulative doses (16, 64, 256 and 1024 micrograms kg-1). Bisoprolol was about 2 times more effective in suppressing isoprenaline-induced increases in LVdP/dtmax than those in heart rate. 2. In 8 animals which had a partial stenosis of the left anterior descending coronary artery (LADCA), the effects of 3 consecutive doses (50, 200 and 750 micrograms kg-1) of bisoprolol were studied on systemic haemodynamics, regional myocardial perfusion and function. The effects of the drug were compared with those obtained in a group of 9 animals with LADCA stenosis which did not receive any treatment. 3. The lowest dose of bisoprolol (50 micrograms kg-1) increased perfusion of the ischaemic myocardium (which had been reduced from 123 +/- 20 ml min-1 100 g-1 to 42 +/- 11 ml min-1 100 g-1) by 21 +/- 10 ml min-1 100 g-1 (P less than 0.05). In particular the subendocardial layers, which were most severely affected by the stenosis (a decrease from 128 +/- 19 ml min-1 100 g-1 to 20 +/- 6 ml min-1 100 g-1) benefited from the administration of the drug (an increase of 30 +/- 10 ml min-1 100 g-1). Perfusion of the subepicardium was not significantly affected. With the higher dose only a minor additional improvement in perfusion of the ischaemic myocardium was observed. 4. The negative chronotropic response is the most likely factor leading to the improvement in perfusion. 5. Myocardial wall thickening, which decreased from 41 +/- 2% to 9 +/- 4% (P less than 0.05) due to the hypoperfusion, did not improve after administration of the drug. This lack of improvement may possibly be due to the duration of ischaemia before and the magnitude of the flow deficit after bisoprolol administration. 6. Between 15 and 60 min of ischaemia, 5 of the 9 untreated animals had an episode of ventricular fibrillation compared with only 1 of the 8 animals treated with bisoprolol, in spite of an initially larger flow reduction in the treated animals. The more homogeneous flow distribution after bisoprolol might account for the lower incidence of arrhythmias in this group. 7. It was demonstrated that bisoprolol improves perfusion of ischaemic myocardium in anaesthetized pigs even at doses (50.pgkg-1) that only moderately antagonize isoprenaline-induced cardiostimulatory effects.

Nicorandil-induced changes in the distribution of cardiac output and coronary blood flow in pigs.

The present investigation was conducted to study systemic and regional haemodynamic effects of nicorandil, a potent coronary vasodilator, after intravenous or local intracoronary administration in anaesthetized or conscious pigs. Intravenous infusions of nicorandil for 10 min in both anaesthetized (15, 30, 75 and 150 micrograms.kg-1.min-1) and conscious (20, 40 and 80 micrograms.kg-1.min-1) pigs reduced arterial blood pressure, stroke volume, left ventricular end-diastolic pressure (LVEDP) and systemic vascular resistance, but increased heart rate and maxLVdP/dt. Since nicorandil decreased LVEDP at doses which did not affect arterial blood pressure, the drug may be considered as a more potent venodilator than arterial dilator. Nicorandil increased cardiac output only in conscious animals due to a more marked tachycardia (85% after 80 micrograms.kg-1.min-1) than in anaesthetized animals (30% after 75 micrograms.kg-1.min-1). The nicorandil-induced increase in heart rate and maxLVdP/dt, being substantially attenuated in conscious pigs after treatment with propranolol, can be ascribed to a reflex activation of the sympathetic nervous system following the fall in arterial pressure. Although cardiac output did not change in anaesthetized animals, intravenous infusions of nicorandil did cause a redistribution of blood flow in favour of organs such as the heart, adrenals, spleen, small intestine and brain at the expense of that to the stomach and kidneys; hepatic artery and skeletal muscle blood flow did not change. The increase in myocardial blood flow, primarily to the subepicardial layers, was associated with an enhancement in coronary venous oxygen content and was also notices after intracoronary infusions of nicorandil (0.6, 1.5, 3 and 6 micrograms.kg-1.min-1).(ABSTRACT TRUNCATED AT 250 WORDS)

Usefulness of pimobendan in the treatment of heart failure.

The effects of the benzimidazole-pyridazinone pimobendan (UD-CG 115 BS) on systemic haemodynamics, myocardial performance and the distribution of cardiac output were studied in open-chest anaesthetized pigs. After intravenous bolus injections (0.1-0.5 mg X kg-1, n = 7) increases in heart rate (up to 37%), LVdP/dtmax (up to 54%) and decreases in systemic vascular resistance (up to 33%) and left ventricular filling pressure (up to 50%) were observed, while cardiac output was unchanged. Vasodilation occurred in nearly all regional vascular beds, but was most pronounced in the adrenals (200%), followed by stomach (150%), small intestines (130%), heart (125%) and brain (110%). O2-consumption was not affected in spite of the increases in heart rate and myocardial inotropy. To evaluate the direct effects on the myocardial, pimobendan was also infused (1-5 micrograms X kg-1 X min-1, n = 7) directly into the left anterior descending coronary artery. In addition to a marked vasodilation of the coronary bed (140%), also a lowering of the left ventricular filling pressure (up to 20%) and cardiac output (15%) was observed, but no changes in regional myocardial function, LVdP/dtmax and systemic vascular resistance occurred. Immediately after intracoronary bolus injections (1 mg X kg-1, n = 4), vasodilation of the coronary vessels was apparent, but myocardial contractility was not affected. This may explain that cyclic AMP content, determined in biopsies excised 30 s after injection, was unaltered. It may be concluded that pimobendan exerts actions on the cardiovascular system which may be useful in the treatment of heart failure.

HLA-DR antigens in epithelioid cell granulomas of sarcoidosis, using semithin frozen sections. A concept about granuloma formation.

Mediastinal lymph nodes of 11 patients with Sarcoidosis were studied. The immunoperoxidase technique using monoclonal antibody to HLA-DR antigen revealed on conventional frozen sections epithelioid cell granulomas with intense staining. Localization of this HLA-DR + material on or in cells in these granulomas was possible with 1 mu semithin frozen sections. Epithelioid cells as well as multi nuclear giant cells were seen in these sections with membrane bound HLA-DR antigens. Some problems about HLA-DR antigens in relation with antigen handling, the presence on epithelioid, (and) giant cells and granuloma formation will be discussed.