Effect of decreased glucose concentration on cerebrovascular tone in vitro.

We studied the effect of decreased glucose concentration on cerebrovascular tone in vitro. Segments of rat middle cerebral arteries (MCA) were isolated, cannulated at both ends with glass micropipettes, and pressurized to 85 mm Hg. Decreasing the glucose in the extraluminal bath and luminal perfusate from 5.5 mmol/L to 1.0 or 0.5 mmol/L for 1.5 hours each had no significant effect on the diameter of the arteries. When all the glucose was removed from the extraluminal bath and luminal perfusate for 1.5 hours, the MCA dilated by 23% [252 +/- 24 (SD) microns to 311 +/- 7 microns (P < .5, n = 7)]. This dilation was 80% of the maximum dilation produced by removal of Ca+2 from the bathing solutions. Neither removal of the endothelium nor inhibition of the ATP-sensitive K channels with 10(-5) mol/L glibenclamide altered the response of the isolated MCA to the removal of glucose. We conclude that rat MCA are relatively more resistant to substrate limitation compared to the brain as a whole.

Stimulation of alpha 2 adrenoceptors dilates the rat middle cerebral artery.

BACKGROUND: Because alpha 2 adrenoceptor agonists are used as adjuncts to anesthetics, their effects on the cerebrovascular circulation are of prime importance. We studied changes in the diameter of rat middle cerebral arteries after stimulation of alpha 2 adrenoceptors with UK14,304. METHODS: Rat middle cerebral arteries were isolated, cannulated at each end with a glass micropipette, and pressurized to 85 mmHg. The middle cerebral arteries were immersed in a bath (37 degrees C) containing physiologic saline solution, and luminally perfused with physiologic saline solution (100 microliters/ min). Changes in vessel diameter were measured after magnification with a microscope. RESULTS: Resting diameter of the middle cerebral arteries was 239 +/- 13 microns (n = 8) for the first study. A dose-dependent dilation was produced by addition of UK14,304 to the extraluminal bath; a 10-15% increase in diameter occurred at a concentration of 10(-4)M. The dilations produced by UK14,304 were blocked with selective alpha 2-antagonists, idazoxan and rauwolscine, but not by the selective alpha 1-antagonist, prazosin. The dilations could be blocked by removal of the endothelium, or the nitric oxide synthase inhibitor, N-nitro-L-arginine methyl ester (10(-5) M). The inhibitory effects of N-nitro-L-arginine methyl ester were reversed with the addition of 10(-3) M L-arginine, but not 10(-3) M D-arginine. Furthermore the dilation produced by UK14,304 was completely abolished with pertussis toxin (100 ng/ml). CONCLUSIONS: It was concluded that the stimulation of alpha 2 adrenoceptors with UK14,304 produced a dilation in the rat middle cerebral artery that (1) was dependent on intact endothelium, (2) involved nitric oxide, and (3) acted via a pertussis toxin-sensitive G protein.

Permissive role of NO in alpha 2-adrenoceptor-mediated dilations in rat cerebral arteries.

Dilations produced with UK-14304, a selective alpha 2-adrenoceptor agonist, in rat middle cerebral arteries (MCAs) were blocked after removal of the endothelium or inhibition of nitric oxide synthase (NOS). After endothelium removal or inhibition of NOS, the addition of subthreshold doses of an exogenous nitric oxide (NO) donor, S-nitroso-N-acetylpenicillamine, restored the dilations produced by UK-14304. In a similar manner the guanosine 3',5'-cyclic monophosphate (cGMP) analogues 8-bromoguanosine 3',5'-cyclic monophosphate and N2,2'-O-dibutyrylguanosine 3',5'-cyclic monophosphate restored the dilations of MCAs after endothelial removal. Because NO cannot be synthesized and released in MCAs after inhibition of NOS, it cannot be directly responsible for the dilation. The basal release of NO from the endothelium acts permissively in the vasodilation by maintaining adequate levels of cGMP. Removal of this basal release of NO by removal of endothelium or inhibition of NOS abolishes the alpha 2-adrenoceptor-mediated dilation.

Labetalol for the control of elevated blood pressure following coronary artery bypass grafting.

In a multicenter study, the efficacy and safety of intravenous (IV) labetalol for the control of elevated blood pressure were studied in the intensive care unit (ICU) in 65 patients within 4 hours following coronary artery bypass grafting (CABG). Patients with pre-existing ventricular dysfunction, bradycardia, bronchospastic disease, or postoperative complications were excluded. All patients were monitored with a thermodilution pulmonary artery catheter. Entry criteria were a systolic blood pressure (SBP) greater than 140 mm Hg or diastolic blood pressure (DBP) greater than 90 mm Hg for at least five minutes. Intravenous labetalol was loaded incrementally (5, 10, 20, and 40 mg at 10-minute intervals) to a maximum cumulative dose of 75 mg, until either SBP decreased 10% or DBP decreased 10% and was less than 90 mm Hg. Responders were entered into a 6-hour maintenance period, and received 5 to 40 mg of IV labetalol every 10 minutes as needed for blood pressure control. Hemodynamic data and temperature were recorded at baseline, just before each dose of labetalol during the loading period, and at the end of the maintenance period. Alternative therapy was given in the case of nonresponse or adverse events. Intravenous labetalol successfully controlled post-CABG hypertension in 55 of 65 patients (85%); of these, 46 responded to 35 mg or less. Although 28 patients required no further labetalol in the maintenance period, in the others dosage varied from 5 to 400 mg. Reductions in SBP and DBP were associated with moderate reductions in pulse pressure (SBP-DBP) and heart rate (HR). Cardiac index decreased by 18.5%, with a 12.5% decrease in stroke index and 8.1% decrease in HR. Systemic vascular resistance did not increase significantly. Four patients (6%) developed hypotension related to IV labetalol. There was one death due to perioperative myocardial infarction, which was unrelated to labetalol use. The mechanism of action of IV labetalol in controlling hypertension after CABG surgery seems to be moderate negative inotropy and chronotropy. Its alpha-blocking effects seem to be important in preventing reflex vasoconstriction. This is directly opposite to the primary vasodilator effect found when IV labetalol is used to control nonsurgical hypertension. Because of these actions, labetalol should be avoided or used with caution in patients with preoperative and postoperative cardiac dysfunction. In patients with normal left ventricular function, IV labetalol appears to be a safe, effective agent in controlling post-CABG hypertension, with the added potential benefit of enhanced myocardial oxygen balance.