Pharmacology of H 394/84, a dihydropyridine neuropeptide Y Y(1) receptor antagonist, in vivo.

The object of the present paper was to investigate the in vivo pharmacological profile of the dihydropyridine neuropeptide Y Y(1) receptor antagonist 1,4-Dihydro-4-[3-[[[[3-[spiro(indene-4,1'-piperidin-1-yl)]propyl]amino]carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridine dicarboxylic acid, dimethylester (H 394/84). The renal vasoconstrictor response to neuropeptide Y in anaesthetized rats was dose-dependently antagonized by H 394/84 (ID(50) value=41+/-4 nmol/kg/min), whereas the renal vascular responses to noradrenaline and angiotensin II were only slightly affected by H 394/84 (500 nmol/kg/min). In pigs pretreated with reserpine and transection of sympathetic nerves (depleted of noradrenaline), H 394/84 dose-dependently antagonized renal and femoral vasoconstrictor responses evoked by sympathetic nerve activation (neuronally released neuropeptide Y) and exogenous neuropeptide Y. Significant inhibition was seen already at 1.0 nmol/kg/min, when plasma levels of the antagonist reached 29+/-4 nM. Around 70% of the antagonism remained 90 min after H 394/84 was given. The disposition of H 394/84 fits a biexponential model with initial and terminal half-lives of 2.6 and 48 min, respectively. H 394/84 (100 nmol/kg/min) did not inhibit vascular responses to neuropeptide Y Y(2) receptor-, alpha-adrenoceptor- or purinoceptor-activation in the pig in vivo. It is concluded that H 394/84 is a potent neuropeptide Y Y(1) receptor antagonist with rather long duration of action in vivo. The selectivity and specificity in vivo is more than 100-fold, and H 394/84 antagonizes vascular responses to exogenous and endogenous, neuronally released, neuropeptide Y with similar potency.

Immediate and long-term results comparing coronary versus biliary tubular-slotted stents to treat old obstructed saphenous vein grafts.

Stenting of old obstructed saphenous vein grafts improves immediate angiographic results and long-term clinical outcome compared to standard balloon angioplasty. Comparison of results and long-term clinical outcome between different types of stents in the treatment of vein graft disease is scarce. The authors studied two matched groups of 33 patients each, receiving either coronary or biliary tubular-slotted stents in old vein graft lesions to compare immediate results and long-term clinical outcome. Patients in the two groups were matched for age and left ventricular function. Baseline angiographic characteristics, the minimal luminal diameter (MLD) (0.68 +/- 0.56 mm vs 0.61 +/- 0.51 mm, p = 0.9), and diameter stenosis (DS) (81 +/- 14% vs 82 +/- 15%) were similar between the groups. After stenting, the MLD (3.15 +/- 0.65 mm vs 3.37 +/- 0.63 mm, p = 0.9) and residual stenosis (-7 +/- 19% vs -11 +/- 21%) were also similar. The in-hospital major complications (myocardial infarction and death) (one vs eight, p = 0.01) and the combination of major and minor (bleeding and vascular) complications (eight vs 17, p = 0.02) were higher in the biliary stent group. At long-term follow-up, both groups of patients had high but comparable rates of major cardiovascular events (39% vs 45%, p = 0.62). Kaplan-Meier event-free survival analysis did not show any statistically significant difference in event-free survival (log-rank statistic 0.98). The authors conclude that patients receiving biliary stents had higher rates of immediate minor and major complications, but at long-term follow up, major cardiovascular event rates were comparable between the two groups of patients.

Results of saphenous vein graft stent implantation: single center results from use of oversized balloon catheters.

The results and complications of a single-center experience of stent implantation in old saphenous vein grafts (SVGs) need to be defined. The authors studied their initial consecutive 92 patients (125 stents, 1.4 stents/per patient) with a mean age of 67+/-9 years. The patients' mean saphenous vein graft (SVG) age was 10+/-4 years, and the mean left ventricular ejection fraction was 46%+/-15. Patient population included unstable angina (65%), stable angina (10%), myocardial infarction (21%), and silent ischemia (4%). The authors implanted 122 Palmaz-Schatz/biliary and three Gianturco-Roubin stents. They aimed at a balloon-artery ratio of 1.1/1.0. Procedural success, defined as stent deployment with <50% stenosis without death/Q-wave myocardial infarction/coronary artery bypass grafting (MI/CABG) was 95%. The mean luminal diameter (MLD) increased from 0.6+/-0.5 to 3.3+/-0.8 mm (p<0.001) and mean SVG stenosis diameter was decreased from 80%+/-14 to -10%+/-11 (p<0.001). Angiographic SVG lesions exhibited thrombus (17%), ulceration (38%), and plaque rupture (28%). Sixty-two patients were treated with warfarin and aspirin and 30 with ticlid and aspirin. Complications included death in three patients (3.3%) who sustained subacute stent thrombosis, and two of three had Q-wave MI. Distal embolization occurred in seven patients (8%); six of seven sustained a non Q-wave acute myocardial infarction (AMI); and one of seven a Q-wave MI. Eight (9%) patients had major groin hematoma, two had pseudoaneurysm (2.2%), one had arteriovenous (A-V) fistula (1.1%), two had vascular surgery (2.2%), nine had blood transfusion (9.8%), and three had stent migration (3.3%). Single-center experience with stents in SVGs indicates a highly successful procedural and angiographic immediate result. However, it was complicated by significant risk of non Q-wave MI due to distal coronary embolization which may affect prognosis.

Percutaneous transluminal coronary angioplasty failures in patients with multivessel disease. Is there an increased risk?

In recent years, there has been a nationwide trend toward performing percutaneous transluminal coronary angioplasty in patients with multivessel coronary artery disease. The clinical course of 57 consecutive patients who required emergency first-time coronary artery bypass grafting operations were reviewed to assess for difference in outcome between the 28 patients (49%) with single-vessel disease and the 29 patients (51%) with multivessel disease. The two groups were similar in preoperative characteristics except for a higher proportion of chronic obstructive pulmonary disease in the patients with multivessel disease (p = 0.03). Twice as many patients with multivessel disease were in shock (single-vessel disease = 4 [14%], multivessel disease = 8 [28%], p = not significant) en route to the operating room and significantly more patients with multivessel disease required on-going cardiopulmonary resuscitation (single-vessel disease = 0 [0%], multivessel disease = 5 [17%], p = 0.03). Significantly more coronary artery bypass grafts were placed in the patients with multivessel disease (single-vessel disease = 1.5 +/- 0.6, multivessel disease = 2.9 +/- 0.7, p < 0.01), which required longer aortic clamping time (p = 0.02) and cardiopulmonary bypass time (p < 0.01). There were seven postoperative deaths; all but one occurred in patients with multivessel disease (single-vessel disease = 1 [4%], multivessel disease = 6 [21%], p = 0.05). According to multivariate analysis, incremental risk factors of mortality were preoperative shock (p < 0.01), urgent or emergency percutaneous transluminal coronary angioplasty (p = 0.06), and multivessel disease (p = 0.12). Despite a similar incidence of myocardial infarction (single-vessel disease = 8 [29%], multivessel disease = 12 [41%], p = not significant), patients with multivessel disease had a higher incidence of cardiac morbidity (single-vessel disease = 4 [14%], multivessel disease = 11 [38%], p = 0.04) and noncardiac morbidity (single-vessel disease = 4 [14%], multivessel disease = 12 [41%], p = 0.02). By multivariate analysis, incremental risk factors of morbidity were preoperative shock (p < 0.01), multivessel disease (p = 0.02), and ejection fraction < 50% (p = 0.07). In the subset of patients with multivessel disease, preoperative shock, ejection fraction < 50, and an age of 60 years or greater were associated with higher morbidity and mortality. In conclusion, the risk of percutaneous transluminal coronary angioplasty failure is considerably higher in patients with multivessel disease. In certain subsets of patients with multivessel disease, coronary artery bypass grafting would be a safer procedure when compared with percutaneous transluminal coronary angioplasty for initial myocardial revascularization.

Chlormethiazole attenuates the derangement of sensory evoked potential (SEP) induced by ICV administration of NMDA.

Administration to anaesthetized rats of N-methyl-D-aspartate (NMDA 30 nmol ICV) induced a profound derangement of stimulation evoked potential (f-SEP) and also autonomic excitation with an increase in arterial blood pressure and heart rate. These effects were antagonised by pretreatment with dizocilpine (0.5 mg/kg IV). Pretreatment with chlormethiazole (20 mg/kg IV 26 min before NMDA) also markedly diminished the derangement of f-SEP. At the end of the registration period 2 h after NMDA the SEP had recovered to 72.7 +/- 3.4 (% of control; mean +/- SEM) in saline-treated rats as compared to 96.1 +/- 5.6% in chlormethiazole treated animals (P < 0.01). In contrast to dizocilpine, chlormethiazole alone had no effect on heart rate or blood pressure and did not alter the autonomic effects of ICV NMDA. These results demonstrate that chlormethiazole can antagonise some NMDA-receptor mediated functions, even though there is no evidence that it is an NMDA antagonist.

Hemodynamic effects of calcium antagonists with high or low vascular selectivity.

Infusion of felodipine and verapamil in increasing doses to anesthetized spontaneously hypertensive rats induced a progressive fall in arterial blood pressure (BP). To estimate the cardiac action of the different drugs, we also measured changes in cardiac output (CO) and velocity of flow (dF/dT) by a Doppler flow probe placed on the ascending aorta. Infusion of verapamil induced a parallel decrease in mean arterial BP, CO, and cardiac inotropy (as estimated by max. dF/dT). In contrast, upon felodipine administration, the decrease in arterial BP was accompanied by an initial small rise in dF/dT. A decrease in dF/dT was observed only after high doses of felodipine, which caused pronounced levels of hypotension.

Increase of renal sympathetic nerve activity by metoprolol or propranolol in conscious spontaneously hypertensive rats.

1 Mean arterial pressure (MAP), heart rate (HR) and renal sympathetic nerve activity (RSNA) were recorded in conscious spontaneously hypertensive rats (SHR). 2 Infusion of metoprolol (4 mumol kg-1 h-1) or propranolol (1.5 mumol kg-1 h-1) reduced HR and significantly increased RSNA. 3 Administration of metoprolol caused a sustained decrease of MAP starting in the third hour of infusion. In contrast, administration of propranolol induced a biphasic response in MAP. It is suggested that the increase of RSNA after both beta-adrenoceptor blocking drugs is due to a decrease in arterial baroreceptor activity.

Atrial natriuretic peptide and the natriuresis due to acute beta-blockade in conscious hypertensive rats.

Acute beta-adrenoceptor blockade in rats is known to produce a natriuresis of hitherto uncertain cause. To investigate this phenomenon plasma atrial natriuretic peptide (ANP) concentrations were measured in groups of conscious metoprolol-treated and control rats. In the active treatment group the blood pressure decreased slowly, as expected, settling at a lower level after 2 hours, and the mean sodium excretion doubled 1 hour after metoprolol administration. This natriuretic effect was maximal after 40-60 minutes and thereafter slowly declined towards basal values. The period of enhanced sodium excretion was associated with a significant rise (68%) of the mean ANP plasma concentration. It suggested that this increase in plasma ANP concentration can mediate the acute natriuretic effect beta-adrenoceptor blockade.

Effect of felodipine on renal hemodynamics and excretion in the dog.

The effects of felodipine on renal hemodynamics and excretion were evaluated in the anesthetized dog. Unilateral renal arterial infusion of felodipine produced ipsilateral increases in the absolute and fractional excretion of sodium and water which were greater than those of potassium; these effects occurred in the absence of changes in mean arterial pressure, renal blood flow, or glomerular filtration rate. There were no significant effects on renal hemodynamic or excretory function in the contralateral kidney. The unilateral renal arterial infusion of isotonic saline or vehicle produced no significant effects on renal hemodynamic or excretory function in either ipsilateral or contralateral kidney. Felodipine, a calcium antagonist with vasodilator antihypertensive properties, in doses which do not affect systemic or renal hemodynamics in the dog, increased urinary flow rate and sodium excretion by decreasing renal tubular water and sodium reabsorption. As a vasodilator antihypertensive agent, felodipine possesses potentially advantageous diuretic and natriuretic properties.

The role of prostaglandins in the alpha- and beta-adrenoceptor mediated renin release response to graded renal nerve stimulation.

The role of prostaglandins in the renin release response to renal nerve stimulation (RNS) at different intensities was examined in the anaesthetized dog. The animals were divided into two groups receiving either low or high level RNS, defined by the frequencies of stimulation producing reduction in renal blood flow by 5% or less and 50%. Indomethacin or diclofenac sodium (5 mg/kg i.v.), prostaglandin synthesis inhibitors, did not affect the renin release response to low level RNS but decreased the renin release response to high level RNS by 31 +/- 8% (P less than 0.01). Addition of metoprolol, (0.5 mg/kg i.v.) beta-1-adrenoceptor antagonist, to indomethacin or diclofenac sodium resulted in a greater reduction (68 +/- 6% P less than 0.01) of the renin release response to high level RNS compared to that produced by either drug alone. Metoprolol, alone, reduced the renin release response to high level RNS by 37 +/- 14% (P less than 0.05). Phenoxybenzamine (0.6 microgram . kg-1 . min-1), alpha-adrenoceptor antagonist, into the renal artery practically abolished the renal vasoconstrictor response to high level RNS and reduced the renin release response by 50 +/- 7% (P less than 0.01). Addition of metoprolol to phenoxybenzamine practically abolished the renal vasoconstrictor response and the renin release response to high level RNS; 94 +/- 4% (P less than 0.01). Addition of phenoxybenzamine to indomethacin or diclofenac sodium practically abolished the renal vasoconstrictor response to high level RNS but did not produce any greater reduction of the renin release response than that produced by either drug alone. These findings suggest that low level RNS results in renin release which is not dependent on prostaglandins. High level RNS results in renin release which is partly mediated by beta-1-adrenoceptors and partly related to alpha-adrenoceptors mediated renal vasoconstriction. Prostaglandins are not involved in the renin release deriving from alpha-adrenoceptor mediated renal vasoconstriction.