Enalapril versus atenolol in the treatment of hypertensive smokers.

A randomised crossover study has been done to compare the antihypertensive efficacy of enalapril and atenolol in 45 smoking, hypertensive men. Treatment was started with enalapril 20 mg/d or atenolol 50 mg/d and, if necessary, the doses were doubled after 4 weeks to achieve a sitting diastolic blood pressure < or = 95 mm Hg, after which hydrochlorothiazide was added, if necessary. Both drugs lowered blood pressure significantly. However, enalapril was more efficient in lowering both systolic and diastolic blood pressure; the mean difference was significant after both 4 and 8 weeks in the sitting systolic (11.6 mm Hg and 7.9 mm Hg) and diastolic (3.3 mm Hg and 3.0 mm Hg) pressures and in the erect systolic pressures (8.2 mm Hg and 7.2 mm Hg), and after 8 weeks in the supine systolic pressure, too (8.9 mm Hg). The effect on enalapril was especially marked in moderate (< 20 cigarettes/day) smokers. The need for diuretics was also significantly less in the enalapril group. It appears that angiotensin-converting enzyme inhibitors may be superior to beta-adrenoceptor blockers in the treatment of hypertensive smoking patients.

Exogenous GTP increases cyclic GMP and inhibits thrombin-induced aggregation of washed human platelets: comparison with ATP, adenosine and guanosine.

The effects of exogenous guanosine 5'-triphosphate (GTP), guanosine, adenosine 5'-triphosphate (ATP) and adenosine on platelet aggregation, serotonin secretion and cyclic nucleotide accumulation were studied using thrombin-stimulated washed human platelets. GTP (10 microM-1 mM) dose-dependently inhibited thrombin-induced aggregation and serotonin secretion. The inhibition of aggregation was accompanied by an increase in platelet cyclic GMP. GTP did not affect cyclic AMP concentration. Adenosine (1 microM-1 mM) dose-dependently inhibited thrombin-induced aggregation and serotonin secretion, and increased cyclic AMP. ATP at high concentrations (100 microM-1 mM) inhibited aggregation and serotonin secretion, and 1 mM ATP increased cyclic AMP. Guanosine was relatively ineffective in preventing aggregation and serotonin secretion and did not affect cyclic GMP. The rank order of inhibition of thrombin-induced aggregation of washed human platelets was adenosine > GTP > ATP > guanosine. In conclusion, exogenous GTP inhibits thrombin-induced aggregation and serotonin secretion of washed human platelets by increasing cyclic GMP. The results raise the possibility of a cell membrane site of action for GTP in platelets which mediates the activation of soluble guanylate cyclase suggesting that GTP may have a local antithrombotic effect also in vivo.

Endothelium-dependent and -independent effects of exogenous ATP, adenosine, GTP and guanosine on vascular tone and cyclic nucleotide accumulation of rat mesenteric artery.

1. The effects of exogenous guanosine 5'-triphosphate (GTP) and guanosine on vascular tone and cyclic nucleotide accumulation of noradrenaline-precontracted endothelium-intact and endothelium-denuded rat mesenteric artery rings were compared with the effects of the known purinoceptor agonists adenosine 5'-triphosphate (ATP) and adenosine. 2. GTP (10 microM-1 mM) dose-dependently relaxed endothelium-intact mesenteric artery rings by producing a rapid initial response followed by sustained relaxation resembling the relaxant response to acetylcholine. GTP also slightly relaxed endothelium-denuded artery rings. The acetylcholine- and GTP-induced relaxations of endothelium-intact rings were attenuated by NG-nitro L-arginine methyl ester (L-NAME, 330 microM) which attenuation was reversed with L-arginine (1 mM). 3. Guanosine (10 microM-1 mM) relaxed both endothelium-intact and -denuded artery rings in a dose-dependent manner. The relaxations were more pronounced in endothelium-intact preparations and were only slightly attenuated by L-NAME (330 microM). 4. ATP (1 microM-1 mM) and adenosine (10 microM-1 mM) dose-dependently relaxed endothelium-intact and -denuded artery rings. The responses were more pronounced in endothelium-intact vascular preparations. 5. GTP (100 microM) and guanosine (100 microM) increased guanosine 3':5'-cyclic monophosphate (cyclic GMP) accumulation in both endothelium-intact and -denuded artery rings corresponding to the relaxations observed. The concentrations of adenosine 3':5'-cyclic monophosphate (cyclic AMP) were not affected. 6. ATP (100 microM) increased cyclic GMP concentration of endothelium-intact artery rings. The concentrations of cyclic AMP were not affected by ATP (100 microM) and adenosine (100 microM) in endothelium-intact and -denuded vascular preparations.7. These results provide evidence that exogenous GTP and guanosine relax precontracted endothelium-intact and -denuded rat mesenteric artery rings by increasing cyclic GMP accumulation. The response to GTP of endothelium-intact rings can mainly be explained by the release of endothelium-derived relaxing factor (EDRF), but that of guanosine is only partly due to EDRF, and is a combination of endothelium-dependent and -independent effects. The endothelium-independent response of GTP and guanosine is a direct, unknown effect on smooth muscle and guanylate cyclase.

Modification of nitrovasodilator effects on vascular smooth muscle by exogenous GTP and guanosine.

The effects of exogenous guanosine 5'-triphosphate (GTP) and guanosine on nitroglycerin-, sodium nitrite- and SIN-1-induced guanosine 3',5'-cyclic monophosphate (cyclic GMP) accumulation and smooth muscle relaxation were studied using endothelium-denuded rat mesenteric artery rings precontracted with noradrenaline. Preincubation of contracted artery rings with GTP (100 microM) or guanosine (100 microM) before eliciting relaxations with nitrovasodilators significantly shifted the dose-response curves of nitrocompounds to the left and augmented the increases in cyclic GMP. GTP and guanosine alone also induced cyclic GMP accumulation in pre-contracted artery rings. These effects of GTP and guanosine on nitrovasodilator responses were not related to the preincubation period (0-30 min). The present results raise the possibility of a cell membrane site of action for GTP and guanosine, which mediates the activation of soluble guanylate cyclase and leads to increased nitrovasodilator-induced cyclic GMP accumulation and arterial smooth muscle relaxation.

Cigarette smoking alters sympathoadrenal regulation by decreasing the density of beta 2-adrenoceptors. A study of monitored smoking cessation.

We report the effects of monitored smoking cessation on adrenergic regulation in chronic smokers. The beta 2 adrenoceptor density of mononuclear leukocytes (MNLs) and plasma catecholamines was analyzed before cessation and 2, 3, and 8 weeks after cessation. We found a progressive increase in beta-adrenoceptor density after smoking cessation. During smoking the beta-adrenoceptor density was 1.456 +/- 83 (mean +/- SEM) binding sites per cell (n = 10), whereas 3 weeks after cessation the density was 1,774 +/- 157 sites per cell (n = 10; p less than 0.05), and at 8 weeks, 1,900 +/- 227 sites per cell (n = 8; p less than 0.05), representing an overall increase of 23%. Smoking cessation had no effect on binding affinity nor on lymphocyte subgroup distribution. The density of MNL cell beta-adrenoceptors in age-matched nonsmoking men was higher, at 1,896 +/- 271 sites per cell, than that of the chronic smokers before cessation, 1,419 +/- 117 sites per cell (n = 14; p less than 0.01). Plasma epinephrine decreased as a result of cessation from 0.36 pmol/ml (0.26-0.44, 95% confidence interval; baseline) to 0.26 pmol/ml (0.20-0.32) at 8 weeks (p less than 0.05), and norepinephrine decreased from 2.09 pmol/ml (1.38-2.80) to 1.69 pmol/ml (1.14-2.24; p = 0.06). We conclude that stopping smoking progressively increases beta 2-adrenoceptor density on MNL cells. Eight weeks after cessation the adrenoceptor density reaches the corresponding level of nonsmokers. These reversible changes in adrenergic regulation after smoking cessation may be associated with the relatively rapid reduction in cardiovascular disease risk among ex-smokers.

[Interaction between the arterial wall and thrombocytes in smokers]. / Interaktion mellan artärvägg och trombocyter hos rökare.

Smoking is per se a major risk factor in cardio-vascular diseases. It causes atherosclerosis and blockage particularly in the aorta and the leg arteries. The components of tobacco smoke damage the endothelium, increase arterial contractility, and accelerate the formation of plaque therein. The mechanisms of the effect of smoking on the genesis of atherothrombotic diseases have been studied in inter alios identical twins where the one smokes and the other does not. Smoking activates the sympathetic nerves and affects their regulation. Tobacco smokers show signs of activated thrombocyte function and increased sensitivity to vasoconstriction, which provokes a counter-reaction in the arterial walls. The observations emphasize the importance of vaso-active agents for the development and complications of atherosclerosis.

Exogenous GTP enhances the effects of sodium nitrite on cyclic GMP accumulation, vascular smooth muscle relaxation and platelet aggregation.

Exogenous guanosine triphosphate (GTP) (1-2 x 10(-4)M) resulted in increased concentrations of cyclic GMP both in endothelium denuded rat mesenteric artery (RMA) and in human ADP-stimulated platelets. Sodium nitrite (3.3 x 10(-4)M) relaxed precontracted RMA by 34%. When the arteries were preincubated with GTP (2 x 10(-4)M) sodium nitrite administration resulted in a significantly greater relaxation (58%) of the RMA with concomitant 2-fold increase in cGMP. Sodium nitrite (1 x 10(-4)M) had an inhibitory effect on ADP-induced platelet aggregation. Preincubation with GTP enhanced significantly the sodium nitrite-induced inhibition of ADP-induced platelet aggregation with a simultaneous 5-fold increase in cGMP. These results indicate that exogenous GTP enhances the sodium nitrite-induced stimulation of guanylate cyclase and thus enhances the effects of sodium nitrite on arterial smooth muscle and platelets.

Decreased cyclic AMP accumulation in lymphocytes in response to adrenaline and prostacyclin after n-3 polyunsaturated fatty acid supplementation in man.

The effect of supplementation with n-3 polyunsaturated fatty acids on beta-adrenoceptor function in lymphocytes has been studied in ten healthy male volunteers. Ten Max-Epa capsules containing 320 mg n-3 polyunsaturated fatty acids per capsule were given for 3 weeks, and the cyclic AMP accumulation response in lymphocytes to adrenaline and the prostacyclin analogue iloprost (ZK 36374) were assessed before and after supplementation. After supplementation about 30% less cAMP was accumulation by the lymphocytes in response to either adrenaline or iloprost. Propranolol inhibited the adrenaline-induced increase in cAMP both before and after supplementation, but the difference in the basal cAMP concentration between the groups still persisted. Adrenaline stimulation after pre-incubation of the lymphocytes with the alpha-adrenoceptor antagonist phentolamine resulted in an even more pronounced difference between pre- and post-supplementation cAMP concentrations. The results suggest that fish oil supplementation may lead to decreased responsiveness of adenylate cyclase to catecholamine and prostaglandin stimulation.

Decreased beta-adrenergic receptor density and catecholamine response in male cigarette smokers. A study of monozygotic twin pairs discordant for smoking.

The effect of long-term cigarette smoking on beta-adrenoceptor density and catecholamine response was studied in 10 monozygotic male twin-pairs discordant for smoking, with an average discordance time for smoking of 23 years (range, 12-35 years). The density of beta-adrenergic receptors was 40% lower in the lymphocytes of smoking twins compared with their nonsmoking cotwins (beta-receptor density, 6.7 +/- 1.2 and 11.1 +/- 1.8 fmol/10(6) cells, respectively; p less than 0.05). The corresponding apparent Kd values were 31.7 +/- 5.5 and 26.7 +/- 5.4 pM, respectively. Stimulation of the lymphocyte beta-receptors resulted in significantly lower levels of cyclic adenosine monophosphate in the smokers compared with the nonsmokers (16.2 +/- 3.3 vs. 29.2 +/- 6.5 pmol/10(6) cells, p less than 0.05). When subjected to submaximal exercise, the smokers had a lower level of cyclic adenosine monophosphate in plasma (25.9 +/- 1.2 vs. 28.6 +/- 1.0, p less than 0.05) and a net decrease was seen in plasma free fatty acids in the smokers compared with a net increase in the nonsmokers (-15% vs. +19%, p less than 0.01). The total plasma catecholamine level was, in the basal state, significantly higher in smokers compared with nonsmokers (74.8%, p less than 0.05). The intrapair difference in plasma norepinephrine predicted well the intrapair difference in beta-receptor density (r = -0.84, p less than 0.001). We conclude that the autonomic neurohumoral response evoked by cigarette smoking results in downregulation of beta-adrenergic receptors in long-term smokers.

Enhanced activation of the renin-angiotensin-aldosterone system in chronic cigarette smokers: a study of monozygotic twin pairs discordant for smoking.

Plasma renin activity (PRA) and aldosterone concentration were measured before and during submaximal exercise in 10 male monozygotic twin pairs who were discordant for smoking. In nine twin pairs PRA was higher in the smoker both at rest and during exercise. The mean PRA was 99% higher at rest and 84% higher during exercise than in nonsmokers. Plasma aldosterone levels were higher at rest in seven smokers and during exercise in eight smokers compared with the respective nonsmokers. The mean aldosterone level at rest was 23% and during exercise 40% higher in the smokers than in the nonsmokers. Chronic smoking induces increased PRA, which results in increased aldosterone formation, presumably via enhanced generation of angiotensin II. This may partly explain the greater vasoconstrictive reactivity typical of the arteries of chronic smokers.

Vasoactive and atherogenic effects of cigarette smoking: a study of monozygotic twins discordant for smoking.

The mechanism by which atherosclerotic disease is induced by cigarette smoking has not yet been identified unequivocally. Chronic cigarette smoking and the generation of vasoactive prostanoids and the size of carotid atherosclerotic plaques were studied in nine pairs of identical male twins discordant for smoking for over 20 years. The urinary excretion of 2,3-dinor-thromboxane B2 (thromboxane B2 metabolite) of the smoking twin was significantly higher (on average 1.8 times higher) in every pair and that of 2,3-dinor-6-keto-prostaglandin F1 alpha (prostacyclin metabolite) was significantly higher (on average 1.3 times higher) in eight of the nine pairs. The ratio of excretion of these metabolites was significantly higher, being 4.0 (95% confidence interval 2.7 to 5.4) among the smokers compared with 2.9 (2.1 to 3.8) among the non-smokers, thus favouring a mechanism of vasoconstriction. Excretion of the thromboxane B2 metabolite was related to the urinary concentrations of nicotine metabolites. Atherosclerotic plaques detected by ultrasonography in the carotid arteries were significantly larger among smokers but did not correlate with the urinary excretion of prostacyclin and thromboxane B2 metabolites or intensity of smoking. Smoking was concluded to induce activation of platelets by an effect mediated by nicotine. The increased prostacyclin production, on the other hand, suggested a compensatory mechanism for the general vasoconstrictive properties of cigarette smoking.

Physical exercise provokes platelet desensitization in men who smoke cigarettes--involvement of sympathoadrenergic mechanisms--a study of monozygotic twin pairs discordant for smoking.

Since chronic smoking is known to be a dominant risk factor for morbidity and mortality in cardiovascular diseases related to enhanced atherogenesis and arterial thrombogenesis, the mechanisms causing these effects are of interest. The present study aims to assess the basic biochemical and haemorheological parameters among male monozygotic twinpairs, who have been discordant for smoking in average for over 20 years. Because smoking is known to cause enhanced sympathoadrenergic activation, the study was designed to further stimulate this by means of physical exercise. The platelet aggregation in vitro and serum-thromboxane B2 (S-TxB2) did not differ at rest, but after exercise smokers' platelets were desensitized to all doses of adrenaline and low doses of ADP as well as collagen and the levels of S-TxB2 were lower than among nonsmokers. This finding was supported by the decreased release of serotonin and TxB2 during aggregation induced with adrenaline. The leucocyte counts were significantly higher among smokers at rest and haematocrit as well as platelet counts showed the same tendency. Fibrinogen tended to be be elevated among smokers after exercise and together with haematocrit levels implicated increased blood viscosity. FVIII, vWF and beta-thromboglobulin did not differ. In conclusion we suggest that in smokers the significant exhaustion of platelets to in vitro stimulation might be a consequence of continuous platelet activation during physical stress. This phenomenon together with our other findings implies that the sympathoadrenergic system has a multiple role in vivo, which needs further research to elucidate the mechanisms involved in the effects of smoking on cardiovascular diseases.