This study aimed to determine the mechanism of hypertension associated with nitric oxide synthase inhibition. Intravenous injections of JV G -nitro-L-arginine, a nitric oxide synthase inhibitor, produced a sustained increase in systemic blood pressure and a decrease in heart rate in anesthetized dogs, whereas iV G -nitro-D-arginine had no effect. L-Arginine reversed the pressor response. yV G -Nitro-L-arginine-induced hypertension was markedly attenuated or abolished by treatment with hexamethonium; this inhibition was still observed when the blood pressure fall caused by the ganglionic blocking agent was compensated by continuous infusion of angiotensin II. In dogs treated with phentolamine in a dose sufficient to lower blood pressure to the level similar to that elicited by hexamethonium and to suppress the pressor response to norepinephrine, the hypertensive effect of JV G -nitro-L-arginine was not attenuated. We conclude that hypertension caused by the nitric oxide synthase inhibitor is associated with an elimination of nitroxidergic neural function rather than an impairment of the basal release of nitric oxide from the endothelium. 4 -6 Intravenous injections of NO synthase inhibitors raise systemic blood pressure in anesthetized and conscious rats and anesthetized guinea pigs, rabbits, and dogs, 7 -11 and intra-arterial injections decrease blood flow and increase vascular resistance. 1213 The pressor and vasoconstrictor effects of NO synthase inhibitors are prevented by L-arginine but not by D-arginine. The hypertensive effects of NO synthase inhibitors are considered to be due to the suppression of the basal release of NO from the endothelium of resistance vessels. However, whether the NO involved originates solely from the endothelium has not been fully determined.NO transmits information from nonadrenergic, noncholinergic vasodilator nerve to smooth muscle in dog and monkey cerebral arteries.14 - 16 In addition, the presence of NO synthase in perivascular nerve has been demonstrated histochemically.17 Therefore, NO is thought to act as a transmitter, 18 In a recent study, we observed that intraluminally applied L-NA potentiates the neurally induced vasoconstriction, as does extraluminal L-NA (Zhang et al, unpublished data).We undertook the present study to elucidate whether elimination of neurogenic vasodilator control is involved in the hypertension induced by L-NA administered to anesthetized dogs. Methods Thirty-two mongrel dogs of both sexes (9-16 kg) were used for study. All animals were fed standard chow and water ad libitum and were housed according to institutional guidelines at the Shiga University of Medical Sciences. These studies were approved by the Animal Rights Committee, Shiga University of Medical Sciences. Dogs were anesthetized with sodium pentobarbital (25 mg/kg i.p.) and were intubated. Supplemental doses of the anesthetic were applied via the femoral vein when necessary. The animals were permitted to breathe spontaneously. Arterial systolic and diastolic blood pressures were moni...

The effects of nipradilol, an ocular hypotensive drug, on isolated canine retinal central arteries and on retinal arterioles in vivo were investigated. Nipradilol (10^–9 to 10^–5 mol/l) produced a dose-related relaxation of the arterial strips contracted with prostaglandin F_2α which was not influenced by timolol or indometacin. The median effective concentration of this drug was five times that of glycerol trinitrate (GTN). The nipradilol-induced relaxation in the endothelium-intact strips was not influenced by N^G-nitro-L-arginine, a nitric oxide synthase inhibitor, but was abolished by oxyhemoglobin and methylene blue. Treatment with high concentrations of sodium nitroprusside abolished the response to nipradilol, as observed with that to GTN. Retinal arterial strips responded to isoproterenol with a slight relaxation which was depressed by nipradilol. In anesthetized dogs, intra-arterial injections of nipradilol dilated the retinal arterioles in the ocular fundus; the dilator potency was approximately one fifth that of GTN. It is concluded that nipradilol dilates canine retinal arteries in vitro and arterioles in vivo, possibly due to activation of soluble guanylate cyclase and increased production of cyclic guanosine monophosphate that are associated with nitric oxide liberated from the molecule itself in the tissue but not derived from the endothelium and perivascular nerve. Beta adrenoceptor blocking action was determined in the retinal artery.

Functional role and anatomic location of nitroxidergic nerves were determined in dog retinal arteries and arterioles. Isolated retinal central arteries responded to nicotine with relaxations that were not influenced by atropine, timolol, or indomethacin and damage of the endothelium, but were abolished by hexamethonium, methylene blue, and oxyhemoglobin. The relaxation was abolished by NG-nitro-L-arginine (L-NNA), a nitric oxide (NO) synthase inhibitor, and was restored by L-arginine. Relaxations caused by NO were not affected by L-NNA. Transmural electrical stimulation at 5 Hz relaxed the strips; the relaxation was abolished by L-NNA and tetrodotoxin. In anesthetized dogs, intraarterial injections of nicotine dilated retinal arterioles in the fundus oculi. This effect was abolished by L-NNA and restored by L-arginine. Intravenous injections of L-NNA constricted retinal arterioles, the effect being prevented by hexamethonium. There were nerve bundles and fibers containing NO synthase immunoreactivity in the adventitia and media in the retinal artery. These findings are consistent with our hypothesis that NO liberated from vasodilator nerves acts as neurotransmitter in dog retinal arteries and arterioles, and the arteriolar muscle tone is regulated by vasodilator nerve activity in vivo.